>>WELCOME EVERYONE. IT IS A PLEASURE TO SEE YOU, ALL BEIT VIRTUALLY. THANK YOU FOR JOINING THIS ROUND TABLE, WE COULDN'T DO IT WITHOUT YOUR PARTICIPATION. AND THESE MEETINGS ARE VERY IMPORTANT TO NIAMS AS WE LEARN ABOUT EMERGING AREAS IN THE FIELD AND HOW WE MIGHT MAKE A DIFFERENCE. I WILL NOW TURN THE MEETING OVER TO THE NIAMS DIRECTOR DR. LINDSEY CRISWELL FOR OPENING REMAR REMA. DR. CRISWELL. >>THANK YOU, JONELLE. GOOD MORNING EVERYONE, I'M DR. LINDS SHY CRISWELL, DIRECTOR NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES. WELCOME Y'ALL TO OUR ROUND TABLE ON CARTILAGE PRESERVATION AND RESTORATION IN KNEE OSTEOARTHRITIS. WE ARE HOPING TODAY'S MEETING WILL HELP TO GENERATE ADDITIONAL INTEREST IN THE TOPIC OF CARTILAGE PRESERVATION RESTORATION AMONG THE NIAMS COMMUNITY AND TO THAT END THE MEETING IS BEING VIDEOCAST AND RECORDED AND WILL BE AVAILABLE FOR VIEWING ON THE NIH VIDEOCAST ARCHIVE. SO WE GREATLY APPRECIATE YOUR ATTENDANCE TODAY AS WELL AS -- AS YOUR EFFORTS TO GATHER FEEDBACK FROM YOUR COLLEAGUES. THE INFORMATION YOU PROVIDED IN PREPARATION FOR THE ROUND TABLE HELPED TO SHAPE OUR AGENDA, AND WILL SUPPLEMENT TODAY'S DISCUSSION. I WANTED TO THANK DR. TED XANG FOR AGREEING TO LEAD THIS MEETING AND ORGANIZING THE ROUND TABLE HAS BEEN A TEAM EFFORT INVOLVING IN MEMBERS OF OUR INSTITUTE. SO OUR DIVISION OF EXTRAMURAL RESEARCH I WOULD LIKE TO ESPECIALLY RECOGNIZE DR. GAIL LESTER WHO SERVES AS DIRECTOR OF THE DIVISION, DR. PAE, ANALYST RESPONSIBLE FOR MUCH OF THE BEHIND THE SCENES WORK AND PROGRAM DIRECTORS, INCLUDING DR. LEXI BELGUN, DR. ANTHONY, DR. MARKWITS AND DR. CHUCK WASHABAU. I WOULD ALSO LIKE TO RECOGNIZE STAFF FROM ANALYSIS POLICY PLANNING BRANCH WHO PLAYED KEY ROLES PUTTING THIS ROUND TABLE TOGETHER. DR. STEPHANIE BURRO, CHIEF OF THE BRANCH, DR. JONELLE DRUGAN, DR. VAN NGUYNEY AND DR. THOMAS JACKSON. BEFORE I GO OVER -- I WOULD LIKE TO PROCEED WITH INTRODUCTIONS BY THE GROUP. FIRST DR. BOB CARTER WHO SERVES AS DEPUTY DIRECTOR OF THE INSTITUTE. I WANTED TO INVITE DR. CARTER TO SAY A FEW WORDS AT THIS TIME. BOB. >>GOOD MORNING. DELIGHTED TO BE HERE WITH Y'ALL, PARTICULARLY OLD FRIENDS AND HOPEFULLY NEW FRIENDS. THIS HAS BEEN A LEONG TIME BIRTHING. WE HAVE BEEN WORKING ON THIS GOOD YEAR AND A HALF AT LEAST AND TED HAS BEEN IN THE MIDDLE AND APPRECIATE HIS WILLINGNESS TO WORK WITH US AND BE FLEXIBLE AND WORK WITH WHAT WE THINK IS AN EXCITING AGENDA. THERE'S AN AWFUL LOT TO TALK ABOUT WHEN IT COMES TO REGENERATIVE MEDICINE APPROACHES OR HOW TO PRESERVE CARTILAGE IN PATIENTS WITH OA. IT IS A HUGE AREA IT IS DIFFICULT AND FRAUGHT WITH PROBLEMS PARTICULARLY LOT OF THINGS GOING ON WHICH THERE IS NOT MUCH DATA ALSO ALL SORTS OF DIFFERENT THINGS BEING TRIED WITHOUT MUCH DOCUMENTATION WHAT THEY ARE. BUT I WANT TO INSTEAD OF FOCUSING ON THOSE PROBLEMS I HOPE WE CAN FOCUS TODAY ON WHAT THE HOPE IS. WHERE IS THE PROMISE, THE LIGHT THAT WE CAN SEE COMING? WHERE IS THE HOPE? WE THINK WE HAVE TO CHANGE HOW WE TREAT OA. WE CAN'T REPLACE THE KNEES AND ALL THE PEOPLE THAT NEED IT IN ANOTHER 10, 20 YEARS, WE DESPERATELY NEED NEW WAYS TO REVERSE AND PREVENT REGRESSION OF OA. WHAT WE ARE DOING TODAY IS WHERE ARE THE POSSIBILITIES, HOW CAN WE -- WHAT SHOULD WE THINK OF THE TERMS OF HOW WE ARE GOING TO GET THERE. SO HOPE WITH THAT FOCUS REALLY LOOKING FORWARD TO SOME LEARNING A LOT AND GOOD DISCUSSION AND THANK YOU FOR ALL FOR PARTICIPATING. >>THANKS, BOB. IT IS ALSO IMPORTANT FOR YOU TO KNOW THAT NOT ONLY ARE THE LEADERSHIP AND STAFF OF THE NIAMS PARTICIPATING IN THIS ROUND TABLE, BUT SINCE TODAY'S DISCUSSION INTERSECTS WITH THE PORTFOLIOS OF OTHER NIH AND HHS COMPONENTS, WE ASKED OUR COLLEAGUES TO JOIN US HERE TODAY. THUS WE ARE FORTUNATE TO HAVE REPRESENTATIVES FROM THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. THE NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH AND THE U.S. FOOD AND DRUG ADMINISTRATION. THEIR INFORMATION IS LISTED IN THE ROSTER AND THEY WILL INTRODUCE THEMSELVES SOON. NEXT I WILL ASK EACH PARTICIPANT IN THE MEETING TO INTRODUCE YOURSELF TO PROVIDE A SENSE OF THE BREADTH OF THIS GROUP THAT WE HAVE ASSEMBLED TODAY. IN THE INTEREST OF TIME, WE WON'T HAVE OTHER NIAMS STAFF LISTED ON THE ROASTER INTRODUCE THEMSELVES AT THIS TIME BUT ASK THEY INTRODUCE THEMSELVES WHEN SPEAKING. NOW WHEN DR. XING CALLS YOUR NAME UNMUTE AND SHARE YOUR NAME, INSTITUTION AND THE EXPERTISE RELEVANT TO TODAY'S DISCUSSION. TED. >>GOOD MORNING, EVERYONE. MY NAME IS TED, TED ZHENG, PROGRAM DIRECTOR OF NIAMS AND MY RESEARCH PORTFOLIO IS CLINICAL OSTEOARTHRITIS AND DIAGNOSTIC TOOLS. OVER THE LAST YEAR I WOULD LIKE TO TAKE THIS LEAD AND BEEN HAS BEEN PLEASURE TO WORK WITH EACH OF YOU TO PREPARE THIS ROUND TABLE MEETING. THANK YOU. I WANT TO THANK EVERY ONE OF YOU FOR PARTICIPATING TODAY'S MEETING. I'M GOING TO CALL YOUR NAME LIKE DR. CRISWELL SAID, JUST BRIEFLY STATE YOUR NAME, INSTITUTE AND AFFILIATION, ONE OR TWO SENTENCE TO HIGHLIGHT YOUR AREA OF EXPERTISE RELATED TO THE ROUND TABLE. I WILL START WITH CO-CHAIRS AND GO BY THE LIST. BASED ON ALPHABETIC ORDER OF YOUR LAST NAME. DR. CONSTANCE CHU PLEASE. >>HI, GOOD MORNING. I'M CONNIE CHU, VICE CHAIR OF RESEARCH STANFORD UNIVERSITY. I'M ORTHOPEDIC MEDICINE SPORTS MEDICINE AND ARTHROSCOPY. ACTIVE RESEARCH IN NIH FUNDED WHERE I GOT MY START WITH NIH, FOR MORE THAN 20 YEARS IN JOINT PRESERVATION AND PREVENTION OF OSTEOARTHRITIS. >>THANK YOU. DR. SCOTT RODEO. >>GOOD MORNING, FIRST GOOD MORNING TO CONNI CONNIE. I'M SCT RODEO, ORTHOPEDIC SURGEON SPECIAL SURGERY NEW YORK CITY I COME AT THIS AS CLINICIAN AND SCIENTIST. I TAKE CARE OFFER ATHLETES IN GIANTS FOOTBALL TEAM, RESEARCH SIDE WE USE NUMBER OF ANIMAL MODELS TO STUDY POST TRAUMATIC OA TENDON LIGAMENT REPAIR, IS AS VICE CHAIR AT HHS SO I COME AS CLINICIAN AND SCIENTIST. >>THANK YOU, SCOTT. >>DR. DR. AMBIKP BAJPAYEE. >>I HEAD THE MOLECULAR BIOELECTROSTATICS AND DRUG DEVELOPMENT WE ARE INTERESTED IN DESIGNING ELECTRICALLY CHARGED BIOMATERIALS FOR APPLICATIONS IN DRUG DELIVERY AND IMAGING OF NEGATIVELY CHARGED AVASCULAR TISSUES HARD TO PENETRATE. SO WE HAVE A SPECIAL FOCUS HERE ON CARTILAGE REPAIR AND TREATING OSTEOARTHRITIS FOR WHICH WE DESIGN SUSTAINED RELEASE THERAPIES USING CATIONIC PEPTIDES PROTEINS AND EXOSOMES. HAPPY TO BE HERE. THANK YOU FOR INVITING ME. DR. BAJPAYEE. >>DR. FRANKS BARRY. >>I'M FRANK BARRY, MY CURRENT AFFILIATION IS AS DIRECTOR OF THE TRANSLATIONAL MEDICINE INSTITUTE AT COLORADO STATE UNIVERSITY. MY AREA OF RESEARCH FOCUS IS MESENCHYMAL STROME A.M. CELL THERAPY DEVELOPMENT INST OWE ARTHRITIS AND CARTILAGE REPAIR. VERY MUCH WITH TRANSLATIONAL INTEREST AND VERY HAPPY TO BE PART OF THE DISCUSSION TODAY. >>THANK YOU. DR. STEPHANIE BRYANT. >>GOOD MORNING. EVERYONE. MY NAME IS STEPHANIE BRYANT, I'M HERE AT THE UNIVERSITY OF COLORADO BOULDER. I'M IN THE DEPARTMENT OF CHEMICAL AND BIOLOGICAL ENGINEERING AS WELL AS MATERIAL SCIENCE AND ENGINEERING. I'M AN HE CAN ENGINEER BY TRAINING. AND MY RESEARCH REALLY FOCUSES ON DESIGNING HYDRO GELS FOR PROMOTING CARTILAGE REGENERATION. I'M LOOKING FORWARD TO BEING PART OF THIS. THANK YOU SO MUCH. >>THANK YOU. OUR HEART LUNG AND POLLUTE. DR. DENIS BUXTON PLEASE. >>GOOD MORNING, I'M DENII BUXTON, DIVISION OF CARDIOVASCULAR SCIENCE. I LEAD THE NHLBI PROGENITOR CELL BIOLOGY TRANSLATIONAL CONSOR CONSORTIUM. AND ALSO MUCH -- SOME OF THE CLINICAL TRIALS IN CELL THERAPY FOR NHLBI. >>THANK YOU. SO DR. JENNIFER ELISSEEFF. MY NAME IS JENNIFER ELISSEEFF, BIOMEDICAL ENGINEERING JOHNS HOPKINS AND WORK ON STEM CELLS AN HYDRO GELS FOR CARTILAGE REPAIR AND NOW MOVING TO SENESCENCE AND INFLAMMATION PATHWAYS ASSOCIATED WITH OSTEOARTHRITIS AND CARTILAGE DAMAGE. NICE TO BE HERE. THANK YOU. >>DR. ANDREAS GOMOLL. LOOKS LIKE WE ARE MISSING HIM. >>I DON'T THINK HE'S ON. >>DR. DANIEL GRANDE. >>GOOD MORNING, EVERYONE. I'M DANIEL GRANDE, SCIENTIST, I'M AT NORTH WELL HEALTH NEW YORK, DEPARTMENT OF ORTHOPEDIC SURGERY. I'M INTERESTED IN MANY CARTILAGE REPAIR FOR A LEONG TIME AT THIS POINT. ALSO WE HAVE A ACTIVE PROGRAM IN REGENERATIVE MEDICINE HERE. THANK YOU. >>THANK YOU. >>DR. FARSHID GUILAK. >>I'M FARSHID GUILAK. WASHINGTON UNIVERSITY ST. LOUIS AND SHRINERS HOSPITALS FOR CHILDREN IN ST. LOUIS AND MY RESEARCH IS FOCUSED ON MOSTLY OSTOSTEOARTHRITIS,S AND RHEUMATD ARTHRITIS AND DEVELOPING CELLULAR TISSUE ENGINEERING THERAPIES TO TREAT THEM AND MOST RECENTLY I'LL PRESENT TODAY ON THE APPLICATION OF SYNTHETIC BIOLOGY TO REPROGRAM STEM CELLS AS DRUG DELIVERY VEHICLES FOR ARTHRITIS. >>THANK YOU. DR. MARK HOCHBERG >>GOOD MORNING. I'M PROFESSOR OF MEDICINE EPIDEMIOLOGY PUBLIC HEALTH UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE IN BALTIMORE AND DIRECTOR OF THE MEDICAL CARE CLINICAL CENTER FOR THE VA MARYLAND HEALTHCARE SYSTEM. AND YOU SEE THE BALTIMORE VA MEDICAL CENTER BEHIND ME ME. I WORKED IN THE FIELD OF OSTEOARTHRITIS CLINICAL EPIDEMIOLOGIC RESEARCH FOR ABOUT 40 YEARS. AND I WILL BE TALKING ON SMALL MOLECULES FOR CARTILAGE REGENERATION, SOMETHING FOR WHICH I HAVE NO PERSONAL EXPERIENCE. >>THANK YOU, MARK. DR. JOHNNY HUARD. >>I'M JOHNNY HUARD, CHIEF OFFICER OF THE STEADMAN PHILIPPON RESEARCH INSTITUTE AND DIRECTOR OF MEDICINE PROGRAM HERE IN VAIL, COLORADO. I HAVE BEEN WORKING ON STEM CELL THERAPY FOR OSTEOARTHRITIS FOR A WHILE NOW AND I'M ALSO INVOLVED IN BIOLOGICAL APPROACH TO REDUCE INFLAMMATION TO ALIENATION OF SENESCENCE CELLS AND DEVELOPING BLOOD FIBROSIS APPROACH. THANK YOU FOR HAVING ME. >>AND OUR FROM FDA. DR. LARISSA LAPTEVA, >>TISSUES ADVANCED THERAPIES IN THE CENTER FOR BIOLOGICS EVALUATION RESEARCH AT THE FOOD AND DRUG ADMINISTRATION. IN ADDITION TO THAT MAYBE MORE IMPORTANTLY I'M ALSO RHEUMATOLOGIST, BORN AND RAISED IN NIAMS, MORE THAN 20 YEARS AGO WHERE I FINISHED FELLOWSHIP AND WORKED AS A CLINICAL INVESTIGATOR FOR A WHILE AND THEN MOVED TO FDA. I'M ALSO COMBINING MY WORK AT THE AGENCY WITH THE CLINICAL CARE IN THE RHEUMATOLOGY CLINIC IN NIAMS UP UNTIL THIS DAY. LOOKING FORWARD TO THE DISCUSSION. THANK YOU FOR INVITING ME. >>GLAD TO HAVE YOU BACK, LARISSA. DR. CHRISTIAN LATTERMANN PLEASE. >>AMYE LEONG. YOU ARE NEXT. >>GOOD MORNING, EVERYONE. AMYE LEONG FROM SANTA BARBARA, CALIFORNIA PRESIDENT AND CEO OF HEALTHY MOTIVATION. MY CHARGE IS TO BRING TO YOU AND OTHERS PATIENT PERSPECTIVE, A PATIENT PERSPECTIVE ON THIS. IT HAS STARTED LIKE SOME OTHERS, BORN OUT OF NIAMS EARLY, EARLY ON AT THE START OF NIAMS ACTUALLY. DR. STEVEN KATZ AND I STARTED TOGETHER, THE SAME YEAR HE AS DIRECTOR AND MYSELF AS APPOINTED TO THIS NIAMS STEERING COMMITTEE ADVISORY COMMITTEE. DELIGHTED TO BE HERE. I BRING THE PERSPECTIVE OF A LIFE LIVED FOR A LEONG, LEONG TIME WITH VARIOUS FORMS OF ARTHRITIS, ULTIMATELY CULMINATING IN OA. I FIND IT VERY INTERESTING THESE GROUPS OF MEDICINE OR DISEASES ARE CLUMPED SO CLOSELY TOGETHER THAT WE PATIENTS AND THE PATIENT WORLD, PUBLIC WORLD OF IT IS SO CONFUSED BY THAT. SO I'M LOOKING FORWARD TO BRINGING THIS MESSAGE, MY BUSINESS BACKGROUND IS IN ORGANIZATIONAL DEVELOPMENT STRUCTURE ADVOCACY COMMUNICATIONS, PROCESSES AND I HOPE THAT CAN BE HELPFUL TO Y'ALL. THANK YOU. >>THANK YOU, AMYE. >>DR. CAROLYN LUTZKO. I SAW YOUR NAMES HERE. DR. MICHAEL MONT. >>OKAY. THANK YOU, TED AND THANK YOU, EVERYONE, CERTAINLY AN HONOR TO BE HERE. SO I'M AN ORTHOPEDIC SURGEON AT SINAI HOSPITAL AT BALTIMORE, WHERE I DO MY CLINICAL WORK. I'M ALSO THE DIRECTOR OF CLINICAL STUDIES AT NORTH WELL IN THE SAME SYSTEM AS DANIEL GRANDE WHO JUST PRESENTED HIMSELF. I'M WELL KNOWN FOR -- I HAVE ONE OR TWO NIH GRANTS ON THE FIELD OF AVASCULAR NECROSIS OR OSTEO NECROSIS CO-HEADS WITH STANFORD AND HOPKINS BUT WE ARE FROM MY WHOLE CAREER WE HAVE BEEN DOING CLINICAL STUDIES OF VARIOUS INJEINJECTABLES FOR TREATMENT OF KNEE OSTEOARTHRITIS. WE HAVE FOUR OR FIVE CLINICAL STUDIES ONGOING RIGHT NOW. SO REALLY LOOKING FORWARD TO THIS PROGRAM, I LIKE DOING HIP AND KNEE REPLACEMENTS BUT IT IS MY LIFE LEONG PASSION TO SAVE PEOPLE FROM NEEDING THOSE PROCEDURES. WELCOME, EVERYONE. THANK YOU. >>THANK YOU. DR. GEORGE MUSCHLER, >>PLEASURE TO JOIN TODAY I'M GEORGE MUSCHLER, ORTHOPEDIC SURGEON AND BIOPROFESSIONAL ENGINEER AT CLEVELAND CLINIC. MY CLINICAL PRAXIS IS ONCOLOGY BUT HOW HIP AND KNEE ARTHROPLASTY AND RUN THE JOINT RESERVATION CENTER WHERE WE HAVE ONGOING CLINICAL TRIALS AND REGISTRY TO LOOK AT EFFICACY OF BIOLOGICS. MY RESEARCH BACKGROUND IS STARTED IN HARVEST AND ISOLATION AND QUANTITATIVE METRICS TO MEASURE PERFORMANCE OF CELL POPULATIONS AVAILABLE TO US FROM BONE MARROW AND BONE. HELPING WITH STANDARDS DEVELOPMENT IN THAT AREA. AND RECENTLY DEVELOPING A PLATFORM FOR AUTOMATION OF IMAGE PROCESSING AND CELL PROCESSING FOR MSC AND IPS CELLS AS SOURCE FOR CARTILAGE. ' >>THANK YOU. OUR COLLEAGUE FROM NIDCR. >>HELLO. THANK YOU FOR THE INVITATION TO PARTICIPATE IN THIS ROUND TABLE DISCUSSION. I'M SENIOR INVESTIGATOR AT THE NIDCR ON THE NIH CAMPUS AND I WORK ON SKELETAL STEM CELLS. MY LAB FOCUSES ON CHARACTERIZING THESE CELLS. DETERMINING THE ROLE THEY PLAY IN DISEASE, IN PARTICULAR HOW TO USE NECESSARY CELLS IN SKELETAL REGENERATION. >>THANK YOU. DR. DANIEL SARIS. >>GOOD MORNING, EVERYBODY. THANK YOU FOR THE INVITATION AND I FEEL HONORED AND EXCITED TO BE PART OF THIS ROUND TABLE. MY NAME IS DANIEL SARIS, ORTHOPEDIC SURGEON IN ROCHESTER, MINNESOTA MAYO CLINIC. THE LARGER PART WAS IN THE NETHERLANDS WHERE WE RAN THE TRIALS THAT LED TO CELL THERAPY REGISTRATION IN THE EMA AND THE FDA SPACE FOR CARTILAGE REPAIR. I MOVE TO MINNESOTA IN 2018 AND BECAME PROFESSOR OF REGENERATIVE MEDICINE AT MAYO CLINIC. I RUN THE ORTHOPEDIC SPORTS MEDICINE RESEARCH AND CARTILAGE BIOLOGY TRANSLATIONAL LAB AND WE ARE FORTUNATE TO HAVE INDs OPEN FOR CELL BASED JOINT PRESERVATION I FEEL STRONGLY ABOUT FROM A PERSONAL, FROM PROFESSIONAL PERSPECTIVE AND HAVING BEEN PAST PRESIDENT OF THE INTERNATIONAL CARTILAGE REPAIR AND JOINT PRESERVATION SOCIETY. LOOK FORWARD TO TODAY, THANKS FOR THE INVITE. >>THANK YOU. DR. SHANE SHAPIRO. >>I'M SHANE SHAPIRO, I WORK AT MAYO CLINIC SOUTHERN CAMPUS IN FLORIDA. I'M CLINICIAN AND SCIENTIST, A MEDICAL ORTHOPEDIST IN SPORTS MEDICINE PHYSICIAN, HAVE BEEN USING INJECTABLE BIOLOGICS AND NON-CELLULAR REGENERATIVE THERAPIES FOR A NUMBER OF YEARS AND CONDUCTING TRANSLATIONAL STUDIES, SOME RANDOMIZED CLINICAL TRIALS, AND ALSO DISCOVERY SCIENCE WHERE WE PARTNERED WITH COLLEAGUES IN MULTIPLE DISCIPLINES LOOKING AT EXTRA CELLULAR VESICALES. AS SUCH I HAVE FILED EIGHT FDA INDs FOR NOVEL REGENERATIVE THERAPIES, AND LOOKING FORWARD TO THIS GREAT DISCUSSION, THANK YOU FOR HAVING ME. I TOO GOT MY START AT THE NIH AS AN INTRAMURAL RESEARCH TRAINEE AT NHGRI AS PART OF THE HUMAN GENOME PROJECT. COUPLE OF DECADES AGO. SO NICE TO BE BACK AND PARTICIPATING. >>THANK YOU. DR. DAN WHITE. >>GOOD MORNING. CERTAINLY AN HONOR TO BE HERE. I AM A PHYSICAL THERAPIST AND ASSOCIATE PROFESSOR AT THE UNIVERSITY OF DELAWADELAWARE. MY MANGER OF STS PHYSICAL ACTIVITY IN SEDENTARY BEHAVIOR USING MONITORING DEVICES AND WE DO THESE STUDIES TYPICALLY IN LARGE COHORT STUDIES AND WE HAVE AS WELL AS CLINICAL TRIALS AND CURRENTLY I HAVE A FDA ASKED ME TO DO AN IDE WHICH WE GOT APPROVED TO LOOK AT STEM CELLS, MESENCHYMAL STEM CELLS FROM BONE MARROW ASPIRATE AND LOOKING AT CHANGES IN PHYSICAL ACTIVITY FROM THIS IN PEOPLE WITH KNEE OSTEOARTHRITIS. ALSO LIKE TO CONGRATULATE SCOTT RODEO WITH THE TWO AND 0 GIANTS START FIRST FILE IN A LEONG TIME SO THANK YOU FOR HELPING THE TEAM WITH THAT. >>LEONG SEASON. >>DR. LATTERMANN JOIN US. >>HELLO, GOOD MORNING. APOLOGIZE FOR THE DELAY. I HAD TO GET MY POWERPOINT. MY NAME IS CHRISTIAN LATTERMANN CHIEF OF SPORTS BRIGHAM WOMEN'S HOSPITAL IN BOSTON AND DIRECTOR FOR MASS GENERAL BRIGHAM. MY RESEARCH INTERESTS ARE IN CLINICAL TRIALS IN CARTILAGE REPAIR AND ORTHO BIOLOGICS AS WELL AS IN BASIC SCIENCE. THE ETIOLOGY OF POST TRAUMATIC OSTEOARTHRITIS, PARTICULARLY WITH FOCUS ON INFLAMMATION. GOOD MORNING. GLAD TO BE PART OF THIS. >>THANK YOU FOR JOINING US. ALSO CAROLYN LUTZKO. >>GOOD MORNING. I APOLOGIZE, HAVING SOME TECHNICAL TROUBLE HERE. BUT I AM A PROFESSOR PEDIATRICS AT UNIVERSITY OF CINCINNATI, IN CINCINNATI CHILDREN'S HOSPITAL. MY AREA OF RESEARCH IS CELL AN GENE THERAPY. FOCUSED ON MANUFACTURING AND PREPARATION OF CELL PRODUCTS EXVIVO FOR PHASE 1 AND 2 CLINICAL TRIALS. >>THANK YOU, CAROLYN. DR. CRISWELL, HAPPY TO REPORT ALL PARTICIPANTS EXCEPT DR. GOMOLL PRESENT. BACK TO YOU. >>I'M BLOWN AWAY BY THE INCREDIBLE EXPERTISE WE ASSEMBLED HERE. THANK YOU ALL, REALLY EXCITED TO HAVE YOU JOINING US. T BEFORE WE BEGIN OUR SUBSTANTIVE DISCUSSION I WOULD LIKE TO PROVIDE CONTEXT FOR THE ROUND TABLE. AS YOU KNOW KNEE OSTEOARTHRITIS IS A DEGENERATIVE CONDITION CHARACTERIZED BY WEARING AWAY OF CARTILAGE IN THE KNEE. AND THIS GRADUAL WE ARE AND TEAR PROGRESSION OF KNEE OSTEOARTHRITIS LEADS TO DEVELOPMENT OF BONE SPURS AND WORSENING PAIN. THUS, IT IS A VERY IMPORTANT AREA FOCUS FOR NIAMS AND FOR OUR PUBLIC HEALTH MISSION. REGENERATIVE MEDICINE HAS BROUGHT HEALTH APPLICATIONS IN KNEE OSTEOARTHRITIS, USED FOR DEVELOPING METHODS TO REGROW, REPAIR OR REPLACE DAMAGED CARTILAGE. SO THE GOAL OF THIS PARTICULAR MEETING IS TO DISCUSS THE CHALLENGES, THE GAPS AND THE OPPORTUNITIES FACING THE FIELDS OF REGENERATIVE MEDS SIN AS RELATES TO CARTILAGE PRESERVATION AND RESTORATION IN KNEE OSTEOARTHRITIS. OVER THE LEONG TERM DISCUSSIONS OF THESE ROUND TABLES HAVE HELPED SHAPE THE INSTITUTE THINKING ABOUT AREAS TO PURSUE ACROSS OUR BASIC TRANSLATIONAL AND CLINICAL PORTFOLIOS. I'M PARTICULARLY INTERESTED IN LEARNING ABOUT WAYS WHICH NIAMS CAN FURTHER ENGAGE WITH RESEARCHERS TO SUPPORT THIS CRITICAL WORK AND CONTRIBUTE TO THE ADVANCEMENTED OF REGENERATIVE MEDICINE. NOW TO SET A FEW QUICK GROUND RULES. WE WANT TO LEARN FROM YOU, THE EXPERTS ABOUT THE BROAD LANDSCAPE OF REGENERATIVE MEDICINE AND IMPLICATIONS FOR KNEE OSTEOARTHRITIS. THUS WE DON'T WANT THE PRODUCTIVITY OF THIS ROUND TABLE TO BE LIMITED BY FOCUSING ON FUNDING AND DEVELOPMENT OF SPECIFIC FUNDING OPPORTUNITY ANNOUNCEMENT. NIAMS RECOGNIZES TODAY'S TOPIC PRESENTS MANY EXCITING AND INNOVATIVE OPPORTUNITIES FOR DISCOVERING AND WILL BE CALLING ON EACH OF YOU FOR YOUR INPUT OVER THE COURSE OF THE ROUND TABLE TO SHARE YOUR EXPERIENCES ABOUT CARTILAGE PRESERVATION AND RESTORATION RESEARCH TODAY AS WELL AS FOO UTURE OPPORTUNITIES AS YOU SEE THEM. WE WILL ALSO POST SUMMARY OF TODAY'S DELIBERATIONS ALEONG WITH LINK TO RECORDING THE VIDEOCAST ON THE NIAMS WEBSITE. WE WILL LET YOU KNOW WHEN SUMMARY IS AVAILABLE AND ENCOURAGE YOU TO SHARE WITH THOSE CANVAS FOR INPUT IN ADVANCE OF THE MEETING. SOME FINAL QUICK REMINDERS BEFORE I TURN THINGS TO OUR CHAIR, DR. DRUGAN. SHE HAS A FEW THINGS TO SHARE ABOUT LOGISTICS. JONELLE. >>THANK YOU, DR. CRISWELL. A QUICK REMINDER THIS MEETING IS VIDEOCAST AND I JUST LEARNED FROM SOME OF MY COLLEAGUES WE HAVE 70 VIEWERS SO FAR. AND THAT NUMBER WILL ONLY GROW BASED ON EXPERIENCE THAT PEOPLE WILL TUNE IN THROUGH THE DAY, PROMISE THESE 70 OSTEOARTHRITIS ARE NOT ALL MY FRIENDS AND FAMILY SO THERE'S CLEARLY PEOPLE OUT THERE WHO ARE IN SCIENTIFIC COMMUNITY WHO ARE INTERESTED IN WHAT WE ARE TALKING ABOUT TODAY. WE ASK OUR INVITED PARTICIPANTS TO PLEASE KEEP YOUR VIDEO ON FOR THE DISCUSSION PORTION OF THE MEETING TO HELP DISCUSSION CO-CHAIRS TO KNOW WHO IS ON DURING THE DISCUSSION. STAFF KEEP YOUR CAMERAS OFF P UNLESS YOU ARE SPEAKING AND IF YOU ARE SPEAKING INTRODUCE YOURSELF SINCE YOU WERE NOT INTRODUCE WHEN DID DID AS ROLL CALL. TO EVERYONE, PLEASE MUTE YOUR MICROPHONE UNLESS SPEAKING. IF YOU WOULD LIKE TO SPEAK DURING THE DISCUSSION RAISE YOUR HAND BY CLICKING ON THE PARTICIPANT ICON AT THE BOTTOM OF THE SCREEN. AT THE BOTTOM OF THE PARTICIPANT WINDOW YOU WILL SEE AN OPTION TO RAISE YOUR HAND. THE CO-CHAIR WILL CALL ON YOU TO SPEAK, NIAMS PROGRAM STAFF AND TED MAINLY WILL LOOK FOR CO-CHAIRS TO LOOK FOR RAISED HANDS AND HE WILL MONITOR THE CHAT FOR COMMENTS. WE HAVE JUST LEARNED FROM EXPERIENCE THAT WE PREFER FOR YOU TO MAKE YOUR COMMENTS VERBALLY BECAUSE THAT LEADS TO A MORE ROBUST DISCUSSION. PLEASE REMEMBER TO LOWER YOUR HANDS WHILE SPEAKING. DAVE IS GOING TO BE DOING TIME KEEPING. I'M RUSHING THROUGH THESE REMARKS SO WE CAN STAY ON TIME. ONE OTHER THING YOU WILL SEE ON THE AGENDA WE HAVE A PHOTO FOR A GROUP LUNCH, COUPLE OF PEOPLE ASKED ABOUT THAT, IT IS NOT A TYPO. WE WILL TAKE A SCREEN SHOT OF OUR GROUP. IT IS A TRADITION AS WE HAVE TAKEN PHOTOS AT ALMOST EVERY NIAMS ROUND TABLE AND THIS IS SOMETHING WE DIDN'T WANT TO GIVE UP DURING THIS PERIOD OF VIRTUAL MEETINGS. DR. CRISWELL, GIVE YOU AN OPPORTUNITY TO TAKE QUESTIONS BEFORE TURNING THE MEETING OVER TO OUR CO-CHAIRS. THANK YOU. >>THANK YOU FOR YOUR PARTICIPATION, LOOKING FORWARD TO A PRODUCTIVE DISCUSSION. BEFORE WE BEGIN, ARE THERE ANY QUESTIONS? >>HEARING UP IN I WILL TURN IT TO DR. ZHENG. >>WE WILL STAR START. DR. ROAD, DR. CHU, YOU ARE ON. >>THANK YOU, EVERYBODY. IT GIVES ME GREAT PLEASURE TO INTRODUCE THE FIRST SPEAKER. SO AMYE LEONG WILL TALK TO US ABOUT THE PATIENT PERSPECTIVE. I WANT TO HIGHLIGHT MORE ABOUT HER BACKGROUND. SO SHE WAS 18 YEARS OLD WHEN SHE RECEIVED THE DIAGNOSIS OF RHEUMATOID ARTHRITIS. THIS WAS FOLLOWED BY OSTEOPOROSIS DIAGNOSIS. SHE WAS WHEELCHAIR BOUND IN SIX YEARS AND SHE SPENT FIVE YEARS IN A WHEELCHAIR. SHE HAD MORE THAN 22 SURGERIES AND 20 JOINT REPLACEMENTS OVER THE SUBSEQUENT YEARS. DURING THIS TIME SHE DEVELOPED AMERICA'S LARGEST NETWORK OF YOUNG ADULT EDUCATION AND ADVOCACY PROGRAMS. SHE STARTED A CONSULTING FIRM AND DECIDED THAT SHE WAS GOING TO GET OFF OF DISABILITY AND SHE HAS REALLY BROUGHT THE PATIENT PERSPECTIVE TO BARE OVER NUMBER OF YEARS WORKING WITH NOT JUST NIAMS BUT PCORI AHRQ, AND IS RECOGNIZED BY PRESIDENT BUSH FOR HER CONTRIBUTIONS, SO WE ARE REALLY THRILLED THAT SHE IS ABLE TO KICK OFF OUR MEETING. PLEASE JOIN ME TO WELCOME AMYE LEONG. >>THANK YOU, DR. CHU. I AM DELIGHTED TO BE HERE FIRST OF ALL, THANK YOU SO MUCH, DR. CRISWELL AND GREAT, GREAT NIAMS TEAM. AS SOMEONE PREVIOUSLY SAID, THEY GREW UP IN NIAMS. AND I AM ONE OF THOSE PEOPLE NOT WHO GREW UP WITHIN THE SYSTEM BUT GREW UP ALONGSIDE THE SYSTEM. WHO ASKED TO JUMP THE RIVER AND COME OVER ON OCCASIONAL BASIS. MY INVOLVEMENT STARTED WITH ARE YOU SURE YOU WANT TO INVITE A PATIENT TO THIS RESEARCH ROUND TABLE? TO WHY DON'T WE INVITE PATIENTS IN AN OPPORTUNITY TO BRING ALL STAKEHOLDERS TOGETHER. YOU CAN SEE THE TRAJECTORY. TODAY WE AND THE FIELD OF MEDICINE IF YOU WILL, IN THE FIELD OF STRUCTURAL MEDICINE, CALL THIS PATIENT ENGAGEMENT. I'M SO EXCITED TO HAVE BEEN A PART OF THIS IN THE VERY BEGINNING. THOUGH WE DIDN'T KNOW WHAT NAME IT WAS. SO THE KINDS OF THINGS WE WILL TALK ABOUT IN THE VERY BRIEF TIME I HAVE WITH YOU AND SOMETIMES I WILL SPEAK VERY FAST, I ASK YOU TO BEAR WITH ME, 30 YEARS AGO A LOT OF THESE ORGANIZATIONS DID NOT EXIST. HOWEVER BECAUSE OF THESE ORGANIZATIONS OBVIOUSLY THE NATIONAL INSTITUTE OF ARTHRITIS MUSCULOSKELETAL AND SKIN DISEASES, THE NIH DIRECTORS OFFICE, ABSOLUTELY. U.S. BONE AND JOINT DECADE, ABSOLUTELY. AT THE GLOBAL LEVEL I HAVE SERVED FOR 15 YEARS AS THEIR INTERNATIONAL SPOKESPERSON. THE ARTHRITIS FOUNDATION HERE IN THE UNITED STATES BECAME MY HOME BASE. I WANT TO THANK DR. JASON KIM FOR HELPING THE SLIDES, BECAUSE IT IS NOT JUST MY PERSPECTIVE, IT IS A PERSPECTIVE THAT WE ARE SEEING IN THE PUBLIC HEARING FROM THE PUBLIC AND WANT TO SHARE THAT WITH YOU A GREAT DEAL. THE GLOBAL ALLIANCE FOR MUSCULOSKELETAL HEALTH, NAMES, NIH, PCORI AND THE FDA A. CXFC DISCROW SURE I SERVE AS FOUNDING MEMBER OF PATIENT -- DISCLOSURE I SERVE AS PATIENT ENGAGEMENT ADVISORY COMMITTEE OUT OF CDRH AT THE FDA. SO ANOTHER GREAT HOME FOR AND OPPORTUNITY FOR PATIENTS TO ENGAGE. NEXT SLIDE. SO VERY QUICK VISION STATEMENT OF THE ARTHRITIS FOUNDATION, IN TERMS OF SCIENCE, BUT DON'T LOOK AT IT AS JUST THAT OWNED BY THE AF, IT IS A STATEMENT THAT ACTUALLY BINDS US ALL TOGETHER TO RELIEVE THE BURDENS OF OSTEOARTHRITIS PATIENTS THROUGH SCIENCE. CRITICAL PIECE. IN THIS DAY AND AGE, LET ME GO ON, IN THIS DAY AND AGE, GIVING IDEA THE ARTHRITIS FOUNDATION IS CON VIE NOR IN IMPORTANT MEET -- CONVENER IN IMPORTANT MEETINGS. YOU CAN SEE OUR FDA PERSON THERE, MARK HOPBURG IS REPRESENTED, MANY OF YOU IN THE AUDIENCE NOW HAVE PARTICIPATED. MOVING ONWARD. YOU CAN SEE THAT DR. RODEO, DR. BROADER, MANY OTHERS HAVE BEEN PART OF THIS. DR. MUSCHLER ALSO VERY MUCH LEADERS IN THIS AREA. SO IT IS NOT JUST ARTHRITIS FOUNDATION THING, BUT IT IS AN OPPORTUNITY THROUGH OTHER CONNECTED ENTITIES TO BEGIN TO WORK TOGETHER TO SHARE THE WEALTH TO MOVE FORWARD TOGETHER. I WANT TO ADDRESS FEW PUBLIC MISCONCEPTIONS, THE LIST IS TEN TIMES BIGGER THAN THIS BUT CERTAINLY AS YOU GO THROUGH AND READ IT YOU CAN COME BACK TO THE SLIDE AT YOUR OWN WILL BUT THERE IS A LOT OF MISCONCEPTIONS. THE FIRST THING IS THE FIRST IS EVERYBODY SAYS IT, NOTHING CAN BE DONE. FOR MY OA AND MY OA ARM OR KNEE OR OA ELBOW. WHATEVER THAT BODY PART IS, AND I KNOW FOCUS IS ON CARTILAGE TODAY, THE KNEE IN PARTICULAR BUT THE WIDER PERCEPTION OF THE PUBLIC IS THAT WHEN THERE IS A PERCEPTION OF A HITCH IN THE GET ALEONG, THAT'S A COLLOQUIAL WAY OF SAYING ITS HURTS, I CAN'T FUNCTION WIT, I CAN'T DO WHAT I NORMALLY DO WITH IT. WHAT HELP CAN I GET? IF YOU HAVE DONE A SEARCH ON THE INTERNET YOU SEE THE PUBLIC MISCONCEPTIONS ARE RAMPANT. THEREFORE IS THAT RIGHT TANS, UNPROVEN REMEDIES THOSE KINDS OF THINGS OCCUR. BUT THERE IS HIGH INTEREST. TO GET FROM THIS SLIDE IS THE LITTLE SQUIGGLY LINES THAT REPRESENT THE BLUE KNEE PAIN AND THE GREEN SHOULDER PAIN, THESE ARE THE KINDS OF SEARCH WEB SEARCH TRENDS THAT HAVE BEEN GOING ON AND PRODUCED BY GOOGLE FOR OUR REVIEW WHICH IS VERY INTERESTING SO THE TOP TWO IN TERMS OF WHERE PEOPLE ARE TRYING TO GO TO SEARCH ARE KNEE AND SHOULDER. BUT THERE IS A CLOSE ALIGNMENT WITH HIP AS WELL. SO THERE IS A LOT OF DESIRE OUT THERE. THESE ARE -- THE NUMBERS ARE IN THE MILLIONS HERE IS ANOTHER THAT SAYS NOT JUST ABOUT THE KNEE, IT IS BEYONDS THE KNEE, THE KNEE IS THE MOST RESEARCHED JOINT IN OA BUT NOT ALL PATIENTS ARE AFFECTED IN KNEE AS YOU KNOW. TOTAL JOINT REPLACEMENTS ARE A GOOD OPTION BUT AS DR. CRISWELL SAID WE CAN'T KEEP DOING THIS. THERE ARE TOO MANY PEOPLE GETTING THEM. HI MYSELF AM OWNER OF 20. SUCCESSFULLY OVER THE PAST LAST YOU WERE TEEN YEARS BUT NEWEST IS NOT DOING SO WELL. AND ALSO LOOKING AT KNEE OA AND HIP OA, IN THE MILLIONS HIGHER UP IN TERMS OF WHAT PEOPLE ARE SEEKING, WHAT THEY WANT TO DO ABOUT IT, THEN WHEN YOU LOOK AT THIS IS NUMBER OF PUBMED RESULTS THAT OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS ARE THE LOWEST WHEN COMPARED TO ALZHEIMER'S DIABETES AND CANCER LOT OF INTEREST BY PATIENTS BUT THE DIVERSITY PIECE IS INTERESTING. SO THE KNEE OA, THERE IS AGAIN HIGH, HIGH INTEREST THERE IS MORE INTEREST WHEN COMPARED IN OTHER DISEASE SPECIFIC AREAS, CANCER DIABETES, ALZHEIMERS HIGH INTEREST AREAS. BUT RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS ARE VERY, VERY LITTLE. THIS IS FACTORED IN THE MILLIONS. I PUT THIS RESEARCH STUDY UP ABOUT DIVERSITY LOOKING AT OA IN CHINA FOR THE FIRST TIME. WHAT THEY FOUND WAS CHINESE MEN FROM CHINA ACTUALLY HAD AN 80 TO 90% LESS INCIDENCE OF OA THAN MEN. IN THE UNITED STATES. THE ARTICLE WAS QUICK TO SAY THERE WERE WHITE MEN IN THE UNITED STATES. SO I THINK THAT IS A VERY INTERESTING POINT ABOUT DIVERSITY. I THINK IT WAS MAYO CLINIC, ONE CLINIC ANNOUNCED TODAY THAT THEY ARE STARTING TO APPEAR A DIFFERENCE BETWEEN RACIAL CONFIGURATIONS IN SOME OF THE EARLY WORK. SO THOSE ARE KINDS OF THINGS WE NEED AND WANT AS PATIENTS TO CONSIDER. SOMETHING THAT HELPS US FOR US BUT IS MORE LIKE US. KNEE, VERY CLEARLY WE NEED MORE CLINICAL TRIALS. WE NEED MORE CHALLENGING RESEARCH QUESTIONS. I'M SO DELIGHTED TO BE PART OF NIAMS RESEARCH ROUNDS TABLES. THIS IS THE TIME WHEN WE ARE ROLLING UP OUR SLEEVES AND SAYING HEY, HOW ABOUT IF I TALK TO YOU ABOUT THIS AND THIS, HOW ABOUT IF WE SIT DOWN AND MAP THIS THING OUT TOGETHER, IN WAYS YOU HAD NOT DONE BEFORE. SO THINKING OUTSIDE OF YOUR BOX. OUTSIDE YOUR INSTITUTION, YOUR DISTINCT AREAS OF SPECIALTY, BUT DOING WHAT I CALL THE JEFF BEZOS APPROACH. YOU BRING IN ALL THE APPROPRIATE PEOPLE YOU NEED TO BRING IN AND YOU SIT THEM DOWN AND YOU GIVE THEM ALL KINDS OF FOOD BUT YOU LOCK THE DOOR. YOU SAY PLEASE COME UP WITH IDEAS AND PRIORITY, LET'S MOVE IT FROM HERE.ED THE A FOUNDATION IS INTERESTED IN MOVING TO RESEARCH PHASE THEMSELVES. SO THE ARTHRITIS FOUNDATION MOST KNOW IS A PATIENT ADVOCACY PATIENT EDUCATION ORGANIZATION. HOWEVER, RECENTLY THEY ARE ANNOUNCING STILL ANNOUNCING TWO PARTICULAR THINGS, ONE THAT WAS ANNOUNCED YET AND ONE ANNOUNCED TWO MONTHS AGO. THE ONE ANNOUNCED TWO MONTHS AGO IS THE PIKASO PROJECT. SO THEY POOLED TOGETHER EIGHT INSTITUTIONS AND UNFORTUNATELY I CANNOT TELL YOU WHAT THEY ARE, OTHERWISE THEY WILL KILL ME BECAUSE IT IS PREMATURE, GETTING AN EARLY IN ON THIS. 50 PLUS WORLD CLASS SCIENTISTS, HUNDREDS OF PEOPLE WITH HIGH RISK OA AND TESTING EXCITING LOW COST DRUGS COMPARATIVE EFFECTIVENESS RESEARCH. SO THEY WILL BE EMBARKING ON THAT VENTURE STARTING IN 2023. THE MORE RECENT ONE WHICH WAS ANNOUNCED YESTERDAY, AT THE ANNUAL MEETING OF THE AMERICAN ORTHOPEDIC FOOT AND ANKLE SOCIETY IS A RESEARCH PARTNERSHIP WITH THE ARTHRITIS FOUNDATION AND AOFAS THAT WILL ESTABLISH SEVERAL MERITS. SO THIS IS WHAT IS HAPPENING, IT IS NOT GOING AWAY, THERE IS MORE OF IT. I WANT TO LAST LEND ON THIS IF YOU GIVE ME THREE MORE MINUTES I APPRECIATE IT. THE PICTURE ON THE RIGHT IS THE LOWER HALF OF ME TODAY. YOU ARE SEEING THE SHOULDERS AND UP PART OF AMYE. THE SHOULDERS AND BELOW IS WHAT YOU ARE SEEING ON THIS PICTURE. MY LEG IS IN A FULL LEG VERY BRIGHT PINK CAST. WHY? BECAUSE I HAVE A TIBIA THAT DOES NOT SUPPORT THE TOTAL KNEE JOINT REPLACEMENT THAT WAS PUT IN. A YEAR AND A HALF AGO. THIS IS A NEW SCENARIO. IT IS ABOUT QUALITY OF BONE. SO WHEN I THINK ABOUT ANYTHING, I ALWAYS THINK ABOUT QUALITY. QUALITY OF THE FOOD, FRESHNESS OF THE FOOD, QUALITY OF THE BONE THAT WILL BE HOLDING A PROSTHESIS. AND HOW LONG CANNA HAPPEN? HOW LONG CAN I DO THAT? IN THE MEANTIME, BEFORE WE CAN COME UP WITH A SOLUTION WHICH IS THIS PICTURE GETTING ME BACK INTO WHAT I USED TO DO, YOGA, WALKING, THOSE KINDS OF THINGS, IS A LONG HAUL SO PERSONALLY QUITE EFFECTIVELY PATIENTS WANT ANSWERS NOW. NOT TEN YEARS FROM NOW, NOT FIVE YEARS FROM NOW. THEY WANT TO BE ABLE TO HOLD THEIR BABY, THEY WANT TO PICK UP THEIR BABY, PICK UP THEIR CHILD, THEY WANT TO WORK BECAUSE AS YOU KNOW, DISABILITY FROM ARTHRITIS IS AMONG THE TOP DISABLING CONDITIONS IN THE UNITED STATES AS WE KNOW TO BE COUNTING IT SO THESE ARE BIG, BIG PROBLEMS. WE NEED YOU, I NEED YOU. THAT IS WHY I'M SO EXCITED TO BE HERE TO BEGIN TO SEE MORE A BROADER PERSPECTIVE ABOUT WHAT IT IS THAT YOU DO, WHAT IT IS YOUR EXPERTISE IS AND HOW WE CAN WORK TOGETHER TO MOVE THIS ALONG FASTER BETTER MORE EFFICIENTLY. AND TO REALLY ADDRESS THE PATIENTS' NEEDS. APPRECIATE YOUR HELP. AS YOU CAN SEE THIS -- I LIKE MOSAIC AND THAT IS WHAT I WANT TO TALK ABOUT. I WANT YOU TO ALWAYS THINK ABOUT THE BONES AND CARTILAGE AND JOINTS WHAT YOU TALK ABOUT AND WORKING ON BUT TO ME IT IS HOW I FUNCTION. THIS IS A BIG REQUEST. AND THE REQUEST IS AS YOU GO BACK TO YOUR RESEARCH LAB TO YOUR PETRI, TO YOUR DESIGNS AND GENETIC STUDIES THINK ABOUT EVERY ONE OF THOSE CELLS REPRESENTING AMYE. ME. ACTUALLY REPRESENTING ONES YOU LOVE. THESE ARE REAL PEOPLE. REAL LIVES. THAT CAN BE HELPED BY YOUR IDEAS AND YOUR CONNECTEDNESS. I LOOK FORWARD TO TODAY. LET'S GO ABOUT IT AND DO SOME GREAT STUFF. THANK YOU SO MUCH. >>THANK YOU SO MUCH FOR THOSE COMPELLING WORDS. >>WHAT DO YOU SEE AS MOST IMPORTANT BARRIERS TO PATIENTS ENROLLING IN CLINICAL TRIALS? >>ACTUALLY WORKING ON THAT NOW, PATIENT ENGAGEMENT. LACK OF INFORMATION, KNOWLEDGE AND LACK OF PEOPLE WHO LOOK LIKE THEMSELVES, LEADING THE CHARGE. SOING THE IMPORTANT YOUR NAME IS ON IT AND YOUR EXPERTISE IS DRIVING IT BUT BEFORE YOU IS SOMEBODY LIKE ME. DOESN'T HAVE TO BE ME BUT LIKE ME WHO SAYS THIS IS GOOD FOR ALL OF US. THIS IS GOING TO ADVANCE. THE MORE YOU ARE GIVING OF YOUR -- WHAT YOU KNOW ABOUT THE DISEASE, WHAT YOU KNOW ABOUT THE PAIN, WHAT YOU KNOW IN TERMS OF FUNCTION. THESE ARE IMPORTANT CONCEPTS. EXAMPLE, POST TRAUMATIC STRESS. MANY OF YOU KNOW I LIVE IN SANTA BARBARA, CALIFORNIA, I USED TO LIVE IN MOTESETO AND OUR FAMILY WAS AFFECTED BY THE FIRES AND MUD SLIDES, WE LOST OUR HOUSE AND ALMOST LOST OURSELVES IN ALL OF THAT. IN THE BEGINNING OF 2018 AND IT HAS TAKEN US TWO YEARS TO RECOVER JUST HAVING A HOUSE. WE LOST EVERYTHING. I LOST CHINA THAT GOES BACK FOUR GENERATIONS IN MY FAMILY IN CHINA. I LOST SO MANY WONDERFUL PICTURES. BUT THE STRESS FROM ALL THAT, NOT ONLY THE STRESS OF THE TRAUMA BUT THE STRESS OF THE BUILDING BACK PART HAS INTRODUCED A WHOLE DIFFERENT FOUNDATION FROM WHICH WHICH IMMUNE SYSTEM NOW MORE CONGESTED QUITE FRANKLY, TO TRY AND WORK AND TO BE ON MY SIDE, THAT HELPS. HAS. THANKS FOR THE QU. >>AMYE, WE ALL WANT TO DO THESE CLINICAL TRIALS BECAUSE THAT IS HOW WE WILL GET SOME ANSWERS BUT I THINK MOST OF US FIND THE BIGGEST OBSTACLE IS THE PATIENTS DON'T WANT TO BE RANDOMIZE, THEY HEAR THIS 50/50, MAYBE TRY TO GET LESS THAN 50/50 FOR THE -- SO DO YOU HAVE ANY HINTS FOR US THAT THAT IS WHAT I FIND MOST OF US FIND IS BIGGEST OBSTACLE FOR ADVANCING -- >>THAT IS A WEBINAR OF A WHOLE DIFFERENT NATURE. YES, THERE ARE THINGS YOU CAN DO. T YOU HAVE TO REMEMBER WE DO NOT HAVE YOUR EDUCATIONAL BACKGROUND. WE DON'T HAVE A SCIENCE MINDED APPROACH TO DRAWING CONCLUSIONS. MUCH OF THE PUBLIC I SAY IN A BROAD FASHION, THERE IS A RANGE EVEN IN THAT. ARE BASED ON YOUR PERCEPTIONS. WHO YOU KNOW, WHAT YOU KNOW, YOUR ACCESS EVEN DOWN TO ETHNICITY OF HOW YOUR PARENTS RAISE YOU IN TERMS OF PROBLEM SOLVING. IS THERE A LOCAL PATIENT GROUP ORGANIZATION PREFERABLY, NOT JUST A GROUP MEETING, AN ORGANIZATION THAT CAN BE HELPFUL BUT THERE ARE WAYS THAT CAN BE DONE. QUITE HONESTLY, THE FACT IS, IN THE THE RHEUMATOLOGY COMMUNITY, THAT IS LARGER COMMUNITY RESEARCH COMMUNITY, THAT WE BELONG TO, THAT IS NOT REALLY AN ACTIVE TOPIC. IT SHOULD BE. ABSOLUTELY SHOULD BE. SO WE CAN BEGIN PROCESS. IS THAT YOUR RESPONSIBILITY? PROBABLY NOT BUT I WILL TALK TO ARTHRITIS FOUNDATION, I WILL TALK TO THE ALLIANCE FOR GLOBAL MUSCULOSKELETAL ACTION. I WILL TALK TO A LOT -- PCORI DOES DIFFERENT KINDS OF OPPORTUNITIES THAT HELPS PEOPLE UNDERSTAND THE SCIENTIFIC METHODOLOGY, THAT IS REALLY IMPORTANT. ONCE THEY UNDERSTAND THAT, OK O. SO THEY MAY NOT LIKE IT, THEY MAY NOT KNOW, THEY SHOULDN'T EVEN KNOW BUT THE FACT IS YOU HAVE TO TELL THEM A LITTLE BIT BUT THEN SCOOT OVER IT. BUT THAT IS ANOTHER CONVERSATION SO BE HAPPY TO ENTERTAIN THAT LATER. >>I WILL TAKE THE MIC AS PREROGATIVE TO STAY NEAR ON TIME. MY PLEASURE TO INTRODUCE CONNIE CHU WHO INTRODUCED HERSELF EARLIER BUT BRIEFLY PROFESSOR AND VICE CHAIR OF RESEARCH AT STAN -- ALSO DIRECTS THE JOINT PRESERVATION CENTER AND CHIEF OF SPORTS MEDICINE AT THE VA NEAR STANFO STANFORD. ACCOMPLISHED SCIENTIST, EXTENSIVE FUNDING, HER WORK IS FOCUSED ON CARTILAGE REPAIR REGENERATION AND CARTILAGE IMAGING WHERE SHE PUBLISHED EXTENSIVE WILL I SO SHE WILL TALK ON BLOOD DERIVED THERAPIES FOR OA. >>U THAT, SCOTT. AMYE, ALSO, THANK YOU FOR INTRODUCING WHAT WILL BE THE PRIMARY THING OF MY TOPIC, THAT IT IS NOT CARTILAGE OF BONE CHANGES IN ISOLATION BUT RATHER BLACKING AT PEOPLE AS -- LOOKING AT PEOPLE AS INDIVIDUALS, AND TAKING A MORE SYSTEMS BASED APPROACH TO OSTEOARTHRITIS. SO I AM THANKFUL FOR THIS OPPORTUNITY TO TOUCH ON THIS ASPECT OF OSTEOARTHRITIS BY TALKING ABOUT BLOOD DERIVED BIOLOGIC THERAPIES FOR OSTEOARTHRITIS. SO MY APPROACH TO OSTEOARTHRITIS HAS BEEN EARLY DIAGNOSIS AND EARLY TREATMENT TO PREVENTED OR DELAY ONSET OF OSTEOARTHRITIS. SO REALLY THE GOAL IS TO TRANSFORM OUR CLINICAL APPROACH FROM SAYING OH, THERE IS NOTHING WE CAN DO OR PALIATION, TOWARDS PREVENES AND TOWARDS EARLY TREATMENT THERAPIES. SO BLOOD REALLY REFLECTS WHAT IS GOING ON IN THE HUMAN BODY. AND I AM IN SPORTS MEDICINE, AND THE PUBLIC, THE AMERICAN PUBLIC LOVES SPORTS. AND SO I WAS IN PITTSBURGH AT THE TIME WHEN WE WERE BATTLING FOR ONE OF OUR SUPERBOWL CHAMPIONSHIPS, AND THE ANC CHAMPIONSHIP FINALS, TOURISM CL AND THE SUPERBOWL WAS TWO WEEKS AWAY. SO AT THAT TIME HE RECEIVED A NEW TREATMENT A NEW TREATMENT. NOT ONLY WAS HE BACK ON THE FIELD BUT HE CAUGHT TWO INNING TOUCHDOWNS AND NAMED SUPERMVP. THE LITERATURE OF ASTHMA EXPLODED AND IS MOST PEOPLE KNOW ERP IS TOUTED AS BEING USEFUL FOR EVERYTHING FROM TREATING BALDNESS TO ALL ACHES AND PAINS SO OF COURSE IT HAS BEEN EVALUATED AND USED IN THE TREATMENT OF OSTEOARTHRITIS. I JUST WANT TO HIGHLIGHT SOME OF THE EARLIER ARTICLES GOT IT RIGHT. HE GOT NOT JUST PLATELETS BUT HE GOT PLASMA AND IT IS A PROMISING TREATMENT FOR ATHLETES IN BLOOD AND ALSO THERE IS INCLUDING TIGER WOODS HAVE PUBLICLY RECEIVED PRP TREATMENT THE PUBLIC INTEREST HAS GROWN FROM THERE. PRP IS ILL DEFINED GENERALLY, HOWEVER, IT IS A BLOOD PRODUCT AND REGULATED AS A BLOOD PRODUCT. THE USE GOES BACK DECADES. WE HAVE HEARD MANY DEFINITIONS, BUT ESSENTIALLY IN THE CODES OF FEDERAL REGULATIONS IT STATES CLEARLY IN 640.34, PRP PRODUCTS SHOULD HAVE AT LEAST 250,000 PLATELETS PER MICROLITER. SO THOSE WHO MEASURED THE PLATELET COUNTS KNOW SOME HAVE THAT, ALREADY IN THEIR PLASMA. AND OTHERS HAVE LEVELS BELOW THIS. SO IN THE USE FOR OSTEOARTHRITIS, THE QUESTION IS, DOES THIS WORK? I THINK THAT IS VERY DIFFICULT TO ANSWER FOR VARIETY OF REASONS, LOOK AT STUDIES OVER THE YEARS DOING SOME OF MY OWN RESEARCH AND ALSO READING STUDIES OF OTHERS, IT BILLS DOWN TO IT DEPENDS, DEPENDS ON THE QUALITY OF PATIENT HEALTH AND THEIR BLOOD AT THE TIME THE AUTOLOGOUS PRP IS PREPARED. A RECENT STUDY, HAVING TROUBLE ADVANCING. VERY WELL DONE STUFF OUT OF VAILIA, A RANDOMIZED PLACEBO CONTROLLED CLINICAL TRIAL. THEY LOOKED AT A RELATIVELY EARLY OA POPULATION. SO AMYE SHOWED EMAILS AND I KNOW MY OWN INBOX IS FLOODED WITH EMAILS FROM PEOPLE WHO ARE LOOKING FOR THIS TREATMENT AS ALTERNATIVE TO JOINT REPLACEMENT. IN THIS STUDY THAT THEY LOOKED AT EARLIER GRADES OF OSTEOARTHRITIS AND REALLY SHOWED THAT THERE WAS NO DIFFERENCE MANY THE MAIN OUTCOMES BETWEEN PLATELET RICH PLASMA AND SALINE. THEIR MAIN PLATELET COUNT DID MEET FDA ROLES. SO I KNOW THEIR CRITICISMS OF THIS STUDY, I WOULD ENCOURAGE EVERYONE WHO IS INTERESTED TO READ IT THOROUGHLY INCLUDING THE ADVANCE PLEASE, THE APPENDICES, BECAUSE I -- THE QUALITY OF THIS STUDY IS QUITE GOOD IN MY OPINION. MY OWN WORK, THIS IS STILL ONGOING, AT SIX MONTH FOLLOW-UP WED 100% FOLLOW-UP IN THE PATIENT REPORTED OUTCOMES. ESSENTIALLY THE MEAN OUTCOMES DO SHOW IMPROVEMENT IN PAIN STIFFNESS AND FUNCTION. THOSE WHO NOW REACHED TWO YEARS, FOLLOW-UP, I EVALUATED SOME IN CLINIC, AFTER THEY FILLED OUT THEIR PATIENT REPORTED OUTCOMES. WHAT I CAN SAY IS WE DO SEE SYMPTOMATIC FUNCTIONAL IMPROVEMENT, I WILL SHOW YOU THE GATE STUDIES. CAN WE GO BACK PLEASE. WE ARE DOING GATE STUDIES AND LOOK AT PROTEOMIC PROFILES OF INJECTED PRP. WHAT THIS SHOWS IS THAT PATIENTS WHO REPORT PAIN RELIEF, THEY VISIBLY WALK BETTER. IF WE CRITICALLY ROOK AT OUR DATA, IT IS LESS THAN HALF OF PATIENTS WHO HAVE THIS SUSTAINED IMPROVEMENT THROUGH SIX MONTHS, NOW THROUGH TWO YEARS. THOSE PATIENTS RAVE ABOUT THE TREATMENT. BUT I CAN GO NEXT DOOR INTO THE NEXT PATIENT ROOM AND FIND ANOTHER PATIENT WHO IS NOT AS HAPPY M. SO YOU CAN SEE WHERE THE IDEA THAT PRP WORKS FOR KNEE OA CONTINUES TO PERPETUATE ITSELF BECAUSE SOME PATIENTS AFTER RECEIVING THIS TREATMENT DO HAVE SUSS SANESYMPTOMATIC AND FUNCTIONAL RELIEF. IF WE -- SUSTAINED SIMILAR TO MADIC RELIEF. IF WE DRAW DOWN AND LOOK AT PREDICTORS OF RESPONSE I COME UP EMPTY. THESE ARE OUR PROPOSED OUTCOMES. AND THE ONLY THROUGH PCA ANALYSIS, WE DID FIND A FEW CYTOKINES THAT DID NEGATIVELY RELATE, THE HIGHER LEVELS OF CYTOKINES, THE MORE PAIN PATIENTS REPORTED AT BASELINE BUT THESE DIDN'T PREDICT HOW WELL THE PATIENT WOULD RESPOND. SO SEVERAL YEARS AGO WE LOOKED AT THE PRP AND COMPARED THE PRP FROM OLDER MALES WITH KNEE OSTEOARTHRITIS AND THAT OF YOUNG HEALTHY PRIMARILY MEDICAL STUDENTS. WE FOUND THE PRP FROM OLDER MALES DEPRESSED CHONDROCYTE METABOLISM AND UPREGULATED INFLAMMATION. SO I HOPE THE MOVIES IN THE NEXT SLIDE WILL WORK. WHAT I AM SHOWING HERE IS GIVING THE THE PRP TO MONOCYTE CULTURES AND FINDING THAT THE PRP FROM THE YOUNG HEALTHY MOUSE INDUCED THE FORMATION OF THE M 2 MACROPHAGE PHENOTYPE. WHEREAS IF WE GAVE THE PRP THE OLDER MALES, IT INDUCED THE M 1 PHENOTYPE. O SO I WANT TO TAKE US BACK TO SOME OF THE PARABAYOUSIS STUDIES DONE BY TOM RANDO NOW PUBLISHED IN 2004, 2005 WHERE THEY CONNECTED THE BLOOD SUPPLY OF YOUNG MICE, REALLY THESE STUDIES SHOULD GIVE A LOT OF HOPE. THE OLDER MICE WITH AGED STEM CELLS IN AGED SYSTEM, ACTUALLY WHEN CONNECTED TO BLOOD SUPPLY AND ALSO THE MILIEU OF YOUNGER MICE, STEM CELLS SHOWED GREATER REGENERATIVE CAPACITY. OTHERS HAVE SHOWN HEALTHIER HEARTS, IN WYSS COREY, BETTER MEMORY. THESE STUDIES ILLUSTRATE THERE ARE CIRCULATING FACTORS IN THE BLOOD THAT HELP TO PROMOTE AND CAN KICK START AND JUMP START REGENERATION IN OLDER INDIVIDUALS AND EVEN PEOPLE WHO HAVE DISEASE. BUT THE FLIP SIDE IS, IF YOU LOOK AT THE ACTUAL DATA THE YOUNG MICE WHO WERE CONNECTED TO THE OLDER MICE, THEIR PROLIFERATIVE STATUS, INFLAMMATORY STATUS WAS LORE THAN THAT OF YOUNGER MICE CONNECTED TO OTHER YOUNG MICE. SO WHAT THIS MYLIGHTS IS THERE IS GOOD BLOOD AND BAD BLOOD. THERE ARE ANYTHINGTIVE INHIBITOR FACTORS IN BLOOD OF OLDER MICE. THIS IS AN AREA PRIMED FOR RESEARCH. WYSS COREY WENT TO SHOW YOU CAN GIVE INJECTIONS OF FRESH YOUNG PLASMA AND SEE IMPROVED LEARNING MEMORY IN AGED MICE AND THEY HAVE DONE CLINICAL TRIALS IN THIS AREA. MORE RECENTLY, CONVOY'S GROUP HAS SHOWN PLASMA DILUTION WILL ATTENUATE NEUROINFLAMMATION IN OLDS MICE SO THIS TO ME IS VERY EXCITING. THEY FURTHER SHOWED -- THEY ALSO LOOK AT USE OF ANTI-SINOLITIC AGENT, A PERIPHERALLY ACTIVE AGENT AND THEY FOUND THE PLASMA DILUTION HAD GREATER ANTI-INFLAMMATORY AND REJUVENATIVE EFFECTS BEEN THE ANTI-SINOLITIC AGENTS, WE HAVE IN OUR GROUP TODAY JOHNNY HUARD, JENNY ELISSEEFF AND OTHERS WHO ARE ACTIVELY WORKING ON ANTI-S XENOLYTICS SO GREAT TO HEAR THEIR PERSPECTIVES. BACK TO WHAT WE CAN DO TODA TODAY. THISS AMYE'S QUESTION, WHAT PATIENTS ARE IS INTERESTED IN. THE YOUNG PRP SHOWED LOWER LEVELS OF INFLAMMATION WITH RED IN OUR SCALE REFLECTING HIGHER LEVELS OF INFLAMMATION. BUT I WANT TO POINT OUT IT WASN'T EVERYONE, THIS YOUNG MAN CERTAINLY SHOWED HIGH LEVELS OF INFLAMMATION. AND I LATER LEARN HE FREQUENTED MCDONALDS. SO THINGS WE CAN THINK OF HEALTH PROMOTION, LIFE SPAN PROMOTION IS THINGS WE READ ABOUT. AFTER EATING A FAST FOOD BURGER NEGATIVE THINGS HAPPEN AND PROMOTION AND INFLAMMATION HAS BEEN FOUND SO PROFOUND IT IS LIKENED TO HAVING A BACTERIAL INFECTION. SO WHAT I REALLY LIKE TO HIGHLIGHT IS THAT BLOOD TREATMENTS PARTICULARLY IN OUR ATHLETICALLY GIFTED YOUNG ACTIVE ATHLETES, THEIR BLOOD LIKELY HAS MORE REGENERATIVE FACTORS THAN WHAT IS IN OUR OLDER PATIENTS WITH OSTEOARTHRITIS WHO AREN'T ABLE TO EXERCISE, EXERCISE IS SHOWN TO ENHANCE THE QUALITIES AND THE PLATELET RICH PLASMA AND ALSO STEM CELL FACTORS THERE IS AN EMERGING LITERATURE ON THE GUT MICROBIOME JOINT CONNECTION AND AMYE ALREADY TOLD US THE STRESS OF LOSING HER HOME REALLY CHANGED THE INFLAMMATORY ENVIRONMENT. SO THESE ARE SYSTEMIC FACTORS AND I WANT TO HIGHLIGHT WE NEED TO TAKE THIS AS A SYSTEMS BASED APPROACH AND THINK HOW WE CAN OPTIMIZE SYSTEMIC BIOLOGY FOR JOINT HEALTH. I BELIEVE THIS WILL BE REFLECTED IN THE BLOOD WHICH CIRCUMSTANCE RATES THROUGHOUT THE SYSTEM. AND PRP IF USING AS TREATMENT FOR OUR BONE MARROW SO PREPARATIONS WILL LIKELY BE ENHANCED IN REGION OPERATIVE CAPACITY. THIS IS OPINION RIGHT NOW. BUT THESE ARE THE STUDIES, THAT CAN REALLY HIGHLIGHT WHETHER DIET AND LIFESTYLE IMPROVEMENT TODAY CAN IMPROVE SYMPTOMS. THESE ARE AREAS WHERE PATIENTS CAN ALREADY START FOLLOWING GUIDELINES SHOWN TO BE HEART HEALTHY FOR THE BRAIN AND OVERALL HEALTH IN GENERAL. THANK YOU FOR YOUR ATTENTION. HAPPY TO TAKE QUESTIONS OR TO DONATE TIME BACK TO THE PROGRAM. >>TWO QUESTIONS, WE HAVE BEEN CHATTING BEHIND THE SCENES AND WE ARE GOING TO TAKE TEN MINUTES OUT OF THE LUNCH AND FIVE MINUTES OUTS OF THE BREAK TO GET US CAUGHT UP SO IT IS MORE IMPORTANT WE HAVE A DISCUSSION. >>I HAVE A QUESTION. >>YES. >>GREAT TALK. THANK YOU. THE AUSTRALIAN STUDY YOU MENTIONED WAS PRP CONCENTRATION THAT WAS FAIRLY LOW BY OTHER TYPES OF PRP. DEVICES. SO IN YOUR STUDY WHICH YOU DID SHOW SOME POSITIVE RESULTS, WHAT WAS YOUR PERCENT -- CONCENTRATION ABOVE BASELINE, HOW DID IT COMPARE WITH THAT STUDY? >>YES. SO MINE WAS SIMILAR TO THAT STUDY. SO REALLY FOR US TO DO THIS TRIAL, THIS IS AT THE VETERANS HOSPITAL, WE WEREN'T ABLE TO MAKE OUR OWN PRP OR HAVE DEFINED CONCENTRATIONS IN THESE COMMERCIALLY AVAILABLE SYSTEM, IT WAS THE OLD SYSTEM AND WE HAVE BEEN ABLE TO HAVE A WORK AROUND, AND CONTINUE WITH THAT. I HEAR WHAT YOU ARE SAYING, OTHERS DO AND STUDIES SHOW IS IT 5X BASELINE, 3X BASELINE. WE WERE RIGHT AROUND CLOSE TO WHERE THE AUSTRALIAN STUDY WAS. >>OKAY. THANK YOU. >>YES. >>I THINK WE C WE CAN GET CUSTD PRP TO SAY THIS IS IS A GOOD SPECIMEN, CAN WE USE THIS DATA TO IDENTIFY CHARACTERIZE PRP. >>YES. I THINK MANY IN THIS ROOM ARE IS LOOKING INTO THOSE QUESTIONS, AND REALLY ONE OF THE FIRST STEPS IS THE PARABAYOUSIS STUDIES AND EARLIER IN VITRO STUDY, FOR SOME PEOPLE, PARTICULARLY HOLDER PEOPLE WITH MORE SEVERE DISEASE, THERE ARE LIKELY FACTORS IN THEIR BLOOD WE DON'T WANT TO CONCENTRATE WITH PRP TYPICALLY YOU ARE CONCENTRATING A LITTLE BIT. SO POTENTIALLY THINGS LIKE IF YOU CAN IDENTIFY WHAT THE BAD FACTORS ARE, THEY CAN BE REMO REMOVED. AND I KNOW OTHERS WILL SPEAK ON SMALL PROTEINS OR EXOSOMES. WE CAN SHOW SOME THINGS TO BE BENEFICIAL, THOSE CAN POTENTIALLY BE ENHANCED OR PATIENTS EVALUATED TO SEE WHETHER THEY FALL INTO A REGENERATIVE PHENOTYPE AND WOULD BE CANDIDATES FOR USE OF THEIR OWN BLOOD OR NEED SOME OTHER FORMULATION. >>DR. HOCHBERG HAS A QUESTION. >>I JUST UNMUTED MYSELF. SO THE PREPONDERANCE OF EVIDENCE FOR PRP, DOES NOT SUPPORT ITS USE. DESPITE THE FACT IT IS EXTENSIVELY USED, PARTICULARLY IN PRACTICE OF SPORTS MEDICINE, P FOCI TRY ORTHOPEDIC SURGERY, THE RECOMMENDATIONS OF THE ARTHRITIS FOUNDATION AND THE AMERICAN COLLEGE OF RHEUMATOLOGY, AMERICAN ACADEMY OF ORTHOPEDIC SURGEON, THE VA DEPARTMENT OF DEFENSE, THESE RECOMMENDATIONS FOR THE NON-SURGICAL MANAGEMENT OF KNEE OSTEOARTHRITIS,S DO NOT RECOMMEND USE OF PRP. >>I THINK THAT -- I USE IT IN MY PRACTICE AT THE VA AND I THINK THE WAY I THINK ABOUT IT IS WE ARE USING IT IN YOUNGER PATIENTS WITH LESS SEVERE DISEASE, I TELL ALL MY PATIENTS THAT IT DOESN'T WORK WITH EVERYONE. MY OPINION BASED ON EARLY STUDIES IS HEALTHIER THEY CAN GET THEMSELVES THE MORE LIKELY IT IS THEIR BLOOD, SO THIS IS ESSENTIALLY WHAT I HAVE TALKED ABOUT. WHAT WILL BE USED BLOOD AND PLATELETS WHICH IS REALLY THERAPY WE ARE USING BE MORE LIKELY TO HAVE BENEFICIAL EFFECTS IN THAT IN SOME INSTA INSTANCES, THE BLOOD SHOULDN'T BE CONCENTRATED AND USED. I DON'T THINK WE HAVE THE ANSWER. THE AMOUNT OF INJECTIONS THAT HAVE BEEN GIVEN WOULD SUBSTANTIATE NO SIGNIFICANT SAFETY CONCERNS, REALLY THE QUESTION IS EFFICACY AND THE QUANTITATIVE MR WORK HAS NOT SHOWN REGENERATIVE CAPACITY. >>SO THE QUESTION IS WHETHER TO RECOMMEND OR PROVIDE A TREATMENT WHICH WHILE SAFE HAS NOT BEEN SHOWN EFFICACIOUS IN CONTROLLED CLINICAL TRIALS. I WOULD SAY MY COLLEAGUES HERE AT THE VA IN MARYLAND WHO ARE IN POSIATRY AND ORTHOPEDICS ALSO USE PRP INJECTIONSS. MY FELLOWS REFER PATIENTS FOR PRP INJECTIONS. BUT THE ISSUE WOULD BE WHAT ABOUT FOR SYMPTOMATIC THERAPY, ONE CAN CONSIDER SALIENT INJECTIONS SO THE ISSUE IS WHETHER THERE IS EVIDENCE OF REGENERATIVE CAPACITY UNQUOTE. IN THE PATIENT WITH NIKOS ARTHRITIS. WHO IS DIFFERENT FROM THE YOUNG ATHLETE WITH A ISOLATED CARTILAGE DEFECT IS WE WILL DISCUSS DURING THE DAY TODAY. I WILL GO BACK ON MUTE. >>TWO MORE QUESTIONS, DR. WHITE. >>THANK YOU FOR THAT WONDERFUL PRESENTATION DR. CHU. IT IS INTRIGUING WITH HEALTHY LIFESTYLE ASSOCIATED RESPONSE SEEMS TO PRP OR AT LEAST THAT IS HYPOTHESIZED. ANYONE DELVED INTO THAT LOOKING AT OBJECTIVELY MEASURE HOW ACTIVE SOMEBODY ACTUALLY IS, MAYBE IN ADDITION TO THEIR DIET AND QUALITIES OF HEALTHY LIFESTYLE AND RESPONSE TO PRP INJECTION? I HAVEN'T COME ACROSS THAT AT ALL BUT INTRIGUED BY YOUR STATEMENT WITH REGARDS TO THAT. >>I THINK YOUR BACKGROUNDS CERTAINLY WITH WEARABLES AND MEASURING THINGS, LEFT TO HAVE FURTHER DISCUSSIONS WHERE WE ARE WORKING TO IMPLEMENT THOSE TYPES OF PROGRAMS INTO ACTUALLY CLINICAL PRACTICE. AT THE VETERANS HOSPITAL HERE. THESE ARE ALL THINGS THAT I THINK NEED TO BE LOOKED AT. THANK YOU FOR BRINGING THAT UP. >>GREAT. THANKS. >>ONE LAST QUICK QUESTION. WE TRY TO STAY ON PROGRAM LALE BIT HERE. >>I HAD A COMMENT REGARDING CUSTOMIZATION OF PRP. SOME OF US HAVE SHOWN IF YOU WANT TO USE PRP FOR SKELETAL MUSCLE, AND IF YOU BLOCK TGF BETA 1 YOU GET BLOOD FIBROSIS AND IMPROVE BENEFIT OF PRP. WE DID THE SAME FOR CARTILAGE WITH VGF AND ANGIOGENESIS FOR PFP WITH CARTILAGE REPAIR. I BELIEVE CUSTOMIZATION OF PRP MAYBE MORE THAN MINIMAL MANIPULATION OF THIS PRODUCT SO I WOULD LIKE TO ASK CONNIE, WHAT HAPPENED IF YOU INJECT PRP BUT TREAT PATIENT WITH FIBROTIC DRUG, LOSARTIN OR KOZAR OR BLOOD VEGF THAT PREVENT CUSTOMIZATION OF PRP BUT THE SAME BENEFIT ON CARTILAGE. >>THANKS, I THINK WHAT YOU ARE TALKING ABOUT IS COMBINATION TYPE THERAPY WHERE YOU ARE LOOKING AT NOT JUST LOOKING AT WHETHER THIS HAS REGENERATIVE CAPACITY BUT BLOCKING SOMETHING THAT MAY BE INHIBITING REGENERATION. AND YOUR OTHER WORK WITH ANTI-XENOLYTICS, TAKING THE APPROACH TO ADDRESS BOTH SYSTEMIC ASPECT AND ALSO THE LOCAL JOINT ENVIRONMENT I THINK THOSE TYPES OF TAKING A BROADER LOOK BEYOND CARTILAGE AND BEYOND BONE AND ADDRESSING THE JOINT ALONG WITH SYSTEMIC COMPONENTS PARTICULARLY RELATED TO AGE AND OTHER DISEASE PROCESSES. CRITICALLY IMPORTANT, THANK YOU FOR HIGHLIGHTING THAT >>GEORGE DO YOU WANT TO ASK A QUICK QUESTION? YOU HAVE YOUR HAND UP. >>MY ONE QUESTION IS CONNIE, YOU POINTED OUT THERE IS A SIGNIFICANT PART OF SUCCESS OR FAILURE OF CURRENT TREATMENT WHICH IS CHOOSING THE RIGHT PATIENT. THERE ARE PATIENTS WE CAN GUESS OR LESS LIKELY TO RESPOND SO VARIOUS AREAS OF DISEASE OR STABILITY OF THE JOINT OR PAST HISTORY, WEIGHT AND AGE. THEN THERE ARE PATIENTS WHO MAY BE BAD DONORS BECAUSE BLOOD COMPONENTS AT THE TIME WHEN WE WANT TO TREAT THEM, ARE FLAWED. OTHER THAN THE WORK YOU ARE DOING WHERE WE ARE MEASURING COMPONENTS IN THE PRP AND CHARACTERISTICS IN THE PATIENTS ARE WE DESIGNING STUDIES TO ALLOW US TO ANSWER THESE TWO IMPORTANT QUESTIONS WHO TO TREAT AND WHO NOT TO TREAT. >>ID THINK THOSE STUDIES A CRITICALLY IMPORTANT. I HAVE SOME UPCOMING STUDIES WHERE WE WILL TRY TO ADDRESS THAT BUT IT IS NOT -- IT IS SOMETHING THAT I THINK FOR THE BROADER COMMUNITY, THIS IS A WAY TO APPROACH THIS, THAT WE NEED TO DEFINE DIFFERENT SUB TYPES. I KNOW YOU HAVE DONE WORK IN THIS AREA. SO DEFINING STRUCTURAL SUB TYPES, DEFINING MOLECULAR SUB TYPES. ALSO LOOKING AT DISEASE PRIOR TO SYMPTOM ONSET IS CRITICALLY IMPORTANT. STUDY AFTER STUDY, HAS SHOWN THAT REALLY IT IS ONLY ADVANCED BONE ON BONE STRUCTURE DISEASE OR PATIENT REPORTED OUTCOMES START TO TRACK. YET ALL THESE DEVELOP EARLIER LIKE A HEART ATTACK, YOU DON'T REALLY KNOW UNTIL EVERYTHING CULMINATES AND CATASTROPHIC FAILURE AND PATIENTS ARE IN PAIN ALL THE TIME AND THEN REALLY IT IS TOO LATE. BRING IT BACK TO EARLY OA PRE-OA ARE VERY, VERY IMPORTANT >>THANK YOU. >>THANK YOU. SO MUCH. IT GIVES ME GREAT PLEASURE TO INTRODUCE MY CO-CHAIR, SCOTT RODEO. WHO HAS REALLY BEEN DRIVING THOUGHT LEADER IN THE AREA OF REGENERATIVE MEDICINE, HE IS ACCOMPLISHED CLINICIAN SCIENTIST NIH FUNDED, HE IS VICE CHAIR RESEARCH HOSPITAL FOR SPECIAL SURGERY, I KNOW DR. WHITE WAS ALSO A GIANTS FAN. HE'S BEEN TEAM PHYSICIAN FOR PRO FOOTBALL AND OTHER SPORTS FOR MANY, MANY YEARS. HE'S GOING TO TALK CONCEPTS UNDER ROLE OF STEM CELLS IN OSTEOARTHRITIS. >>THANK YOU, CONNIE. LET'S MOVE AHEAD. LET'S TALK CELL THERAPY DISCLOSURES ARE HERE. NOT GOING DIRECTLY RELEVANT EXCITE HONESTLY. I WILL START ASKING THE QUESTION WHAT IS A STEM CELL? ARE THERE ANY TRUE QUOTE UNQUOTE STEM CELLS WE CAN USE TODAY. WE CAN USE CELLS FROM BONE MARROW ADIPOSE TISSUE, PERINATAL TISSUE, AMNIOTIC MEMBRANE, CORED BLOOD AND THINGS LIKE THAT, UNDERSTAND UNIVERSAL STEM CELL CRITERIA INCLUDE UNSPECIALIZED CELLS THAT HAVE POTENTIAL FOR SELF-RENEWAL, THEY DIVIDE ASIMILAR METICALLY TO TWO DAUGHTER CELLS ONE COPY OF ORIGINAL AND SECOND DAUGHTER CELL DIFFERENTIATE, THERE'S MULTI-POTENT DIFFERENTIATION CAPACITY GIVES YOU A SENSE OF THE DIFFERENTIATION CAPACITY. UTILIZED CELL SOURCES CONTAIN FEW IF ANY STEM CELLS BY FORMAL CRITERIA. MANY KAPLAN CLASSIC 1991 PAPER FOR DEFINING MESENCHYMAL STEM CELL BACK IN THE 1960s AND 70s, SPUE FRIEDENSTEEN INTRODUCED BONE MARROW AND KAPLAN INTRODUCED MESENCHYMAL STEM CELLS IN 1991, PROGENY BECOME COMMITTED TO PHENOTYPIC PATHWAY LEADING TO DIFFERENTIATION. THIS IS A CONCEPT BACK THROUGH THE '90s, ORAL CAPLAN AND OTHERS WORK. HE TALKED ABOUT EXTRINSIC FACTORS AS WELL AS INTRINSIC FACTORS IN THE CELLS WITH EACH STEP TO CONTROL THE CHARACTERISTIC PHENOTYPE OF CELLS AS THEY GO THROUGH THE DIFFERENTIATION PROCESS. HE CONCLUDED THE ISOLATION MITOTIC EXPANSION AND SITE DIRECTED DELIVERY OF AUTOLOGOUS STEM CELLS CAN GOVERN THE RAPID AND SPECIFIC REPAIR OF SKELETAL TISSUES. 26 YEARS LATER, WE RECOGNIZE REVISED CONCEPT AS FAR AS WHAT IS STEM CELL, BECAME EVIDENT THAT BIOLOGIC EFFECT OF EXOGENOUS CELLS CAN BE DUE TO PRODUCTION OF ANTI-INFLAMMATORY AND IMMUNE MODULATING MEDIATORS, PROBABLY MODIFY LOCAL ENVIRONMENT, AFFECT LOCAL RESIDENT CELLS. THIS IS A QUOTE FROM CAPLAN I URGE WE CHANGE THE NAME TO MEDICINAL SIGNALING CELLS TO ACTIVELY REFLECT THE FACT THESE CELLS HOME IN ON SITES OF INJURY, AND THEY SECRETE BIOACTIVE FACTORS THAT BOTH HAVE IMMUNE MODULATING PROPERTIES, POTENTIALLY REGENERATIVE. HE QUOTED FURTHER INDEED PATIENT OWN SITE SPECIFIC TISSUE SPECIFIC RESIDENT STEM CELLS CONSTRUCTED NEW TISSUE STIMULATED BY THESE BIOACTIVE FACTORS. WE RECOGNIZE EXOGENOUS CELLS MAY FUNCTION BY MODIFYING THE INJURY ENVIRONMENT, RATHER THAN DIRECTLY CONTRIBUTING TO HEALING. SO AT THE END OF THE DAY, THIS INTRODUCE CONCEPT OF STIMULATION OF EXTRINSIC THE INTRINSIC STEM CELL NICHE THAT EXISTS AND MAKE TISSUES PRE-NATAL AS WE GO THROUGH THE TALK WE UNDERSTAND HOW EXOGENOUS CELLS WE CAN USE HOW THEY INTERACT WITH INTRINSIC STEM CELL NICHE RESIDENT TISSU TISSUR TALK LATER ON EXOSOMES EXOSOMESL SKIP THIS IN THE INTEREST OF TIME, DANIEL WILL TALK ABOUT EXOSOMES BUT THESE EXTRA CELLULAR VESICALES RELEASE CELL CARTILAGE IF YOU WILL AND PRESENT POTENTIAL TO OBTAIN BENEFITS OF CELL THERAPY WITHOUT CELL CULTURING AND EXOSOMES ARE COMPLEX, ONE OF THE FUNDAMENTAL MECHANISMS IS INDUCTION OF POLARIZATION TO MACROPHAGES CONTRIBUTING TO ANTI-INFLAMMATORY IMMUNE MODULATING PROPERTIES OF CELLS. CELLS WE CAN USE TODAY EXOGENOUS CELLS MARROW ADIPOSE PERINATAL TISSUE AND AGAIN INTRINSIC STEM CELL NICHE. WE WILL COME BACK TO THIS AS WE GO THROUGH THIS. WE TALK ABOUT CELLS MSCs, THE S IS STROMAL CELLS. MESS CHIMAL STROMAL CELLS AND STANDARD CRITERIA PUT FORTH BY INTERNATIONAL SOCIETY FOR PLASTIC GENE THERAPY, AND DIFFERENTIATION CAPACITY SO KEEP THIS IN MINE. THIS IS BASIC DEFINITION AND THIS IS IMPORTANTLY BASED ON CELL BEHAVIOR IN VITRO. IN CULTURE. GEORGE MADE SOME VERY IMPORTANT CONTRIBUTIONS IN THIS FIELD AND INTRODUCED CONCEPT CONNECTIVE TISSUE PROGENITOR, PROBABLY A BETTER TERM TO USE, WITH CELLS WE ARE IMPLANTING IN OUR CLINICAL APPLICATION HETEROGENOUS POPULATION OF TISSUE RESIDENT CELLS AND CAN PROLIFERATE AND GENERATE PROGENY WITH CAPACITY TO DIFFERENTIATE IN ONE OR MORE -- DIFFERENTIATE TO CONNECTIVE TISSUES, WE CAN MEASURE PROGENITOR CELLS BY COUNTING COLONY FORMING UNITS IN CULTURE, EACH REGENERATIVE CELL IN CELL FOR COLONY. I WOULD SUBMIT THE TERM MSC SHOULD BE USED TO REFER TO CULTURE EXPANDED POPULATION OF CELLS THAT MEET THESE CRITERIA, IMAGING FOR CELL THERAPY AND SHOULDN'T USE THE TERM TO DESCRIBE HETEROGENOUS POPULATIONS OF NATIVE CELLS WITH UNDEFINED PROPERTIES IN VIVO. THIS GETS SOME OF THE POINTS LAST DISCUSSION FROM CONNIE'S TALK, THE HETEROGENEITY IN FORMULATIONS AND NEED TO CHARACTERIZE WHAT WE ARE PUTTING TO OUR PATIENTS. HOW MIGHT CELLS WORK? SEEM TORR SYMPTOM MODIFYING AS FAR AS IMPROVING SYMPTOMS TYPICALLY PAIN AND SWELLING IN PATIENTS. AGAIN BACK TO PARACRINE MECHANISM VIA ANTI-INFLAMMATORY MEDIATORS AND VARIOUS IMMUNE MODULATING FACTORS. THEY WAY ACT ON SYNOVIAL CELLS IN THE JOINT FOR IMMUNOMODULATION AND SYMPTOM MODIFICATION. THINK OF OSTEOARTHRITIS. OTHER PART OF THIS IS CAN CELLS STRUCTURE MODIFYING? CAN THEY INDUCE TRUE TISSUE GENERATION. TO THAT THEY NEED TO ACT UPON CHONDROCYTE IN JOINT, SYNOVIAL CELLS, BOB MARROW BEREAVED CELLS TO INDUCE -- BONE MARROW DERIVED CELLS TO INDUCE TISSUE REGENERATION. THIS IS A PIE IN THE SKY AS FAR AS USING CELL THERAPIES TO INDUCE TWO STRUCTURE MODIFICATION. WITH THAT BACKGROUND ABOUT CELL THERAPY WE CAN CONSIDER THE ROLE IN TREATMENT OF OSTEOARTHRITIS. INFLAMMATION PLAY AS CRITICAL ROLE IN PATHOPHYSIOLOGY OF OSTEOARTHRITIS. THIS IS A GROUP ON THIS DOPE NEED TO GET INTO DETAIL BUT IMPORTANT TO POINT OUT OA IS COMPLEX PROCESS CHARACTERIZED BY INVOLVEMENT OF COURSE IN NUMEROUS CELLS AND TISSUES, CARTILAGE SUBCHONDRAL BONE, SYNOVIUM. WE KNOW INNATE IMMUNE CELLS, MACROPHAGES MK CELLS PLAY IMPORTANT ROLE IN EARLY INFLAMMATORY RESPONSE AND ADAPTIVE IMMUNE CELLS, T AND B CELLS CONTRIBUTE TO DEVELOPMENT OF CHRONIC RELAPSING SYMPTOMS IN OUR PATIENTS. OBVIOUSLY INFLAMMATION I IS A HIGHLY COMPX PROCESS. ANTI-INFLAMMATORY AND IMMUNE MODULATING EFFECTS OF CELLS IS CONTEXT DEPENDENT. THE DIAGRAM GIVES A SENSE, MSCs, MESENCHYMAL STROMAL CELLS FROM MARROW OR ADIPOSE TISSUE, STANDARD SOURCES, THESE CAN PROMOTE ENDPLAYMATION WHEN IMMUNE SEASONAL IS UNDERACTIVATED. MSCs DECREASE INFLAMMATION WHEN IMMUNE SYSTEM IS OVERACTIVATED. SUPPRESS IMMUNE SUPPRESSERS THAT SWITCH FROM PRO INFLAMMATORY TO ANTI-INFLAMMATORY PHENOTYPES, HOW COMPLEX THESE CELLS ARE. THEY ARE MEDIATED BY POLARIZATION OF PROINFLAMMATORY M 1 TO PANT INFLAMMATORY PHENOTYPE. SO SUMMARIZED A LOT OF WORK IN INTEREST OF TIME, CLEARLY THE CELL THERAPIES MODULATE INFORMATION AND UNDERSTANDING IS THESE THERAPIES WORK VIA PRODUCTION OF HOST OF ANTI-INFLAMMATORY AND IMMUNE MODULATING FACTORS AND BIOLOGY IS COMPLEX, ILLUSTRATED HERE, JUST GIVE YOU A 30,000-FOOT VIEW. I WANT TO INTRODUCE THE CONCEPT THESE IMPORTANT INTERACTIONS BETWEEN MSCs AND IMMUNE CELLS SUBTYPES WHETHER SYSTEMIC OR LOCAL IMMUNE CELLS IN THE JOINT ENVIRONMENT. WE KNOW MCs CAN DIRECTLY AFFECT SYNOVIAL INFLAMMATION. THIS IS WORK FROM A GROUP IN NETHERLANDS USING MOUSE MODEL OF EXPERIMENTAL OA. INDUCED SIGH EWE VIETIS OR DISSEMINATION OF MEANIAL ME IN THIS CUSS MODEL. THEY FIND SYNOVIUM IN ANIMALS. IF THEY TREAT THE ANIMALS, TREAT WITH ADIPOSE DERIVED CELLS, THEY FOUND SUPPRESSION OF ACTIVATED MACROPHAGES, THEY SEE DOWN REGULATION OF VARIOUS PROINFLAMMATORY MEDIATORS. DECREASE IN OSTEOCYTE FORMATION. YOU CAN SEE PROACTIVELY SYNOVIAL ACTIVATION SIGH KNEW VIETIS SCORES IN THESE ANIMALS SO BASIC LABORATORY ANIMALS DO DEMONSTRATE DIRECT EFFECT OF MSC ON THAT SYNOVIAL INFLAMMATORY PROCESS. MORE WORK AT MSC AND HOW MEDIATED BY CELLS IN INNATE IMMUNE SYSTEM, IMPORTANT FROM GROUP IN ROT TEARDAM. THEY REPORT SYSTEMICALLY ADMINISTERED MSCs ARE PHAGOSIGH THOSED BY MONOCYTES THAT LEADS TO POLAR -- PHAGOCYTOSED BY THIS PHENOTYPIC SWITCH. THESE PRIME MONOCYTES INDUCE UPREGULATION OF T REGULATORY CELLS TO YOUR ADAPTIVE IMMUNE RESPONSE, LEADS TO INDUCTION OF LONG TERM ADAPTIVE IMMUNE RESPONSE UPON DIFFERENTIATION OF THESE AFFECTED MONOCYTESES AFTER THEY PHAGOCYTOSE CELLS, DIFFERENTIATE IN IMMUNE MACROPHAGES. THIS IS INTERESTING BECAUSE THE DATA SUGGESTS THE BIOLOGICAL ACTIVITY OF INFUSED CELL MAYBE INDEPENDENT OF CELLULAR ACTIVITY. CHALLENGES HYPOTHESIS THAT AFFECTS OF MSCs ARE MEDIATED BY THE SECRETOME. THE ADDITIONAL SIGNALING CELL FROM CAPLAN YEARS AGO SO IMPORTANT REARE ACTION BETWEEN CELLS MSCs AND IMMUNE CELLS WHICH LEADS TO DISCUSS MORE ABOUT THE ROLE OF MACROPHAGES IN OA DEVELOPMENT AND PROGRESSION, GROUP FROM FRANCE WITH CHRISTIAN, THEY IMPORTANT POINT OUT HOW MACROPHAGES ARE IMPORTANT INFILTRATES IN OA. BUT MACRO BIOLOGY IS COMPLEX. PEOPLE DISCUSS TWO POPULATION MACROPHAGES RESIDENT MACROPHAGES, PRESENT IN THE JOINT, AS WELL AS MONOCYTE DERIVED MACROPHAGES FROM CIRCULATION IN THE INTERACTION BETWEEN THESE POPULATIONS IS CRITICALLY IMPORTANT. MACROPHAGE BIOLOGY IS VERY COMPLEX WITH THESE CELLS INFILTRATING ANA BOLLIC AND CATABOLIC, THERE ARE PRO INTORY AND ANTI-INFLAMMATORY MACROPHAGES IN OA SO FOLLOWING THE THEME ABOUT MACROPHAGES, OTHER WORK HERE THAT THEY WENT ON THE SAME GROUP FROM FRANCE, JUST TO SUMMARIZE THE PATHWAYS DISCUSSED. THERE IS INFLAMMATORY SIGNALING PATHWAYS ACTIVATED IN SETTING OF OSTEOARTHRITIS. AND THAT DOES ATTRACT CIRCULATING PROINFLAMMATORY MONOCYTE DERIVED MACROPHAGE, THE M 1 POPULATION WHICH THEN WILL INFILTRATE THE JOINT, THESE PROINFLAMMATORY MACROPHAGES DO CARRY OUT PHAGOSITIC FUNCTION BUT THEN BEGIN TO SECRETE ANTI-INFLAMMATORY MEDIATORS. WHICH CAN ULTIMATELY HAVE ROLE PERHAPS IN PROMOTING WOUND REPAIR. THIS LEADS POLARIZATION FROM THIS M 1 PROINFLAMMATORY TO THE ANTI-INFLAMMATORY PHENOTYPE. FAILURE OF THIS ORCHESTRATED MACROPHAGE RESPONSE FROM SYNOVIAL MEMBRANE OR FAILURE OF RESOLUTION LEADS TO CHRONIC INFLAMMATION, CONTRIBUTING TO PERSISTENT SYMPTOMS. WHAT ABOUT USING MSDs TO TARGET THESE MACROPHAGES? SINCE THEY HAVE SUCH A CRITICALLY IMPORTANT ROLE AND CLEARLY MSCs INTERACT WITH IMMUNE CELLS, HOW CAN MSCs HAVE THERAPEUTIC IN THE JOINT HERE? SO AGAIN MSC ENABLE SWITCH FROM PROINFLAMMATORY TO ANTI-INFLAMMATORY SUB SETS. MOLECULAR MECHANISM ARE COMPLEX BUT NUMEROUS FACTORS INCLUDING TNF ALPHA, PBE 2, EXTRA CELLULAR VESICLES PLAY A ROLE. SO WE HAVE THE DAMAGE JOINT, AGAIN PROINFLAMMATORY MACROPHAGES INFILTRATE AND NOW MSCs ARE SUPPLIED TO THAT PATIENT, DOSED IN THE KNEE EXOGENOUSLY. THAT CAN AFFECT THE MACROPHAGE POPULATIONS AND POTENTIALLY LEAD TO ANTI-INFLAMMATORY PHENOTYPE. WE KNOW MSC DERIVED EXTRA CELLULAR VESICALES TRANSPORT MOLECULES, THAT CAN'T BE SECRETED INCLUDING PROTEINS ENZYMES, AND OTHER FACTORS, YOU WILL HEAR MORE ABOUT THIS IN THE TALK FROM DANIEL SARIS. MSC DERIVED VESICALES ARE SHOWN TO PROMOTE ANTI-INFLAMMATORY MACROPHAGE PHENOTYPE, AN IMPORTANT PRINCIPAL IN OUR DISCUSSIONS LATER ON. SO THAT BACKDROP, WHAT DOES THIS MEAN AS TREATING OUR PATIENT? THEY AFFECT QUALITY SYMPTOMS FROM KNEE OA. 12 PATIENTS WITH KNEE OA TREATED WITH SINGLE INTRAARTICULAR INJECTION OF 1, 10, OR 50 MILLION BONE DERIVED CELLS, NO ADVERSE EVENT, THEY DID REPORT SIGNIFICANT IMPROVEMENT IN OUTCOME MEASURES YOU CAN SEE THE SYMPTOM SCALE ON THE RIGHT SID SIDE. YOU DO SEE IMPROVEMENT IN PATIENT SYMPTOMS AND THEY HAVE THE MOST RELEVANT IMPROVEMENTS IN OUTCOME MEASURES. THIS GROUP WENT TO USE MRI TO LOOK AT CARTILAGE MORPHOLOGY AND COLLAGEN CONTENT USING RELAXATION TIME MEASUREMENTS. THIS SCORE DIDN'T CHANGE SO THOUGH SYMPTOM MODIFYING MAYBE NOT STRUCTURE MODIFYING IN JOINTS. THEY DID FIND CARTILAGE CATABOLIC BIOMARKER AND MRI SCORE LOWER DOSE, SYNOVIAL SCORE IN THE RIGHT, HIGH DOSE RED LINE, LOWER SINUVITIS SCORE. THEY FIND PROPORTION OF PRO-INFLAMMATORY MONOCYTES AND MACROPHAGES DECREASED IN H JOINTS TREAT WITH MSC. THEY HAD A PANEL OF ANTI-INFLAMMATORY MARKERS THEY SURVEYED IN MSC SAMPLES, THEY FOUND THIS PANEL WAS PREDICTIVE OF PATIENT OUTCOME MEASURES OVER 12 MONTHS. THIS DATA PROVIDE PREDICTIVE SELECTION CRITERIA WE CAN USE IN STUDIES OF CELL THERAPY IN PATIENTS. IN SYMPTOMATIC IMPROVEMENT, BRIEFLY META ANALYSES, HERE IS ONE THAT RANDOMIZED TRIALS RETROSPECTIVE STUDIES OVER 500 PATIENTS REPORT IMPROVEMENTS IN ANALOG SCORES, NO ADVERSE EVENTS IN PATIENTS. META ANALYSIS, VISUAL IMPROVEMENTS, YOU CAN SEE IN THE FOREST PLOT HERE, THERE ARE STUDIES THAT DEMONSTRATE IMPROVEMENT WITH CELL THERAPY. THE NEXT QUESTION, ARE THESE CELLS STRUCTURE MODIFYING? CAN WE REGENERATE TISSUE? LITERAL STEM CELLS FOR PATIENT IS POTENTIAL FOR REGENERATION OF STRUCTURALLY FUNCTIONALLY NORMAL TISSUE, BASED ON DEMONSTRATED MULTI-LINEAGE DIFFERENTIATION POTENTIAL CELLS WHICH IS SHOWN IN VITRO. THERE IS LIMITED EVIDENCE FOR TRUE TISSUE REGENERATION BY IMPLANTED CELLS, LIMITED BY NOW EXOGENOUS CELLS WILL INT INTERCO-TO HOST TISSUED DIFFERIATE TO HUMAN -- INTER COLLATE TO HOST TISSUES. TO UNDERSTAND REGENERATION WE NEED TO KNOW IMPORTANT TO UNDERSTAND HOW TISSUE GENERATION OCCURS. IT IS FELT TISSUE GENERATION IN ADULT MAMMALIAN TISSUE IN ORGANS IS ORCHESTRATED BY IMMUNE RESPONSE H COMPLEX BIOLOGY BUT PLAY CRITICAL ROLE IN TISSUE REGENERATION. NEUTROPHILS IN PRO INFLAMMATORY MACROPHAGES INFILTRATE THE JOINTS. WE HAVE INJURED JOINT ARTHRITIC JOINT, PTOA B JOINT, M 1 MA CASH FLOW PHAGOINFILTRATE THE JOINT IN RESPONSEOBTAINFLAMTORY MEDIATORH POLARIZED PHENOTYPE BUT THE PROLONGED DAMAGE CAN LEAD TO UNRESOLVED INFLAMMATION THAT LEADS TO FIBROSIS RATHER THAN TRUE TISSUE REGENERATION. THIS IS IMPORTANT BIOLOGIC CHALLENGE HERE. THIS GETS BACK TO THE INTRINSIC STEM CELL NICHE, WE ARE TALKING POTENTIAL TO REGENERATE TISSUE. MANY HARBOR A POPULATION OF INTRINSIC REGENERATIVE CELLS, THESE ARE LOCALIZED TO WALLS OF BLOOD VESSELS, PICTURE BOTTOM RIGHT IMPORTANT PAPER FROM BACK IN 2008, DEMONSTRATING THE PRESENCE OF THESE CELLS. WE KNOW EXOGENOUS CELLS PRODUCE SIGNALING MOLECULES THAT STIMULATE THESE INTRINSIC PROGENITOR CELLS. THIS IS PROBABLY THESE INTRINSIC CELLS THAT INITIATE TISSUE HEALING AND REGENERATION. SO POTENTIAL TO INDUCE REGENERATION LIKELY DUE TO STIMULATION OF INTRINSIC STEM OR PROGENITOR CELLS THAT RESIDENT IN MANY TISSUES USE THE TERM CONNECTIVE TISSUE REGENERATIVE BACK TO GEORGE MUSCHLER'S WORK AS WELL. OUR STUDY ANIMAL MODEL, POTENTIAL FOR CELLS TO REGENERATE TISSUE IN THE OA JOINT. THIS GROUP FROM CHINA USE RAT KNEE OA MODEL. ACL TRANSSECTION MODEL, ANIMALS TREAT WITH BONE MARROW DERIVED MANY,SC OR THE EXOSOMES AND FOUND BONE MARROW DERIVED AN EXOSOMES ALLEVIATED THE CARTILAGE DESTRUCTION AND SOME BONE REMODELING IN THIS RAT MODEL. YOU CAN SEE OA SCORE DIFFERENT IN THOSE ANIMALS WITH EXOSOMES OR BONE MARROW DERIVED CELLS. FOUND REDUCED JOINT DAMAGE AND CHANGES IN SUB -- MICROCT TO MEASURE MICROSTRUCTURAL PROPERTIES IN BONE. SO THEY FELT THESE BONE MARROW DERIVED CELLS OBSERVED BENEFICIAL EFFECT BY REDUCING CELL SENESCENCE AND APOPTOSIS OF CHONDROCYTES. SO IMPORTANT DISCUSSION LATER TODAY. WE ARE NOT HUMAN CLINICAL STUDIES, ANY EVIDENCE CELLS STRUCTURE MODIFY, THERE'S EARLY EVIDENCE, CHRIS IN KOREA, GROUP OF PATIENTS TREATED WITH INTERARTICULAR INJECTION OF OUTGAS ADIPOSE DERIVED MSC SO THEY OBTAINED CELLS AND CULTURE THE CELLS, SO THIS IS IN KOREA, THE CELLS REJECT AFTER THREE WEEKS CULTURE, THEY EXTENSIVELY TESTED CELLS FOR CELL NUMBER, VIABILITY, PURITY, IDENTITY, SO DO THE APPROPRIATE ANALYSES ON THEIR CELLS, PRIOR TO IMPLANTATION. STUDIES THREE DOSES IN A SMALL GROUP OF PATIENTS. THEY FOUND IMPROVEMENTS IN THEIR PATIENT OUTCOME MEASURE BUT IMPORTANTLY REJECTED EVALUATION WITH MRI AND ARTHROSCOPY DID FIND THE SIZE OF CARTILAGE DEFECT DECREASED IN THE VOLUME OF CARTILAGE INCREASED IN THE COMPARTMENT SEEN GRAPHICALLY HERE. THEY FOUND BIOPSY GENERATED HIGHLIGHT CARTILAGE EARLY EVIDENCE HERE CULTURE EXPANDED CELLS MAY IN FACT BE STRUCTURE MODIFYING. SIMILAR STUDY FROM PAIN, RANDOMIZE TRIAL ALLOGENEIC, CULTURE EXPANDED MARROW CELLS, INTRAARTICULAR INJECTION IN JOINTS OF KNEE OA PATIENTS CONTROLLED WITH HYALURONIC ACID INJECTION. AND THE CELL TREATED PATIENTS HAD IMPROVEMENTS IN THEIR PATIENT OUTCOME MEASURE BUT IMPORTANTLY ON MRI USING RELAXATION TIME MEASUREMENTS OF CARTILAGE FOUND IMPROVEMENT IN CARTILAGE QUALITY AND THOSE PATIENTS TREATED WITH CELLS. CULTURE EXPANDED CELLS. SO POTENTIAL FOR CELL TO INDUCE TISSUE REGENERATION. SO TO CONCLUDE, I WOULD SUBMIT WE CURRENTLY HAVE LITTLE ABILITY TO USE TRUE STEM CELLS DEFINED BY ANY FORMAL CELLULAR OR MOLECULAR CRITERIA. BUT THERE IS DATA TO SUGGEST SYMPTOM MODIFICATION. CELL THERAPY HOLDS POTENTIAL FOR SYMPTOMS IN KNEE OA. THIS PARACRINE AFFECT AFFECTING LOCAL TISSUE MICROENVIRONMENT BY PRODUCTION OF ANTI-INFLAMMATORY AND IMMUNE MODULATING FACTORS, CLEARLY ERR ACT WITH LOCAL AND SYSTEMIC IMMUNE CELL SUBTYPES IN KNEE OA JOINT. PLAY A CRITICAL ROLE IN MACROPHAGE POLARIZATION. THE OTHER SIDE OF THE COIN TO ABILITY TO MODIFY STRUCTURE AND REGENERATE TISSUE THERE'S POTENTIAL. WHAT WE NEED IS MOVE TO ABILITY TO PICK OUT CELL SORTING TO ALLOW SELECTION OF DESIRED CELL POPULATIONS, FOLLOWED BY CULTURE EXPANSION OF THOSE CELLS AND MAYBE IMPORTANTLY ELIMINATION OF THE UNDESIRED CELLS. THIS SUGGESTS NIEDERHUBER TO IDENTIFY MARKERS OF PURITY POTENCY AND BIOLOGIC ACTIVITY SO WE CAN AFFECT CHARACTERIZE AND SELECT OPTIMAL CELL POPULATION. I RECOGNIZE TISSUE REGENERATION MAY OCCUR VIA STIMULATION OF INTRINSIC PROGENITOR CELLS RESIDENT IN TISSUE. I WILL STOP THERE. THANK YOU. >>THANK YOU, SCOTT. THIS IS OPEN FOR QUESTIONS. I HAVE A QUICK QUESTION REGARDING -- SO MANY ANIMAL STUDIES IN PARTICULAR USE YOUNG ANIMALS. ARE THERE STUDIES SHOWING WHETHER MACROPHAGE POLARIZATION AFFECTS FROM CELLS FROM OLDER INDIVIDUALS OR INDIVIDUALS WITH DISEASE STATES, DO THEY SIMILARLY INDUCE M 2 POLARIZATION? >>NOT SEEING MUCH, VERY GOOD QUESTION, IN THE ANIMAL STUDIES LARGELY BEEN EXPERIMENTAL OA S NEXTUVITIS, D, MANYM MOLDS LIKE THAT WE NEED CLINICAL STUDIES IN OUR PATIENTS AND THAT IS WHY IN OUR CLINICAL STUDIES WE NEED TO REALLY CHARACTERIZE PHENOTYPE OF PATIENTS SO I DON'T -- HAVE NOT SEEN MUCH EXAMINED THAT IMPORTANT QUESTION. >>SO DAN GRANDE. >>APPRECIATE -- HI. SCOTT, APPRECIATE YOUR WONDERFUL TALK. I WANTED TO YOU TO PERHAPS FOLLOW-UP WITH RESPECT TO DO YOU THINK THAT SOME OF THE STUDIES ARE ALLO GENIC, SOME ARE AUTOLOGOUS, WHAT ARE YOU THINK IS THE DIFFERENCE, IS THERE AN IMPORTANT DIFFERENCE BETWEEN CULTURED MSCs VERSUS USING SAY BMAP WHERE YOU HAVE THE INTERACTION OF THE OTHER CELLS AND THE CROSS SIGNALING, VERSUS PURE COB CENTRATION OF CULTURED MSCs? >>HUGE DIFFERENCE. THE POORLY CHARACTERIZED NATIVE CELL PREPARATION, WE USE WITH BONE (INAUDIBLE) THESE UNCULTURED CELLS, HETEROGENOUS POPULATIONS, VERY VARIOUS POPULATION CULTURE OF CELLS, CULTURE CERTAIN CELL DOMINATE THE CULTURE SO THEY ARE VERY DIFFERENT. SO ALLOGENEIC, IF WE USE THAT PREPARATION IT GIVES THE POTENTIAL TO CHARACTERIZE THOSE CELLS PRE-OPERATIVE SO WE HAVE SOME IDEA OF THE PROFILE OF THOSE CELLS. SO THOSE WILL BE VERY DIFFERENT POPULATIONS AND IF WE MOVE TO ALLOGENEIC CELL SOURCES THEN WE CAN DO APPROPRIATE CELL SORTING, CULTURE EXPANSION OF THE DESIRED CELLS IN THOSE PREPARATIONS. THEY CHARACTERIZE WHAT WE ARE PUTTING IN PATIENTS. I SUBMIT TO ALL OF US CLINICIANS IS USING ALL THESE THERAPIES, WHETHER CELL THERAPY OR PRP QUESTION, WE NEED AN ALLOQUAT OF THAT MATERIAL AND CARRY OUT OUR LABORATORY, WHATEVER TESTS WE CAN DO TO CHARACTERIZE THE PURITY, POTENCY, ACTIVE WHATEVER IT IS, WE IDENTIFY THE SENTINEL MARKERS THAT ARE PRACTICAL AND CORRELATE PATIENT OUTCOMES. CLINICAL OUTCOMES IMAGING OUTCOMES WITH OUR CELL CHARACTERIZATION. >>THANK YOU. >>PAM ROBEY HAS A QUESTION. >>THANK YOU FOR THAT OVERVIEW, SUCH A WONDERFUL OVERVIEW. THIS IS MORE OF A QUESTION GENERALLY TO THE FIELD. THAT IS, DON'T YOU THINK IT IS TIME TO ACTUALLY START USING NAMES THAT ARE MORE DEFINED IN MANY THE CELL POPULATIONS WE ARE USING? YOU REVIEWED NICELY THE HISTORY BLIND THE TERM MESENCHYMAL STEM CELL, I THINK GIVEN THE FACT THAT WE NOW KNOW THAT THINGS TOSSED TO THAT BUCKET ARE QUITE DIFFERENT, THAT WE NEED TO START GIVING CELLS SPECIFIC NAMES, BONE MARROW DERIVED ADIPOSE DERIVED. THERE'S MANY TIMES PEOPLE DON'T IDENTIFY THEIR CELL SOURCE. WE KNOW THESE CELLS ARE INTRINSICALLY DIFFERENT. THIS IS VERY IMPORTANT IN TERMS OF CLINICAL APPLICATION, THAT DEFINING THE CRITICAL QUALITY ATTRIBUTES DEPENDS ON THE CELL SOURCE. DIFFERENT CELL SOURCES MAY HAVE VERY DIFFERENT AFFECTS. SO IF WE WANT TO TRY TO COMPARE ONE STUDY TO ANOTHER, WE NEED TO KNOW MORE ABOUT THE TISSUE SOURCE AND WHAT THE CRITICAL QUALITY CHARACTERISTICS ARE, OF THAT POPULATION. WANT YOUR THOUGHTS ON THAT SUBJECT AND SURE GEORGE PROBABLY HAS THOUGHTS TO. >>MY RESPONSE IS AMEN. YOU SAY THE PROBLEM WELL AND EXPERTS IN THE FIELD HELP US, COULDN'T AGREE MORE. GOES WITHOUT SAYING, YOU STATED THAT WELL. WE NEED TO DO THAT. CLEARLY WE NEED TO CHARACTERIZE WHAT WE ARE PUTTING IN THE PATIENT. >>THANK YOU, CHRISTIAN LATTERMANN. >>SCOTT, THANK YOU VERY MUCH FOR THAT OVERVIEW. THAT WAS BEAUTIFUL. ONE OF THE QUESTIONS THAT I WRESTLE WITH LOOKING AT CHRONIC INFLAMMATION IN THE CONTEXT OF PTOA AND TRY TO COMPARE TO CHRONIC INFLAMMATORY CONDITIONS, WE COME BACK TO THIS CONCEPT OF RESOLUTION OF INFLAMMATION. YOU HAVE MENTIONED THAT ALSO YOU TOLD US VERY MUCH ABOUT THE M 1 M 2 MACROPHAGE SWITCH THAT STILL CELLS ARE ACTING ON. ONE OF THE CLINICAL QUESTIONS I ASK MYSELF AND I WANT YOUR OPINION, DO WE DEAL WITH THE SITUATION WHERE WE HAVE TOO LITTLE INTRAVESICULAR RESPONSE TO THE INJURY OR DO WE DEAL WITH SITUATION WHERE WE HAVE TOO MANY FACTORS THAT ARE PREVENTING AN APPROPRIATE RESPONSE? BECAUSE WE DO HAVE AN INTRINSIC HEALING RESPONSE THAT STARTS BUT SOMEHOW IT FAILS. I'M TRYING TO FIGURE OUT BASICALLY WHAT DO YOU THINK IS HAPPENING HERE? >>MY SIMPLE ANSWER OR CONCEPT IS THAT CLEARLY RIGHT. THERE IS INJURY INDUCE TRAUMA INDUCES INFLAMMATION. INFLAMMATION TURNS ON INTRINSIC HEALING RESPONSE, GOOD THING. PROBLEM IS IT IS CHRONIC UNRESOLVED INFLAMMATION THAT YOU TAKE A LEFT TURN GO DOWN THE WRONG PATHWAY SO MAYBE WITH INJURY YOU -- THE INTRINSIC INNATE SYSTEMS ARE FOR TISSUE GENERATION ARE HEALING ARE STIMULATED BUT CHRONIC INFLAMMATION THEY LEAD YOU THE WRONG PATHWAY IF YOU WILL, THAT IS INSTEAD OF REGENERATIVE TISSUE YOU GO TO FIBROSIS PATHWAY. INFLAMMATION IS HIGHLY COMPLEX BUT IN MY MIND CHRONIC UNRESOLVED INFLAMMATION IS PRIMARY FACTOR. AS PROBLEM WITH ANY DISEASE STATES. >>SO THE QUESTION THAT I'M TRYING TO GET AT IS WE CAN SHUT DOWN INFLAMMATION RELATIVELY QUICKLY EVEN IN A KNEE JOINT. WE HAVE DONE THAT IN CLINICAL TRIALS WE HAVE DONE WITH CORTISOL FOR EXAMPLE BUT QUESTION, IS THAT A GOOD THING, JUST TIMING ISSUE? OR IS IT JUST SOMETHING THAT IS TOO TEMPORARY AND BASICALLY WILL GO DOWN THE WRONG PATH BECAUSE SYSTEM IS OVERCOME BY FACTORS THAT WILL OVERWHELM ANY RESTORATION OF HOMEOSTASIS SO TO SPEAK NO MATTER WHAT. SPEAKER5: COMPLEX BECAUSE I THINK WE NEED A MORE NUANCED APPROACH, IF YOU HIT WITH CORTICOSTEROID, NICE WORK BUT MAYBE INFLAMMATION IS VERY COMPLEX, THERE ARE MEDIATORS, CYTOKINES MAYBE BLOCK OTHERS WE DON'T AND THEN YOU HAVE TIMING ISSUES. SO WE ARE TIP OF THE ICEBERG AS FAR AS UNDERSTANDING HOW WE AS CLINICIANS MODULATE INFLAMMATION. THAT IS OUR CHALLENGE. YOU HAVE PATIENTS IN THE OFFICE IN CLINIC, SWOLLEN KNEE, I CAN PUT A STEROID IN BUT SO VARIABLE, TIMING OF INJURY, OTHER FACTORS IN THAT PATIENT'S KNEE. DO I NEED TO REPEAT THIS THERAPY. I THINK WE NEED A MUCH MORE REFINED APPROACH TO MANAGING INFLAMMATION. >>DANIEL WHITE. >>THANK YOU FOR THE WONDERFUL PRESENTATION, DR. RODEO. WONDERING IF YOU CAN COMMENT ON THE QUALITY OF THE CLINICAL TRIALS THAT HAD CLINICAL OUTCOMES IN PARTICULARLY INTERESTED IN WHETHER BLINDING WAS DONE, WAS THERE A PLACEBO IN ADDITION TO STEM CELL? WHAT PEAKS MY QUESTION ABOUT THIS IN OTHER PRP STUDIES THERE'S VARIABLE AND QUALITY AND WE MOW PLACEBO MAKES A DIFFERENCE WITH CLINICAL OUTCOMES AND GIVEN NO BENEFICIAL EFFECTS STRUCTURAL SO FAR, I UNDERSTAND PRELIMINARY STUDIES BASIC QUESTION HOW MUCH IS THIS PLACEBO EFFECT? >>GREAT QUESTION. OVERALL STUDY METHODOLOGY,S MODERATE TO POOR IN A LOT OF STUDIES WHAT YOU CAN SAY ABOUT A LOT OF LITERATURE, THE ISSUE TO CHARACTERIZE TWO THINGS, DR. ROBEY BROUGHT ONE, CHARACTERIZE WHAT WE ARE PUTTING IN PATIENT, SO CALLED ME MEBO INFORMATION. MINIMAL, BIOLOG BIOLOGICAL, WHAT CELLS ARE USING PRP HOW WOULD -- IT WAS OBTAINED PREPARED ET CETERA, WE NEED TO CHARACTERIZE WHAT IS PUT IN THE PATIENT AND OTHER SIDE THE PATIENT PHENOTYPE BACK TO CONNIE'S EARLIER QUESTION. PATIENT AGE GENDER MEDICAL CO-MORBIDITIES. ALL THESE ISSUES. STUDIES OFTEN DON'T HAVE ALL THAT INFORMAT INFORMATION. S COMMENT, WE FOOD THAT DATA IN OUR CLINICAL STUDIES. BE IMPORTANCE OF NIGH FOR WELL DESIGNED CLINICAL TRIALS WHICH ARE CHALLENGING. THAT IS IS WHAE NEED IN THIS FIELD. >>REALLY GREAT TALK. ENJOYED THAT. I WAS PART OF THE ACADEMY PANEL, ABOUT TEN PEOPLE, WE HAD TO PUT SOME TREATIES TOGETHER ON ALL THE HIGH LEVEL STUDIES FOR TREATING THE OA MESENCHYMAL CELLS, IT ENDED UP BEING EXACTLY WHAT YOU SAID, VERY INCLUSIVE AND EVERYBODY USING DIFFERENT CONCENTRATIONS OF CELLS WITH DIFFERENT PROCUREMENT TECHNI TECHNIQUES. DO YOU THINK IT IS POSSIBLE THIS GROUP COULD PUT TOGETHER A TREATISE FOR GOING FORWARD ON THIS IS THE MINIMAL -- MAYBE THIS IS MINIMAL INFORMATION YOU SHOULD TRY TO COLLECT ON YOUR TAKING -- THIS IS THE WAY TO CONDUCT SOME OF THE STUDIES SO WE HAVE A LITTLE MORE STAND STANDARDIZATION SO WE DO IT AGAIN MANY FIVE YEARS WE HAVE A BETTER HANDLE ON THIS FIELD? COULD THAT BE A RESULT OF THIS MEETING? >>LOOK AT PAPER FROM BOB LAPROD 2017 IAN MURRAY, TOOK US DOWN DOING THIS, SUGGESTING THE FACT THAT WE SHOULD CHARACTERIZE, MAYBE WE NEED TO REVISIT THAT AND WE HAVE A MORE REFINED ABILITY OR ABILITY TO HAVE A MORE REFINED ANALYSIS BUT CLEARLY POINTS OUT IMPORTANCE OF CHARACTERIZING FORMULATION OF PATIENTS IN ADDITION TO CHARACTERIZING THE PATIENT, RECIPIENT. >>DAN YOU HAD YOUR HAND UP A WHILE, DID YOU STILL HAVE A QUESTION? >>THANKS CONNIE. THANK YOU VERY MUCH, SCOTT. IT WAS MORE REFLECTION, QUESTION TO SCOTT AND MAYBE INFO FOR THE GROUP. SCOTT WHERE DO YOU SEE ROOM FOR MAKING BETTER STEPS IN USING STEM CELL BASED THERAPIES AND I WILL OPEN TO CARTILAGE REPAIR AND OSTEOARTHRITIS. I LIKE TREATING SOONER RATHER THAN LATER SO AFTER REVIEWING THIS AND SHARING THAT BE US WHERE YOU TAKE IT WHETHER YOU SEE RESEARCH HAS BEEN ALREADY. FOR GROUP LARGER INFORMATION, IMPORTANT TO KNOW WE HAVE BEEN DOING THESE ALLOGENEIC MSC WORK, TREATING PATIENTS WITH ALLOGENEIC MSC, FOR THE REASON DR. ELISSEEFF SAID AND DR. LATTERMANN REFERRED TO, MSCs ARE BETTER GAUGING THE JOINT AND PROVIDING APPROPRIATE IMMUNE MODULATION THAT ARE INJECTION OF CORTICOSTEROIDS ARE. SO MY FEELING IS THAT WE SHOULD TREAT BLACK BOX OF MSCs BECAUSE WE DON'T UNDERSTAND THEM FULLY AS A BENEFICIAL ASPECT AS PART OF OUR THERAPY BEING SMARTER THAN WHEN WE USE AUTOLOGOUS OR WHEN WE USE EXTERNALLY APPLIED CHEMICALS BUT MY QUESTION IS, WHERE DO YOU THINK US TAKING MSCs AS PART OF THERAPEUTICS SHOULD GO FROM RESEARCH PERSPECTIVE? >>CHARACTERIZING THE CELL FORMULATION, I THINK IDENTIFYING THE OPTIMAL CELL FORMULATION FOR DIFFERENT TISSUE, ONE SIZE DOESN'T FIT ALL, ONE FOR TENDON DIFFERENT THAN CARTILAGE DIFFERENT FOR MUSCLE AND BONE. CHARACTERIZE WHAT WE NEED TO TREAT SPECIFIC TISSUE PATHOLOGY AND CHARACTERIZE CELL POPULATION AS PAM ROBEY ARTICULATED. ANOTHER AREA IS INTERACTION WITH INTRINSIC STEM CELL, PROGENITOR CELL POPULATION IN TISSUES AND IMPORTANT ROLE OF IMMUNE CELLS IN THAT PROCESS. THE PARACRINE EFFECT OF THESE MATERIAL YOUR EXOSOME WORK WILL GET TO THAT. THESE MOLECULES FROM CELLS, HOW DOES THAT AFFECT INTRINSIC PROGENITOR CELLS IN TISSUES? >>FULLY AGREE BUT ALSO WHAT THAT MEANS IS INTERESTING FOR OUR FIELD TO RESPONDS TO THAT YOU HAVE TO GO ALLOGENEIC IF CHARACTERIZIZATION AND RELIABILITY EVAPORABILITY IS A BIG THING AND COLLEAGUES FIND IT CONSIDERABLE CHALLENGE BECAUSE REGULATORY BURDEN ON ALLOGENEIC WORK. HOW DO YOU SEE THAT HAPPEN? >>THOSE ARE CHALLENGES FOR US, THAT'S THE REGULATORY SIDE OF THINGS AND THE NEED TO CONTINUE TO RELATIONLATORY ENVIRONMENT LANDSCAPE INVOLVES. >>MOVING ON, THEY ASKED US TO DO SO. WITH THAT I WILL -- WE WILL MOVE TO DR. MARK HOCHBERG, PLEASURE, PROFESSOR MEDICINE EPIDEMIOLOGY AND PUBLIC HEALTH UNIVERSITY OF MARYLAND. HE IS HEAD OF DIVISION OF RHEUMATOLOGY AND CLINICAL IMMUNOLOGY AS WELL AS VICE CHAIR IN THE DEPARTMENT OF MEDICINE, AT UNIVERSITY OF MARYLAND. BRIEFLY MENTION VERY DISTINGUISHED AWARDS FROM DR. HOCHBERG OVER THE YEARS FROM THE DISTINGUISHED CLINICAL INVESTIGATOR WORK, AMERICAN COLLEGE OF RHEUMATOLOGY, LIFETIME ACHIEVEMENT AWARD FROM ORSE, PAST PRESIDENT OF THE U.S. BONE AND JOINT INITIATIVE. VERY ACCOMPLISHED IN HIS FIELD. HE IS CURRENTLY PI BALTIMORE CLINICAL SECTOR FOR THE OA INITIATIVE. HE WILL TALK TO US ON THE ROLE OF CHONDROGENNIC SMALL MOLECULES. THANK YOU, DR. HOCKBU HOCK BERG. >>THANK YOU DR. RODEO AND DR. CHU. I WAS TASKED TO SPEAK ON CARTILAGE REGENERATION BY CHONDROGENNIC SMALL MOLECULES. AS I MENTIONED DURING THE INITIAL PART OF THIS MEETING I HAVE NO PERSONAL EXPERIENCE IN THIS. LET ME MOVE FORWARD I GUESS. I'M SHOWING DISCLOSURES FOR THE REASON THERE'S TWO COMPANIES WHICH ARE IN IN BOLD PRESENTING TATTED FROM BOTH COMPANIES IN TERMS OF SMALL MOLECULES. WE ARE TALKING OSTEOARTHRITIS THERE IS ONE USE OF THE TERM DEGENERATIVE DURING THE FIRST TWO HOURS OF THIS MEETING. AND BUT MAJORITY OF PEOPLE HAVE USED DEGRADATION. . SO AS DR. RODEO JUST POINTED OUT, THIS IS AN IMMUNE MEDIATED INFLAMMATORY CONDITION. WE HAVE ACTIVATION OF THE CHONDROCYTE, INITIALLY IN SO CALLED IDIOPATHIC OSTEOARTHRITIS, PRESUMABLY STIMULATED BY ABNORMAL BIOMECHANICAL LOAD WHICH LEADS CHONDROCYTE TO GENERATE INFLAMMATORY CYTOKINES INFLAMMATORY CYTOKINES SIMPLISTICALLY WILL LEAD TO DEGRADATION OF THE CARTILAGE MATRIX MEDIATED BY ENZYMES PRODUCED BY THE CHONDROCYTE WITH THE ASSOCIATED SUBCHONDRAL BONE CHANGES. PEOPLE IDENTIFIED ROLES FOR BONEMORPHO GENIC PROTEIN, TGF BETA AND WINT PATHWAY LIGANDS WITH REGARD TO SUBCHONDRAL BONE CHANGES. I WON'T TALK ABOUT THAT VASCULAR ENVATION OF THE ARTICULAR CARTILAGE, ET CETERA. I WILL FOCUS ON CHONDROCYTE CHANGES THAT ARE CURRENTLY OSTEOARTHRITIS AND THESE SUMMARIZE IN THE UPPER RIGHT HAND BOX IN THIS SLIDE WHICH COMES FROM PAPER PUBLISHED TEN YEARS AGO. SO THERE IS CHONDROCYTE PROLIFERATION. INITIALLY INCREASE IN MATRIX SYNTHESIS. SO WE WANT TO HARNESS THIS REGENERATIVE CAPACITY OF THE CHONDROCYTE AS IT PROLIVE RATES IN CURTILAGE. WITHOUT PRODUCTION OF INFLAMMATORY CYTOKINES, WITHOUT PRODUCTION OF TISSUE DESTRUCTIVE ENZYMES AND TRYING TO RESTORE NORMAL PHENOTYPE TO THE CONT CONTRACYTE. -- CHONDROCYTE. IT'S BEEN DISCUSSED ABOUT THE ROLE OF INFLAMMATORY CYTOKINES, AND IMMUNE SYSTEM IN PATIENTS WITH OSTEOARTHRITIS AND DEVELOPMENT OF OSTEOARTHRITIS. I WANT TO MENTION THERE'S A ROLE FOR ANTI-INFLAMMATORY CYTOKINES WHICH ARE PRODUCED BY THE CHONDROCYTE INCLUDING IL 4 AND IL 10 AND THERE'S SOME WORK NOW IN TERMS OF TRYING TO LOOK AT IL 10, PROTEIN NOT SMALL MOLECULE IN TERMS OF ITS EFFICACY FOR OSTEOARTHRITIS AND CARTILAGE REGENERATION. SO THE STRATEGIES DISCUSSED INCLUDE REPAIR STRATEGIES, WE HAVEN'T TALKED MICROFRACTURE OF THE SUBCHONDRAL BONE, AUTOLOGOUS CHONDROCYTE TRANSPLANTATION. THE USE OF MESENCHYMAL STEM CELLS OR STROMAL CELLS AS WELL AS TISSUE ENGINEERED CARTILAGE. ALL THESE HAVE BEEN OR WILL BE DISCUSSED DURING THE WORKSHOP TODAY. KEY FOR THIS IS CARTILAGE REGENERATION. HOW WE STIMULATE CARTILAGE PROGENITOR CELLS OR RESIDENT CHONDROCYTES. SO THIS WILL LEAD ME TO SMALL MOLECULE COMPOUNDS. I WANT TO SITE THIS PAPER AND I DON'T KNOW IF YOU CAN SEE THE CITATION ON THE BOTTOM OF THE SLIDE. WHICH COMES FROM -- EXCUSE ME FOR A SECOND. LEE AND COLLEAGUES FROM CHINA PUBLISHED IN BIOMEDICINE AND PHARMACO THERAPY IN 2020. SO THESE AUTHORS THAT SYSTEMATIC REVIEW OF BENCH BIOMEDICAL PRE-CLINICAL OR ANIMAL STUDIES AS WELL AS HUMAN STUDIES OF SMALL MOLECULES. WHICH PROMOTE CHONDROGENNIC DIFFERENTIATION OF STEM CELLS, SO GOING FROM THE STEM CELL TO THE CHONDROCYTE, NOT TO THE OSTEOCYTE OR OSTEOBLAST OR MUSCLE CELL. OR CHONDROCYTE PROLIFERATION OF CHONDROCYTE PROGENITORS ASSOCIATED WITH MATRIX SYNTHESIS. BEFORE PRESENTING THEIR DATA, I WANT TO MENTION A PAPER BY LEE AND COLLEAGUES THIS IS A DIFFERENT GROUP. THIS WAS PUBLISHED IN OPEN LIFE SCIENCES THIS YEAR 2022 WHERE THEY IDENTIFIED CHONDROCYTE CELL RECEPTORS WHICH CAN BE ENGAGED BY SMALL MOLECULES. THESE RECEPTORS ALL LEAD TO THE CHONDROCYTE INCREASING MATRIX SYNTHESIS, SYNTHESIS OF MATRIX COMPONENTS. THESE INCLUDE GROWTH FACTOR ASSOCIATED WITH RECEPTORS INCLUDING THOSE FROM THE TGF BETA BMP SUPERFAMILY, IGF 1, FIBROBLAST GROWTH FACTOR, AND EPIDERMAL GROWTH FACTORS. THEY IDENTIFY HORMONES ASSOCIATED RECEPTORS INCLUDING ESTROGEN RECEPTOR, PROGESTERONE, AND RECEPTORS FOR ACTIVE METABOLITES OF VITAMIN D. THE PPAR RECEPTORS, ALPHA BETA AND GAMMA, INTEGRINS WHICH BINDS TO MOLECULE THE EXTRA CELLULAR MATRIX. THEN LRP AND FIZZLE PROTEIN WHICH ACTIVATE THE WINT BETA CATENIN SIGNALING PATHWAY. LET'S LOOK AT THIS FIGURE FROM THE PAPER BY LEE ET AL IN TERMS OF SMALL MOLECULES PROMOTING CHONDROGENESIS. THEY THEN IDENTIFY SEVERAL SMALL MOLECULES, WHICH CAN BIND CELL SURFACE RECEPTORS TO PROMOTE CHONDROGENESIS FROM CHONDROCYTE PRECURSORS. SO THESE INCLUDE PROSTAGLANDINS, RESVERETROL, ONE PRESUMED ACTIVE COMPONENTS, FROM GRAPES, WHICH CAN ACTIVATE CIRCULAR PATHWAYS. WE WILL SKIP AROUND, SYNBA STATIN AND OTHER STATINS, MELATONIN. STATINS AGAIN HERE, MELATONIN HERE. GLUCOCORTICOIDS, AND THEN SMALL MOLECULES WHICH CAN ACTIVATE HEDGEHOG SIGNALING PATHWAYS. AGAIN HERE YOU HAVE STATINS ACTIVATING WINT SIGNALING, ACTIVATION OF BMP SIGNALING. ACTIVATION OF TGF BETA. AND ACTIVATION OF HORMONE RECEPTORS SO SMALL MOLECULES WHICH CAN ACTIVATE CELL SURFACE RECEPTORS AND LEAD TO CHONDROGENESIS FROM PRECURSORS. THESE FIGURE IDENTIFIES SMALL MOLECULES, WHICH LEAD TO CHONDROCYTE PROLIFERATION OF EXISTING CHONDROCYTES AND INCREASE MATRIX SYNTHESIS. SO HERE WE HAVE WINT SIGNALING PATHWAY, AND THIS GROUP IDENTIFIED GLUCOSAMINE FOR EXAMPLE. SOMETHING IN LABORATORY AND PRE-CLINICAL MODELS SUGGESTING IT MAY HAVE STRUCTURE OR DISEASE MODIFYING EFFECTS. BUT THERE IS NOT SHOWN TO BE EFFICACIOUS IN HUMAN STUDIES. WHEN WELL CONTROLL CONTROLLED. N BINDING TO RECEPTOR AS WELL AS AKT TUGNALLING PATHWAYS. SOLITRASIDE TO TGF SIGNALING IS SMALL MOLECULE, THE ACTIVATED FORM OF VITAMIN D 125 HYDROXY VITAMIN D, GROWTH HORMONE AND VITAMIN D SIGNALING AS WELL AS ESTROGEN AND OTHER COMPOUNDS TO ERK SIGNALING. ALL WITH DOWN TREATMENT EFFECTS LEADING TO ANALOG PHENOTYPE OF THE CHONDROCYTE. ANOTHER GROUP HAS LOOKED AT NARRATIVE REVIEW OF SMALL MOLECULES FOR CHONDROCYTE REGENERATION. THIS IS CHEN AND COLLEAGUES IN CELLULAR AND MOLECULAR LIFE SCIENCES IN 2021. THEY PUBLISHED A NARRATIVE REVIEW ON DEVELOPMENT OF FUNCTIONAL ARTICULAR CHONDROCYTES FROM CELLS OR PROGENITOR CELLS AND CHONDROCYTE EXPANSION, RELEVANT TO THE WORK OF IMPLANTATION OR STRUCTURAL HYDRA GELS FOR IMPLANTATION AS WELL ASTHMA ANYPLACE RATION CHONDROCYTE PHENOTYPE INCLUDING INHIBITION INFLAMMATION AND REGULATION OF CHONDROCYTE METABOLISM. THIS FIGURE WHICH IS TAKEN FROM THEIR PAPER SHOWS WAYS OF DIFFERENTIATING PLURIPOTENTIAL STEM CELLS Z, MESENCHYMAL STEM CELLS, STROMAL CELLS, TRANSDIFFERENTIATING FIBROBLASTS IN FUNCTIONAL CHONDROCYTES WITH SMALL MOLECULE WHICH IS ARE LISTED ON THE SLIDE. AS WELL AS POTENTIAL ROLE OF STAT STATINS FROM ISOLATED CHONDROCYTES TO CAUSE EXPANSION FORMING FUNCTIONAL CHONDROCYTES WHICH CAN BE THEN USED FOR CELL THERAPY DESCRIBED BY DR. RODEO AND AS DISCUSSED BY OTHERS DURING AFTER THE BREAK. THIS GROUP ALSO IN THE SECOND PART OF THEIR PAPER, SUMMARIZE DATA ON MORE THAN 170 COMPOUNDS PREVIOUSLY OR CURRENTLY UNDER INVESTIGATION. IN PRE-CLINICAL MODELS AS ANALGESIC AGENTS OR POTENTIAL DISEASE MODIFYING OSTEOARTHRITIS DRUGS DESIGNED TO INHIBIT STRUCTURAL PROGRESSION VIA ANTI-CATABOLIC PATHWAYS, OR ANTI-INFLAMMATORY PATHWAYS. DISAPPOINTINGLY THESE AUTHORS CONCLUDED THAT NONE HAVE HAD A SIGNIFICANT LONG TERM EFFECT IN PRE-CLINICAL MODELS. NONE EFFECTIVE IN HUMAN STUDIES. SO WHERE DOES IT TAKE US? THESE AUTHORS DESCRIBE WAYS ONE SCREENS FORMAL MOLECULES AND THEY DESCRIBING A MOSTIC METHODOLOGIES OF SCREENING SMALL MOLECULES TO SEE IF ONE IDENTIFY SMALL MOLECULES WHICH AFFECT CHONDROCYTE REPLICATION OR PROLIFERATION OR LEADING TO THE DEVELOPMENT OF ANABOLIC PHENOTYPE. SO SAMIMED, BIOSPLICE THERAPEUTICS EMPLOYED THIS TECHNOLOGY TO IDENTIFY POTENTIAL SMALL MOLECULE WINT SIGNALING PATHWAY MODULATORS. HIGH THROUGH PUT SCREENING. IDENTIFY ONE COMPOUND SM 0690. 03690. NOW CALLED (INAUDIBLE) ADMINISTERED AS A SINGULAR INTRAARTICULAR INJECTION. STUDIED BY (INAUDIBLE) AND COLLEAGUES IN OSTEOARTHRITIS CARTILAGE IN 2018 AND 2019 IN PRE-CLINICAL MODELS SHOW THIS COMPOUND REDUCE RELEASE MATRIX DEGREE DATING ENZYMES AND INFLAMMATORY CYTOKINE PRODUCTION SO IT WAS ANTI-CATABOLIC AND INCREASED ANABOLIC TIFTED OF CHONDROCYTES IN VITRO AND IN VIVO IN PRE-CLINICAL MODELS OF OSTEOARTHRITIS. SO IT WAS ANTI-CATABOLIC AS WELL AS ANABOLIC AND DEMONSTRATED MOLECULAR MECHANISMS WHICH HAD THIS PANT CATABOLIC AND ANABOLIC EFFECT. SO THIS MOLECULE WAS SHOWN TO UPREGULATE WNT SIGNALING OR DOWN REGULATE THE WNT SIGNALING WHICH CONTRIBUTES TO OA PROGRESSION. MODULATE WNT SIGNALING TO ANTI-INFLAMMATORIER IS SO COLLEAGUES CONDUCTED A SERIES OF PHASE 1 AND PHASE 2 STUDIES AND INTERIA THE I CAN LAR INJECTION APPEARED SAFE WELL TOLERATED ADMINISTERED AS A SINGLE ARTICULAR INJECTION. THE PHASE 2 STUDIES DEMONSTRATED POTENTIAL THERAPEUTIC DOSE AND TARGET POPULATION WITH UNILATERAL SYMPTOMATIC KNEE OSTEOARTHRITIS MEANING THEY HAVE SINGLE JOINT INVOLVEMENT OR BILATERAL SYMPTOMATIC KNEE OA BUT MORE PAIN IN ONE THAN THE OTHER KNEE WITHOUT BIDE SPREAD PAIN. INTERARTICULAR INJECTION WAS NOT ONLY EFFECTIVE SYMPTOMATICALLY BUT ALSO UNCREASE THICKNESS BY JOINT SPACE WITHSTANDING KNEE RADIOGRAPHS SO THE COMPANY IS TAKEN THIS INTO PHASE 3 STUDIES FOR SYMPTOM IMPROVEMENT AS WELL AS STRUCTURE MODIFICATION. THESE HAVE BEEN COMPLETED, BUT RESULTS ARE PENDING. I LOOKED ON CLINICALTRIALS.GOV AND RESULTS ARE STILL PENDING. WHAT ABOUT OTHER SMALL MOLECULE? THIS IS ADEN SCENE. IT SIGNALS THROUGH THE 2A RECEPTOR AND ATTENUATES THE INFLAMMATORY RESPONSE IN CHONDROCYTES BY LEADING TO DOWNSTREAM INHIBITION OF NF KAPPA B AS WELL AS UPREGULATION AND RELEASE OF THE ANTI-INFLAMMATORY CYTOKINE THAT I MENTIONED EARLIER INTERLEUKIN 10. ADMINISTRATION OF LIPOSOMAL ADEN SCENE WAS FOUND EFFICACIOUS IN RODENT AS WELL AS MURINE MODELS. THIS IS SHOWN IN TWO PAPERS CITED AT THE BOTTOM OF THE SLIDE. ONE BY BEKISZ, OTHER BY CAI PUBLISHED IN OBESITY REVIEWS THIS YEAR. ADENOSENE IS DEVELOPED AS A TREATMENT FOR POTENTIAL TREATMENT FOR PATIENTS WITH OSTEOARTHRITIS. BY INCORPORATION INTO LIPOSOMES AND IT IS SHOWN YOU CAN HAVE ACTIVATION OF A 2A RECEPTOR BY INTERARTICULAR INJECTION OF LIPOSOMAL ADENOSINE, IT SLOWED OA PROGRESSION IN TWO MODELS OF ESTABLISHED OSTEOARTHRITIS. AS WELL AS MURINE MODEL OF OBESITY INDUCED OSTEOARTHRITIS AND RAT MODEL OF POST TRIAL OSTEOARTHRITIS. ALTERED TGF B ACTIVATION AND POST RECEPTOR SIGNALING FOR A PATHWAY ASSOCIATED WITH CHONDROCYTE HYPERTROPHY AND TERMINAL DIFFERENTIATION AND MODULATEDNA TO A PATHWAY ASSOCIATED WITH CHONDROCYTE PROLIFERATION AND MATRIX PRODUCTION. STUDIES HAVE BEEN CONDUCTED IN A DOG MODEL OF OSTEOARTHRITIS AND NOT YET PUBLISHED SO I WON'T PRESENT THEM AT THIS FORUM, BUT ANOTHER POTENTIAL SMALL MOLECULE WHICH MAYBE EVE DA I SHUTS FOR CHONDROCYTE PROLIFERATION AND REGENERATION. BEING COGNIZANT OF THE TIMELY STOP HERE AND THERE ARE SMALL NOVEL COMPOUNDS IDENTIFIED THROUGH HIGH THROUGH PUT SIGNALING AND KNOWN MECHANISTIC PATHWAYS WHICH TARGET CARTILAGE REGENERATION AND THESE HAVE POTENTIAL FOR FUNCTION DISEASE MODIFYING DRUGS IN PATIENTS WITH OSTEOARTHRITIS THERE IS A LONG WAY TO GO TO REALIZE THIS AS FUTURE TREATMENT. SO I WANT TO THANK YOU FOR YOUR ATTENTION. SHOWING YOU (INAUDIBLE) HALL HERE FOR OVER 200 YEARS, USE FOR MEDICAL EDUCATION. HOPEFULLY BEFORE THE NEXT CENTURY WE WILL HAVE EFFECTIVE SMALL MOLECULE TREATMENTS FOR CARTILAGE REGENERATION FOR OUR PATIENTS WITH OSTEOARTHRITIS. >>WONDERFUL TALK. GREAT I DON'T HAVE VIEW. I THINK ABOUT CARTILAGE REGENERATION I THINK IN THIS WHOLE WEBINAR TODAY OA I DICHOTOMIES A IN CARTILAGE REGENERATION, AS A DIFFERENT GROUP OF PATIENTS, CARTILAGE CLINICALLY WE DO THERE SINGLE FOCAL CARTILAGE DEFECTS. EARLY IN ARTHRITIC KNEE BUT DIFFERENT THAN CHANGES IN BONE SHAPE, BONE MORPHOLOGY, SYNOVIUM, CARTILAGE BONE, NOT AMENABLE TO PER SE CURRENT TECHNIQUE REGENERATE CARTILAGE IN THE JOINT, THAT'S GREAT BUT THINK ABOUT CARTILAGE REPAIR REGENERATION FOR SMALLER FOCAL EFFECTS WHICH BRINGS I THINK THE IMPORTANT NEED FOR EARLY IDENTIFICATION. CHRONIC WORK WITH IMAGING WE ALL RECOGNIZE WE NEED BETTER WAYS TO IDENTIFY THE PATHOLOGY ONCE STRUCTURAL CHANGES IN THE JOINT BIGGER CHALLENGE IS STRUCTURAL CHANGES CLINICALLY SILENT. EARLIER EXAMPLE HEART ATTACK, OR THE DIABETIC PATIENT, THE EARLY PATHOLOGY IS CLINICALLY SILENT TIME WE DETECT END STAGE ORGAN DISEASE, THE COW IS OUT OF THE BARN. JUST A POINT FOR THE NEED FOR EARLY DIAGNOSIS. SO REGENERATE TISSUE. >>I WOULD FULLY AGREE WITH YOU. AND I THINK THAT'S WHY WE NEED TO IDENTIFY PEOPLE WHO DON'T HAVE ALREADY ESTABLISHED GRADE 3, 4 OR EVEN STAGE 2 DISEASE. WE NEED TO IDENTIFY PEOPLE WHO HAVE SYMPTOMS. DON'T AS YET HAVE RADIOGRAPHIC CHANGE. BUT MAY HAVE CHANGES ON MAGNETIC RESONANCE IMAGING. INTERVENING THERE TO TRY TO PREVENT DEVELOPMENT OF THE STRUCTURAL CHANGES WE SEE ON RADIOGRAPHS. ONCE WE HAVE STRUCTURAL CHANGES ON RADIOGRAPH, PARTICULARLY ONCE WE HAVE JOINT SPACE NARROWING ON THE RADIOGRAPH AND WE HAVE SUBCHONDRAL BONE CHANGES, I THINK IT IS GOING TO BE VERY DIFFICULT UNLESS WE HAVE TWO STAGE RESPONSE, ONE WHICH IS ANTI-CATABOLIC RESPONSE IN ORDER TO PREVENT FURTHER CARTILAGE DEGRADATION AND THEN COME IN WITH SOMETHING TO PROMOTE CARTILAGE REGENERATION. THAT REQUIRES TWO STAGE RESPONSE OR TWO STEP RESPONSE UNLIKELY TO OCCUR WITH SINGLE SMALL MOLECULE. MAY OCCUR WITH GENE THERAPY, MAY OCCUR WITH PROTEIN THERAPY AND MAY OCCUR WITH STEM CELL THERAPY. OR CELLULAR THERAPY. BUT IS UNLIKELY I THINK TO OCCUR WITH SMALL MOLECULE THERAPY. >>WHOLE ISSUE I TRIED TO HIGHLIGHT SYMPTOM MODIFICATION VERSUS STRUCTURE MODIFICATION. IMPORTANT GOALS BUT PERHAPS DIFFERENT. >>AMBIKA HAS HER HAND UP. >>THANK YOU FOR THAT TALK DR. HOCHBERG. HOW MANY HUMAN STUDIES YOU REFER TO UTILIZE DELIVERY SYSTEMS FOR DELIVERING THESE SMALL MOLECULES, I ASK THAT QUESTION AS SMALL MOLECULES HAVE SHORT RESIDENCE TIME INOR INSIDE THE JOINT SO THE THE MODE OF DELIVERY IS NOT IMPLANTABLE INJECTION IT IS DIFFICULT TO GET A LONG TERM RESPONSE WITH THESE ONE SHOT INJECTIONS INTRAOCULARLY. SO WHEN YOU SAY THAT MANY -- INTERARTERIOLY, WHEN YOU SAW STUDIES DON'T CORRELATE WITH PRE-CLINICAL, HOW MANY OF THOSE UTILIZE ANY DELIVERY SYSTEMS OR WERE THEY ONLY DIRECT INJECTION OR ORAL INJECTION? >>IN THE REVIEW CONDUCTED THAT I CITED, THE SMALL -- MOST OF THE SMALL MOLECULE STUDIES WERE IN HUMANS, ACTUALLY ORAL SMALL MOLECULES ORALLY ADMINISTERED AS OPPOSED TO INTERARTICULARLY ADMINISTERED. ONCE WE INTERARTICULARLY ADMINISTER VERY SHORT RESIDENCE TIME AS YOU MENTIONED SOME OF THE NEWER STUDIES WHICH ARE NOT CITED IN THAT PAPER ARE USING FOR EXAMPLE, LIPOSOMAL ADMINISTRATION OR TRYING TO COMBINE THIS WITH HIGH LURE ONTIC ACID TO -- HYALURONIC ACID TO TAKE ON THE BINDING OF HA TO CELL SURFACE RECEPTORS ON THE CHONDROCYTE TO GET INTERNALIZED BY ENDOCYTOSIS. YOU BRING UP AN IMPORTANT POINT ABOUT SHORT RESIDENCE SMALL MOLECULES WHEN GIVEN BY THEMSELVES INTERARTICULARLY. ALSO DELIVERY INTO CARTILAGE. WE TARGET SITES OR CHONDROCYTES IF WE ENABLE LONGER TERM RETENTION THE JOINT USING HYALURONIC ACID, WE ARE NOT ENSURING DELIVERY TO TISSUE TO REACH CHONDROCYTE SO THAT IS ANOTHER AREA WHERE DELIVERY IS EXTREMELY IMPORTANT FOR ANY OF THESE DRUGS TO TRANSLATE. >>RIGHT BECAUSE YOU HAVE TO GET DIFFUSION INTO THE MATRIX IN ORDER TO APPROACH CHONDROCYTE. >>THANK YOU. >>I MAY HAVE GOTTEN YOU CLOSER TO ON TIME. >>TED YOU WOULD LIKE TO TAKE OVER AND GIVE INSTRUCTIONS NOW? >>JONELLE? >>I CAN DO THAT. THANK YOU, EVERYBODY, THIS WAS A GREAT DISCUSSION AND I THINK IT IS MORE IMPORTANT THAT WE HAD SUCH ROBUST DISCUSSION THAN THAT WE STAYED ON TIME. THE DOWN SIDE IS WE ARE GOING TO HAVE SHORTER TIME FOR LUNCH. AS I SAID EARLIER WE WOULD LIKE A GROUP PHOTO BEFORE WE BREAK FOR LUNCH SO WE HAVE IT FOR OUR ARCHIVES AND WHEN WE TALK ABOUT IMPORTANCE OF OUR ROUND TABLES WE HAVE A VISUAL RATHER THAN A TEXT HEAVY SLIDE. IF EVERYBODY WHO WANTS TO BE IN THE PICTURE INCLUDING NIAMS STAFF WHO ARE INVOLVED WOULD LIKE TO TURN ON THE CAMERAS, I'M GOING TO ASK DAVE TO TAKE A PICTURE. THEN WE CAN START THE CLOCK OFF PICTURE FOR 20 MINUTES FOR LUNCH. >>OUR NEXT SPEAKER IS DAN GRANDE. HE IS DIRECTOR ORTHOPEDIC RESEARCH AT THE FEINSTEIN MEDICAL RESEARCH PART OF THE HOSPITAL SYSTEM IN NEW YORK. I THINK WE HAVE HEARD OF AUTOLOGOUS CHONDROCYTE IMPLANTATION, THE FIRST FDA APPROVED CELL PER THINK IN ORTHOPEDICS. DAN DID THE PRE-CLINICAL STUDY THAT LED TO THAT BREAK THROUGH. SO WE ARE PLEASED HE COULD TALK TO US ABOUT MATRIX BASED THERAPIES IN TISSUE ENGINEERED CARTILAGE. >>THANK YOU, EVERYONE. THANK YOU CONNIE FOR THE KIND INTRODUCTION. I WILL FOCUS VERY NARROW AREA WHICH IS THIS CONCEPT OF MY TRICKS BASED THERAPIES AND TISSUE ENGINEERED CARTILAGE. THIS IS A VIN DIAGRAM WE DID YEARS AGO WITH -- FOR THE NATURE REVIEW RHEUMATOLOGY ARTICLE THAT I WROTE WITH MYCOLOGS AND BASICALLY THIS COMBINATION OF SCAFFOLDS AND CELLS AND THEIR INTERACTION WITH TISSUE ENGINEERING AS YOU CAN SEE, THESE DIFFERENT CELL DIFFERENT SCAFFOLD TYPES, ET CETERA. THE FIRST TISSUE ENGINEERING WAS DEVELOPED BY LANGER WHERE THEY USE PGA SUTURES AND CHONDROCYTES AND YOU CAN SEE ON THE RIGHT A NICE ME IN THIS CUSS OUT OF THAT, THAT WAS THE FIRST STEP TOWARD TISSUE CARTILAGE ENGINEERING, WE WILL TALK ABOUT ACI IN A FEW MINUTES BUT THE UTILITY OF SCAFFOLD TISSUE ENGINEERING IS THAT IT PROVIDES A 3-D SPATIAL FILLING SURGEON FRIENDLY WITH RESPECT TO BEING ABLE TO IMPLANT CELLS IN A CONTROLLED FASHION COMPARED TO THE ORIGINAL AC I. THIS OF COURSE LED TO MANY STUDIES LOOKING AT PGA PLA PLGA CONSTRUCTS, HERE IS SOMETHING FROM A WORK WITH LISA FRIED HARVARD YEARS AGO BUT THE IMPORTANT THINGS IS THAT FORMING STABLE CARTILAGE HELPS REDUCING FIBROUS OR VASCULAR INFILTRATION INTO A CARTILAGE CONSTRUCT. THAT IS VERY IMPORTANT FOR CONTINUITY OF CARTILAGE. SOME OF THE CONCEPTS FOR CELL BASED THERAPIES INVOLVE IDENTIFYING SOURCES OF CELLS, WHETHER WE USE PRIMARY AUTOLOGOUS CHONDROCYTES SORRY FOR MISSPELLING, BONE MARROW OR LIPO ASPIRATE STEM CELLS. THEY REQUIRE EXPANSION, A METHOD RETAINING IN SITU AND THEN THE PHENOTYPIC STATE CHONDROGENNIC EFFECT HOW THEY FORM OR DIRECT FUNCTIONAL TISSUE FORMATION. AS CONNIE MENTIONED HEARSAY THE ORIGINAL WORK THAT WE DID IN ACI WAS CHONDROCYTES SUSPENSION BUT HELD IN PLACE BY PERIOUTSIDE YUM SO THERE WAS NO -- DEVELOPED FOR CHONDRAL LESIONS ALONE NOT'S CENTRAL CHONDRAL NECESSARILY, THEY ARE SUSPENDED WITH THAT. OF COURSE THE NEXT GENERATION WHICH ASSISTED IN THE CONCEPT OF TISSUE ENGINEER CARTILAGE MATRIX ASSISTED ACI WHERE WE GROW THE CELLS ON A SCAFFOLD, COLLAGEN SCAFFOLD FOR LOCALIZATION WITHIN A DEFECT. NEXT GENERATION OF THAT IS SOMETHING DEVELOPED BY NOVACART 3-D, IT IS THE SAME CONCEPT OF ACI BUT THEY ARE ALLOWED TO BE EXPANDED MINIMALLY AND THEY USE A DIFFERENT MATERIAL BIPHASIC COLLAGEN SCAFFOLD, I WILL SHOW YOU IN A MINUTE BUT CURRENTLY U.S.DA FDA TRIALS RIGHT NOW U U.S. PHASE 3 AND THE PRODUCT IS REGULATED AS A BIOLOGIC DEVICE IN COMBINATION PRODUCT TAKE SMALL BIOPSY OF CARTILAGE, EXPAND AND PUT ON A SCAFFOLD AND IN A CONTROLLED BUY REACTOR SITUATION WHERE YOU GET REALLY GOOD REGENERATION OR NOT REGENERATION BUT EXPRESSION OF THE CHON CRYOGENIC PHENOTYPE. YOU CAN SEE HERE THIS IS THE MEME PAIN USED BY THEM, IT IS IN THE -- MEMBRANE, IT IS A BIPHASIC SCAFFOLD THAT HAS A LOT OF PROPERTIES DIFFERENT FROM ALL THE OTHER AVAILABLE SCAFFOLDS WITH REGARDS TO -- WITH REGARDS TO COLLAGEN. YOU CAN SEE ALSO THAT THEY GET GOOD INFILTRATION OF THE CHONDROCYTES INTO THE SCAFFOLD. THE WAY THAT THE SCAFFOLD IS -- AS THEY PURPORTED TO BE THAT HAS BETTER PHENOTYPIC EXPRESSION MORE AGGREGATE SYNTHESIS THAN MONOLAYER CULTURE AND COMPARED TO SOME OF THEIR COMPETITORS. THIS IS A -- FROM THEIR PRODUCT YOU CAN SEE THEY HAVE VERY GOOD TYPE 2 STAINING, THEY HAVE GOOD STABBING WITH DMMD, CLINICAL EVIDENCE ON ARTHROSCOPY AND BIOPSY SHOWS DECENT CARTILAGE REPAIR CARTILAGE WITH EXPRESSION OF TYPE 2 COLLAGEN, AND AGRICAN AND NICE RESURFACING. SO T A THE END OF THE DAY THEY PROVIDE CLINICAL EVIDENCE FOR IMPROVED PAIN AND FUNCTION AND BOTH RETROSPECTIVE STUDY THEY DID AS WELL AS PROSPECTIVE STUDY THIS IS TWO YEARS FLOW UP. ONE THING DR. GUILAK WILL TALK MORE IN DETAIL BUT AS I MENTION THESE WERE FOCAL DEFECTS, AS DR. ROBEY MENTIONED BEFORE THE BREAK, FOCAL DEFECTS ARE DIFFERENT ANIMAL OR PATIENT RATHER THAN OA SO DR. GUILAK DEVELOPED A CONCEPT FOR USING BASICALLY USING A WOVEN SCAFFOLD MATERIAL, RESORBABLE ALSO TO SEED CELLS, BE ABLE TO RESURFACE ENTIRE DEFECTS ENOUGHS JOE ARTHRITIC PATIENTS. HE WILL TALK NEXT LEVEL HE HAS ALREADY DONE FOR -- WITH THAT CONCEPT. THE NEXT GENERATION -- NEXT THING ON THE HORIZON IS BIOPRINTING. HERE IS WORK WE DID WITH ETH AND ZURECK USING A CARTILAGE ECM ADDED TO THE BIOLINK. WITH THAT YOU CAN DO SOMETHING WE HAVEN'T DONE BEFORE TO ACHIEVE ZONAL REORGANIZATION THAT HAS BEEN A REAL CHALLENGE FOR RESEARCHERS IN THIS AREA, HOW TO RECONSTRUCT SUPERFICIAL MIDDLE AND DEEP ZONES OF CARTILAGE RECAPITULATING THAT CAGE, THAT IS SOMETHING WE NEED TO DO. AS I MENTIONED TISSUE ENGINEERED CARTILAGE NEEDS TO INTEGRATE WITH SURROUNDING CARTILAGE AS WELL AS SUBCHONDRAL BONE, MECHANIC A.M. PROPERTIES MATCH OF THE ADJACENT TISSUE. ENGINEERING CARTILAGE COPES WITH INFLAMMATORY MEDIATOR, THAT WOULD BE ELEGANTLY PRESENTED BY DR. GUILAK. THE IDEA RECAPITULATING THE ZONAL ARCHITECTURE OF CARTILAGE IS IMPORTANT. NOW I WILL MOVE TO MATRIX BASED APPROACHES TO CARTILAGE REPAIR, ONE THAT IS VERY NEAR AND DEAR IS AUTOLOGOUS MATRIX INDUCED CHONDROGENESIS. WE USE THE MICROFRACTURE TECHNIQUE TO PLACE A COLLAGEN SCAFFOLD IN THE MATRIX, IN THE DEFECT. RECENT SYSTEMATIC REVIEW LOOKED AT AUTOLOGOUS AMIC VERSUS MATRIX ASSISTED ACI. THEY FOUND AMIC PERFORMED BETTER FOR THE CHONDRAL DEFECTS AT 40 MONTHS. THE RATE OF COMPLICATIONS WAS LOWER IN THE AMIC GROUP AND TEGNER AND VAST SCORES EQUIVOCAL BUT LYSOME AND IDKE CELLS EXCEEDED THE ACID IN FAVOR OF AMIC. THAT IS SOMETHING TO KEEP IN MIND WHEN WE TALK ABOUT COST BENEFIT RATIO IS FOR SYSTEM OF THESE PRODUCTS AND APPROACHES. I DID A EDITORIAL FOR NATURE REVIEWS, ON NEWER CONCEPT WHICH I THINK HAS A LOT OF PROMISE BUT NOT WIDELY DEVELOPED AND THAT IS THE CONCEPT OF USING SCAFFOLDS WITH LOADED WITH MOLECULES THAT WOULD BE ALLOW FOR MIGRATION OR ZONAL MIGRATION INTO SCAFFOLD BY HOMING. YOU CAN SEE USING THE BODY'S OWN ABILITY TO HEAL IN THAT CONTEXT. BST CARGEL IS A CHITOSAN PRODUCT SIMILAR ARCMIC AND ADJUNCT TO MICROFRACTURE AND USE BLOOD OR PRP TO COAGULATE OR POLYMER RISE THE MATERIALS IN VIVO. FILL AS WELL AS CALL OF REPAIR, USING T 2 MAPPING MRI. BETTER SCORES, MUCH BETTER FILL OVERALL. BIOCART LAG IS ANOTHER ADJUNCT MATERIAL FOR MICROFRACTURE. IT IS ALLOGRAPH, DEHYDRATED, MIX WITH PRP. THE IDEA IS THAT IT IMPROVES REPIR OF TISSUE. YOU HAVE BETTER COLLAGEN TYPE 2 FORMATION IN A TREATED GROUP. BASICALLY THE OPTIONS FOR CARTILAGE HAVE REPAIRED, THAT REMAIN THE SAME FOR THE LAST 20 YEARS, ALLOGRAPH TRANSPLANTATION. ACI WHICH IS MACI, PAL LOW GRAPH, PARTICULATED OR MINCED AUTO GRAPH. INDICATED FOR FOCAL DEFECT BUT OFF LABEL EXPANDED TO INCLUDE EARLY OA. MICROFRACTURE YIELDS WANING CLINICAL EFFECT DUE TO PRODUCTION OF FIBROCARTILAGE. WHILE OTHER YIELD OSTEO CHONDRAL ALLOGRAPH YIELD HIGH LINK CARTILAGE, OTHERS ARE WHAT WE CALL HYALIN LIKE AND NOT THE PARTICULAR ARC CONNECT CHURL CARTILAGE. WE ALSO HAVE TO THINK ABOUT CONUNDRUM, CELLS ARE EXPENSIVE SO IF YOU HAVE TO DO MACI OR OTHER, THESE ARE QUITE EXPENSIVE FOR THE PATIENT, THESE -- EVEN IF YOU USE ALLOGRAPH THEY ARE 15 TO 16,000, EXPENSIVE PROPOSITION. THIS MATERIAL FROM ARAGONITE. WE HAVE A LONG HISTORY USING CORALS AS A SCAFFOLD FOR BONE REPAIR BUT NOT CARTILAGE. SEES THIS CONCEPT AS INFLUENCE SIDE OF THE POORS INFLUENCE MSC DIFFERENTIATION. THEY FOUND THAT THIS CONCEPT TO GET GOOD BONE HEALING LETS CREATE A BIPHASIC IMPLANT BY CREATING FOR'STY AT THE CHONDRAL PHASE, LEADING TO REGENERATION OF HIGHER END CARTILAGE, SO THEY CAME UP WITH THIS WAY TO DRILL HOLES OF A SPECIFIC PROPRIETARY DIAMETER THAT ALLOWS FOR CELLS TO COME UP INTO IN A MODEL OF OSTEO CHONDRAL DEFECT CELLS COMING UP FROM THE MARROW TO BECOME CONTRACYTES OR DIFFERENTIATE -- CHONDROCYTES. SO WORK DONE BY SUSAN SKY IN VITRO MODEL TO GET MECHANISM OF ACTION, DONUT SHAPED HUMAN CART LAG FROM A PATIENT -- FROM CADAVER PUT THE IMPLANT IN YOU CAN SEE OVER TIME NICE CARTILAGE FLOW ENHANCED THROUGH DRILL HOLES. YOU CAN SEE CHONDROCYTES MIGRATE ACROSS THE TYPE OF THE SCAFFOLD AS WELL AS FROM UNDERNEATH. THIS IS SHOWING STUDIES LIKE TRACING THE CELLS. SO THEY HAVE A MECHANISM OF ACTION FOR THAT MATERIAL FOR THAT. EVENTUALLY THEY MOVE TO A GOAT MODEL, THERE ARE NICE COLLAGEN TYPE 2 AND NICE AGRICAN FORMATION IN DEFECTS MICROCT SHOWING VERY NICE REPAIR OF THE SUBCHONDRAL BONE. FIRST IN MAN WAS DONE IN EASTERN EUROPE, THEY RECEIVED THE 2016 CE MARK AND MOVED TO NUMBER OF THINGS. ONCE THE FOCAL DEFECT IN PATIENTS ARE DOING WELL THEY ADDED PATIENTS WITH KL 2 AND 3 DEGENRE ACTIVE JOINT DISEASE TO THE MIX. THIS IS SHOWING MMRIs, GOOD REPAIR, NICE BIOPSY, NICE COLLAGEN TYPE 2 STAINING AS WELL AS (INAUDIBLE) STAINENING THOSE PATIENTS. THE CLINICAL EXPERIENCE SO FAR WITH COHORT OF 126 MAS126 PATIENTS RESULTED INE BREAK DOWN OF THE PATIENTS BUT THE BOTTOM LINE IS WITH MRI RESULTS YOU HAVE A GOOD FILL OVER TWO YEARS, THE PRIMARY END POINTS FOR THE SCORES ALSO VERY GOOD. THESE ARE PATIENTS WITH MILD TO MODERATE OA. THIS IS THE FIRST DEVICE MATRIX BASED DEVICE NOW APPROVED IN THE U.S. RECENTLY, APPROVED FOR OA AS WELL AS CARTILAGE REPAIR. WHAT I WOULD LIKE TO SAY IN SUMMARY, I THINK WE NEED TO LOOK AT CARTILAGE REPAIR AND OA IN GENERAL AS WE NEED TO LOOK AT IT AS AN INTEGRATED APPROACH TO HOW WE LOOK AT IT, PUTTING IMPLANT IN WITHOUT LOOKING AT SAY MMP INHIBITOR OR SOME OTHER MOLECULE OR IS WRONG WE NEED TO LOOK AT THE ENTIRE PICTURE HAVE INTEGRATED APPROACH TO CARTILAGE REPAIR. WITH THAT, THANK YOU. I APPRECIATE BEING HERE TODAY. >>NICE OVERVIEW, IMPLANT BRINGS UP THE IMPORTANCE OF PAYING ATTENTION TO SUBCHONDRAL BONE AS WELL, ONE CONCERN OF COROLLARY MATERIALS IS SLOW RESORPTION IN REMODELING, LOOK AT THEIR DATA, BETTER THAN TRADITIONAL CORAL STAY AROUND FOREVER AND IS A MISMATCH IN YOUR MATERIAL PROPERTIES OF THESE MATERIALS SUBCHONDRAL BONE SO THAT IS ONE CONCERN, JUST A COMMENT COMES UP WITH ANY BIPHASIC MATERIALS. THE SECOND IS, THIS ISSUE OF CARTILAGE REPAIR, OSTEOARTHRITIS THAT SLIDE SHOWED A MOMENT AGO THE COMPANY CAME TO TALK TO US ABOUT IMPLANT, FOUR IMPLANTS, MOST OF US AS CLINICIANS, THAT'S CALLED OSTEOARTHRITIS. NOT GOING TO DO FOUR IMPLANTS. CURIOUS HOW FIELD IS EVOLVING LOVE TO FOLLOW PATIENTS BECAUSE THAT GETS TO THE ISSUE OF PATIENT SEPARATE IMPLANT -- DEFECTS YOU ARE TREATING, THERE ARE CHANGES IN BONE GEOMETRY, REALLY FAVORABLE TO HEALING REMODELING, I DON'T KNOW. THOSE ARE -- COME UP VERSUS USING THESE THINGS FOR MORE TYPICAL SINGLE FOCAL CHONDRAL DEFECT. >>THANK YOU, DAN, I WANT TO FOLLOW-UP ON THAT, THE RADIOGRAPHIC CRITERIA, I BELIEVE YOU SAID WAS KL 2 TO 3. >>YES. >>THERE WERE ABOUT HUNDRED PLUS PATIENTS TREATED. >>124. >>CAN YOU GO MORE IN DETAIL ON THE OUTCOMES OF THAT ARM OF THE STUDY? THOSE ARE ARTHRITIC KNEES. RAID YES GRAPHIC GENE. >>ACTUALLY KEN MY COLLEAGUE DID THAT STUDY. ON BEING NON-CLINICIAN. I DON'T HAVE UNFORTUNATELY MORE DATA ON THAT. I'M SORRY. DEMONSTRATE GOOD OUTCOMES CLINICAL PROMs AS DAN SHOWED THEM. WE HAVE THE SAME TREATING MULTIPLE DEFECTS MANY THE KNEE, WE TRULY REGENERATE CARTILAGE AND THAT HARSH ENVIRONMENT, MOB WE WOULD LIKE TO, I DON'T KNOW THE ANSWER. >>I AGREE WITH YOU, IT IS A FIRST STEP IN THAT DIRECTION. CERTAINLY THE FACT THAT THEY HAVE GOTTEN APPROVAL FOR OA IS THEY CONVINCE THE FDA. DR. LATTERMANN HAS A QUESTION. >>I CAN ANSWER THAT, I WAS INVOLVED IN THIS STUDY. AND I HAD ONE PATIENT I PLANTED FIVE OF THESE. WHO RELIABLY FAILED. ONCE YOU START PUTTING MORE THAN TWO IN, TWO OF THESE IMPLANTS IN, FAILURE RATE IS HIGH. UP TO TWO IMPLANTS EVEN IN KO 3 CLASSIFIED X-RAYS, THEY DID VERY WELL. THIS IS ONE OF THOSE SUBGROUPS LOOKS LIKE KL 3 AND WE KNOW HOW DIFFICULT THAT IS TO DIFFERENTIATE, SAY A TWO OR SOMETIMES A 1. CLINICALLY THEY ACTUALLY NOT THAT HARD TO ARREST IS THAT. THAT IS A CONSIDERATION TO YES EARLY OA. IT WORKS IN THOSE PATIENTS, ESTABLISHED OA STILL GOING TO BE A CHALLENGE. ITCH ANOTHER COMMENT, THAT IS FOR YEARS WE HAVE HAD DIFFERENT TECHNIQUES AND TECHNOLOGIES THAT ARE SUCCESSFUL IN TREATING CARTILAGE DEFECTS. WE HAVE A FEW THE ACI FOR OVER 20 YEARS WE HAVE OSTEO CHONDRAL LOW GRAPH, WE CAN TREAT CARTILAGE DEFECTS WHAT WE CAN'T TREAT IS PROGRESSION OF DISEASE. THAT IS WHAT WE NEED TO FIGURE OUT AND I THINK THAT'S WHAT WE NEED TO -- WHAT WE NEED TO FOCUS ON. WE ARE TALKING ABOUT EARLY OSTEOARTHRITIS BECAUSE CARTILAGE IS A CASUALTY. WE HAVE EXPERIENCE ALL TIME AND SURGEONS ON THE CALL KNOW THAT, IT IS EXTRAORDINARILY DIFFICULT TO PATIENT EVEN IF YOU GO WITH ULTRA SCOPE WHO IS AT THAT JUNCTION BETWEEN 1 TO 2 CHONDRAL CHANGES, WHERE YOU SAY IT IS NOT BAD ENOUGH TO DO -- AND THERE'S ONE FOCAL LESION. IF YOU TREAT THE FOCAL LESION YOU GO BACK ISN'T TWO YEARS LATER AND THAT FOCAL LESION LOOKS BEAUTIFUL AND THE REST OF THE JOINT IS BROKEN DOWN. THAT'S THE TYPE OF PATIENT WE NEED TO IDENTIFY. AND TREAT DIFFERENTLY. THAT'S THE PATIENT THAT IS ON THE PAST OSTEOARTHRITIS AND THAT IS BASICALLY WHAT WE NEED TO STUDY >>THAT BRINGS UP THE QUESTION OF HOW DO WE STAGE THOSE PATIENTS AND WHAT MARKERS CAN BE USED BECAUSE WE DON'T HAVE GOOD MARKERS FOR EARLY OA YET. DO WE >>THE BIG SEARCH, YOU CAN -- IT IS NOT GOING TO BE -- I THINK IT NEEDS TO BE A COMBINATION OF IMAGING AND MOLECULAR MARKERS AND POSSIBLY SYSTEMIC MARKERS WE ALL HAVE PATIENTS THAT JUST GO ALONG GO ALONG AND ONE DAY IT IS LIKE SOMETHING SWITCHED. AND HOW YOU CAN NO LONGER MANAGE THEIR DISEASE OR THEY GO INTO PHASE OF RAPID PROGRESSION. THOSE ARE SWITCHES. THIS IS ONE OF THE RESEARCH NEEDS, WHAT ARE THE HOW DO WE SUBTYPE OA DO A BETTER JOB STRUCTURALLY THAN LAWRENCE WHICH WAS DEVELOPED IN THE 50s, 1950s. AND YOU HAVE PATIENTS THAT HAVE OSTEO DIET BUS STILL HAVE A JOINT SPACE AND OTHER WHOSE HAVE NO OSTEOCYTES BUT THEY HAVE CHONDRAL FLATTENING. SO THE GRADING NEEDS TO BE BETTER STRUCTURALLY AND ALSO INCLUDE MECHANICAL AND BIOLOGICAL AND MOLECULAR PROFILING IN TO THE ALGORITHM. >>WHAT WE CALL OSTEOARTHRITIS IS 25 DIFFERENT CONDITIONS. >>MAYBE MORE THAN THAT. AT LEAST WE CAN SUB CATEGORIZE BETTER THAN WE DO NOW. >>THE PRACTICAL ANSWER SEPTEMBER OF 2022 IS IMAGING. MR. QUANTITATIVE MR. WE LIKE THESE SERUM BIOMARKERS OR URINE BIOMARKERS OR SYNOVIAL FLUID BIOMARKERS. WE ARE NOT THERE BUT WE USE IMAGING NOT PERFECT AND HETEROGENEITY. AS WE CHARACTERIZE THE PHENOTYPE LEADS TO POTENTIAL PRECISION MEDICINE APPROACH. ONE SIZE DOES NOT FIT ALL. PATIENT NEEDS -- THIS NEEDS PRP, THIS ONE NEEDS TO BE SMALL MOLECULE, THIS PATIENT WILL DO (INAUDIBLE) IF YOU DO NOTHING. >>THOSE PATIENTS EXIST. TREAT THE PATIENT NOT THE MRI. >>SHOULD WE -- ANY OTHER QUESTIONS, SHOULD WE MOVE ON? >>I HAVE A QUESTION. >>LARISS LARISSA. SHE HAS HER >>KNEW FOR THE NICE OVERVIEW OF THE CHONDROCYTE IMPLANTATION PRODUCTS. I WILL TAKE MY REGULATORY HAT OFF AND PUT MY SCIENTIFIC ON SO I HAVE A QUESTION FOR YOU ABOUT YOUR THOUGHTS ON WORKING WITH SOME OF THESE PRODUCTS, HOW CAN WE POSSIBILITY ACHIEVE MORE FORMATION VERSUS CARTILAGE, NO MATTER HOW WELL THEY PERFORM SOMETIMES NOT WELL, IN VIVO EVENTUALLY WAS YEARS, THE FIBROCARTILAGE FORMATION WITH THESE PRODUCTS SO ANY THOUGHTS ON THIS? >>I THINK ACTUALLY DANIEL SARIS WAS INVOLVED WITH THIS. THERE WAS A EFFORT BY A COMPANY THAT IS NO LONGER DOING TIGENICS WHICH LOOKED AT HOW THE PERFORMANCE OF THE CHONDROCYTE WAS BEFORE IMPLANTATION. SO IN OTHER WORDS WE KNOW THAT WE EXPAND CHONDROCYTES FOR PERIOD OF TIME IN CULTURE, THEY DIFFERENTIATE. SO WHEN WE PUT THEM BACK IN, EARLY ACI WITH THE ADDITION OF THE HYPERPLASIA OF THE PERIOUTSIDE YUM, HOW THE CHONDROCYTES BEHIND IN THOSE PRODUCTS IS IMPORTANT AND WAYS TO ENSURE ADEQUATE MATURATION. THE NOVA CARD HAS MADE THAT A BETTER APPROACH TO THAT IN THE SENSE THEY HAVE A MORE ROBUST CARTILAGE FORMATION BECAUSE AS I MENTION YOU HAVE GOOD CARTILAGE IT WILL RESIST FIBROUS. BUT FIBROUS INVASION. BUT THE REAL PROBLEM I THINK IS THE SITE OF ARCHITECTURE OF CARTILA CARTILAE HAVE THAT UNIQUE ENGINEER -- IF YOU WANT TO CALL IT DIVINE ENGINEERING BUT THE ARCADE IT IS WAY THE COLLAGEN FIBERS ARE ORIENTED, HAS NOT BEEN REPRODUCED BY ANYONE. WE MIGHT AS WELL PUT IN A PLUG OF EAR CARTILAGE OR RIB CARTILAGE BECAUSE IT IS JUST -- IT HAS NO STRUCTURAL INTEGRITY AS FAR AS I'M CONCERNED, AS FAR AS THE ORGANIZATION OF THE CYTOARCHITECTURAL LEVEL. THAT IS A KEY CHALLENGE FOR US. THAT WOULD BE SOME OF MY COMMENTS ON THAT. >>THANK YOU, THE REAL ISSUE IS DURABILITY OF THE EFFECT. TWO OR THREE YEARS DOWN THE ROAD WE SEE DATA, OTHER SURGERIES NEEDED OR OTHER THINGS HAPPENING. SO REALLY TRYING TO DO UP FRONT A PRODUCT BETTER WITH EVENTUAL HYALIN CARTILAGE FORMATION WOULD BE A GOAL HERE. >>WE CAN MOVE ON >>PLEASURE TO ENTER DEUCE MY FRIEND AND COLLEAGUE DANIEL SARIS, PAST PRESIDENT OF THE ICRS, CURRENTLY ON THE ORTHOPEEDIC STAFF MAYOR CLINIC ROCHESTER WHERE HE FIRST PROGENITOR, PROFESSOR REGENERATIVE MEDICINE AT MAYO CLINIC. HE TRAINED AT AMSTERDAM, COMPLETED Ph.D. IN THE NETHERLANDS, BIOLOGICAL JOINT RECONSTRUCTION AND HE'S DEPARTMENT OF ORTHOPEDICS FOR 17 YEARS, PART OF THE FOUNDING MEMBER AND ORGANIZER FOR REGENERATIVE MEDICINES IN UTRECHT. HE ESTABLISHES JOINT PRESERVATION APPROACHES IN EUROPE AND THE USA AND TALK ABOUT THE ROLE OF EXOSOMES AND EXTRA CELLULAR VESICALES. >>THANK YOU VERY MUCH, SCOTT FOR ORGANIZATION OF PUTTING THIS TOGETHER. PROVIDING ME WITH CHALLENGE OF READING UP DOING SOME THINKING ON WHAT I FEEL ABOUT THIS. WHAT THE SCIENCE SAYS AND WHAT I FEEL COMFORTABLE SHARING. THAT WAS AN INTERESTING ONE. SO I WAS ASKED TO ADDRESS THE ROLE IF ANY FOR USING EXTRA CELLULAR VESICLES OR EXOSOMES FOR TREATMENT OF OSTEOARTHRITIS. FAIR TO SAY THERE IS A ROLE, THERE ARE CONSIDERABLE CHALLENGES AND I WOULD LOVE DISCUSS WITH GROUP REALITIES WHERE WE ARE NOW AND WHERE WE ARE GOING TO BE. I KNOW TOLD US PREPARATION WHICH IS METICULOUS DON'T SAY THE SOLUTION IS MORE MONEY AND I WILL STICK TO THAT. NOT GOING TO SAY WE NEED MORE MONEY. WE NEED MORE UNDERSTANDING FIRST. BUT I DO -- I KNOW I'M PREACHING TO THE CHOIR, I FEEL THAT WE AS WE DO SO IN OUR SCIENCE AND GRANTS AND PRESENTATIONS NEED TO BE WARE OF THE FACT FOR THE UNITED STATES NUMBERS ARE DAUNTING BECAUSE NUMBER OF PEOPLE WITH SYMPTOMATIC OA IS 11, 12% AT THE MOMENT, EXPECTED TO DOUBLING IN 15 YEARS WHICH HAS ECONOMICAL BURDEN. WE DID SOME MODELING FOR ASIA, INCLUDING INDIA AND CHINA. IF YOU LOOK AT THE VOLUME OF PEOPLING THE EFFECTED BY THIS, IT IS CONSIDERABLE. WITH CONSIDERABLE ECONOMIC DRIVE TO DO SO SO DON'T DISREGARD THE FACT IT IS SEVERE DISEASE, WHO CONSIDERED IT SEVERE DISEASE, UP THERE WITH CANCER, PSYCHIATRIC CHALLENGES AND CARDIOVASCULAR AND WE SHOULD ZOOM IN FOR NEEDS WE HAVE AS A FIELD. THAT IS ALL I NEED TO SAY ABOUT THAT PAR PA. MONEY FOR US TO FIND NOT THROUGH THIS PROGRAM AND NOT TODAY. IF YOU LOOK AT THE LITERATURE ABOUT EXTRA CELLULAR VESICALS WE DID THIS WEEK, I NEED TO THANK MY FRIEND AND COLLEAGUE FOR HIS WORK PREPARING THIS. IT IS CLEAR IT IS RAPIDLY DEVELOPING YOUNG FIELD WITH INCREASING NUMBER OF PUBLICATIONS ON EXOSOMES AND EXTRA CELLULAR VESICALES BUT ALSO STILL VERY EARLY DAYS. IF YOU COMPARE THIS TO ANY TOPICS DISCUSSED TODAY, THERE'S WAY LESS PUBLICATIONS. YOU CAN SEE THERE SEEMS TO BE A SHIFT OF PUBLICATIONS ON MSCs. TO MAYBE NOW SHIFT ON PEOPLE SAYING YOUR LAB AND YOU DO WORK ON MSC, OUR MOVE TO FOCUS ON EXOSOMES BECAUSE MAYBE MORE COMPLEX TO USE CELLS AND MAYBE USE OFF THE SHELF TECHNOLOGY WHERE WE USE EXOSOMES AS END PRODUCT OF MSC OR END PRODUCT OF SOME OF THESE CELLULAR COMMUNICATION METHODS TO INFLUENCE OSTEOARTHRITIS OR INFLUENCE OTHER DISEASES. THIS SLIDE SHOWS THE RAPID INCREASE IN THE FIELD BUT ALSO STILL LIMITED KNOW HOW. WHICH IS INTERESTING BECAUSE THE FIRST DESCRIPTIONS OF WHAT I THINK WAS MEANT TO BE THE DESCRIPTION OF EXOSOMES WAS PLATELET DUST, THAT IS WHAT IT SAYS IN THE PAPER THAN 1960s. AND WE ARE TRYING TO DEFINE THIS IS SIMILAR TO DISCUSSION THAT DR. RODEO AND WE ALL HAD EARLIER ON IN OUR UNDERSTANDING OF MSC. WE ARE STILL TRYING TO DEFINE WHAT EXOSOMES AND WHICH DIFFERENT EXOSOMES ARE THERE. THEY PLAY A ROLE IN INTRACELLULAR COMMUNICATION. THEY THEREFORE PLAY ROLE IN CELLULAR RESPONSE, TISSUE RESPONSE TO TRAUMA, DISEASE, MALIGNANCY AND ALSO RESTORE HOMEOSTASIS. INTERESTINGLY ENOUGH ONGOING EVIDENCE THAT NOT ONLY DO EXOSOMES PLAY ROLE IN CELL TISSUE OR TISSUE CELL COMMUNICATION, THEY CHANGE WHAT IS IN THE EXOSOME OR WHAT THE EXOSOME DOES WITHIN THE TISSUE LISTENING TO THE ENVIRONMENT WHICH THEY ARE BEING SECRETED. THIS MEANS IT IS A SMART FEEDBACK SYSTEM, WHICH FOR ME IS SUPER INTERESTING BUT IT CREATES A FUNDAMENTAL CHALLENGE IN THE CONCEPT OF USING THEM OFF THE SHELF INSTEAD OF MSCs OR OTHER CELL SOURCES. MORE DYNAMIC THAN THEY ARE CURRENTLY BEING THOUGHT OF THAN THE WAY I UNDERSTAND THE SCIENCE BEING DISCUSSED. I STILL THINK THE FIELD IS YOUNG, EARLY DAYS, THERE ARE COUPLE OF EXPERT CENTERS HERE IN THE UNITED STATES, WHERE I THINK WE ARE STILL TRYING TO FIGURE OUT WHAT IS EXOSOME AND WHAT ARE OTHER CELL SECRETORY MECHANISMS AVAILABLE THAT ARE SIMILAR AND HOW DO THEY KNIFER FROM EACH OTHER. AT THE MOMENT WE ARE STILL IN A PHASE SEPARATION OR COLLECTION OF EXOSOMES AND FUNCTIONAL DESCRIPTION IS BEING DONE BY THINGS WE CAN SEE AND MEASURE IN ELECTRON MICROSCOPY, SIZE DETERMINATION, EARLY STUDIES THAT FOCUS ON EXOSOME FUNCTION. IT IS ONE OF THE CHALLENGES IN THE THERAPEUTIC APPLICATION OF EXOSOMES, TRYING TO FIGURE HOW TO GET IT FROM THE FLUID OR TISSUE THEY ARE FUNCTIONING IN. THE WAY I READ LITERATURE, THERE ARE FOUR WAYS AT THE MOMENT SIMPLE RELIABLE IS ULTRA CENTRIFICATION, HAS ADVANTAGES BUT DOWN SIDES AS WELL BECAUSE ON INDIVIDUAL PATIENT TO PATIENT BASIS IT WILL BE DIFFICULT TO MAKE THIS APPLICABLE. AS YOU TRY TO DO FOR LARGER VOLUMES AND COHORT THERE WILL BE LIMITATIONS ON FLEXIBILITY AND EFFECTIVENESS OF CHOICE. THERE ARE MORE SPECIFIC METHODS SUCH AS SIZE TECHNIQUES WITH ULTRA FILTRATION AND CHROMATOGRAPHY AND PRETTY DIFFICULT HOW TO UP SCALE THOSE. MAYBE EXOSOME PRECIPITATION FILTERING IN RUDIMENTARY WAY UP SCALE, BUT ONCE WE START UNDERSTANDING SPECIFIC EXOSOME FUNCTIONS THEREFORE LIKELY THAT IMMUNE AFFINITY CAPTURE BASED TECHNIQUES WOULD BE LIKELY TO ADDRESS CERTAIN EXOSOMES TO BE EXTRACTED AS MAYBE TRYING SECRETE FROM MSC CONTROLLED ENVIRONMENT OR EVEN SYNOVIAL FLUID CONTROLLED ENVIRONMENT THAT PREDICTABLY CREATE EXOSOME POPULATION YOU WANT TO FIND MANY A MORE INDUSTRIAL ENVIRONMENT. SEEMS TO BE FAR AHEAD OF THE FIELD BUT LEARNED IF YOU DON'T KNOW HOW TO UPSCALE AND MAKE APPLICABLE YOU HAVE TO WONDER WHAT THE FUNDAMENTAL RESEARCH NEEDS TO BE STEER US TOWARDS, THIS IS STILL VERY MUCH WHERE THE EXOSOME FIELD IS AT. SO WHAT IS THERE AND HOW IS THIS GOING TO BE APPLICABLE TO OA TREATMENT, WAS THE QUESTION WE TRIED TO READ MORE. IT IS CLEAR AS I REFERRED TO BEFORE, MS A FIELD UNDERSTANDING THE ROLE OF MSCs IN IMMUNE MODULATORY BUT ALSO IN SECESSION OF BIOACTIVE FACTORS, THAT IS VERY MUCH FOCUSED ON THE ROLES OF EXOSOMES AS INTRACELLULAR MECHANISM. IT IS CLEAR AS WE HEARD TODAY AND HAVE SEEN BEFORE, THERE IS AN EFFECT OF MSCs ON OSTEO ARTHRITIC JOINTS ON DEGENERATION, SYNOVIAL PROCESS, WE ARE STILL IN THE PROCESS OF GAINING BETTER UNDERSTANDING OF THAT. BUT IT IS CLEAR EXOSOMES PLAY A ROLE IN THAT. THEREFORE WE SEE THESE JUNE YUP SLOPE IN PUBLICATION ON EXOSOMES SINCE WE NOW MORE ACCEPT AND UNDERSTAND THAT THE PARACRINE FUNCTION OF MSC MIGHT BE MORE IMPORTANT THAN TISSUE DIFFERENTIATION AND REGENERATION FROM MSC PER SE. THEREFORE MAKES SENSE THAT YES THERE IS A HYPOTHESIS THAT'S STRONG ENOUGH INITIAL IN VITRO EVIDENCE THAT EXOSOMES DO PLAY A ROLE IN THE POSSIBILITIES AND IN THE PORTFOLIO OF MAYBE DOING SOMETHING IN EARLY PHASE INTERVENTION OF THIS CASCADE OF THINGS THAT EVENTUALLY IT WAS OSTEOARTHRITIS. THERE ARE FEW REVIEW PAPERS THAT STEER US TOWARDS BETTER UNDERSTANDING. THERE ARE SOME PAPERS THAT SHOW MECHANISMS OF ACTION AND MOST OF THEM ARE ARE NOW MSC DERIVED EXOSOMES AND HOW DO THEY PROTECT CARTILAGE OR HOW DO THEY PROTECT BONE FEE FORMATION OR MODULATE SYNOVIAL INFLAMMATORY PROCESSES THEY ARE SUFFICIENT EVIDENCEED FROM EXOSOME BASE RESEARCH MAINLY FROM MSC DERIVED EXOSOME DERIVED MSC THAT THERE IS A CHONDRAL PROTECTIVE EFFECT THERE IS CHONDRAL SUPPORTIVE EFFECT THROUGH BOTH CHONDROCYTE APOPTOSIS AND MACROPHAGE ACTIVATION. WHICH IS THE DISCUSSION DR. LATTERMANN AND ROBEY HAD BEFORE. THE PAPERS IN MY UNDERSTANDING, SAY THAT THERE IS STILL A GREAT HETEROGENEITY, NOT ONLY IN THE CELL LINES LOOKED AT TO STUDY EXOSOMES BUT ALSO IN THE PREPARATION OF THE SECRETOMES AND PANEL MODELS IN VITRO MODELS, AND UNDERSTANDING HOW TO USE SECRETOMES OF RESOLUTION OF INFLAMMATION AND CARTILAGE REGENERATION, WE TOOK A LITTLE BIT OF PEAK IN ROLE OF EXOSOMES IN OTHER FIELDSES I GET THE SENSE ONCOLOGY FIELD IS FURTHER AHEAD IN UNDERSTANDING AND APPLICATION IN SOME OF THE MALIGNANCIES. CARDIOVASCULAR FIELD? SIMILAR PHASE AS WE ARE IN NOW. WHEN WE DID SEARCH FOR CLINICAL TRIALS THERE ARE MORE THAN 30 REGISTERED CLINICAL TRIALS ON CLINI CLINICALTRIALS.V THAT CIRCLE EXOSOME APPLICATION BUT TWO-THIRDS ARE DIAGNOSTIC PURPOSE, THERAPEUTIC PURPOSES AND ALL BY FIVE OR SIX IN THE ONCOLOGY FIELD. NONE AS FAR AS I WAS ABLE TO FIND IN OUR SEARCH TWO WEEKS AGO ARE IN THE OSTEOARTHRITIS OR REGENERATION CARTILAGE FIELD. I FEEL THE BASIC SCIENCE SHOWS IN WHATEVER ANIMAL MODEL YOU CHOOSE, THERE IS SUFFICIENT EVIDENCE MSC BASED EXOSOMES PLAY A ROLE IN SOME WAY SHAPE OR FORM INFLUENCING BENEFICIALLY ROLE OF CARTILAGE REPAIR AND OUTCOME OF CARTILAGE REPAIR THERE, IS A SOLID REASON TO STUDY THIS. SO THEREFORE THE CHARGE FOR TODAY'S EXPLORATION WAS USEFUL. THERE ALSO SEEMED SUFFICIENT EVIDENCE THAT SYMPTOMATIC RELIEF FROM OSTEOARTHRITIS COMPLAINTS MEASURED BUT SYNOVIAL FLUID OR THICKENING OR CHANGES CAN BE MODIFIED BY THE APPLICATION OF EXOSOMES, WE ARE THINKING DOSING AND CLIMBING, THINKING INTERACTIONS WITH THE GOAL THERAPEUTIC TISSUES SO THAT NEEDS TO BE SOLVED. THERE ARE MORE CHALLENGES AT THE MOMENT THAN REAL SOLUTIONS AND TO ME THERE IS NOT A CLEAR PATH FORWARD YET. IT IS DIFFICULT TO UNDERSTAND HOW WE HARVEST THEM, DIFFICULT HOW TO DELIVER THEM. THERE ARE SOME BUY LOGICAL CHALLENGES IN THE -- BIOLOGICAL CHALLENGES IN THE INTERARTICULAR ENVIRONMENT WHICH IS SIMPLER TO SOLVE IF WE GO FOR ORGAN SOLUTIONS OR INTRAVASCULAR SOLUTIONS. IT IS DIFFICULT TO UNDERSTAND WHAT WOULD BE THE IDEAL SOURCE FOR MSC TO ISOLATE EXOSOME FROM AND IF YOU WANT TO UPSCALE, HOW TO COLLECT EXOSOMES IN AN EFFICIENT MANNER FROM MSC POPULATION. WOULD BE A DIFFERENT CHALLENGE. BUT I DON'T THINK WE NEED TO ADDRESS THAT YET. WE ARE IN THE PHASE TO LOOK AT MECHANISTIC EXPLORATION AND UNDERSTANDING, THE ROOT OF DELIVERY AND DOSAGE. FREQUENCY PATIENT SELECTION COMES LAST. BUT THERE CLEARLY IS A EXCITING OPPORTUNITY TO USE EXOSOMES FOR TREATMENT OF OSTEOARTHRITIS. I WOULD SAY THAT BUNDLING OF FORCES FOCUS RESEARCH PROJECTS AND PROTOCOLS AND PROBABLY CON SOURCE IS IMPORTANT AND MAYBE THIS GROUP CAN PLAY A ROLE IN SOME WAY SHAPE OR FORM. I THINK WHAT IS IMPORTANT AND MENTIONED BY DR. RODEO, STANDARDIZATION OF PROTOCOLS AND DESCRIPTION OF WHAT IS MY EXOSOME I'M WORKING ON HOW DID I GET IT, HOW DO OTHERS USE IT REPRODUCIBLY IN THE SAME WAY. THOSE ARE NEEDED BEFORE WE CAN START THINKING ABOUT CLINICAL TRIALS IN OSTEOARTHRITIS. I FEEL THE LIBERTY OF SCIENTIFIC EXPLORATION IS PROBABLY A LITTLE BIT BIGGER IN ONCOLOGY FOR OBVIOUS REASONS. I THINK THERE IS EVEN A POSSIBILITY OF ENGINEERING EXTRA CELLULAR VESICALES AND EXOSOMES WHICH IS MORE CONTROLLABLE. THAT IS NOT REALISTIC FOR CELLS, MIGHT BE POSSIBLE TO ENGINEER FULL EXOSOME IN A WAY THERAPEUTIC OPTION DIFFERENT THAN APPLYING SMALL MOLECULES. THERE ARE THOUGHTS USING MSC EXOSOMES FROM YOUNGER DONORS TO BE STORED IN THEIR LIFE LATER ON WHICH IS SOMETIMES ALLEVIATE CHALLENGES THAT WE KNOW. USED AS A VESICLE FOR DRUG DELIVERY. THAT IS WHERE WE STAND WITH OUR UNDERSTANDING AND I FEEL CONFIDENT AND CHALLENGED ENOUGH TO SAY THAT PRE-CLINICAL EVIDENCE SUGGESTS THAT MSC DERIVED EXOSOMES JOINT HOMEOSTASIS AND MAY PREVENT OSTEOARTHRITIS IN ANIMAL MODELS THERE'S ANTI-INFLAMMATORY EFFECTS IN PATIENT CARE THAT SHOULD BE TRIED WHEN WE KNOW HOW TO DO SO SAFELY. SIGNALING OF EXOSOME CHANGES AS THEY ARE ENVIRONMENTS THAT CHANGE. I THINK AS I SAID BEFORE THAT IS A FUNDAMENTAL CHANGE TO OFF THE SHELF USE BECAUSE WE MAY NOT BE SMART ENOUGH TO DESIGN THE EXOSOME THAT NEEDS TO BE USED FOR CHANGING ENVIRONMENT THAT THE PATIENT PRESENTS US WITH. SO I THINK THAT FOR NOW WE SHOULD TRY TO FOCUS AND CONCENTRATE THE RESEARCH AND CREATE ROBUST FOUNDATION OF UNDERSTANDING BEFORE WE END UP IN APPROACHES WE HAVE SEEN WITH THE OTHER TECHNOLOGIES. THAT IS ALL I HAVE FOR YOU IN THIS BUT I THINK IT IS EARLY BUT EXCITING FIELD. THANK YOU VERY MUCH FOR THE CHALLENGE. >>THANK YOU, DANIEL. GREAT SUMMARY, IT NEEDS TO FURTHER WORK. LIKE EVERYTHING ELSE, CHARACTERIZATION OF THESE PREPARATIONS IS SO CRITICAL. >>AGREE. >>NICE TALK, DANIEL. DO YOU HAVE SOME SUGGESTIONS FOR HOW TO CHARACTERIZE EXOSOME? >>NO, I DON'T. THAT IS NOT AN EASY ANSWER, I FEEL PRETTY EARLY ON, IT IS THE CONTENT OF THE EXOSOME AND WHAT IS IN THERE. THAT IS WHY WE NEED TO UNDERSTAND SOME FACTORS IN THE EXOSOME ARE PUT IN THE EXOSOME AND SECRETED BY THAT CELL AND ENVIRONMENT AT THAT TIME. THAT MEANS WE NEED TO REVISIT THAT PART OF OUR UNDERSTANDING OF SOME OF THE MECHANISMS THAT WE ARE LOOKING AT. I THINK JUST LOOKING AT SURFACE MARKERS OF THE EXOSOME WILL BE ENOUGH BECAUSE IT IS ABOUT THE CONTENT MORE. WE ARE TOO EARLY A PHASE, MAYBE MY UNDERSTANDING IS TOO LIMITED TO BE ABLE TO SAY WHAT THE ROLE OF THAT EXOSOME IS GOING TO BE IN THE BIOLOGICAL SYSTEM, IT'S SECRETED IN. WE NEED TO WORK ON THAT BEFORE WE CHARACTERIZE THEM WELL ENOUGH. HAPPY TO ENTERTAIN INPUT FROM OTHER EXPERTS ON THE PANEL TODAY. I DO THINK THAT ONE WAY OF IMPROVING OUR UNDERSTANDING OF FUNCTION IS WE CAN USE CONTROL ENVIRONMENT SUCH AS VARIATION OF SYNOVIAL FLUID, VARIATIONS OF MSC POPULATIONS, STUDYING THEIR EXOSOME RESPONSE FROM DEFINABLE CHALLENGES AND THERE IS EXCITING WORK DONE IN VANDERBILT AND OTHERS, ALSO IN ASIA, THE PROGRESSION IS QUICKLY, IT IS STILL TOO EARLY TO SAY WE NEED TO DO THIS AND THIS AND THIS PANEL. SO THE PAPER ON EXOSOMES IS STILL PENDING. >>IF WE ACCEPT IT EXSOMES REPRESENT THE CELL CARGO SIGNALING MOLECULE FROM CELLS WE GET TO A POINT ONE DAY USING EXTRA CELLULAR VESICALES AND NO CELLS ANY MORE. >>I THINK THE ANSWER COULD BE YES. NOT CERTAIN YET. THAT IS A FAVORITE QUOTE. CELLS ARE SMARTER THAN SURGEONS AND THAT IS WHY I THINK CELL LISTENS TO ITS ENVIRONMENT, IT DOES WHAT THE ENVIRONMENT SEEMS TO NEED AND SECRETE WHAT IS THE ENVIRONMENT NEEDS. I ALSO THINK THE MOMENT CELLS ARE SMARTER THAN SCIENTISTS, YES, IT IS POSSIBLE SCOTT AND I THINK WE SHOULD BE TRYING TO GO THAT DIRECTION. IT WOULD BE THAT YOU HAVE AN AS PARTICIPANT OF SYNOVIAL FLUID FROM THE PATIENT JOINT. YOU CHALLENGE THE MSC POPULATION WITH SYNOVIAL AS PARTICIPANT AND WE CAPTURE THE EXOSOMES THAT SECRETES AND APPLY THOSE TO PATIENTS KNEE OR OTHER JOINTS. MIGHT BE SOMETHING MORE CREATIVE. >>I THINK WE STILL NEED TO KNOW WHAT IS IN THE EXOSOMES AND HOW THAT MIGHT CHANGE WITH THE PATIENT OR THE CELL PRODUCING IT. MUCH LIKE UPS OR FEDEX TRUCK DRIVING DOWN THE ROAD AND WE HAVE PACKAGES IN THEM, MAYBE ONLY ONE OR TWO DESIGNATED FOR YOU OR THAT YOU WANT TO HAVE OPEN. >>MOST -- NEIGHBOR AT THE CORNER HAD NINE BOXES EVERY DAY >>THANK YOU. LOOKING AND IF THERE IS NO FURTHER QUESTIONS WE CAN MOVE TO DR. GUILAK'S TALK. FARSHID IS WELL KNOWN, THE PROFESSOR OF ORTHOPEDIC SURGERY WASU AND DIRECTOR OF RESEARCH FOR THE ST. LOUIS SHRINERS HOSPITAL. HE HAS WON THREE KAPPA DELTA AWARDS AND RECENTLY ELECTED TO THE NATIONAL ACADEMY OF ENGINEERING. HIS CONTRIBUTIONS TO MECHANOBIOLOGY AND MECHANIC KNOW MEDICINE, LOOKING FORWARD TO YOUR DISCUSSION ON GENE EDITING FOR ARTHRITIS. >>THANK YOU DR. CHU AND ORGANIZERS FOR THIS FANTASTIC SYMPOSIUM SO FAR. THERE'S BEEN A NUMBER OF CELL BASED THERAPIES FOR VARIOUS FORMS OF ARTHRITIS, MOSTLY IN TRY THOUGHT TREAT FOLKAL DEFECT, LESS SO RHEUMATOID ARTHRITIS, AS WE HEAR TODAY VARIOUS APPROACHES FOR OSTEOARTHRITIS. IN PARTICULAR, THESE FORMS OF ARTHRITIS ARE VERY IMPORTANT TARGET BECAUSE HOW DEBILITATING THEY ARE, THIS PATIENT ON THE RIGHT WAS GOT A HIP REPLACEMENTED AGE 18 AND SECOND HIP ON THE BOTTOM AGE 22, HE NEEDS A JOINT REPLACEMENT SO ANYTHING WE CAN DO TO TRY TOLL PRESERVE JOINTS LIKE THIS, IN THE KNEE OR THE HIP OR OTHER JOINTS BECAUSE OF THE DISABILITY CAUSED COULD BE VERY IMPORTANT. WE HEARD STEM CELL THERAPIES AND DR. RODEO GAVE A BACKGROUND. I PUT FORTH THAT ALL STEM CELL THERAPIES ARE NEITHER STEM CELLS NOR THERAPIES. Z WHAT IS OFFERED ARE CELLS EVEN IF THEY ARE CELLS, JUST A MIX OF DIFFERENT TYPES OF NON-STEM CELLS, NON-THERAPEUTIC CELLS >>BEING ADVERTISED AS YOU SEE SPECIALIZED CELLS THAT KNOW WHAT YOU NEED, WHERE YOU NEED IT, AUTOMATICALLY GO WILL, BECOME IT, THEY SOLVE EVERYTHING AND TURNED OUT UNTRUTHFUL, THESE CELLS DON'T HOME TO SITE OF INJURY, THEY DON'T DO EXACTLY WHAT THEY NEED TO DO. AND THEY ARE GOING -- THERE HAVE BEEN A NUMBER OF REPORTS OF OFF TARGET EFFECTS OF CELL INJECTION SO THEY ARE NOT HARMLESS, THEY CAN HAVE CASES OF OVERGROWTH AND HYPERPLASIA HIGH PER TROPHY OSSIFICATION IS COMMON IN CARTILAGE REPAIR AND MEDICAL TOURISM LIKE A MUCOUS PRODUCING NOSE LIKE ORGAN OR TUMOR FORMATION AND VERY BAD CASE OF COMPLETE VISION LOSS IN PATIENTS FEW YEARS AG AGO. ONE BIGGEST IE WE HAVE IN OUR FIELD IS THERE ARE VERY FEW PROSPECTIVE RANDOMIZE TRIALS PERFORMED AND THIS WAS ALLUDED EARLIER, MANY STUDIES DON'T HAVE CONTROL GROUPS. WE SAW FROM SOME DATA PRESENTED, SOME ARE DOSE RESPONSES WITHOUT A PLACEBO GROUP. UNFORTUNATE LITTLENESSES HALF STEM CELL CLINICAL TRIALS ARE EVER PUBLISHED. STEM CELLS REGARDED INFLAMMATORY RESPONSE COMMON TO ARTHRITIS INCLUDING OSTEOARTHRITISST OSTEOARTHRITIS, RHEUMATOID ARTHRITIS DRIVEN BY KEY CYTOKINES COMMON INTERLEUKIN 1, TNF ALPHA, INTERLEUKIN 6 AND MAYBE 17 IN CERTAIN CASES. WE MAY HEAR MORE ABOUT DRUG DELIVERY BUT THE PROBLEM IS CLEARANCE AND DELIVERY TO JOINT AND CARTILAGE IF THAT'S THE TARGET. WE HAVE MANY TARGET IN OA BUT ONE THAT'S ATTEMPTED IS INHIBITOR OF INTERLEUKIN 1 ANAKINRA OR AND IT HAS A SHORT HALF LIFE OF TWO HOURS IN THE JOINT AND THERE'S BEEN SOME EVIDENCE TO SAY HELPFUL IN RA, EVEN EARLY PTOA FOLLOWING ACL ENTRY BUT LONG TERM STUDIES DIDN'T SHOW SUCCESS. INCREDIBLE STUDY RECENTLY WITH THE (INAUDIBLE) TRIAL, IL 1 BETA ANTIBODY, 10,000 PATIENTS STUDIED WITH THROMBOSIS. POST HOC THEYNALSIS, THERE WAS A SIGNIFICANT REDUCTION OF 40% HAD RATIO OF .58 FOR JOINT REPLACEMENT. SUGGESTING THAT IF POTENTIALLY DELIVERED PROPERLY, COMPOUND SUCH AS INHIBITOR OF INTERLEUKIN 1 COULD BE TREATMENT FOR OSTEOARTHRITIS. THIS WAS NOT THE MAIN GOAL STUDY SO MORE WORK NEEDED TO DETERMINE THIS BUT THIS IS ONE LARGE EFFECT SIZE EVER SEEN IN OSTEOARTHRITIS RELATED STUDY. WHY CAN'T MSC BE ABLE TO DO THIS? MAJOR ADVANTAGES IN BONE MARROW OR ADIPOSE READILY ACCESSIBLE MULTI-POTENT CAPABILITY BUT VERY POOR HOMING RETENTION IF INJECTED, LIMITED UNCONTROL THERAPEUTIC RESPONSES WHICH ARE QUITE WEAK FROM ANTI-INFLAMMATORY STANDPOINT. DIFFERENTIATE WITHOUT DIRECT QUEUES OR CONTEXT OR MATRICES, ONE ISSUE IS VARIABILITY, THERE IS SOME DISCUSSION FROM DR. ROBEY IN THE CHAT SINGLE CELL ANALYSIS. BUNCH OF SINGLE CELL ANALYSIS ON BONE MARROW MSC ADIPOSE DEFINED BY VARIOUS ISOLATION PROCEDURES. NOT ONE CELL TYPE THERE, MIX OF 2 TO 7, SOMETIMES TEN CELL POPULATIONS IN THIS PLOT SINGLE CELL ANALYSIS. PURPORTEDLY LESS THAN ONE IN TEN THOUSAND ARE STEM CELLS WE CALL MSCs. THE OTHER TOPIC WAS THAT OF INFLAMMATION AND RESOLVING INFLAMMATION. WE NEED INFLAMMATION FOR WOUND REPAIR AND TISSUE REPAIR BUT WE NEED TO FORM INFLAMMATION THAT RESOLVES SO INITIAL ONSET OF INFLAMMATION AND RESPONSE TO WOUND, RESOLUTION PHASE AND POST RESOLUTION PHASE WHERE ADAPTIVE IMMUNE CELLS CAN CLEAN THINGS UP. THE PROBLEM IS NOT RESOLVING INFLAMMATION, BUT CHRONIC INFLAMMATION. THIS IS PRESENT IN MANY FORMS OF ARTHRITIS OR INJURY. OBESITY AS RISK FACTOR FOR ARTHRITIS, WHERE LEVELS OF CYTOKINES ARE CONTINUOUSLY HIGH. NOT ONLY HIGH BUT IN FLAIRS THESE CAN BE DIE YOUR HONORRAL OR CIRCADIAN ON DAILY BASIS OR ENVIRONMENTALLY TRIGGERED AND DRUG THERAPIES CURRENTLY FOR RHEUMATOID ARTHRITIS ARE HIGH LEVEL PROTEIN THERAPIES. SUPPRESS THE IMMUNE RESPONSE AND NUMBER OF SIDE EFFECT INCREASE INFECTION RISK. WE WILL HEAR PROTEIN DELIVERY WORKING WELL IN CERTAIN CASES MASSIVE RESEARCH BUT WHERE IT FAILS ARE THINGS LIKE I DESCRIBED, HIGH LEVELS ANTI-CYTOKINE BIOLOGIC DRUGS THAT RESPOND TO STIMULUS LIKE ENVIRONMENTAL TRIGGER OR CIRCADIAN TRIGGER HAVE RAPID RESPONSE TIMES OF MINUTES TO HOURS AND BE THERE AND BE DELIVERED FOR MONTHS OR YEARS. ONE REASON EXOSOMES ARE NOT LONG TERM DELIVERY INSTEAD OF CELLS IS CELLS CAN DELIVER CONTINUOUSLY DRUGS FOR LONG TIME EXOSOMES AS WE SAW POTENTIAL STRENGTH DELIVERED REPEATEDLY AND OVER AND OVER. WE THINK ABOUT THIS, OUR GOAL WAS TO DEVELOP TECHNIQUES TO CREATE SMARTER CELLS THAN WE JUST HEARD ABOUT. TO USE SYNTHETIC BIOLOGY TO CREATE CELLS THAT CAN SELF-REGULATE PROVIDE APPROPRIATE DRUGS APPROPRIATE TIMES IN RESPONSE TO STIMULI. THINK ABOUT DRUG DELIVERY AND PROTEIN, IT IS HAVING A LEAKY BUCKET OF DRUGS, PATIENT SIDE THE BODY, THE DRUG LEAKS OUT AND WHEN FINISHED REPLACE THE BUCK OR REFILL WHICH MANY CASES WILL WORK. IF YES USE GENE THERAPY APPROACHES, WITH CONSTITUTIVE PROMOTER WE HAVE LARGE AMOUNTS OF DRUG GUSHING OUT. IN CERTAIN CASES SUCH AS HEMOPHILIA, THIS MAYBE A GOOD APPROACH. GENE THERAPIES WITH INDUCIBLE PROMOTERS LIKE HAVING A FAUCET YOU CAN TURN ON AND OFF, BUT NEED TO KNOW WHEN TO TURN ON AND OFF TO FIGHT INFLAMMATION. A CELL HAS A SENSOR, DELIVER DRUGS WHEN IT SENSES ANY OTHER TRIGGTRIGGER. WE THOUGHT WE CANE A CELL LOOK AT RECEPTORS, INTERNAL GENE CIRCUITS AND APPROPRIATE OUTPUT PATHWAYS WHETHER CYTOKINE INHIBITORS PAIN TARGETS OR ANABOLIC FACTORS, AND REPROGRAM USING CRISPER CAS 9 ENGINEERING IN IPSCs IN OUR CASE. DEVELOP CELLS WITH INFLAMMATORY RESPONSE, WE CAN COME IN TO LEAK IT ON GENETIC BASIS IN ITS PLACE PUT FEEDBACK LOOP TO CREATE BIOLOGIC DRUGS. IT IS REPROGRAMMABLE CELL LIKE iPHONE YOU PUT THESE LITTLE APPS INTO THE iPHONE AND APPS ARE DESIGNED TO DELIVER WHAT WE NEED DELIVERED. FIRST WORK DONE BY GRADUATE STUDENT JONATHAN ON FACULTY AT VANDERBILT, HE DEVELOPED IL 1 AND TNF RESPONSE SYNTHETIC CIRCUITS. ACTED BY CYTOKINES HE THEN LOOKED AT EFFECTOR GENES AND IN THIS CASE FOUND CCL 2 WAS ONE OF THE BEST MARKERS OF TNF OR IL 1 ACTIVITY OUTSIDE THE CELL. FROM THAT HE WAS ABLE TO BUILD SYNTHETIC GENE CIRCUIT WITH TNF RECEPTOR OR IL 1 AS TARGET. WHEN IT WAS ACTIVATED AND CRL 2 WAS ACTIVATED, ALSO TOOK ONE ALLELE AND CREATED THE INHIBITOR DRUG FOR TNF OR IL 1 AS THE OUTPUT. INSERT TNF -- WHEN THE CELLS SEE TNF INSTEAD OF TWO COPIES OF CCL 2, IT MAKE IT IS INHIBITOR WHICH GOES BACK AND BLOCKS TNF ACTIVITY. WHEN WE DO THIS EVERYTHING WORKED IN H VITRO AND MORE RECENTLY TESTED THIS IN A MODEL OF RHEUMATOID ARTHRITIS, MOLECULES SUCH AS IL 1 TNF ARE IMPORTANTOR IMPORTANT PLAYERS. TO KEEP CELLS IN PLACE THEY WERE ENGINEERED TO A SMALL DISC OF CARTILAGE WHERE THEY SAT SUBCUTANEOUSLY SINCE THE ENVIRONMENT FOR INFLAMMATION AND DELIVERED DRUGS SYSTEMICALLY THEY SHOWED NICELY HAVING DRUG DELIVERY IN THIS ON DEMAND SYSTEM, COULD ALLEVIATE PAIN SENSITIVITY, RED IS TREATED GROUP, INCREASED OR DECREASE PAIN THRESHOLD IN THE CONTROL AND CONTROL TREATED GROUPS SIGNIFICANTLY INCREASED. ON AN ON DEMAND BASIS. WE SAW COMPLETE -- NEVER ACCOMPLISHED BY DRUG THERAPIES IN RHEUMATOID ARTHRITIS. WE USE IT AS A MODEL BECAUSE WE KNOW THE INFLAMMATORY TARGETS SO WELL STILL NEED TO IDENTIFY IN OSTEOARTHRITIS. WE HAVE NOW SEVERAL OTHER APPROACHES USING, iPHONE PROGRAM APPS INTO IT, WE HAVE APPS BUILT TO FIND OURSELVES OR FIND MY iPHONE BY USING LUCIFERASE OR GFP, WE CAN TAG SIGNAL TO ANTI-CYTOKINE THERAPY AND GET SIGNAL INTENSITY. WE CAN TURN ON AND OFF SYSTEM EXOGENOUSLY, USING THINGS LIKE TEAT OFF OR ON SYSTEM SO IF YOU TEMPORARILY WANT TO SHUT OFF THE GENE CIRCUIT WE CAN DO IT WITH TETRA CYCLINE RESPONSIVE ELEMENT. THESE ARE IPSCs TRUE STEM CELLS WITH PLURIPOTENT CAPABILITY SO WE CAN BUILD U SELF-DESTRUCT SIGNALS IF THEY ESCAPE FROM THE CONSTRUCT AND NEED TO BE ELIMINATED. MOST RECENTLY WE HAVE BEEN TRYING TO DEVELOP SYSTEMS THAN CAN DISTINGUISH DIFFERENT CYTOKINES AND RESPONSES BECAUSE AS WE HEARD EARLIER THERE, IS NO ONE ANTI-CYTOKINE THERAPY THAT IS GOING TO TREAT ALL THE DISEASE OR ALL OA, WE CAN IDENTIFY FINGERPRINTS USING MICRORNA SIGNATURES ACTIVATED BY PRESENCE OF DIFFERENT CYTOKINES AND WE CAN BUILD GENE CIRCUITS BASED ON THESE. IN THE LAST FEW MINIS WILL TELL YOU ABOUT TWO OTHER CIRCUITS WE BUILD THAT HAVE BEEN FUN. ONE IS A FORCE RESPONSIVE TOUCH SENSOR DELIVERING DRUGS IN RESPONSE TO MECHANICAL LOADING. ARE MECHANICALLY SENSITIVE. BONE GROWS WHEN YOU LOAD IT, MUSCLE GROW, CARTILAGE DOES THE SAME THING, IT HAS MECHANIC KNOW SENSITIVITY, YOU CAN SEE A PIECE BEING SUPPRESSED CAUSING CALCIUM SIGNAL. WE TRACK DOWN SENSORS ON THE CELLS THAT ARE RESPONSIBLE FOR MECHANIC KNOW TRANSDUCTION AND ISOLATED TO THE FAMILY, PARTICULARLY TRIP V 4 AS PRIMARY MECHANIC KNOW SENSORS AND CARTILAGE. WITH THAT KNOWLEDGE WE THEN WENT AND BUILT SYNTHETIC GENE CIRCUITS MECHANIC KNOW GENETICS H. WE BUILT GENE CIRCUITS WHERE MECHANICAL LOADING VIA TRIP V 4, TO DO THAT WE ISOLATED SIGNALING CHANNELS LOOK AT THE MECHANIC KNOW TRANSDUCTION PATHWAYS DOWNSTREAM, USE BIOINFORMATICS AND CHAIRMAN SEQ TO FIND NODE AND HUB GENES THAT ACTIVATE RESPONSE AND BUILD GENE CIRCUITS USING CRISPER OR LENTIVIRAL APPROACHES TO TAG DRUG ON TO THE MECHANICCAL LOADING PATHWAY. SO GENE ARRAY DATA SHOWING ACT VISION OF ION CHANNEL BY CHEMICAL OR MECHANICAL MEANS, YOU CAN SEE THAT THE RESPONSE IS QUALITATIVELY AND QUANTITATIVELY SIMILAR FROM CHIPOTLE CHIP SEQ,Y POST DOC BOB MIMS AND A STUDENT BUILD MECHANIC KNOW SENSITIVE MOTIFS, WHERE THEN MECHANICAL LOADING ACTIVATE PRODUCTION OF OUR DRUG, FAVORITE DRUG IN THIS CASE IL 1 RA SO EASY TO MEASURE AND DOESN'T DO ANYTHING UNLESS IS, UL 1. ONCE WE TRANSDUCE INTO EXPLANTS AND CHONDROCYTES AND INTO ENGINEER CONSTRUCTS, WE CAN SHOW DIFFERENT TIME AND DOSE DEPENDENT RESPONSES, THIS IS LUCIFERASE ACTIVITY, SHOWING THE RESPONSE TO ACTIVATING ION CHANNEL WHETHER NF KAPPA B RESPONSIVE CIRCUIT OR PT GS 2 RESPONSIVE CIRCUIT IN TERMS OF MAGNITUDE AND DURATION. WE BUILT CIRCUITS WITH PREDEFINED RESPONSES OR DRUG DELIVERY, DURATIONS AND RECOVERY TIMES. WE ALSO SHOWED WHEN YOU MECHANICALLY LOAD THEM YOU CAN GET PRODUCTION OF IL 1 RA IN RESPONSE TO LOADING WHICH THE CELLS DON'T NORMALLY MAKE. FINALLY, THE MOST RECENT APPROACH IS TO CREATE A CLOCK, GENE CIRCUIT BASICALLY ONE BASED ON THE CIRCADIAN CLOCK OF THE CELL, SO THAT WE CAN DO DIE YOUR HONORRAL DRUG DELIVERY. THIS IS IMPORTANT BECAUSE AS I SHOWED YOU, FLAVORS FLARES CAN BE DIE R HONORRAL AND RECENT AREAS OF -- DIURNAL, MATCHING DRUG DELIVERY TO TIME OF DAY, BECAUSE INFLAMMATION GOES UP AND DOWN AND FOR EXAMPLE IN RHEUMATOID ARTHRITIS PEAK AROUND 3 IN THE MORNING RARELY WHEN DRUGS ARE GIVEN SO WE LOOK AT THE CORE CLOCK GENES IN CHONDROCYTES AND THEY HAVE STABLE -- THIS IS A MOUSE IN PA DARK INCUBATOR THAT PSYCHS A WEEK AFTER TAKEN OUT. YOU CAN SEE IT FLASHING AND USING THIS CONCEPT OF CHRONOTHERAPY WE CAN EXCITE GENE CIRCUITS THAT DELIVER DRUGS AT SPECIFIC TIME OF DAY ON THE CONTINUING BASIS FOR ARTHRITIS TARGETING EARLY MORNING. WE CREATED CLOCK GENE CIRCUITS BY HR 2 AND OTHER CLOCK COMPONENTS DRIVING OUR DRUG, IN FACT ENGINEERED TO CARTILAGE Z THESE CELLS OSCILLATE ON A 23, 24 HOUR BASIS AND SHOWED CIRCADIAN GENE EXPRESSION OF OUR DRUG AND CIRCADIAN PROTEIN PRODUCTION OF DRUG DELIVERY. ONCE IMPLANTED IN MICE THEY SYNCHRONIZE WITH THE MOUSE AND DELIVER FIVE TIMES MORE DRUG DURING THE NIGHT CYCLE THAN THE DAY CYCLE. ONE MORE EXAMPLE, CONCLUDE THERE AND SAY THAT WE CAN TAKE STEM CELLS AND MAKE THEM EVEN SENATOR AND BETTER BY EDITING THEIR GENOME THEIR EPIGENOME, CREATE ARTIFICIAL GENE CIRCUITS WITH CONTROLLED OUTPUTS, REPACKAGE AS GENE THERAPY, CELL THERAPY, IMPLANT THERAPIES OR HOPEFULLY EVENTUALLY ENTIRE JOINT RESURFACING THERAPIES FOR VARIOUS FORMS OFFER ARTHRITIS. I'LL CONCLUDE THERE, THANKS TO COLLABORATORS AN LAB WHO DID THIS WORK AND NIH AS WELL AS SHRINERS AND ARTHRITIS FOUNDATION. FROM THE >>THANK YOU. THANK YOU FOR THAT TOUR INTO THE FUTURE AND SO MANY EXCITING CONCEPTS YOU PUT INTO RESEARCH AND BROUGHT TO NICE STUDIES. I WANTED TO ASK ABOUT THE IMPLANT, WHERE YOU HAVE ENGINEERED CELLS WITHIN CARTILAGE CONSTRUCT. SO WHEN PEOPLE INJECT THAT AND OTHER THINGS INTO THE BODY IT'S RESORBED. CAN YOU COMMENT HOW LONG THIS IMPLANT LASTS AND HOW LONG THE CELLS SURVIVAL WITHIN THE CARTILAGE MATRIX? >>GREAT QUESTION, THE REASON WE USE THAT AS IMPLANT, IT IS AVASCULAR AND IT SHIELDS THE CELLS, THEY ARE ENCASED SO THEY CAN'T CRAWL AWAY. CARTILAGE IMPLANTED SUBCUTANEOUSLY LIKE THIS OR IN A JOINT, LASTS MONTHS OR YEARS. KELSEY COLLINS IN OUR GROUP TESTED THIS OUT FOR SIX MONTHS SO FAR, WE HAVE SOME THAT ARE I THINK STILL GOING. BUT AT LEAST SIX MONTHS THOSE ARE JUST SITTING THERE AND THEY DON'T GET ENCAPSULATED BECAUSE CARTILAGE IS NON-STICK AND CELLS DON'T ATTACH TO IT AND CAUSE ANY PROBLEMS. SO FOR OUR PURPOSES AT LEAST SIX MONTHS IF NOT LONGER. >>FANTASTIC. LOOKING FOR QUESTIONS I WILL ASK ANOTHER ONE. I THINK WHAT YOU ARE SHOWING IS VERY EXCITING. HOW WOULD YOU ENVISION TRANSLATING SOME OF THIS IN TO CLINICAL PRACTICE? >>THAT IS ALSO A -- >>CLINICAL RESEARCH FIRST. >>WE WON'T SKIP THAT STEP. THAT IS ONE OF OUR BIGGEST CHALLENGES IS SCALE UP AND DOSING BECAUSE WE NEED TO KNOW EXACTLY HOW MANY CELLS WE NEED. THERE ARE ALL DIFFERENT WAYS TO CONTROL THE OUTPUT BESIDES CELLS NUMBER SO WE DON'T WANT TO HAVE IMPLANTS HUGE BUT THERE IS GOOD EVIDENCE FOR HAVING LONG TERM BIOMATERIAL IMPLANTS IN THE BODY. SOMETHING LIKE NOR PLANT IMPLANT SUBCUTANEAIOUSLY DELIVERS, BIRTH CONTROL HORMONES OVER PERIOD OF COUPLE OF YEARS WE FOLLOWED THAT NOW DEVELOPED FLEXIBLE HYDRO GEL RODS THAT CAN BE INJECTED WITHOUT SURGERY SUBCUTANEOUSLY AS A TRANSLATIONAL APPROACH. FOR A CELL POPULATION, WE ARE THINKING WE ARE GOING TO HAVE A REPROGRAMMED ALLOGENEIC MASTER CELL WE ARE GOING TO USE BECAUSE IT WOULD BE WAY TOO EXPENSIVE TO TRY TO DO THESE EDITS AND TESTING ON PERSONALIZED IPSCs TO CREATE IPSC TO REPROGRAM IT, TEST IT, QUALITY CONTROL, TALKING MILLIONS OF DOLLARS PER IMPLANT VERSUS BANK OF SHELF IMPLANTS. SO A WE HAVE TO SCALE UP TO MID SIZE ANIMALS AND MAKES SURE IT WORKS AND THEN HOPEFULLY OVER THE NEXT DECADE TO CLINICAL STUDIES. >>SCOTT HAS HIS HAND UP SO WE WILL GO TO SCOTT AND THEN A FEW OTHERS. >>FARSHID BRINGS UP AN IMPORTANT POINT, AFFECT MECHANICAL LOAD ON CELLS. ALL THE TUCK ABOUT BIOLOGY AND THIS MACROPHAGE AND THAT AND THIS CYTOKINE BUT THE WHOLE OTHER PART OF THE EQUATION, THIS IS NOT LIVER OR PANCREAS. SO THANKS FOR JUST POINTING OUT THAT CRITICAL IMPORTANT, ALL STUDIES IN BIOLOGY OF CELLS. >>NOT JUST AS A LOAD BEARING TISSUE, IT HAS TO WITHSTAND TEN TIMES YOUR BODY WEIGHT BUT ALSO CAN WE USE AS A SIGNAL TO DRIVE WHATEVER OUTPUT WE WANT. FOR EXAMPLE WE BUILT GENE CIRCUITS THAT DELIVER APT PAIN COMPOUNDS IN RESPONSE TO LOADING AND DO IT DIFFERENT MAGNITUDES OF LOADING ACTIVATION OF CERTAIN ION CHANNEL VERSUS HIGHER THRESHOLD ION CHANNEL. WE CAN TUNE ION CHANNELS DOWN BY MUTATING THEM AND CHANGING ON OFF DYNAMICS. SO THERE IS A LOT OF FLEXIBILITY BUT BECAUSE THERE IS FLEXIBILITY A LOT OF QUESTIONS TO BE ANSWERED. AMBIKA. >>HI, FARSHID, THANK YOU FOR GREAT TALK, EXCITING WORK. GENETIC REPROGRAMMING YOU DO IN THESE CELLS, DO YOU KNOW TIMED RESPONSE IS THIS A APLASTIC EFFECT? HOW LONG DOES THE RESPONSE STAY? AS WE DELIVER THESE REPROGRAM CELLS, WHAT HAPPENS TO SURROUNDING CELLS, DO YOU EXPECT THEM TO CHANGE IN ANYWAY? >>GREAT QUESTION, REPROGRAMMING IS DONE BY CRISPER EDITING IN IPSCs, WE IDENTIFY SINGLE CELL WITH EDITS DONE PROPERLY WITHOUT OFF TARGET EFFECTS. WHICH WE CAN SEQUENCE AND THEN CLONE THAT ONE SINGLE CELL. SO A RELATIVELY NOT COMPLETELY BUT RELATIVELY UNIFORM POPULATION. BECAUSE EVEN CLONED CELLS COME FROM SINGLE CELL ANALYSIS ARE NOT UNIFORM. SO THAT IS THE CELL, THE EDITS CANNOT TRANSFER TO ANY NEARBY CELLS BUT WHAT WE FOUND IN CO-CULTURE, THESE CELLS WILL PROTECT OTHER CELLS AROUND THEM FROM THE CYTOKINE EFFECT. I DIDN'T SHOW IN VITRO DATA BECAUSE IT WAS PUBLISHED A FEW YEARS AGO BUT A SMALL NUMBER OF EDITED CELLS PROTECT LARGE NUMBER OF NATIVE CELLS. >>WHAT IS THE LIFETIME OF THESE EDITED CELLS? >>AS I MENTIONED TO DR. CHU WE HAD THEM SIX MONTHS SO FAR, THAT IS LONGEST AND WE ARE -- THEY ARE ACTIVATABLE AT SIX MONTHS IN THE BODY SUB Q. IF WE INJECT AND DON'T FORM IMPLANT THEY HAVE A LIFE OF TWO DAYS. THEN THEY ARE CLEARED AND GONE. WE MANAGE TO DIFFERENTIATE SOMETHING TO MACROPHAGES THAT WILL STICK AROUND FOR A FEW WEEKS BUT THAT IS WHAT THE CELL INJECTION, WHEREAS THE IMPLANT IS MONTHS OR LONGER. >>THANK YOU. >>GEORGE MUSCHLER. >>I HAVE BEEN FASCINATED BY YOUR WORK FOR A LONG TIME, AND CHALLENGE NOT ONLY OF HAVING A VERY SPECIFIC DRUG BUT ALSO TIMING AND DURABILITY DELIVERY. MY QUESTION, THERE'S TWO QUESTIONS, YOUR STRATEGY TAKING IPS CELLS AND USING THAT AS YOUR PLATFORM ON WHICH TO BUILD STABLE CELL THERAPY, THAT GIVES YOU THE OPPORTUNITY TO ROUND OUT A LOT OF VARIABILITY TAKEN FROM EITHER AUTOLOGOUS CELLS OR DIFFERENT BATCHES OF MSCs FROM THE SAME INDIVIDUAL. TWO QUESTIONS THERE TECHNICALLY DO YOU EXPECT TO NEED TO TAKE I P,S CELLS THROUGH AN MSC TYPE PHENOTYPE ON WAY TO BECOMING THERAPY? OR DO YOU CARE? WHETHER THEY GO THROUGH PARTICULAR MSC PHENOTYPE. RELATED TO THAT WHERE WOULD YOU LIKE TO DELIVER THESE CELLS, CAN YOU FEEL NEED TO MAKE CARTILAGE CELLS THAT DELIVER DRUGS OR BE HAPPY WITH A CELL THAT REMAINS DURABLY RESISTANT AND SYNOVIAL? >>WE DO GO THROUGH, I DON'T CALL IT MSC STATE BUT WE GO THROUGH A STEP WISE DIFFERENTIATION PROTOCOL THAT ONE OF MY POST DOCS DEVELOPED WHICH BASICALLY RECREATES THE STEPS DURING EMBRYO GENESIS OF CARTILAGE. SO 12 DAY CULTURE WE HAVE TO CHANGE MASSIVE NUMBERS OF GROWTH FACTORS DURING THOSE 12 DAYS. THEY ARE IN THAT CHONDROGENNIC PHASE AND FORM CARTILAGE. WE WANT CARTILAGE SO WE DON'T NECESSARY -- THE MOUSE CELLS EASIER, THEY GO THROUGH EARLY MICROMASS PHASE WITH AND AFTER THAT MESENCHYMAL AND TURNED TO CARTILAGE. WE WANT THEM TO FORM STABLE CARTILAGE. AID NEEDS TO BE FUNCTIONAL CARTILAGE, IF SUB Q IT NEEDS TO ENCAPSULATE CELLS, TO PROTECT, SURVIVE IN AVASCULAR ENVIRONMENT AND PREVENT INVASION WHICH MOST CARTILAGE TENDS TO DO THAT. THESE ARE IPSCs SO WE CAN DIFFERENTIATE TO NEURONS, INTO FIBROBLASTIC TYPE CELLS, INTO MUSCLE CELLS, IF THAT WERE POTENTIAL AND WE HAVE DONE THIS WITH SOME ANTI-FIBROTIC CELLS WE DEVELOPED WITH IN COLLABORATION WITH JOHNNY HUARD, DIFFERENTIATED INTO MUSCLE AND IMPLANTED IN MUSCLE TO PREVENT MUSCLE FIBROSIS IN RESPONSE TO TGF BETA. SO STEM PART GIVES YOU FLEXIBILITY IN HOW YOU DIFFERENTIATE IT BUT HOW WE GET THERE FOR THIS WE CARE LESS, MORE THE END PRODUCT THAT MATTERS. >>THANK YOU. HAND OFF TO SCOTT RODEO YOU ARE ON MUTE. >>SORRY; I WAS THINKING -- DR. BARRY IS MANY THE TRANSLATIONAL MEDICINE INSTITUTE AT COLORADO STATE UNIVERSITY. ALSO PROFESSOR CELLULAR THERAPY AFFILIATED WITH REGENERATIVE MEDICINE AT THE NATIONAL UNIVERSITY OF IRELAND, DR. BARRY IS A MAJOR CONTRIBUTOR TO THE FIELD OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE. HIS WORK CONTRIBUTED TO OUR CURRENT UNDERSTANDING OF THE PHENOTYPIC ATTRIBUTES OF MESENCHYMAL STROMAL CELLS, IMPORTANTLY COMMITTED TO DEVELOPMENT OF METHODS FOR AUTOMATED SCALABLE CELL EXPANSION FOR GMP APPLICATION AND THAT WORK COORDINATED CLINICAL TRIALS TO TEST EFFICACY OF STROMAL CELL DELIVERY AND REGENERATIVE ARTHRITIS AND RECIPIENT OF THE MARSHALL AWARD FOR EXCELLENCE FROM THE ORS. ALSO ELECTED MEMBER OF THE ROYAL IRISH ACADEMY LAST YEAR SO WELCOME, WE WILL HEAR TALK ON MSC THERAPY FOR OSTEOARTHRITIS. >>THANK YOU VERY MUCH, DR. RODEO FOR THAT NICE INTRODUCTION. I HAVE TO SAY THIS ENTIRE DISCUSSION HAS BEEN FASCINATING AND INFORMATIVE. VERY PRIVILEGED TO CONTRIBUTE. THE REQUEST WAS TO TALK ABOUT LIMITATIONS AND CHALLENGES IN CLINICAL USE OF BIOLOGICS BUT GOING TO FOCUS ON -- MY DISCUSSION ON MSC BECAUSE THIS IS TOPIC THAT I KNOW MOST ABOUT WAITING FOR SLIDES TO ADVANCE. MOVE TO NEXT SLIDE PLEASE BECAUSE THESE ARE CONFLICTS TO MENTION AT THE BEGINNING OF THE TALK, NEXT SLIDE PLEASE. I WANT TO TALK ABOUT FOR FOUR TOPICS. ONE WHERE WE ARE IN TERMS OF CLINICAL ASSESSMENT OF MSC THERAPY FOR TREATMENT OF OSTEOARTHRITIS, WHAT HAS AND NEEDS TO BE DONE. SECONDLY TECHNICAL STRATEGIES PARTICULARLY AROUND PRODUCTION OF THE CELL PRODUCT PROBLEMS WE ARE AWARE OF THERE. THIRDLY, WHAT WE UNDERSTAND ABOUT MECHANISM OF ACTION OF CELLS TO DELIVER TO THE JOINT AND FINALLY SOME IDEA WAY FORWARD, WHAT WE NEED TO DO IN TERMS OF ADVANCING THE FIELD FORWARD. SO FIRST A QUICK SUMMARY OF WHAT WE HAVE BEEN DOING IN TERMS OF CLINICAL ASSESSMENT OF UTILITY OF MSC TREATMENT IN OSTEOARTHRITIS. SO THE CONTROL IS NOT WORKING FOR ME, SO I WILL ASK YOU PLEASE TO KEEP ADVANCING. THIS IS THE CLINICAL PATHWAY, CLINICAL TRIALS PATHWAY THAT WE NEED TO FOLLOW WHEN WE ARE LOOKING AT EXPANDED MSC TREATMENT FOR ANY CONDITION, THE STANDARD PHASED CLINICAL TRIAL PICTURE WHERE WE GO THROUGH PHASE 1 TO PHASE 4 POST MARKETING ASSESSMENTS AND SUBSEQUENT PHASE WE TREAT BIGGER NUMBERS OF PATIENTS SO PHASE 2 STUDY THINKING ABOUT 100 TO 500 PATIENTS IN PHASE 3 STUDY THINKING A LARGER NUMBER THAN THAT IN ORDER TO BUILD BODY OF EVIDENCE TO BE RELIABLE AND CONVINCING. THIS IS AN INTERESTING PAPER PUBLISHED JUST RECENTLY I BY (INAUDIBLE) WHICH IS ANALYSIS OF THE STATUS OF CLINICAL TRIALS, UTILIZING CULTURE EXPANDED MSC FOR WHOLE VARIETY OF DIFFERENT INDICATIONS LOOKS OVER MULTIPLE YEAR PERIOD YOU CAN SEE HERE THE PHASE 1 STUDIES IN BLUE, PHASE 2 ORANGE FADES 3 IN GRAY. WHAT IS STRIKING ABOUT THIS PICTURE IS THE LACK OF PROGRESSION TO PHASE 3 STUDY SO THERE'S MULTIPLE PHASE 1 TRIAL IN FACT HUNDREDS OF THEM, PHASE 2 TRIALS BUT LIMITED PROGRESSION BEYOND PHASE 2 TO PHASE 3. TRUE FOR EVERY TARGET INDICATION. SO RESULTS OF EARLY TRIALS ARE NOT GOOD ENOUGH OR DESIGN GOOD ENOUGH BECAUSE THE PROGRESSION TOPAZ 3 IS LIMITED. SO THERE IS A PIPELINE BUT THAT PRION IS NOT PROGRESSING. I HAD A QUICK LOOK AT THE CURRENT CLINICAL TRIAL REGISTRY IN THE CONTEXT OF MSC TRIALS FOR OSTEOARTHRITIS. ABOUT 120 OR SO TRIALS LISTED LOOKING AT MSC TREATMENT FOR OA. ABOUT 50 ARE PHASE 1, 60 PHASE 2 AND HANDFUL ARE PHASE 3. LOOK AT PHASE 3 TRIAL ON THE REGISTRY, SIX OF THOSE ARE REPORTED BEING COMPLETED THE REST RECRUITING OR AMONG STATUS OR NOT STARTTH STARTED. ONE IS NOT RELEVANT TO MSC, BIGGEST IS THE MILE STUDY, WHICH IS COMPLETE BUT RESULTS NOT POSTED AS I UNDERSTAND IT. THE OTHER PHASE 3 STUDY LISTED ARE RATHER SMALL AND IT IS HARD TO UNDERSTAND IF THEY REALLY ARE JUSTIFIABLY REFERRED TO AS PHASE 3 TRIALS WHEN THEY REPRESENT THE BODY OF EVIDENCE WE NEED TO HAVE TO ANSWER THE QUESTION CONVINCINGLY WHETHER THIS TREATMENT WORKS OR NOT. SO WE HAVE BEEN DOING CLINICAL STUDIES IN EUROPE VERY QUICKLY SUMMARIZE WHERE WE ARE WITH THIS. WE CARRIED OUT PHASE 1 STUDY WHICH COMPLETED HOE WHICH WAS COMPLETED IN 2015 OR 16. LOOKING AT AUTOLOGOUS EXPANDED ADIPOSE DERIVED CELLS FOR TREATMENT OF MODERATE TO SEVERE OSTEOARTHRITIS OF THE KNEE. SO VERY SIMPLE PROTOCOL, PATIENTS INFER STRONG VASCULAR FRACTION IS REPAIRED, CELLS ISOLATED EXPANDED FROM SPF AND AT THE END OF PASSAGE 2 CELLS ARE DELIVERED BACK TO THE KNEE JOINT OF THE PATIENT, IN THIS PHASE 1 STUDY WE TREATED 18 PATIENTS AND THREE COHORT, LOW MEDIUM AND HIGH DOSE AND THEN IN THE NEXT SLIDE, INCLUSION EXCLUSION CRITERIA ARE SUMMARIZED HERE OBVIOUSLY A VERY COMPREHENSIVE LIST OF INCLUSION AN EXCLUSION CRITERIA, I'M SUMMARIZING THE CRITICAL POINTS, THOSE PATIENTS HAD SYMPTOMATIC PRIMARY OSTEOARTHRITIS OF THE KNEE, AT LEAST KL 2 OR 3, 50 TO # 0 YEARS OLD, WITHOUT ANY SECONDARY OSTEOARTHRITIS OR EVIDENCE OF OA OR OTHER CONDITIONS. NEXT SLIDE. THE STUDY WAS SIX PATIENTS PER GROUP NOT STATISTICAL SIGNIFICANCE. THE OTHER SYMPTOM MODIFYING ONLY THERE WAS NO ATTEMPT MADE TO LOOK FOR DISEASE MODIFIED OUTCOME. BASED ON SMALL STUDY THERE WAS INTERESTING OBSERVATION, SIGNIFICANT REDUCTION IN PAIN SCORES IN ALL THE PATIENTS WITHIN 24 HOURS OF RECEIVING THE TREATMENT. THE NEXT SLIDE A SIGNIFICANT INTRODUCTION IN THE WOMAK SCORE IN THE PATIENT THAT RECEIVED THE SUB TREATMENT. THE OTHER INTEREST OBSERVATION THERE WAS IMPROVEMENT IN SYMPTOMS BUT MOSTLY THE LOWEST CELL DOSE WHICH GAVE RISE RISE TO BEST RESPONSE IN THESE PATIENTS. SO BASED ON THESE OBSERVATIONS AND THE STUDY WAS ENTIRELY SAFE WITH NO ADVERSE EVENTS REPORTED, WE WENT TO PHASE 2B STUDY. THIS IS DESIGNED AS MULTI-CENTER PLACEBO CONTROLLED FULLY RANDOMIZED CLINICAL TRIAL TO ASSESS AUTOLOGOUS EXPANDED ARC TREATMENT IN MICE MODERATE TO SEVERE OSTEOARTHRITIS AND THIS STUDY HAS JUST COMPLETED, IT WAS SEVERELY IMPACTED BY COVID AND WAS BADLY DELAYED AS A RESULT OF COVID SO WE DIDN'T REACH THE END POINT OF 153 PATIENTS THAT WE INTENDED TO. NONETHELESS STUDY IS FINISHED AND THE PRIMARY CLINICAL OUTCOME WILL BE AVAILABLE IN A MONTH'S TIME. THE DESIGN OF THE STUDY IS HOPEFULLY SUFFICIENT TO UNDERSTAND WHETHER THERE IS A STRUCTURE OR DISEASE MODIFYING AFFECT ASSOCIATED WITH THE TREATMENT OPPOSED TO MERELY SYMPTOM MODIFYING EFFECT. SO ALL TOGETHER PATIENTS COME FOR NINE VISITS, THE FIRST TWO ARE FOR SCREENING AND ENROLLMENT. AND FOR COLLECTION OF THE ADIPOSE TISSUE. THIRD IS FOR TREATMENT WITH CELLS AND THEN ALL SUBSEQUENT VISITS UP TO 24 MONTHS ARE FOR RADIOLOGY, CLINICAL ASSESSMENT RADIOLOGY AND MRI. HOPEFULLY WHEN THESE DATA ARE COMPLETED WE WILL HAVE A GOOD IDEA WHETHER THERE IS A TISSUE RESPONSE OR REGENERATIVE RESPONSE ASSOCIATED WITH CELL TREATMENT. AND IF THE RESULTS OF THIS, SIGNAL WE SEE MONTHS'S TIME WHEN WE -- WHEN SIX MONTH TIME POINT POST TREATMENT IS REACHED THEN WE WILL START PLANNING FOR A PHASE 3 LARGE STUDY. WE ALSO SWITCH FROM AUTOLOGOUS TO ALLOGENEIC TREATMENT BECAUSE THE LO LISTICS AND PRACTICALITY OF DOING AUTOLOGOUS EXPANDED CELL THERAPY IN LARGE GROUP IS TOO DIFFICULT. THE IDEA WILL BE IF THINGS LOOK GOOD TO MOVE TO PHASE 3 ALLOGENEIC STUDY WITH SOME IMPROVEMENT AND MANUFACTURING PROTOCOL BASED ON LESSONS LEARNED FROM THE -- WHAT WE HAVE DONE PREVIOUSLY. THE TECHNICAL STRATEGY RELATING TO HOW DO YOU PRODUCE THE CELLS IN THE HIGHLY CONSISTENT REPRODUCIBLE AND HIGH QUALITY FASHION TO USE IN STUDY LIKE THIS AND ULTIMATELY TO USE IN THE WIDE IRPATIENT POPULATION. SOMETHING WE HAVE GIVEN GREAT DEAL OF THOUGHT TO AND TO NEXT SLIDE PLEASE THIS SHOW IT IS MANUFACTURING PROTOCOL WE HAVE USED IN PRACTICALLY EVERY GROUP THAT PREPARES MSC FOR ANY PURPOSE USE PROTOCOL BASICALLY. FROM THE TISSUE, WE EXTRACT THE CELLS AND EXPAND THE CELLS OVER SEVERAL PASSAGES USING A MULTI-STEP PROTOCOL SUCH AS WHAT YOU SEE HERE, WE UTILIZE DIFFERENT QUALITY CONTROL TESTS TO ASSURE -- ASSESS THE QUALITY OF THE CELLS AND MAKE SURE THAT THEY ARE FREE OF ANY MICROBIAL CONTAMINATION, SO ON. AT THE END OF THE CELL EXPANSION PROTOCOL WE USE THE ISCT STANDARD TESTING METHODS TO -- BEFORE CELLS ARE RELEASED. NEXT SLIDE PLEASE. THIS IS WHERE THINGS START TO GET COMPLICATED AND WHAT WE ARE TREADING ON THIN ICE BECAUSE MENTIONED BY DR. ROBEY AND ONE OF THE QUESTIONS SHE ADDRESSED EARLIER THERE ARE DIFFERENT DIFFERENCES PHENOTYPIC DIFFERENCES DEPENDING WHERE THE CELLS ARE ISOLATED FROM, DR. GUILAK MENTIONED MSC PRESENCE ARE A COMPLEX MIXTURE OF CELLS TYPES. IT IS BORRIS THAN THAT. BEKNOW NUMBER ONE, THE CULTURE EXPANDED MSC HAS LITTLE RELATIONSHIP TO IN VIVO CELL PHENOTYPE. NUMBER TWO, A MIX IN HETEROGENOUS POPULATION OF CELLS, THE HETEROGENEITY AND BIOLOGICAL PHENOTYPE IS REALLY DEPENDENT ON THE CULTURE -- PHENOTYPE IS DEPENDENT ON THE CULTURE CONDITIONS, WHEN YOU VARY THE CULTURE CONDITIONS YOU VARY THE PHENOTYPE. I'M SHOWING TYPICAL PROCESS VARIABLES THAT PEOPLE USE ISOLATING EXPANDING MSCs FROM DIFFERENT TISSUES, USING DIFFERENT MEDIA, COMPOSITIONS, WHERE CELLS DELIVERED TO THE RECIPIENT USING DIFFERENT DELIVERY VEHICLE, ALL THESE CONDITIONS HAVE POTENTIAL TO IMPACT BIOLOGICAL PHENOTYPE OF CELL AND INDEED THERAPEUTIC ACTIVITY OF THE CELL. NEXT SLIDE PLEASE. THIS IS A SIMPLE EXPERIMENT WHICH ILLUSTRATES THE POUND I'M MAKING WELL MSC FROM FRESH DONOR CELLS HEALTHY DONOR AND EXPAND UNDER DISTINCT MEDIA CONDITIONS SO SERUM FREE, DIFFERENT CONFIGURATIONS, DIFFERENT COMPOSITIONS OF FEASIBLE EVENTS, THEY PROLIFERATE WELL UNDER CONDITIONS BUT LOOK AT SURFACE PHENOTYPE OF THE CELLS EXPANDED FROM THE SAME DONOR, DIFFERENT MEDIA YOU CAN SEE BASED ON THIS HEAT MAP SURFACE PHENOTYPE DIFFERS DRAMATICALLY WHEN THE GROWTH CONDITIONS ARE VARIED. Z DIFFERENTIATION PROPENSITY OF THE CELLS FROM SAME DONOR VARIES WIDELY DEPENDING ON HOW THE CELLS EXPAND AND I DON'T HAVE THE DATA TO SHOW BUT WE KNOW THE IMMUNOMODULATORY TIFTED OF THE CELLS IS DIFFERENT UNDER CONDITIONS THEY ARE EXPANDED. WE ARE TALKING A PROCESS THAT IS VARIABLE AND GIVES RISE TO CELLS WITH VARIABLE PHENOTYPE, WHEN WE COMPARE DIFFERENT STUDIES, THAT BECOMES DIFFERENT BECAUSE WE ARE NOT ASSURED OF THE CONSISTENCY Z, AN STANDARDIZATION OF CELL PRODUCT. THIS IS SOMETHING WE NEED TO ADDRESS AND IT HASN'T BEEN PROPERLY ADDRESSED TO THIS DATE. NEXT SLIDE PLEASE. THIS SHOWS, THIS IS REALLY IMPORTANT PIECE OF INFORMATION DESPITE PIE LOGICAL VARIABILITY WE SEE IN THE CELL EVEN FROM THE SAME DONOR WHEN UNDER DIFFERENT CONDITIONS WHEN WE USE THE ISCT STANDARD MARKERS NONE OF THESE -- THIS BIOLOGICAL VARIABILITY IS EVIDENT BECAUSE YOU SEE CD 73, CD 19 EQUALLY HIGHLY EXPRESS IN CELLS DESPITE BIOLOGICAL DIFFERENCES THAT WE SEE NEGATIVE MARKERS ALL EQUALLY NEGATIVE DESPITE, SO THESE MARKERS DON'T FULFILL THE PURPOSE, DOING/HIDING MULTITUDE OF SINS, WE NEED TO CHANGE THIS. SO WE HAVE TAKEN A STRONG ENGINEERING APPROACH TO TRY TO STANDARDIZE MANUFACTURING PROTOCOLS FOR MSC DEVELOPING A FULLY ROBOTIC FULL HI CLOSED AUTOMATED MANUFACTURING SYSTEM WHERE NO HUMAN HANDS ARE INVOLVED AND ENTIRE PROCESS FROM HARVEST TO TISSUE TO DONOR TO FILLING VILE OF CELLS BEFORE DELIVERY TO PATIENT IS CARRIED BY ROBOTIC ARMS, THE MONITORING OF THE STATUS OF THE CELLS IS DONE REMOTELY. USING SENSORS. THIS IS AN EXAMPLE, I THINK OF WHERE WE NEED TO GO IN TERMS OF STANDARDIZATION OF THE MSC PRODUCTION METHODOLOGY. NEXT SLIDE PLEASE. SO EVERYTHING DEPENDS ON ROBOTIC ARMS. EVERYTHING DONE IN FULLY STANDARDIZED WAY SO THERE IS NO VARIATION IN THE PROCESS. FROM BATCH TO BATCH. MOVE ON FROM THIS. WE HAVE ALSO DEVELOPED WITH ENGINEERING PARTNER A BONE MARROW AUTOMATED BONE MARROW HARVESTING DEVICE WHICH SUCCESSFULLY CARRIES OUT THE BONE MARROW BIOPSY INTO A FULLY CLOSED VESSEL AND CLOSED VESSEL ENTERS THE AUTOMATED PLATFORM WITHOUT EXPOSURE TO THE ENVIRONMENT THE SPIRE PROCESS FROM THE DONOR RIGHT THROUGH TO THE PATIENT FULLY CLOSED AUTOMATED WITH NO OPERATOR INVOLVED. THIS IS AN EXAMPLE WHERE WE NEED TO GO IN TERMS OF STANDARDIZING MANUFACTURING PROTOCOLS. WE NEED TO STANDARDIZE CONDITIONS AS WELL IN TERMS OF MEDIA AND IDEAL LIE USING DEFINED XENOFREE MEDIA RATHER THAN MEDIA CONTAINING BIOLOGICAL SUPPLEMENTS. IN TERMS OF MECHANISM OF ACTION, I RUN THROUGH THIS QUICKLY BECAUSE IN THE INTEREST OF TIME, WE HAVE TAKEN TWO APPROACHES. TO TRY TO UNDERSTAND MECHANISM OF ACTION. THESE ARE BOTH BASED ON THE PREMISE THAT WHAT IS REALLY IMPORTANT IS PHENOTYPE OF THE CELL ONCE EXPOSED TO THE DISEASE ENVIRONMENT. LOOKING AT THE PHENOTYPE OF CELL IN PLASTIC DISH ISN'T GOING TO TELL US HOW THE CELL RESPONDS. ONCE TRANSPLANTED TO THE IN VIVO ENVIRONMENT, WE NEED TO UNDERSTAND THE RESPONSE OF SURGERY IN VIVO ENVIRONMENT. WE CAN DO THAT TWO WAYS BY TRYING TO REPLICATE IN VIVO ENVIRONMENT IN VITRO EXPERIMENTS SO CALLED LICENSING AND THAT IS WHAT I WILL TALK ABOUT HERE IN THE NEXT SLIDE. WE CAN DEVELOP CONDITIONS WHERE WE TRY TO REPLICATE IN VIVO ENVIRONMENT USING INFLAMMATORY SITE CYTOKINES IL 1 BETA, HYPOXIA, THEN LOOK AT THE RESPONSE OF THE CELLS TO THIS TIME OF CONDITIONING THAT THIS IS POTENTIAL TO PREDICT HOW CELLS RESPOND AND DELIVERED TO THE ENVIRONMENT WITH OA JOINTS. WE HAVE DONE THIS WITH BOP MARROW DERIVED CELLS TAKEN FROM THE SAME DONOR TO TRY TO UNDERSTAND IN A WELL DESIGNED EXPERIMENT, THE VARIABLE RESPONSE OF CELLS FROM DIFFERENT SOURCES. WITHOUT GOING THROUGH THE DATA IN TOO MUCH DETAIL, TAKE HOME MESSAGE IS THERE IS A CHANGE IN PHENOTYPE OF CELLS WHEN EXPOSED TO THESE INFLAMMATORY CYTOKINES, IN GENERAL TERMS ADIPOSE DERIVED CELLS PRODUCE MORE ANTI-INFLAMMATORY CYTOKINES, THAN BONE MARROW CELLS SO THINK THERAPEUTIC EWE UNTIL I HAVE THESE CELLS BASED ON THESE EXPERIMENTS THE RUG ROLLS SUGGEST ADIPOSE DERIVED CELLS ARE MORE USEFUL THAN BONE MARROW DERIVED ESPECIALLY IN CONTEXT OF ANTI-INFLAMMATORY CYTOKINES ANGIOGENIC FACTORS AND ALSO NEUROTROPIC FACTORS. IF I CAN MOVE TO THE NEXT SLIDE. THIS SHOWS RELEASE INFLAMMATORY MOLECULE BUSINESS THE CELLS AN EXPOSED TO THESE LICENSING CONDITIONS YOU CAN SEE THE ADIPOSE DERIVED CELLS QUANTITATIVELY HAD PA HIGHER RESPONSE. MOVING ON THE SAME IS CASE WITH CHEMOKINE RELEASE AND NEXT SLIDE, ALSO WITH PRO ANGIOGENIC FACTORS. THE NEXT SLIDE. THE SECOND EXPERIMENTAL STRATEGY IN TERMS OF UNDERSTANDING MECHANISM OF ACTION IS THROUGH THE FOLLOWING. SO WE DELIVER CELLS TO OA JOINT TYPICALLY A MOUSE MODEL OSTEOARTHRITIS FLUORESCENTLY LABELED THEN SUBSEQUENT TIME POINTS WE RETRIEVE CELLS FROM THE JOINT TO UNDERSTAND HAPPEN TYPE OF CELLS ARE MODULATED DURING TIME OF RESIDING WITH OA JOINTS SO TRANSPLANTED STUDIES ARE USEFUL AND WE LEARNED ABOUT THE BEHAVIOR OF THE CELLS SO WE HAVE DONE THIS IN A NUMBER OF DIFFERENT EXPERIMENTAL STRATEGIES, WE ARE JUST PUTTING THE RESULTS TOGETHER NOW. AND SUBMITTING THE WORK. BUT WHAT WE FOUND IS THERE IS A SIGNIFICANT DIFFERENCE IN GENE EXPRESSION PROFILES BETWEEN CELLS THAT ARE RETRIEVED FROM THE CELLS DELIVERED. NEXT SLIDE PLEASE. SO WE WERE ABLE TO EXTRACT CELLS PURIFY THEM FROM THE OA JOINTS BACK INTO CULTURE UNDERSTAND ABOUT THEIR CHRONOGENICITY AND PHENOTYPE AND LOOK AT PROFILES IN THE RETRIEVED CELLS VERSUS CONTROL CELLS. WE CAN LOOK AT THE GENE PATHWAYS THAT ARE ACTIVATED BY CELLS DURING TIME RESIDE WITHIN OA JOINT AND THIS IS A SNAP SHOT WE SEE SIGNIFICANT CHANGES IN BIOLOGICAL PROFILE OR PHENOTYPE OF THE CELLS, THAT WE RETRIEVE FROM THE JOINTS, SEEMS THOSE CELLS WHICH PERSIST WE CAN RETRIEVE FROM THE OA JOINT HAVE MUCH MORE PROGENITOR PHENOTYPE THAN STARTING POPULATION AS IF THE EXPOSURE TO OA ENVIRONMENT SELECTS FOR THIS PHENOTYPE SO THAT IS REFLECTED IN THE GENE PATHWAY THAT WE ARE SEEING HERE LOOKING AT EXTRA CELLULAR MATRIX ORGANIZATION, POST TRANSLATION HAL MODIFICATION AND SO ON. SO THESE ARE INTERESTING, THEY ARE NOT DONE YET BUT THEY WILL HELP US TO SHED LIGHT ON THE MECHANISM OF ACTION. SO ON THE BASIS OF WHAT I TALKED ABOUT CLINICAL TRIALS MANUFACTURING TECHNOLOGY AND MECHANISM OF ACTION HAVE COME UP WITH RECOMMENDATIONS WHICH REPRESENT -- (OVERLAPPING SPEAKERS) SHARE THEM. IN THE FIRST INSTANCE FOCUS ON STANDARD MANUFACTURING AND THERE'S BEEN NO ATTEMPT AT ALL TO STANDARDIZE MANUFACTURING OF CELLS WE DO NEED TO DEVELOP -- (OVERLAPPING SPEAKERS) >>THAT IS ONE THING -- >>SOMEBODY'S VOICE IS COMING THROUGH HERE. BUT I'M ALMOST DONE. CONSISTENT MANUFACTURING MODELS WITH DEFINED MEDIA ARE CRITICAL THINGS TO PAY ATTENTIATTENTION. THESE SAME STS FORWARD PRETTY EVERY DAY QUESTIONS, BUT THEY HAVE NOT BEEN PROPERLY ADDRESSED. WE NEED AN INTERNATIONAL STANDARD TO DEFINE MSC FOR THERAPEUTIC USE THOUGH ATTEMPTS MADE IN THE PAST TO ACHIEVE IT, IT'S NOTE BEEN SUCCESSFUL SO IT MIGHT BE POSSIBLE FOR THE ORGANIZATIONS LISTED HERE FDA TO SOMEHOW GET TOGETHER TO DRIVE QUESTION FORWARD, IT IS YOU ARE GENERALLY NEEDED BECAUSE WE ARE NOT ABLE TO INTERPRET THE CLINICAL TRIAL DATA PROPERLY UNTIL WE HAVE CONFIDENCE IN THE CONSISTENCY OF MANUFACTURING OF CELL. WE NEED TO ESTABLISH NEW SET OF CRITICAL QUALITY ATTRIBUTES FOR RELEASE, BIOLOGICALLY MEANINGFUL AND DO TELL SOMETHING REALISTIC ABOUT THE CELL SO KNEW DISEASE SPECIFIC POTENCY TESTS ARE CLEAR PREDICTIVE VALUE WE DON'T HAVE CURRENTLY. MY OPINION WE NEED TO RESCIND ISCT RECOMMENDATIONS BECAUSE THEY ARE NOT INFORMATIVE BUT ALSO HIDING PROBLEMS. THIRD QUARTER THEN THINK ABOUT PRODUCING LARGE SCALE ALLOGENEIC USE IT IS POSSIBLE TO THINK ABOUT ELABORATE BIOLOGICAL SO YOU CAN AFFORD TO INVEST LARGE ARRAY OF TESTS TO GET MAXIMUM AMOUNT OF BIOLOGICAL INFORMATION. GENOMIC SEQUENCING SINGLE CELL SEQUENCING MENTIONED ALREADY, IMMUNE ET CETERA. WE CAN AFFORD TO DO THESE TESTS, THIS IS WHAT WE NEED IN TERMS OF PROPER CRITERIA. IN TERMS OF MECHANISM OF ACTION WE NEED MORE INSIGHT INTO WHAT THE CELLS ARE ACTUALLY DOING WHEN DELIVERD TO THE HOST AND WE NEED TO BE CAREFUL TO DISTINGUISH BETWEEN LOCAL DELIVERY AND SYSTEMIC DELIVERY BECAUSE LOCAL DELIVERY AND -- GIVES RISE TO DIFFERENT SET OF RESPONSES COMPARED TO SYSTEMIC DELIVERY. SO LET ME FINISH THERE. THANK YOU ALL VERY MUCH FOR YOUR ATTENTION. >>BEAUTIFUL TALK RIGHT BACK TO CONNIE CHU'S TALK AT THE BEGINNING THE TREMENDOUS HETEROGENEITY ALL THESE FORMULATIONS MAKES IT SO CHALLENGING TO STUDY THEM AND THE NEED TO CHARACTERIZE IDENTIFY SENTINEL MARKERS OF POTENCY PURE REACTIVITY. YOU MAKE IMPORTANT POINT ABOUT ALLOGENEIC PREPARATIONS ALLOW US TO DO THAT, NOT PRACTICAL TO DON AUTOLOGOUS TISSUE. HOW MANY DAYS IS CULTURE EXPANSION YOU USE? >>FOR AUTOLOGOUS STUDY 14 DAYS FROM HARVESTING THE MATERIAL TO DELIVERING THE CELL BACK TO THE PATIENT. IT WAS A MAXIMUM OF 14 DAYS. >>PAM HAS HER HAND UP. >>THANK YOU, COMPREHENSIVE OVERVIEW OF THE CHALLENGES. ONE QUESTION IN TERMS OF EXPERIMENTS WITH LICENSING CELLS, VERSUS THOSE YOU RETRIEVE FROM IN VIVO EXPERIENCE, HAVE YOU HAD COMPARISON BETWEEN THE TWO IN TERMS OF GENE EXPRESSION ANALYSIS WHAT IS UP AND DOWN IN THOSE TWO DIFFERENT TYPES OF POPULATIONS? >>BROADLY SPEAKING THERE IS TWO SETS OF GENES UPREGULATED IN BOTH SETS OF EXPERIMENTS. GENES CALLING FOR ANTI-INFLAMMATORY PROTEINS AND GENES CALLING FOR SECRETED PROTEINS ARE DOMINANTLY UPREGULATED SO PARACRINE RESPONSE OF THE CELLS IS HIGHLY MODULATED BY BOTH IN VITRO LICENSING ENVIRONMENT AND IN VIVO OA ENVIRONMENT. I WOULD SAY WE ARE NOT DONE WITH THIS ANALYSIS YET. SO WE DON'T HAVE THE FINAL STORY YET. >>SECOND QUESTION ABOUT TWO PREVIOUS TRIALS, THERE'S RESPONDER PATIENT AND NON-RESPONDER PATIENTS, COULD BE BECAUSE OF THE PATIENT CONDITION BUT IT ALSO COULD BE BECAUSE OF THE CELL PRODUCT. ARE YOU ABLE TO LOOK AT PRODUCT GIVEN TO RESPONDERS TO SEE IF THERE WAS A PATTERN IN THAT, THAT WAS LIKE A COMMON THEME? >>THAT IS PART OF THE STUDY, TRYING TO COMPARE THE SUB PREPARATION CLINICAL OUTCOME, BECAUSE THE STUDY IS BLINDED WE DON'T KNOW WHERE IT WILL GO BUT IT IS DONE FOR SURE. >>FOR THE FIRST TRIAL, IS THAT AVAILABLE? >>AVAILABLE IN LIMITED WAY FOR THE FIRST TRIAL BUT I THINK THERE WASN'T ENOUGH PATIENTS TO BE CONCLUSIVE ABOUT THAT. IN FACT, IN THE GROUP I HAD 506 WAS POSITIVE AND ONE WAS NEGATIVE SO SNEAD MORE PATIENT DATA TO DO THAT PROPERLY. FORGIVE ME IF I MISINTERPRETED THE DRUG DEVELOPMENT PATHWAYS THAT YOU ARE PURSUING. I KNOW THE TRIALS ARE NOT BEING PERFORMED IN THE STATES BUT YOU MENTIONED GOING FROM AUTOLOGOUS CELLS PHASE 2 TO POSSIBLY SWITCHING OVER TO ALLO IN PHASE 3, WHAT IS THE REGULATORY PLAN FOR THAT APPROACH GIVEN IT WILL LIKELY BE CLASSIFIED A DIFFERENT BIOLOGICS ONCE YOU KNOW FROM ALLO SORRY FROM AUTO TO ALLO? >>I HAVE TO BE HONEST, WE DON'T YET KNOW WHAT THE REGULATORY RESPONSE TO THIS REQUEST IS GOING TO BE. IT IS BASED ON THE FACT WE KNOW LARGE SCALE USE OF AUTOLOGOUS EXPANDED CELLS IS IMPRACTICAL AND NEXT TO IMPOSSIBLE TO ACHIEVE. IT IS TOO COSTLY AND LOGISTICS ARE TOO COMPLICATED SO IF WE PROCEED WITH THIS, WE HAVE TO MAKE THAT SWITCH FROM AUTOLOGOUS TO ALLOGENEIC. ARE NOT ALLOWED TO SAY WHAT THE REGULATOR WOULD REQUIRE EXCEPT WIDE USE OF AL ALLOGENEIC CELL THERAPY APPROVED IN EUROPE AND AT LEAST ONE OTHER INDICATION SO WE MAY HOPEFULLY RELY ON THAT EXPERIENCE. WE MAY HAVE TO GO BACK AND DO COMPARISON STUDIES BUT WE ARE NOT CERTAIN YET ABOUT HOW IT WILL GO. >>MARVELOUS TALK, LOVE THE TALK MORE ABOUT AUTOMATION. MY QUESTION I WILL ASK HERE IS ONE, YOU MENTIONED THAT GENERAL DISFASHION WITH THE ISCT GUIDELINES WHICH ARE WELL INTENTIONED BUT PRIMARILY FOCUSED ON TECHNOLOGY AT THE TIME, FLOW CYTOMETRY. WE NOW AS YOU POINT OUT HAVE NOT INEXPENSIVE BUT SINGLE CELL RNA SEQ AND SINGLE CELL ANALYSIS ARE DONE LARGER SCALE. ARE YOU READY TO GIVE UP ON FLOW CYTOMETRY OR -- AND JUST FOCUS ON THE OTHER TWO OMIC STRATEGIE STRATEGIES? E QUESTION. SECOND, THIS VARIATION YOU HAVE DEMONSTRATED, BETWEEN MSC BATCHES AND CULTURE CONDITIONS, HOW MUCH OF THAT IS CLONAL SELECTION AMONG POLYCLONAL MSC POPULATION AND HAVE YOU BEEN ABLE TO LOOK AT THAT? >>IN RELATION TO THE FIRST POINT I AGREE THE ISCT STANDARDS WHEN PUBLISHED THE INTENTION WAS VERY CLEAR. I THINK THE ISCT HAS MADE SOME NEW RECOMMENDATIONS IN RELATION TO THIS BUT THE FIRST SET OF MARKERS STILL STICK AND EVERY SINGLE PIECE OF INFORMATION YOU SEE ABOUT MSC INVOLVE IT IS SAME MARKERS, BECAUSE THEY ARE EASY TO DO, ALWAYS POSITIVE SO THEY GIVE THIS SENSE OF SORT OF SENSE OF CONFIDENCE WHICH IS NOT MISPLACED. I THINK WE CAN'T AFFORD TO GIVE UP FLOW CYTOMETRY, IF IT IS LARGE SCALE ALLOGENEIC, WE CAN AFFORD TO INVEST HEAVILY IN ELABORATE MATRIX OF TESTS. JUST NEED TO EXPAND CHARACTERIZATION OF SURFACE PHENOTYPE MORE THAN MARKERS WE ARE TALKING ABOUT. PROBABLY SINGLE CELL SEQUENCING OF THE PREPARATIONS TO SOMEHOW DEVELOP STANDARD AROUND THAT. BENEED TO DO THE BIOLOGICAL ASSAYS THAT RELATED TO POTENCY, WHICH WE HAVEN'T BEEN DOING BECAUSE THERE ARE POTENT AND SUB POTENT BATCHES, RIGHT NOW WE ARE NOT ABLE TO TELL WHICH IS WHICH. SO WE DON'T KNOW ENOUGH ABOUT THE CELLS, WE ARE DELIVERING TO THE PATIENTS IN THESE STUDIES. THAT IS LARGE EXTENT OF VARIABLE OUTCOMES BECAUSE THE PRODUCT IS VARIABLE. LARISSA. >>THANK YOU. SO I NOT GOING TO COMMENT ON REGULATORY PATHWAY BECAUSE I HAVE AN ENTIRE PRESENTATION TO TALK ABOUT IT BUT I WOULD LIKE TO ASK A QUESTION, DR. BARRY. I DO NOT WANT TO PUT YOU ON THE SPOT OR ANYTHING BUT JUST TO INVITE YOU TO DISCUSS THIS WITH ME. SO YOU HAVE SHOWN ONE OF YOUR SLIDES THAT PATIENTS WHO RESPOND SHOW IMPROVEMENTS WITHIN THE FIRST 24 HOURS. THEN YOU TALK ABOUT REGENERATIVE EFFECTS AND REPAIRTIVE EFFECTS. SO TELL ME ABOUT THE MECHANISTIC POSSIBILITY OF A CELL THAT GETS INTO INTERARTICULAR JOINT TO DIFFERENTIATE OR BECOME A CELL LOOKS LIKE CELLS IN THAT INTERARTERIAL SPACE CONSIDERING FOR EXAMPLE A LIFETIME OF CHONDROCYTE OR SYNOVIALCYTE INJECTING THE CELLS INTO THE JOINT, HOW DO YOU EXPLAIN THE PEOPLE IMPROVE WITHIN 24 HOURS? I WILL GIVE YOU CONTEXT. YOU ARE NOT PROBABLY THE FIRST TALKING ABOUT IMPROVEMENTS AND I HAVE SEEN DIFFERENT OPINIONS ONE POSSIBILITY IS THESE CELLS ARE JUST GOLD, THEY DO MAGIC THERE. SOME ARE SAYING YOU HAVE AN OSTEO ARTHRITIC JOINT. WHATEVER YOU INJECT THERE, THE JOINT IS THE SIZE OF THE DEGENERATIVE ALSO MAL ALIGNED SOD YOU GET VOLUME, YOU CHANGE THE THE MAL ALIGNMENT A LITTLE BIT, YOU REBALANCE IT SO PEOPLE MAY FEEL BETTER. THEN THERE IS ALWAYS PLACEBO EFFECT IN OSTEOARTHRITIS. WHEN TALKING ABOUT UNCONTROLLED SITUATIONS. SO MAYBE JUST DISCUSS THIS IF YOU COULD THE OBSERVATION OF THE EARLY RAPID RESPONSE >>I THINK IT IS VERY IMPORTANT TO CULTURE WHEN WE REPORT RESULTS VARIOUS STAGES OF TRIAL, THEY MEAN A LOT. RAPID RESPONSE OR IMPROVED RESPONSE IN PATIENTS MAYBE A PLACEBO EFFECT BECAUSE THESE ARE OPEN LABEL STUD STUDYU CAN KNOW WHAT IT IS LIKE IF PATIENT RECEIVES A STEM CELL TREATMENT AND KNOW THEY HAVE RECEIVED A TREATMENT, THERE IS A REASONABLE PROBABILITY THERE IS A STRONG PLACEBO AFFECT. IF THERE IS A PAIN RESPONSE, FUNCTIONAL RESPONSE EARLY AND BIOLOGICAL RATIONALE IT IS TO DO PROBABLY WITH THE UPREGULATION OF ANTI-INFLAMMATORY CYTOKINES BY THE CELLS ONCE DELIVERED TO THE JOINT, WE HAVE SEEN THAT IN THE DIFFERENT STUDIES WE HAVE DONE. SO COULD BE CELLS ARE HAVING SHORT TERM ANTI-INFLAMMATORY EFFECT ON OA ENVIRONMENT THAT MAY LEADS TO POSITIVE PAIN RESPONSE. IN TERMS OF LONGER TERM OUTCOME, CONNECTIVE TISSUE PHENOTYPE OR CARTILAGE CONTRACYTE. IT IS MORE -- CHONDROCYTE, THIS IS INFLAMMATORY OR IMMUNE MEDIATED EFFECTS BY POLARIZING MACROPHAGES TO ANTI-INFLAMMATORY STATE OR BY REDUCING THE ACTIVATION OF T-CELLS. IT IS LIKELY INTERACTION BETWEEN DELIVERED CELLS AND HOST IMMUNE CELLS, THAN IT IS DIFFERENTIATION OF CELLS TO MAKE TISSUE, I DON'T ANY WE KNOW ENOUGH TO BE CERTAIN BECAUSE THESE ARE HARD ENOUGH TO DO THAT IS WHAT I WOULD GUESS AGREE WITH YOU, IT IS A CHALLENGE OF DEVELOPMENT OF THESE TYPES OF PRODUCTS THAT WE DON'T KNOW ENOUGH ABOUT WHAT THEY ARE DOING IN VIVO AND THERE ARE MANY CHALLENGES AND DIFFICULTIES STUDIES THESE. THAT IS ONE OF THE GAPS IN T FELTED TO TRY TO BETTER UNDERSTAND WHAT THEY DO. REGENERATIVE ANTI-INFLAMMATORY EFFECTS ARE GOING TO BE THERE. >>THESE QUESTIONS ARE CRITICAL TO ANSWER OTHERWISE WE WON'T MAKE THE PROGRESS NEEDED. ALL THE TECHNICAL WILL GISTICAL BIOLOGICAL HURDLES THAT YET NEED TO BE OVERCOME BEFORE WE CAN MOVE FORWARD. WE HAVEN'T DONE A GOOD JOB TO DATE. WE NEED TO IMPROVE THIS IS ISSUES. -- THESE ISSUES. >>THANK YOU SO MUCH. TED, WE ARE KIND OF THROUGH THE BREAK TIME, ALMOST ON TIME. SHALL WE MOVE TO LARISSA'S TALK? >>I VOTE TO DO SO. >>DR. LARISSA LAPTEVA IS ASSOCIATE DIRECTOR DIVISION OF CLINICAL EVALUATION PHARMACOLOGY AND TOXICOLOGY. FOR CBER. AS U YOU HEARD HER LINE OF QUESTIONING AND INTRODUCTION SHE IS CLINICIAN SCIENTIST. SHE CONTINUES TO PRACTICE RHEUMATOLOGY AS AN ATTENDING PHYSICIAN IN OUTPATIENT RHEUMATOLOGY CLINIC NATIONAL INSTITUTES OF HEALTH. SHE IS CONTRIBUTING HER TIME AND EXPERTISE TO TALK TO US AN REGULATORY CONSIDERATIONS FOR DEVELOPMENT OF BIOLOGICAL PRODUCTS TO TREAT OSTEOARTHRITIS. >>THANK YOU FOR THE NICE INTRODUCTION. GOOD AFTERNOON, A PLEASURE TO BE PART OF THIS ROUND TABLE DISCUSSION AND PERSONALLY FOR ME IT IS NICE TO COME BACK THE ALMA MATER AND SEE FAMILIAR FACES AND ENGAGE IN INTERESTING THOUGHT PROVOKING CONVERSATIONS. SO I ASKED LAST MONDAY TO GIVE ADDITIONAL TIME BECAUSE I REALIZE THAT ONE OF THE GAPS, THAT'S WHAT I THOUGHT AFTER READING BACKGROUND MATERIALS THAT MAYBE PRESENT IN THE FIELD SCIENTIFIC AUDIENCE AND INVESTIGATORS PARTICULARLY IN MANY CLINICIANS I THOUGHT I WOULD MAYBE EXPLAIN THIS A LITTLE AND DO MULTI-TASKING, GET THE PRESENTATION IN THE I WILL HIGHLIGHT REGULATORY ASPECTS PERTINENT TO DEVELOPMENT OF DRUG AND BIOLOGICAL PRODUCTS FOR OSTEOARTHRITIS AND FDA PERSPECTIVE ON THIS TOPIC. AS YOU CAN SEE FDA REVIEWING REGULAR RATORY WORK ACCOMPLISHED THROUGH FUNCTIONING OF DIFFERENT CENTERS, I COME FROM CENTER FOR BIOLOGIC AND OFFICE OF TISSUE AND ADVANCE THERAPY MY PRESENTATION WILL BE WILL BE FOCUSING ON A NUMBER OF BIOLOGICAL PRODUCTS THAT THE OFFICE REGULATES WHICH YOU CAN SEE HERE. XENOTRANSPLANTATION, THERAPEUTIC VACCINES TISSUE ENGINEER PRODUCTS, THE NUMBER OF OTHERS. BECAUSE WE ARE TALKING REGENERATIVE MEDICINE AND THERAPIES, I WOULD LIKE TO MENTION DEFINITION OF REGENERATIVE MEDICINE THERAPIES THE WAY IT WAS WRITTEN IN 21ST SENTRY CURES ACT, THAT IS WHAT FDA CONSIDERS REGENERATIVE THERAPY. LIB FOR A MINUTE AS I EXPLAIN. FDA IS A REGULATORY AGENCY, EVERYBODY KNOWS, QUITE WELL, AND REGULATION AND RULES ARE EXTENSIONS OF LAWS. THE TWO MAIN LAWS PUBLIC SERVICE ACT BIOLOGICS DRUG DEVELOPMENT IS A BUSINESS, IS HIGHLY DEPENDENT ON INNOVATION AND IT HAS TO GO IN PARALLEL WITH ADVANCEMENT IN SCIENCE AND TECHNOLO TECHNOLOGYS MEDICAL PRODUCT DEVELOPMENT REFLECTIVE AND CONDUCIVE OF THESE ADVANCEMENTS. SO TWO MAIN ONES I NAMED GET UPDATED EVERY FIVE YEARS THROUGH RE-AUTHORIZATION OF THE LAW CALLED PRESCRIPTION DRUG USER FEE ACT TO REFLECT FIELD ADVANCEMENTS AND MEET THE NEEDS OF DAY AND SOMETIMES NEW LAWS ARE WRITTEN AND PASSED SEPARATELY AS WAS THE CASE WITH 21ST CENTURY CURES ACT, WHICH WAS PASSED END OF 2017 AND STUM LATE REGENERAL RATIVE THERAPIES. THAT LAW DEFINED AS CELLULAR THERAPIES, THERAPEUTIC TISSUE ENGINEERING PRODUCTS HUMAN CELL TISSUE PRODUCTS AND COMBINATION OF THE ABOVE, IN P ESSENCE ALL PRODUCTS THAT SUSTAIN EFFECT HUMAN CELLS AND TISSUE. LAWS ANDRAL RATIONS ARE BRING BY LAWYERS AND POLICY MAKERS DRUG DEVELOPMENT DONE BY SCIENTISTS SO FDA FINDS ITSELF IN A POSITION TO EXPLAIN TECHNICAL EXPERTS HOW TO APPLY DIFFERENT REGULATIONS. WE DO IT BY PUBLISHING GUIDANCE, IT IS A PUBLIC PROCESS. THAT IS HOW WE INTERPRET WHICH PRODUCTSES TO CALL AND WHICH NOT TO CALL. REGENERATIVE MEDICINE. I WILL SHOW YOU GUIDANCE ON LAST SLIDE ALTHOUGH WE SEE DIFFERENT PRODUCT PROGRAMS, THE LARGEST BULK OFVATIONAL NEW DRUG APPLICATIONS EACH IND APPLICATION IS A SEPARATE PRODUCT PROGRAM. SO THE LARGEST WE SEE COMES FOR CELLULAR AN GENE THERAPIES. WE USED TO SEE MORE CELL THERAPIES COMPARED TO GENE THERAPY BUT THE TRENDS REVERSED IN 2016 ON THE SLIDE, AND THE PEAK APPLICATION FOR CELLULAR THERAPIES OBSERVED IN YEAR 2020. WAS RELATED TO COVID-19 PANDEMIC. HERE YOU SEE IMPORTANT CONSIDERATIONS FOR DEVELOPMENT OF CELLULAR THERAPIES AND GENE THERAPIES APPLY REGENERATIVE MEDICINES AND THEY OBVIOUSLY APPLY TO PRODUCTS DEVELOPED FOR OSTEOARTHRITIS. ADVANCE THERAPY PRODUCTS ARE EXPECTED TO HAVE PROLONGED THERAPEUTIC EFFECTS WHICH FROM PRODUCT DEVELOPMENT RESULTS IN NEED FOR LONG TERM FOLLOW-UP FOR BOTH EFFICACY AND SAFETY. AS ALLUDED AND DISCUSSED MENTIONED BY MANY PRESENTERS TODAY, THERE ARE CHALLENGE WITH ASSESSING PRECISE MECHANISM OF ACTION. FOR THESE PRODUCTS. YOU SEE OUTGAS THERAPIES. NOT ALLOGENEIC BUT AUTOLOGOUS. EVALUATING BECAUSE IT IS IMPORTANT TO SET UP ESTABLISH APPROPRIATE DOSE OF PRODUCT WHEN GIVEN TO PEOPLE SO EVALUATING POTENCY IN THOSE MAYBE DIFFICULT. WITH CELL THERAPIES AS WELL AS GENE THERAPIES, WITH CELL THERAPIES, IT IS CHALLENGING TO PREDICT HOW CELL POPULATION MAY HAVES IN VIVO WHETHER -- BEHAVIOR IN VIVO WHETHER IT EXPANDS CELLULAR VIABILITY AND THAT BECOMES IMPORTANT HERE. MANY CHALLENGES AS WAS DISCUSSED BEFORE BUT THE PRESENCE OF CHALLENGES DOES NOT REALLY REASON -- IS NOT A REASON NOT TO DO ADEQUATE INVESTIGATION TO BETTER UNDERSTAND WHAT THE PRODUCT DOES, WHERE IT GOES, HOW GENE THERAPIES ARE DISTRIBUTED. WE ASK WHEN PEOPLE COULD SHOW DIFFERENT MECHANISMS OF ACTIONS THAT HAVE BEEN SEEN IN SIMILAR PRODUCTS IN BODY OF LITERATURE, SOME REMOTELY, WE TRIED TO EXPLAIN VERY IMPORTANT. TO IN FACT DEMONSTRATE WHAT IS THE PRODUCT DOES IN PATIENT POPULATION, WHAT IS MECHANISM OF ACTION AND IF THIS IS A PRODUCT THAT CONTAINS CELLS THAT IS THERE TO PROVIDE ANTI-INFLAMMATORY RESPONSES FOR CHONDROCYTES THAT MECHANISM OF ACTION NEEDS TO BE DEMONSTRATED. SO INVESTIGATORS NEED TO HAVE A PLAN IN PLACE STARTING THOSE HOW SPECIFIC PRODUCT ADMINISTRATION MAYBE SUPPORTED BY A PRE-CLINICAL PROGRAM. CELLULAR -- BY DISTRIBUTION DEPEND ON MANY FACTORS INCLUDING IN SITU MICROENVIRONMENT AN DISEASE STATE, COMMUNICATION AND NUMBER OF OTHER FACTORS AND WE EXPECT STUDIES TO BE DONE TO UNDERSTAND WHERE THE PRODUCT GOES. I DID PUT A LINK TO THE RECOMMENDATIONS AND BIODISTRIBUTION STUDIES HERE FROM THE INTERNATIONAL PHARMACEUTICAL REGULATORS PROGRAM. YOU SEE AT THE BOTTOM OF THE SLIDE. FOR PART OF THE WORKING GROUP WRITING THIS PAPER SO WE CONFORM TO THE RECOMMENDATIONS PRESENTED THERE IMMUNOGENICITY IS AN ISSUE WITH BIOLOGICAL PRODUCT IN GENERAL AND CELL AND GENE THERAPIES IN PARTICULAR. TYPICALLY IMMUNOGENICITY IS SOMETHING WE ASK PRODUCT DEVELOPERS TO ADDRESS. IN BASIC PROCEDURES FOR PRODUCT DELIVERY IS ANOTHER IMPORTANT ASPECT OF DEVELOPMENT, BESIDES SAFE ADMINISTRATION OF PRODUCT TO TENDED ANATOMICAL SITE IT IS IMPORTANT TO ENSURE THE PRODUCT IS IN FACT COMPATIBLE WITH THE DEVICE USED FOR ADMINISTRATION. WHATEVER PRODUCT MATERIAL IS DELIVERED WHEN IT FLOWS THROUGH THE DEVICE SHOULD REMAIN VIABLE WHEN IT GETS TO THE TARGET TISSUE. SO FOR MANY DISEASE POPULATIONS IN OSTEOARTHRITIS IS NO EXCEPTION, WHEN A CELL OR GENE THERAPY PRODUCT IS BEING DEVELOPED, DOSE LIMITING TOXICITY ARE NOT READILY OBSERVABLE EARLY IN DEVELOPMENT SO THE DURATION OF FOLLOW-UP FOR THE PRODUCTS THAT WE ARE DEALING WITH MAY TAKE LONGER COMPARED FOR EXAMPLE THAN WITH DRUGS, MAY TAKE LONGER EVEN INITIAL FIRST IN HUMAN STUDIES BUT THIS SHOULD BE TAILORED TO INDIVIDUAL PRODUCTS. WE REQUEST CAREFUL PRODUCT ADMINISTRATION AND INVESTIGATORS SHOULD REMEMBER TO MONITOR WHAT IMMEDIATE REACTIONS AND TO HAVE STAGGERED ADMINISTRATION AND STOPPING CRITERIA IN THE PROTOCOL FOR BOTH INDIVIDUAL SUBJECTS IN THE ENTIRE STUDY, AND I KNOW NUMBER OF FOLKS FROM THE EXTRAMURAL PROGRAM IS PARTICIPATING IN THIS ROUND TABLE, I KNOW YOU GUYS HELP FACILITATE PROTOCOL DEVELOPMENT, YOU SEE PROTOCOLS SO IF YOU SEE PROTOCOL THAT LACKS STOPPING CRITERIA FOR THE TOXICITY PARTICULARLY WHEN IT IS FIRST IN HUMAN STUDY, AND THE CRITERIA SHOULD BE BOTH INDIVIDUAL SUBJECTS AND THE ENTIRE STUDY, IT MAY BE GOOD AND YOU PROBABLY SERVE TO PATIENT SAFETY, GO BACK TO THE INVESTIGATOR AND ASK THEM TO REVISE PROTOCOL, IF YOU DON'T DO THAT WE HAVE TO DO IT WHEN IT COMES -- WHEN THE PROTOCOL COMES TO US. WE HAVE SEEN NEW OSTEOARTHRITIS PROGRAMS WITH CELLULAR PRODUCTS PAIN AND SWELLING AND REACTIVE SINUVITIS WAS OBSERVED IN MAJORITY OF PATIENTS WITH THE INVESTIGATIONAL PRODUCT SO THESE OCCURRENCES ARE NOT THEORETICAL, WE HAVE SEEN BAD THINGS AND THEREFORE IT IS IMPORTANT TO PROCEED CAUTIOUSLY AND CAREFULLY PARTICULARLY WHEN DEALING WITH NOVEL PRODUCT. DURATION OF MONITORING OFTEN DEPENDS ON ANTICIPATED PRODUCT EFFECT AND PRODUCTS WHERE REGENERATIVE EFFECT OR IN VIVO CELLULAR DIFFERENTIATION OR ENGRAFTMENT. WE HAVE SEEN PRODUCTS WHERE ENGRAFTMENT IS EXPECTED. WE SEE MONITORING AND WE RECOMMEND MONITOR FOR AT LEAST ONE YEAR OR LONGER BECAUSE IF WE ARE TALKING ABOUT REGENERATIVE THERAPY YOU SEE DURABILITY OF THE EFFECT AND CONSIDERATION SIS OF THE EFFECT OVER TIME. IN TERMS OF SAFETY LONG TERM WE WORRY ABOUT THINGS LIKE ECTOPIC TISSUE FORMATION. IF CELLULAR DIFFERENTIATION DOES NOT GO IN THE INTENDED DIRECTION AND FOLKS WHO WORK WITH CELL CULTURE KNOW IF YOU INCREASE NUMBER OF PASSAGES IN CULTURE THAT INTRODUCES GENETIC INSTABILITY SO PRODUCT CHARACTERIZATION AGAIN WAS DISCUSSED BEFORE TODAY. AND DURING THE ROUND TABLE, PRODUCT CHARACTERIZATION AND APPROPRIATE PROTOCOL ARE EXTREMELY IMPORTANT IN UNDERSTANDING WHAT THE PRODUCT WILL EVENTUALLY DO IN -- WHEN INTRODUCED TO PATIENTS. A POSSIBILITY OF ACCELERATION OF CARTILAGE DEGRADATION. WHICH IS AN EFFECT THAT IS COMPLETELY OPPOSITE WHAT WE ARE TRYING TO DO BUT THIS IS AGAIN NOT AN UNHEARD OF SITUATION AND THIS SOMETHING TO KEEP IN THE BACK OF OUR MINDS. TUMORIGENITICITY IS ALSO AN ISSUE WITH CELL PRODUCTS INSERTIONAL MUTAGENESIS WOULD BE SOMETHING THAT WE ARE LOOKING NOT TO HAVE IN GENE THERAPY PRODUCTS. SPECIFICALLY FOR GENE THERAPIES FDA RECOMMENDATIONS FOR LONG TERM FOLLOW-UP AFTER TREATMENT WITH GENE THERAPIES AND THE DURATION OF FOLLOW-UP DEPENDS ON THE VIRAL VECTOR CONSTRUCT IN ANY ANTICIPATED POTENTIAL FOR INSERTIONAL MUTAGENESIS. HERE ARE SOME EXAMPLES OF PRODUCT PROGRAMS AND TYPES OF PRODUCTS WE SEE FOR OA DEVELOPMENT, BOTH CELLULAR AND GENE THERAPIES FOR OSTEOARTHRITIS AS WAS DISCUSSED BEFORE, THEY ARE ALSO NUMBER OF AUTOLOGOUS CARTILAGE IMPLANTATION PRODUCTS THAT ARE EITHER APPROVED BEING DEVELOPED IN THE PIPELINE BUT THOSE ARE DEVELOPED NOT NECESSARILY PER SE DEVELOPED WITH DISTINCT CARTILAGE DEFECT, OSTEOARTHRITIS CAN BE PRESENT IN THE JOINT AS CO-MORBIDITY SO TO SPEAK BUT ESSENTIALLY THESE PRODUCTS ARE STILL DEVELOPED FOR DISTINCT CARTILAGE DETECTS. WE ALSO SEE A NUMBER OF INVESTIGATIONAL DEVICE APPLICATIONS. WITH PRODUCTS THAT PRODUCE BIOLOGICAL OUTPUT PURPORTED TO HAVE AFFECT IN OSTEOARTHRITIS. I'M SURE YOU ARE FAMILIAR WITH STANDARDS FOR DEFINING EVIDENCE NEEDED FOR PRODUCT APPROVAL FOR DRUGS AND BIOLOGICS, APPROVAL USUALLY IS BASED ON SUBSTANTIAL EVIDENCE OF EFFECTIVENESS AND EVIDENCE OF SAFETY. AND THAT EVIDENCE SHOULD BE OBTAINED FROM ADEQUATE WELL CONTROLLED STUDIES. AND FOR DEVICES VALID SCIENTIFIC EVIDENCE HAS TO BE THERE TO DETERMINE WHETHER THERE IS A REASONABLE ASSURANCE THE DEVICE IS SAFE AND EFFECTIVE. THESE ARE REGULATORY CONSIDERATIONS AND LYNN GO SO TRANSLATING INTO PLAIN LANGUAGE PREVALENT CONDITIONS LIKE OSTEOARTHRITIS A PRODUCT DEVELOPMENT PROGRAM SHOULD CONSIST OF TWO ADEQUATE WELL CONTROLLED STUDIES, SHOULD BE RANDOMIZED BLINDED AND I HAVE A CLINICAL CONTROL GROUP. FOR THOSE WHO CONDUCTED TRIALS IN OSTEOARTHRITIS POPULATIONS, OR FOR FOLKS IN THE FIELD FOR A WHILE DR. HOCHBERG AND OTHER PARTICIPANTS HAVE DONE TRIALS IN OSTEOARTHRITIS, NOT NECESSARILY WITH BIOLOGICS BUT OTHER COMPOUNDS, YOU PROBABLY KNOW THAT ONE OF THE CHALLENGES THAT PEOPLE OFTEN SITE SPECIFICALLY WITH OA TRIALS IS THAT THERE IS A HIGH PLACEBO RESPONSE BELIEVED TO BE KNOWN WAXING AND WANING SYMPTOMATOLOGY BECAUSE OF DISEASE NATURAL HISTORY AND PEOPLE HAVE OBSERVED EVEN IF YOU ENROLL PATIENTS, WITH MODERATE TO HIGH LEVEL OF PAIN, MOST PEOPLE BY THE END OF THE STUDY, THE PAIN WILL EVENTUALLY SUBSIDE TO SOME MODEST DEGREES AND THAT COULD HAPPEN REGARDLESS OF THE INTERVENTION SO SPECIFICALLY FOR OSTEOARTHRITIS TRIALS WE RECOMMEND AGAINST HISTORICAL CONTROLS, FOR NOVEL PRODUCTS RELY ON EVIDENCE THAT COMES FROM TRIALS WITH CURRENT CONTROL GROUPS. ALONG THE SAME LINES, IN ANY CLINICAL TRIAL WITH OSTEOARTHRITIS POPULATION, POPULATION OF THE DISEASE YOU CHOOSE IT SHOULD BE SOME -- AT LEAST TO THE DEGREE POSSIBLE WELL MATCHED WILL ANTICIPATE PRODUCT EFFECT AND THAT IS WHY IT IS IMPORTANT TO UNDERSTAND WHAT THE PRODUCT ACTUALLY DOES BEFORE YOU ADMINISTER TO PATIENTS. BEFORE THIS ROUND TABLE TED TOLD ME THERE WAS SOME INTEREST IN THE TOPIC WE CALL TISSUE AND THE MEANING OF MINIMAL MANIPULATION AND AUTOLOGOUS USE BUTLY DO THAT PART MAKING DINTS BETWEEN WHAT WE CALL REGULATORY PATHWAYS 351 PATHWAY, AND 361 PATHWAY. NOW REMEMBER I TOLD YOU EARLIER THAT THE TWO LAWS WHICH GOVERN DRUG BIOLOGICAL PRODUCT DEVELOPMENT BY FOOD DRUG ACT AND PUBLIC HEALTH SERVICE ACT. UNDER THE FOOD DRUG AND (INAUDIBLE) ACT, THE RESPECTIVE REGULATIONS WHETHER OUTLINED HERE ON THE SLIDE ANY USE IN THE UNITED STATES OF THE DRUG NOT -- IT IS MARKETING APPLICATION TO FDA THERE IS A DEFINITION WHAT DRUG MEANS FOR DRUG (INAUDIBLE) ACT YOU CAN SEE HERE. NOTE THE LITTLE FOOTNOTE ON THE SLIDE ALL THIS IS APPLICABLE TO BIOLOGICAL PRODUCTS TO WELL KNOWN TO ALL OF US THERAPEUTIC BIOLOGICAL PRODUCTS SUCH AS ANTIBODIES, RECEPTOR FUSION PROTEIN, ANTI-CYTOKINE TREATMENT MORE NOVEL BY SPECIFIC ANTIBODIES. AS WELL AS CELL AND GENE THERAPIES AND TISSUE GENE PRODUCTS. IN ESSENCE DRUGS REGULATED UNDER FOOD DRUG AND BIOLOGICS REGULATED UNDER SECTION 3651 OF THE PUBLIC HEALTH SERVICE ACT. REGULATED IN THE SAME WAY. SO ALL THE CONCEPTS AND CONSIDERATIONS THAT I HAVE SHOWN YOU ON THE PREVIOUS SLIDE RELATE TO THE REGULATION OF BIOLOGICS UNDER THE 351 PATHWAY SHOWN HERE IN RED ON THE SLIDE. SO LET'S TALK ABOUT THE 361 PATHWAY WHICH IS OUTLINED IN THE PUBLIC HEALTH SERVICE ACT BUT BEFORE WE GO INTO PATHWAY, LET'S FIRST LOOK AT THE SUBSET OF BIOLOGICAL PRODUCTS CALLED HUMAN CELLS TISSUES AND TISSUE BASED PRODUCTS ALSO KNOWN AS HCTPSS. SURE YOU HAVE HEARD THIS TERM. THE REASON THESE PRODUCTS WERE DEFINED LIKE THIS AND WHY THE TISSUE WAS EVEN CREATED WAS TO PERMIT THE USE OF DONOR DERIVED OR AUTOLOGOUS HUMAN TISSUES AND CELLS PRIMARILY FOR CORRECTION OF ANATOMICAL DEFECTS OR CELL SUPPLEMENTATION IN LOWER RISK SITUATIONS WHEN THERE IS A GOOD ASSURANCE THERE WOULD BE NO TRANSMISSION OF INFECTIOUS DISEASE DO DONOR TO RECIPIENT. THE DONOR COULD BE A LIVE DONOR OR A -- A CLAYS IS EXAMPLE IS A CORNEAL IMPLANT. JUST REPLACE PROVIDED THE ADEQUATE QUALITY AND PURITY, MANUFACTURER RESPONSIBLE FOR MAKING THE PRODUCT, THERE IS ABSENCE OF TRANSMISSIBLE INFECTION WHICH CAN BE ASSURED THROUGH APPROPRIATE DONOR ELIGIBILITY CRITERIA. YOU CAN DO THE IMPLEMENTATION SURGICALLY. HCCP REGULATION COLLECTIVELY KNOWN AS TISSUE DEFINE TWO THINGS. THEY DEFINE A NUMBER OF THINGS BUT DEFINE TWO IMPORTANT THINGS, IMPORTANT FOR OUR CONVERSATION TODAY. HCTP PRODUCTS WHICH TISSUE MAYBE APPLICABLE, A GROUP OF PRODUCTS WHICH YOU SEE HERE ON THE SLIDE, THEY ALSO DEFINE CRITERIA WHEN HE IS PRODUCTS CAN BE REGULATED UNDER TISSUE AND NOT UNDER SECTION 351 OF PUBLIC HEALTH SERVICE ACT. BY AND LARGE MOST PRODUCTS WHEN THEY ARE INTENDED FOR TREATMENT OF DISEASES, THEY REGULATE UNDER 351 PATHWAY. LET'S TALK ABOUT DEFINITION FIRST. HCTPs ARE HUMAN CELLS AND TISSUE PRODUCTS INTENDED FOR IMPLANTATION TRANSPLANTATION AND FUSION OR TRANSFER TO HUMAN RECIPIENTSS. THEY COVER A RANGE OF PRODUCTS YOU SEE HERE IN T SECOND BULLET. PLEASE KNOW MOST PRODUCTS ARE REGULATED AS DRUGS OR BIOLOGICAL PRODUCTS PARTICULARLY WHEN THEY ARE INTENDED TO TREAT MEDICAL CONDITIONS. OSTEOARTHRITIS WAS NO EXCEPTION HERE. SOME WOULD BE REGULATED UNDER TISSUE IF THEY MEET SPECIFIC CRITERIA, I WILL SHOW YOU IN A MINUTE. THE HCTP REGULATION DEFINE PRODUCTS NOT HCTPs, THESE INCLUDE BLOOD PRODUCTS PLATELET RICH PLASMA AND SERUM. BECAUSE PRODUCTS ARE NOT HCTPs, THEY ARE NOT SUBJECTS TO THE FRAMEWORK OF THE TISSUE OR THE 361 PATHWAYS. A PATHWAY, THEY CANNOT BE MADE AVAILABLE UNDER THIS FRAMEWORK. THE REGS DR. CHU SHOWED US BEGINNING 640 APPLY TO BLOOD PRODUCTS INTENDED FOR TRANSFUSION. NOTHING TO DO WITH TREATING MEDICAL CONDITIONS. THE REASON I ASK FOR A LITTLE MORE TIME, I WANT TO MAYBE DISPEL MYTHS OR EXPLAIN MISCONCEPTIONS. THE FIRST INCEPTION OBVIOUSLY YOU MIGHT HEAR OPRP WOULD BE LEGALLY MARKETED PRODUCT OR LEGALLY MARKETED AS AN HCTP, HUMAN TISSUE PRODUCT. THAT IS NOT CORRECT. BECAUSE PRP IS NOT HCTP, IT DOESN'T FALL UNDER TISSUE. SO I WILL GIVE A LITTLE HISTORY HERE. HCTP REGULATIONS WERE ISSUED THROUGH NOTICE OF COMMON RULE MAKING IN EARLY 2000s. ISSUED IN THREE PARTS AND BECAME COLLECTIVELY KNOWN AS THE TISSUE, THEY BECAME FULLY EFFECTIVE IN MAY OF 2005. SO HERE IS ANOTHER EXAMPLE OF THE MISCONCEPTION WE OFTEN HEAR FDA JUST STARTED REGULATING THIS PRODUCT OR FDA DIDN'T REGULATE THE PRODUCT BEFORE THEY PUBLISHED THEIR DRAFT GUIDANCE IN 2017. THESE STATEMENTS ARE NOT ACCURATE. FDA HAS BEEN REGULATING THESE PRODUCTS UNDER THE SAME FRAMEWORK FOR MORE THAN 17 YEARS, THE GUIDANCE AND MINIMAL MANIPULATION AND HOMOLOGY GUS USE INCLUDE MISDEMEANOR THE LIST OF READING MATERIALS FOR THE ROUND TABLE, AND OTHER RELATED GUIDANCE ABOUT TISSUE WERE WRITTEN TO PROVIDE CLARITY AROUND THE REGULATIONS THEY DID NOT REALLY SERVE TO BRING ANY PRODUCT UNDER THE FDA AUTHORITY. HCTPs CAN BE REGULATED AS I TOLD YOU AS DRUGS OR BIOLOGICAL PRODUCTS. AND THAT IS WHEN THEY ARE INTENDED FOR MEDICAL TREATMENT OF DISEASE CHRONIC MEDICAL CONDITIONS, NEUROLOGICAL CONDITIONS MUSCULOSKELETAL DISORDERS INCLUDING OSTEOARTHRITIS. FDA PRE-MARKET REVIEW APPROVAL WOULD BE REQUIRED FOR THESE PRODUCTS WHICH MEANS THEY CANNOT BE MARKETED WITHOUT APPROVED BIOLOGIC LICENSE APPLICATION AND THEY CAN BE MADE AVAILABLE ASVATIONAL PRODUCTS UNDER ACTIVE IND OR IDE. THE SECOND SCENARIO YOU SEE HERE ON THE SLIDE, WHEN HCTP MEETS SPECIFIC CRITERIA UNDER SECTION 361 PUBLIC HEALTH SERVICE ACT IN THAT CASE HCTP PRODUCT WOULDN'T REQUIRE FDA PRE-MARKET REVIEW AND APPROVAL AS EXPLAINED IN THE CASE OF CORNEAL IMPLANT WHICH IS PRODUCTS LIKE THIS CAN BE MARKETED AND MADE AVAILABLE SO LONG AS THEY MEET THE CRITERIA. PLEASE NOTE HERE MANUFACTURERS OF THESE PRODUCTS STILL HAVE TO REGISTER WITH THE FDA AS FACILITY THAT MAKES HCTPs AND SUBJECT TO SAFETY REPORTING MANUAL REPORTING WHICH MEANS IF SOMETHING HAPPENS WITH HAIR PRODUCT WHEN MARKETED AND IF RELATED TO SAFETY THEY HAVE TO REPORT THIS TO FDA AND WE WILL LOOK AFTER SAFETY OF THESE PRODUCTS TOO. HERE ARE THE FOUR CRITERIA. DEFINED IN TISSUE. PLEASE NOTE ALL OF THESE CRITERIA MUST BE MET IN ORDER FOR HCTP TO BE REGULATED SOLELY UNDER SECTION 361. HERE THEY ARE. THE PRODUCT HAS TO BE MINIMALLY MANIPULATED, INTENDED FOR HOMOLOGOUS USE, NOT COMBINED ANOTHER ARTICLE OR SUBSTANCE AND A PRODUCT HCTP REGULATED UNDER 361 CAN LOOK AT THE SYSTEMIC EFFECT OR P DEPENDENT ON THE METABOLIC ACTIVITY OF THE LIVING CELLS FOR PRIMARY FUNCTION AUTOLOGOUS PRODUCT INTENDED IN THE USE OF FIRST OF SECOND DEGREE RELATIVE OR FOR REPRODUCTIVE USE. HERE IS ANOTHER MISCONCEPTION WHICH I NOT ONLY SAW IN THE RESPONSES TO QUESTIONS, FOR THE ROUND TABLE BUT ALSO HEARD DURING THE DISCUSSION. WE HAVE HEAR FOLKS SAY BECAUSE THIS PRODUCT IS AN AUTOLOGOUS PRODUCT IT IS AUTOMATICALLY HCTP AND AUTOMATICALLY FDA. THIS IS NOT TRUE BECAUSE WE HAVE MEN PLENTY OF AUTOLOGOUS PRODUCTS REGULATED UNDER 351. HCTP MUST IMMEDIATE ALL FOUR CRITERIA TO BE REGULATED SOLELY UNDER SECTION 361. SO THIS GUIDANCE SURE YOU READ IT IF PREPARING FOR THE ROUND TABLE, THIS GUIDANCE DISCUSSES ROLE APPROACH TO SELF-DETERMINATION OF WHAT PRODUCT YOU ARE WORKING WITH AND WHETHER THE PRODUCT WOULD FALL UNDER THE TISSUE REGULATIONS, IT PROVIDE AN ALGORITHM AND TALKS ABOUT THE FIRST TWO CRITERIA WHICH I WILL ALSO DISCUSS TODAY NOT TOO EASY TO MOVE THE SLIDES, NOT SURE WHY. SO THE FIRST CRITERIA SAYS HCTP MUST BE MINIMALLY MANIPULATED. THE REGULATIONS LAY OUT TWO SEPARATE DEFINITIONS OF MINIMAL MANIPULATION. ONE IS STRUCTURAL TISSUES AND THE OTHER IS CELLULAR AND NON-STRUCTURAL TISSUES. WHEN EVALUATING THE MINIMUM NARRATION CRITERIA, IT IS IMPORTANT TO REMEMBER THAT THIS CRITERIA RELATES TO HOW THE HCTP FUNCTION IN THE DONOR, IT IS ESSENTIAL TO EVALUATE PROCESSING STEPS AND BEGIN ANALYSIS WITH THE HCTP AS EXISTED IN THE DONOR. SO THIS MEANS YOU LOOK AT THE PROCESSING FROM START TO FINISH AND IN THE PROCESSING ORDERS TISSUES UTILITY IN THE DONOR, MEANING THAT THE TISSUE LOST ABILITY TO FUNCTION AS IT DID IN THE DONOR, THEN WE WOULD CONSIDER THE PROCESSING TO BE MORE THAN MINIMAL MANIPULATION. GUIDANCE INCLUDES A NUMBER OF EXAMPLES BECAUSE YOU HAVE TO APPLY THESE CRITERIA BASED ON NOT ONLY PROCESS OF MANIPULATION BUT ALSO APPLICATION TO DIFFERENT TISSUES THAT MAY VARY, THE APPLICATION MAY VARY FOR DIFFERENT TISSUES. THE SECOND CRITERIA HERE IS THE HOMOLOGOUS USE. HOMOLOGOUS USE IS DEFINED IN THE REGS AS REPAIR RECONSTRUCTION REPLACEMENT OR SUPPLEMENTATION OF RECIPIENT CELLS OR TISSUES WITH HCTP THAT PERFORMS THE SAME FUNCTION OR FUNCTIONS IN THE RECIPIENT AS IN THE DONOR. KEY POINT HERE TO KEEP IN MIND IS THIS CRITERION RELATES TO THE INTENDED USE OF THE HCTP IN THE RECIPIENT IF YOU INTEND TO USE HCTP FOR THE INTENDED FUNCTION IN RECIPIENT IN ORDER TO MEET HOMOLOGOUS USE CRITERION ACTION HCTP PERFORMED THE SAME BASIC FUNCTION IN THE DONOR. IT IS IMPORTANT TO REMEMBER CLINICAL EFFECT OF TISSUE THAT ARE NOT ALSO BASIC FUNCTION OF THE TISSUE IN THE DONOR, ARE NOT CONSIDERED BASIC FUNCTIONS. THIS MEANS BECAUSE SOMEONE DEMON INVESTIGATORY HUE CAN PERFORM FUNCTION IN THE RECIPIENT, THIS DOESN'T MEAN THE FUNCTION IS NECESSARILY BASIC FUNCTION. SO NEEDLESS TO SAY IF YOU HAVE A PRODUCT THAT IS INTENDED FOR TREATMENT OF MEDICAL CONDITIONS LET ALONE A MYRIAD OF DIFFERENT CONDITIONS, THE SAME PRODUCT HCTP IS NOT INTENDED FOR HOMOLOGOUS USE. I PROMISED TO SHOW YOU GUIDANCE AND I THINK THE FOUR GUIDANCES THAT ARE HERE IN THE BULLETS ARE MUST READ FOR FOLKS WHO ARE DEVELOPING PRODUCTS, THE LINK ON THE SLIDE WILL TAKE YOU TO OUR WEBSITE WHERE YOU CAN FIND OTHER GUIDANCE FOR DIFFERENT DISEASE AND CONDITIONS AND OTHER PRODUCTS THAT REGULATE NOT NECESSARILY CELLULAR PRODUCTS ALONE AS WELL AS ADDITIONAL GUIDANCE ON THE TISSUE BECAUSE I RECOGNIZE WE ARE TALKING ONLY ABOUT ONE GUIDANCE TODAY. BY POPULAR DEMAND. SO THIS LOOKS LIKE MY LAST SLIDE. THANK YOU FOR YOUR ATTENTION. HERE IS MY EMAIL AND THE CONTACT INFORMATION FOR THE OFFICE IF YOU HAVE ANY QUESTIONS DO NOT HESITATE TO SEND YOUR QUESTIONS AND ASK THEM AND WE ARE DEVELOPING MORE ONLINE RESOURCES FOR STAKEHOLDERS PUBLISHED IN THE UPCOMING YEAR. THANKS AND GLAD TO JOIN DISCUSSION. >>THANK YOU SO MUCH. PRETTY CLEAR IN OUR DISCUSSION WE ARE NEEDING BETTER CHARACTERIZATION, WE ARE NEEDING TO KNOW BETTER WHAT WE ARE GIVING PATIENTS SO ALL THOSE AMOUNT TO DOING MORE QUOTE UNQUOTE MANIPULATION AND YOU GET ALL THE WAY UP TO WHAT DR. GUILAK SHOWED WHERE IT IS A VERY INTRICATE CELLULAR ENGIN ENGINEERING SO I WOULD SAY IT IS PROBABLY IMPORTANT FOR US TO AS SCIENTISTS TO WALK AWAY FROM THIS 361 AS A -- I THINK THAT THAT HAS BEEN A I ALMOST WANT TO SAY LOOP HOLE WHERE SO MANY PRODUCTS SO TO SPEAK HAVE GONE OUT TO THE COMMUNITY AND FOR US TO START THINKING WE NEED TO GO BACK TO BASICS AND SAY WHAT PATHOLOGY AND PATHOGENETIC POINT ARE WE TRYING TO CONVENE AT AND HOW IS THIS A BIOLOGIC -- WE ARE TALKING BIOLOGICS BUT WHERE IN THAT PATHWAY IS THIS BIOLOGIC INTENDED OR WE THINK IT ACTS BASED ON RESEARCH WE HAVE DONE IN PRE-CLINICAL MODELS IN VITRO AND MOVE INTO CLINICAL TRANSLATION. I DO WANT TO GET A SPECIFIC CLARIFICATION REGARDING PRP. WIDELY USED AND REALLY THE PRP AS YOU MENTION, IS COVERED UNDER BLOOD. THE WHOLE INTENTION WAS FOR TRANSFUSION WITH PRP BEING DISCUSSED BECAUSE IT IS AN INTERMEDIATE STEP IN THE CREATION OF FRESH FROZEN PLATELETS. FFP AND PLATELET CONCENTRATE. WHY DOES PRP FOLLOW? BECAUSE USE IS OUT THERE, GREATLY EXCEED ANYTHING EVER IMAGINED FOR TRANSPLANTATION -- BLOOD TRANSFUSION. >>WE DO HAVE BOTH ID INVESTIGATIONAL DEVICE APPLICATIONS ANDVATIONAL MU DRUG APPROXIMATE -- INVESTIGATIONAL DRUG APPLICATIONS PRP. WHEN IT WAS INTENDED FOR TREATMENT FOR DISEASE MEDICAL CONDITIONS WE LOOK AT THOSE PROGRAMS. OSTEOARTHRITIS IT IS ONE THING USED FOR WOUND HEALING. SO WE HAVE INVESTIGATIONAL DEVICE EXEMPTION APPLICATIONS FOR POINT OF CARE DEVICE PRP DEVICE COULD BE PRODUCED IF IT HAS EFFECTS ON WOUND HEALING FOR OTHER DISEASES OR CONDITIONS WE SEE THOSE DEVELOPMENT PATHWAYS AND EVALUATIONS AND INVESTIGATION DONE WITH PRP. CURRENTLY OUR USE IN OSTEOARTHRITIS FALLS UNDER A -- PHYSICIAN DISCRETION? HOW WOULD YOU FROM FDA STANDPOINT CHARACTERIZE THE BASIS FOR USE IN OSTEOARTHRITIS >>I DON'T USE IT IN OSTEOARTHRITIS SO -- IT WOULD BE INTERESTING TO UNDERSTAND WHAT YOU ARE TELLING TO YOUR PATIENTS WHEN YOU ARE OFFERING THEM THIS TREATMENT WHETHER -- HOW DO YOU EVEN SAY IT WOULD BE WORKING FOR THEM AND I RECOGNIZE YOU PROBABLY AS YOU EXPLAIN SEE THE EFFECT WOULD BE VARIABLE IN THE ABSENCE OF GOOD INVESTIGATION ANY QUANTIFICATION POTENTIALLY COULD BE AFFECT OF THIS TREATMENT OF THE DISEASE YOU ARE TREATING, IT IS HARD TO SAY, I WOULD BE INTERESTED TO HEARD WHAT YOU HAVE TO SAY BECAUSE YOU ARE USING IT. >>PRIMARILY IN CONTEXT OF MY RESEARCH PROJECT. WE SAY TO PATIENTS THAT WE DON'T KNOW WHAT THE AFFECTS ARE. THOSE WHO I AM TREATING SO PEOPLE WHO VOLUNTEER BUT WE FIND THEY DON'T MEET CRITERIA FOR THE STUDY IF THEY DON'T HAVE MEDICAL CONTRAINDICATIONS WE ARE GIVING THEM INCORRECTION FOR JUST AS A COURTESY. PRIMARILY MY INTEREST IS IN OUTCOMES RESEARCH, IT IS WIDELY USED, IT IS VERY, VERY WIDELY USED. IT SOUNDS LIKE IT IS BASICALLY WOULD YOU SAY OFF LABEL? THERE IS NOT A LABEL >>YEAH. >>NO CHARACTERIZATION. >>I WAS ALWAYS TOLD THE DEVICE IS CLEARED DON'T GET IT BEYOND THAT. IT MAKES IMPORTANT POINT CHOCK RAN MADE ACCURATE POINT PRP IS A LOT OF THAT DATA THAT WORKS. AT THE SAME TIME THIS IS USED, USED EVERYWHERE. NO DOUBT TOO MUCH. PERHAPS OFTEN, INDISCRIMINATELY, THE REALITY IT IS USED. OKAY, THIS IS ACCEPTABLE, THAT TRAIN LEFT THE STATION. HOW TO WE STILL CONTINUE TO STUDY PRP IN OUR CLINICAL TRIALS. RECOGNIZE WE USE AS CONNIE SAID VERY WIDELY. TAKING CARE OF ATHLETES I SEE IT ALL THE TIME. THE EXPECTATION, SPEND MORE TIME TALKING TO AGENTS PLAYERS AND MANAGERS OUT OF IT OR WHY WE DON'T KNOW WHAT IT DOES. THAT IS THE CLINICAL SIDE OF THINGS, IF YOU WANT TO UNDERSTAND. >>I UNDERSTAND COMPLETELY. THAT IS ANOTHER IN RESPONSE TO THE QUESTIONS FOR THE ROUND TABLE. IT IS A CERTAIN THINGS FOR USE IN CLINICAL PRACTICE AND PEOPLE HAVE NO IDEA WHAT THEY DO, WHAT IS THE EFFICACY, I THINK WE OWE THIS TO OUR PATIENTS, TO -- WHEN WE GIVE THEM SOMETHING AS TREATMENT WHEN WE PROMISE TO TAKE CARE OF THEM AND HELP THEM TO GIVE THEM PRODUCTS OR TREATMENTS THAT ARE PROVEN EFFECTIVE. WE ARE NOT HARMING THEM. >>AGREE. THERE ARE SOME HANDS RAISED WE SHOULD GO THROUGH. >>YES. >>GEORGE. >>FASCINATING DISCUSSION. I WAS TRYING TO DECIDE WHETHER CONNIE WAS GOING TO GO TO JAIL OR NOT. SOMEWHERE THROUGH THIS PROCESS. I'M WONDERING, I'M A CLINICIAN, WE HAVE A PROGRAM JOINT PRESERVATION CENTER WE DON'T TALK ABOUT STEM CELLS, THAT PRP PREPARATION IS APPROPRIATION OF PATIENT OWN TISSUE. I DON'T THINK PRP BEING IN A PRODUCT IS THE DEVICE, IT IS THE PRODUCT THEY OFFER, THE PROCESS TO PREPARE THE PRP. AS AICALLY IN ADDITION CLINICIANS CAN TAKE SKIN FROM ONE PART OF THE PATIENT BODY AND PUT IT IN ANOTHER PART OF THE PATIENT BODY AND TAKE FASCIA FROM ONE PART AND USE IT FOR SOME OTHER PURPOSE TO REPAIR ANOTHER TISSUE AND ANOTHER PART OF THE PATIENT BODY. LONG AS YOU ARE NOT NOT MISROPINGSING WHAT YOU ARE DOING AND WHY OR EXPERIMENTING WITH THE INTENT GENERALIZABLE INFORMATION, MY UNDERSTANDING AS A CLINICIAN IS THIS IS PART OF PRACTICE AND OUR OBLIGATION IS TO BE STRAIGHT FORWARD AND HONEST. IN OUR CASE WE HAVE A REGISTRY, WE LOOK AT DATA, I TELL PEOPLE THAT YOUR -- IF I DID A KNEE REPLACEMENT WOULD BE PROBABLY BETTER THAN PRP INJECTION ON YOU BUT DATA SUGGESTS SIX MONTHS AFTER PRP INJECTION YOU ARE BETTER THAN YOU ARE NOW WITH A HIGH PROBABILITY, 80%. SO YOUR CHOICE DELAYED SURGERY OR CONSIDER USING THE PRP. THAT IS BASED ON OUR OWN DATA. I WILL NARROW THIS JUST TO A QUESTION. IT IS -- IS THERE A FRAMEWORK WITH FDA THAT SAYS THIS IS A PART OF PHYSICIAN PATIENT RELATIONSHIP AND PHYSICIAN DISCRETION AND THE PRIMARY PLACE YOU REGULATE IS HOW PEOPLE DESCRIBE AND MARKET RATHER THAN THE ACTUAL DELIVERY OF PRP BY A PHYSICIAN. >>I THINK YOU ACTUALLY TOUCHED UPON NUMBER OF TOPPINGS AND YOU STARTED WITH SKIN TO SKIN OR FASCIA FOR FASCIA. WHERE WILL IS TRANSPORTATION OR RECONSTRUCTION OF CLINICAL DEFECT. OR CORONARY ARTERY BY SURGERY, TAKING SOMEONE'S VEIN AND PUTTING IT DIFFERENT PLACE TO HELP CIRCULATION. THESE ARE THE TYPES OF SITUATIONS WHERE OBVIOUSLY THIS IS PART OF CLINICAL PRACTICE AND THESE ARE TYPES OF SITUATIONS WHERE THE TISSUE WOULD APPLY. WHEN WE ARE TALKING ABOUT GIVING SOME KIND OF CELLULAR PREPARATION FOR THE TREATMENT OF MEDICAL CONDITION, IT IS AN ENTIRELY DIFFERENT FRAMEWORFRAMEWORK COMPLETELY DIT SITUATION FROM REGULATORY PERSPECTIVE H. PRP PRODUCTS ARE USED. AND THEY ARE USED IN VARIOUS SETTINGS. NUMBER OF DEVICES THAT HAVE BEEN SENT TO US AS APPLICATIONS FOR USE OF PRP IN DIFFERENT SETTING SETTIN. COUNSEL ONCE WE SEE INVESTIGATIONS AND THE DEVICE IS IN CLEARANCE AND APPROPRIATE QUALIQUALITY. AS AS LONG AS THE INVESTIGATIONS ARE ALSO ETHICAL AND CONDUCTED APPROPRIATELY IN THE INTEREST OF PATIENTS THIS IS ONE PATHWAY WHERE PRP COULD POTENTIALLY FALL INTO -- THIS IS SOMETHING WE DO. THAT WAS ANSWERS THE QUESTION. IS PATIENT DOCTOR RELATIONSHIPS FROM THE NOTION OF WELL CAN WE STEM CELLS IN THE BATHROOM SOMEWHERE AND UNDER THE PATIENT RELATIONSHIP OFFER IT BECAUSE WE BELIEVE WE WOULD WORK PRP. BECAUSE THAT IS PATIENT DOCTOR RELATIONSHIPS CAN INCLUDE LOT OF THINGS. AGAIN WE OWE THIS TO OUR PATIENTS TO GIVE THEM PRODUCTS THAT ARE BEST QUALITY WE KNOW. >>ANALOGOUS, THE ANALOGOUS IS ASPIRIN. ASPIRIN WE PRESCRIBE ASPIRIN FOR LOTS OF THINGS AND GRANTED THERE'S DATA BUT IF ASPIRIN WAS ALREADY IN USE AND ALREADY DOCUMENTED FOR LOTS OF THINGS BUT FOR -- ANYWAY, THAT'S A LITTLE STUFF. LET ME TURN THINGS OVER TO SHANE. >>SHANE, YES. >>I WANTED TO GO BACK TO THAT CONVERSATION THAT WE HAVE WITH PATIENTS AND HOW IMPORTANT AND VALUABLE AND HOW IN THAT DISCUSSION AND SHARED DECISION MAKING, WE COMMONLY DON'T EXPLAIN MANY TREATMENTS, NO PATIENT ASKS HOW TYLENOL WORKS TO RELIEVE PAIN. THAT IS SOMEWHAT WHAT GEORGE IS SAYING WITH ASPIRIN. WE BELIEVE PRP HAS A THERAPEUTICS AFFECT AND I ALSO WANTED TO AT LEAST HIGH LIGHT THERE MAYBE A LITTLE DISAGREEMENT IN THE PANEL AND IN TERMS OF STATE OF THE CURRENT EVIDENCE BECAUSE THERE'S BEEN A NUMBER OF WELL DESIGNED TRIALS NOT ALL WHICH ARE POSITIVE CERTAINLY SOME OF WHICH ARE NEGATIVE BUT DO -- HAVE BEEN ANALYZED SYSTEMATICALLY AND META ANALYSES TO SEE THERE IS A THERAPEUTIC EFFECT AND SYMPTOM MODIFYING EFFECT FOR PRP. THAT SAME EVIDENCE DOESN'T EXIST NUMBER OF THE OTHER BIOLOGICS DISCUSSED TODAY, THERE IS A REASONABLE EVIDENCE BASED TO HAVE THAT CONVERSATION WITH PATIENTS SO THAT BRINGS BACK AMYE TO THE CONVERSATION AND PATIENT ADVOCACY COLLEAGUES BECAUSE WHEN WE HAVE THESE CONVERSATIONS WITH PATIENTS THIS IS SOMETHING MY GROUP STUDY EXTENSIVELY WITH MY BIOETHICAL COMPLYINGS IN TERMS OF WHAT IS THE PATIENT UNDERSTANDING OF HOW BIOLOGIC THERAPIES WORK AND PATIENTS THAT COMING IN M AS DR. RODEO SAID, ATHLETES, LOOKING FOR THESE TREATMENT, WHAT CAN THEIR UNDERSTANDING AND CAN THEY EVEN UNDERSTAND THE BIOLOGY WE ARE ALL TALKING ABOUT HERE ENOUGH TO GIVE INFORMED CONSENT FOR TREATMENT OF THIS. THESE ARE COMPLEX CONVERSATIONS THAT EVEN IF WE DID KNOW EXACT MOLECULAR MECHANISM OF HOW PRP RELIEVED PAIN, IT IS UNLIKELY PATIENTS WOULD BE ABLE TO UNDERSTAND IT ENOUGH FROM INFORMED CONSENT STANDPOINT. THAT IS THE JOB OF THE CLINICIAN TO SYNTHESIZE IN THE CLINICAL EVIDENCE AND THEN BRING IT DOWN TO LEVEL OF PATIENT UNDERSTANDING SO YOU CAN HAVE APPROPRIATE INFORM CONSENT, IT IS OUR JOB HERE IN THIS GROUP AND PANEL AND SCIENTIFIC COMMUNITY TO FIGURE HOW IT IS THEY WORK. THAT IS DIFFERENT THAN HOW WE TALK TO OUR PATIENTS. THANK YOU. CRITICALLY IMPORTANT ON WHICH PATIENT, WHICH IS MOST LIKELY TO BENEFIT BECAUSE WE ALL HAVE SEEN PATIENTS WHO HAVE IMPROVED FOLLOWING PRP TREATMENT BUT IT ISN'T EVERYONE. GOING BACK TO -- SO NOBODY THINKS THAT'S AN -- BATS AN EYE ABOUT THE LONG HISTORY OF CORTICOSTEROID INJECTIONS. THAT IS ALMOST IN PRIMARY CARE, THAT IS ALMOST THE FIRST LINE INJECTION TREATMENT BUT EVEN GOING BACK TO DR. HINCH'S WORK, CLEARLY VERY CLEARLY IN HIS ORIGINAL PAPER FROM HIS NOBEL PRIZE HE SAYS IT DOESN'T ALWAYS HELP IN OSTEOARTHRITIS. THAT REFLECTS THE DIVERSITY OF OA DISEASE STATES WHICH WE HAVE TALKED ABOUT VERY IMPORTANT, IT IS SOMETHING I DO CLARIFY WITH MY PATIENTS THAT I -- IT IS NOT THE DATA SHOWS OVERALL SO I CAN SPEAK ON MY OWN DATA HAS, I SHOW MAIN BENEFIT. NOT EVERYBODY HAS IMPROVED. THEY HEAR THAT. MOST PEOPLE COMING IN, SCOTT MENTIONED, THEY HAVE GOT ONE THING ON THEIR MIND, I THINK THAT THE PRP WILL BE BETTER THAN THE OTHER INJECTIONS ALREADY. IF A NUMBER OF THEM COME BACK VERY HAPPY BUT IT IS NOT EVERYONE AND IT IS OUR JOB TO FIGURE OUT TO BETTER DEFINE DIFFERENT OA DISEASE STATES AND WITH THERAPYINGS MAY BE MORE APPROPRIATE. FOR PEOPLE IN DIFFERENT STATES OF DISEASE. -- THERAPIES. >>I'M SORRY, GO AHEAD AMYE. >>I WANT TO ADD TO THIS CONVERSATION ABOUT STEM CELLS AND PRP FROM THE PATIENT ANGLE. HEARING TODAY, I THINK THE ONE PIECE OF INFORMATION I BELIEVE MARK INDICATED IS THAT DOD, THE VA, ARTHRITIS FOUNDATION AND AMERICAN COLLEGE OF RHEUMATOLOGY EACH HAVE PUT OUT GUIDELINES THAT SAY NOT RECOMMENDED. I FOUND THAT SHOCKING IN THE SENSE OF NUMBER ONE, CONSISTENCY AND PROMPTED ME PROBABLY 25 QUESTIONS WHEN THE LAST TIME THIS WAS DONE, THIS IS A EMERGING FIELD, WHAT ARE PATIENTS ASKING IN PARTICULAR. IN MY EXPERIENCE IT COMES TO TRUST BETWEEN CLINICIAN AND PATIENT. A TYPICAL QUESTION I AM ASKED AS IF I WERE THE HEALTH CLINICIAN. IF I WERE YOUR DAUGHTER WOULD YOU RECOMMEND THIS TO YOUR DAUGHTER, WOULD YOU RECOMMEND IT TO ME. DIDN'T COME DOWN TO PROCESS, EQUIPMENT, THERE WAS AN ASSUMPTION AND A HUGE LEAP ABOUT WELL, IT IS MY BLOOD. THEREFORE MUST BE OKAY. SPIN OUT THE BAD STUFF AND KEEP THE GOOD STUFF AND THAT WILL HELP ME. WE DO THE COLLECTIVE WE BECAUSE I DON'T AGREE WITH IT, IT IS ALL GOING TO GO -- COME FROM AND GO BACK TO THE CLINICIAN. MAKING SURE A BODY LIKE THIS AT NIAMS WORKING WITH THE FDA HOW IS THE BEST WAY COCHARACTERIZE THIS, TO LOOK AT THE DIFFERENT IMPORTANT ASPECTS OF THAT TO LOOK FOR CONSISTENCY LONGEVITY, QUALITY, ALL THINGS WE HAVE BEEN TALKING ABOUT TODAY ARE INSTILLED INTO THIS ONE PARTICULAR POTENTIAL, IT HAS A LIFE OUTSIDE THE OFFICE KIND OF SCENARIO. IS I DON'T WANT TO SAY CONTAINED BUT MANAGED FROM SYSTEMATIC PROCESS, DR. CHU, CONNIE WAS TALKING ABOUT, TO BE SYSTEMATIC. I THINK THAT IS THE MOST IMPORTANT THING. WOULD I GET IT? THE WAY I FEEL LIKE NOW, NO. >>ASK ME NEXT MONTH. >>THANK YOU, THIS IS IMPORTANT FOR ALL OF US TO HEAR. BECAUSE IF WE WERE TO PROPOSE OR OFFER TREATMENTS TO PATIENTS WE WANT TO AT LEAST SEE GOOD CLINICAL TRIALS DONE WITH THESE TREATMENTS, DEMONSTRATING THAT THE TREATMENTS ARE EFFECTIVE. AND THEY'D ARE SAFE. ANECDOTAL CASES OF EFFECTIVENESS EXIST WITH EVERYTHING. INCLUDING NORMAL SALINE BUT WHEN WE OFFER AGAIN TREATMENTS PARTICULARLY INJECTABLE TO PEOPLE WE NEED TO MAKE SURE THEY ARE EFFECTIVE AND WE CAN'T MAKE SURE THEY ARE EFFECTIVE BASED ON THE EVIDENCE THAT IS OUT THERE THAT'S CONTROVERSIAL OPEN LABEL EARLY STUDIES SMALL STUDIES. MANY CASE SERIOUS, WE NEED GOOD TRIALS, THAT IS ANOTHER I GUESS -- GAP IN THE FIELD WHEN YOU PUT TRIALS AND QUALITYVA QUALITY INVESTIGAO SHOW WHATEVER PRODUCT WE BELIEVE HAVE POTENTIAL, GREAT POTENTIAL IN THEIR APPLICATION REALLY UPHOLD TO THE LEVEL OF EVIDENCE WE ARE WORKING FOR AND LEVEL OF BENEFIT PATIENTS ARE WORKING FOR IN THESE PRODUCTS. A GOOD SEGUE TALKING ABOUT THE DISCUSSION, THE FIRST DISCUSSION QUESTION IS A HUGE QUESTION WHAT EVIDENCE SUPPORTS SAFETY AND EFFICACY OF THE CLINICAL USE STATES OF THE ART REGENERATIVE THERAPY FOR KNEE OA. THIS PARTICULAR QUESTION IS EXTREMELY LARGE BUT OUR DISCUSSION UP TO THIS POINT ON PLATELET RICH PLASMA IS COVERED SOME OF THE ANGLES AND I AM GOING TO PUT OUT THAT I WOULD FAVOR MAYBE A LITTLE BIT ADDITIONAL DISCUSSION ON THIS BUT SPENDING MORE TIME ON WHAT ARE THE EMERGING AND -- QUESTIONS 2 AND 3. TALKING ABOUT EMERGING APPROACHES IN AREAS OF RESEARCH OFFERING NEW OPPORTUNITIES FOR CARTILAGE PRESERVATION AND RESTORATION IN KNEE OA. I WOULD FAVOR SPENDING MORE TIME ON THAT BECAUSE OVERALL SUMMATION OF CLINICAL EVIDENCE FOR MOST COMMON ORTHO BIOLOGICS AS WE HAVE DISCUSSED WITH PRP VERY, VERY IMPERFECT AND PRP TREATMENT OF KNEE OA AS DR. SHAPIRO MENTIONED HAS ARGUABLY THE LARGEST BODY OF EVIDENCE. I WILL THROW OUT MY OPINION HOW MUCH TIME WE SHOULD SPEND ON THIS AND WHETHER TO MOVE TO THE NEXT QUESTION. >>AGREE, CONNIE, WE SPENT A LOT OF TIME ON QUESTION ONE, SAFETY AND EFFICACY, I THINK WE CAN ONE PART PUT IT TO BED. SAFETY, MOST AUTOLOGOUS SEEM TO BE SAFE. SO SECOND PART OF THE QUESTION IS WHERE WE NEED DATA EVE DA SCHISM WHAT SUPPORTS EFFICACY OF AT LEAST OF THESE THERAPIES. WE CAN DISCUSS THAT THE LAST FOUR OR FIVE HOURS DATA IS THERE, MIXED AT BEST. MODEST AT BEST. QUESTIONS TWO AND THREE, IF SOMEONE CAN PUT THEM IN THE CHAT, THE MEAT OF THE DISCUSSION. AS FAR AS PLANNING MOVING FORWARD. EMERGING APPROACHESES IN YARRS OF RESEARCH OFFERING NEW OPPORTUNITIES. WE DISCUSS, EXOSOMES OR GENE THERAPY OR APPROACHES WE HAVE HEARD NOVEL APPROACHES, HAVE A DISCUSSION HOW WE MOVE FORWARD TO FURTHER EVALUATE THESE INNOVATIVE OR EMERGING APPROACHES. WE PRPs IN CELLS PRETTY GOOD NOT THAT THERE AREN'T OUTSTANDING QUESTIONS BUT WHAT IS NEXT ON THE HORIZON? >>YEAH. SHOULD WE TALK -- SHOULD WE FLIP THAT AND ACTUALLY TALK ABOUT BECAUSE WE ARE TALKING ABOUT CLINICAL EVALUATION. SO OR WE CAN JUST GO IN ORDER BUT REALLY THERE ARE CHALLENGES AND GAPS, IN THE CLINICAL EVALUATION OF CLINICAL OUTCOMES THAT IS A MAJOR IMPEDIMENT TO US HAVING THE EVIDENCE WE NEED TO BASE OUR TREATMENT DECISI DECISIONS BUT N ORDER TO QUESTION TWO. DOES JENNIFER, DID YOU HAVE SOMETHING TO SAY? >>I WANT TO BRING UP A POINT THAT POTENTIALLY RELEVANT FOR ALL THEM. T WE TALKED TODAY ABOUT UNDERSTANDING THERAPEUTIC MECHANISMS, BETTER CLINICAL TRIALS BETTER THERAPIES. IT IS STILL GENERAL THERAPIES THAT WE THINK ABOUT, FIELDS SUCH AS CANCER HAVE COMBINATION THERAPIES THAT ARE REALLY MAKE A HUGE DIFFERENCE, THINKING ABOUT CELLS IN IMMUNE SYSTEM HANDLE IMMUNE STROMAL COMMUNICATION WHETHER IT BE STEM CELLS, OTHER STROMAL PARTS THEN TALK IMMUNE RESPONSE. WE HAVE SHOWN THIS POSITIVE FEEDBACK LOOP YOU CAN HIT ONE BUT THEN NOT -- THEY ARE GOING TO FORM BECAUSE YOU ARE NOT HITTING BOTH OF THE PATHWAYS. I REELIZE THIS INCREASES COMPLEXITY OF CLINICAL TRIALS AND IF I BRING IT UP TO PEOPLE THEY JUST SAY IT IS NOT POSSIBLE TO DO THIS TYPE OF TRIAL REGULATORY PATHWAYS TOO DIFFICULT BUT I THINK IT IS POTENTIALLY CRITICAL FOR THE FIELD. >>THANK YOU, DEFINITELY AGREE. WITH SOMETHING COMPLEX AS OA, WE NEED TO TAKE A SYSTEMS BASED APPROACH, JOHNNY HAS DONE SOME CLINICAL TRIALS WHERE HE TRIED TO DO SOME COMBINATION THERAPIES AND HE HAS HIS HAND UP. >>I AGREE WITH JENNIFER, WE TALK ABOUT CARTILAGE BUT I THINK A LOT OF WORK BEING DONE AT CELLULAR SENESCENCE HAVE SHOWN SENESCENCE CELLS ARE DETRIMENTAL FOR CARTILAGE AND MAYBE IN THIS CASE ELIMINATE THEM AND THIS IS KIND OF WHEN WE THINK ABOUT (INAUDIBLE) WE THINK ABOUT PRP OR BMAC OR STEM CELLS SINOLITIC DRUGS CAN BE USED TO SENESCENCE CELLS. THEY DON'T HAVE TO BE USE ALONE, THEY CAN BE USED IN CONJUNCTION WITH STEM CELLS. AND ALSO I WANTED TO SAY FIBROSIS HAS BEEN A BIG PROBLEM FOR SKELETAL MUSCLE BUT TURNS OUT CARTILAGE REPAIR LEAD TO FIBER CARTILAGER WE THINK IS FIBROSIS AND CARTILAGE NOW APPROACH BLOCK TGF BETA 1 REDUCE TGF BETA 1 NOT ELIMINATE BUT REDUCE IT IN CARTILAGE REPAIR. SO WHAT WE HAVE STARTED, IN THE CLINIC, I WANT TO MAKE FINAL POINT ABOUT THE FACT WHEN A PATIENT COME AND SEE A SURGEON AND HE IS THINKING ABOUT JOINT REPLACEMENT, IT IS NOT BECAUSE HE DOESN'T HAVE ANY CARTILAGE IN HIS KNEE. IT IS BECAUSE HE HAS PAIN. WE NOW KNOW STEPS CLEARLY YOU DON'T TREAT KNEE OA YOU TREAT THE PAIN. THEY WOULD LITTLE CARTILAGE SOMETIMES AND HAVE NO PAIN. SO WHAT HE WHICH TRUE TO DO, IS DELAY JOINT REPLACEMENT AS LATE AS POSSIBLE BECAUSE WE ALL KNOW THAT IF YOU GET A JOINT REPLACEMENT AT 55 YOU'RE GOING TO NEED ANOTHER NEED OR HIP AT 75. SO FOR US WE ARE TRYING TO SAY WELL, CAN WE CUT THE PAIN, CAN WE DEVELOP A CONSERVATIVE TREATMENT TO TRY TO DEAL AS LONG AS POSSIBLE THE KNEE OR THE HIP REPLACEMENT. THIS IS WHAT WE HAVE DONE SO WE MOW BMAC IS NOT STEM CELL THERAPY, IT CONTAINS SOME STEM CELLS AND CONTAIN A LOT OF FACTORS SO WHAT WE DID IS COMBINE DM AC TO REDUCE SCAR BUT AT THE SAME TIME WE EWE XENOLYTIC AGENT TO REDUCE SENESCENCE SO WE REDUCE INFLAMMATION IN THE CONTEXT OF OA, REDUCE IT WITH SINOLITIC TREATMENT, WE INJECT DMAC WITH FACTORS IN IT AND AFTER THAT BLOCK THE FIBROSIS. THE GOAL IS TO TRY TO DELAY LONG AS POSSIBLE JOINT REPLACEMENT. THAT IS SOMETHING VERY IMPORTANT BECAUSE PEOPLE DOESN'T COME AND SEE YOU AND SAY I DON'T HAVE CARTILAGE IN MY KNEE, CAN YOU PUT IT BACK IN? THAT WOULD BE AWESOME BUT RIGHT NOW PEOPLE ARE TRYING TO DELAY THIS JOINT REPLACEMENT AS LONG AS POSSIBLE. >>I WOULD AGREE WITH THAT. I'M ON MUTE. >>WE CAN HEAR YOU. >>I HAVE HAD TWO KNEES THAT EAST LASTED 28 YEARS. THE FACT THAT I'M FIVE FOOT ONE, VERY PETITE, ASIAN, AS YOU MIGHT THINK, AND DON'T EAT A LOT OF DAIRY, NO ONE TOLD ME EARLY ON EVER THAT NUTRITION THAT MY JOINTS AND MY BONES NEEDED ALONG THE WAY. I THINK THAT IN TODAY'S HOPEFULLY FAMILY STANDARDS THAT'S DIFFERENT BECAUSE WE ARE VERY NUTRITIONALLY CONSCIOUS NOW SO THAT CAN BE USED TO OUR, I SAY OUR, THOSE WHO TRY TO KEEP PEOPLE MEDICALLY STRAIGHT, IF YOU WILL AND HEALTHY THAT IS ONE OF MY BIG ISSUES DOING SPEECHES JUST TO PATIENTS, IS EVERY ASPECT THOSE KINDS OF THINGS THEY CAN CONTROL, LIFESTYLE, YOU EATING SLEEPING STRESS MANAGEMENT, YOUR WORK LIFE YOUR FAMILY LIFE YOUR CHILDREN, CHILDREN'S LIVE, HOW YOU ARRANGE YOUR DAY, ET CETERA, ET CETERA. IF DR. CHU WERE TO ASK ME AND DR. RODEO ASK ME AMYE, WHAT ARE EMERGING OPPORTUNITIES TO GO INTO FROM A PATIENT PERSPECTIVE? I WANT TO AVOID HAVING TO GO TO DR. HUARD TO GET A JOINT REPLACEMENT BUT I DON'T KNOW I WAIT TOO LONG BY THE TIME THAT HAPPENS. BECAUSE WHEN PAIN EMERGES IT IS SEVERE. I WOULD LIKE TO KNOW EARLIER ON FROM A SELF-ASSESSMENT, THIS CAN BE WRAPPED AROUND JOINT YOUR FINGER, WRAPPED AROUND YOUR WRIST ELBOWS SHOULDERS ANKLE, I HAVE HAD JOINT REPLACEMENTS IN ALL THOSE THAT TELL ME YOU ARE WAITING TOO MUCH ON THE LEFT SIDE OF YOUR LEGS VERSUS THE RIGHT SIDE YOU ARE USING YOUR LEFT ARMOR THAN USING THE RIGHT ARM. THERE IS BODY MECHANICS ACTIVITIES THAT MAY OR MAY NOT BE, HAS TO BE PROVEN FIRST, MAY OR MAY NOT BE HELPFUL BUT TECHNIQUES AND STRATEGIES CAN HELP THE PATIENT DETERMINE HOW SOON OR LATE THEY CAN COME TO YOU FOR THAT KIND OF HELP. FROM ORTHOPEDIC STANDPOINT I NEVER ENCOUNTERED THAT. EVERY TIME I DO IT IS ALWAYS YOU WAITED LONG ENOUGH TO GET HER HERE. THAT WAY CHOICE BECAUSE OF WHAT YOU SAID THEY DON'T LAST THAT LONG SO YOU WANTED TO GET AS GREAT MILEAGE AS YOU CAN. SO DELAY AS MUCH AS POSSIBLE. WHICH ARE TALKING QUALITY OF LIFE, THE ABILITY FOR ME TO ACCOMPLISH MY GOALS AND OBJECTIVES IN LIFE. THAT IS WHAT I WISH. >>THANK YOU. SYSTEMS BASED APPROACH, LOOKING AT SYSTEMIC FACTORS, LIFESTYLE, LOOKING AT XENOLYTICS, COMBINATION THERAPY. WHAT ELSE? ALONG THE LINES OF NEW APPROACH? >>JOHNNY, NICE COMMENTS ABOUT COMBINATION APPROACHES, COMBINING XENOLYTICS OR TGF BETA INHIBITION WITH OUR BIOLOGIC DU JOUR. THREE HANDS RAISED, WE'LL START WITH DR. BARRY. >>THANKS. I WANTED TO MENTION CONTEXT OF EMERGING TECHNOLO TECHNOLOGIES, USE OF INDUCED PLURIPOTENT STEM CELLS AS MODALITY TO EXPLORE, MANY PROBLEMS THAT WE TALKED EARLIER IN TERMS OF CONSISTENCY AND CHARACTERIZATION OF CELLS, MANY PROBLEMS COULD POTENTIALLY GO AWAY IF WE START USING INDUCE PLURIPOTENT STEM CELLS AS THERAPEUTIC. WE ARE EARLY DAYS OF THAT YET. ALSO THE USE OF IPSCs IN MODELING HASN'T HAPPENED NEARLY AS MUCH IN ORTHOPEDIC FEE AS IT HAS IN NEUROLOGY AND THERE'S TREMENDOUS OPPORTUNITIES FOR DEVELOPING NEW ASSAYS AND NEW MODELS, DISEASE SPECIFIC MODEL USING IPSC WE CAN EXPLORE >>IPS INDUCED PLURIPOTENT CELLS, SCALABILITY, MANUFACTURING SCALABILITY, ALL THESE THINGS. >>FIRST THEY PLURIPOTENT, SECONDLY POTENTIALLY HAVE POPULATION THAT WILL GO ON AND ON AND YOU IN PRINCIPLE WON'T HAVE THE PROBLEMS OF SENESCENCE TRANSFORMATION OR CHROMOSOMAL ABNORMALITIES YOU HAVE WITH PRIMARY CELLS, THESE ARE ADVANTAGES, NOT ALL FULLY EXPLOITED YET BUT POTENTIAL IS THERE. >>NOT TO JUMP IN BUT MOST SCALABLE OF CELLS, FOR REASONS FRANK JUST DESCRIBED. >>I AGREE WITH ALL THESE COMMENTS ABOUT IPS AND LARGE PART IS GETTING CONTROL OVER VARIATION. THAT WE HAVE. SO IPS IN CULTURE EXPANDABLE CELLS AND ENGINEERS CELLS, THESE ARE CLONAL CELLS FROM SINGLE GENOMIC BACKGROUND, START FROM SINGLE CELL, CHARACTERIZE AND MON FOR OVER TIME AND THAT THEY ARE NOT ALL STABLE AND THERE ARE DUPLICATIONS AND MUTATIONS IPS CELLS, NOT AS CLEAN UP PLATFORM AS WE LOVE BUT IT WILL IMPROVE. THE COMMENT I WILL MAKE WAS TWOFOLD. ONE WAS WHERE WE ARE LIMITED IN A PLACE WE HAVE OPPORTUNITIES IS -- I DON'T THINK WE WILL MOVE FORWARD VERY MUCH. WITH PRP AS A THERAPY, UNTIL WE HAVE STANDARDS FOR IT. IF WE DID A STUDY WITH THIS OR THAT CENTRIFUGE, I MAY OR MAY NOT WORK. ONE CENTRIFUGE DOESN'T WORK BUT WE DELIVERED A WIDE VARIETY OF -- CENTRIFUGE BECAUSE EVERY PATIENT DIFFERS. UNTIL WE HAVE A WAY TO MAKE A PRP PREPARATION WHERE WE DEFINE WE WANT CONCENTRATION IN THIS RANGE, WE WANT TO ELIMINATE A CERTAIN GROUP CYTOKINES ARE WITHIN THIS RANGE, WE WANT TO ELIMINATE NUCLEATED CELLS OR RED CELLS WITHIN THIS RANGE SO WE HAVE THAT CONTROL, THERE IS HONESTLY NO WAY OR REASON FOR PROSPECTIVE RANDOMIZE TRIAL, NOT GOING TO MEAN ANYTHING EVEN IF SUCCESSFUL OR FAIL BECAUSE ONLY PROVE ONE AND ONLY ONE THING THAT WE WILL WANT TO CHANGE IN THE FUTURE. SO I'M NOT A GREAT FAN OF INVESTING LOTS OF ENERGY DESIGNING A PROSPECTIVE RANDOMIZE PRP TRIAL UNLESS ALL THOSE VARIABLES. THIS SPEAKS TO SOMETHING AMYE BROUGHT UP, WE ALSO STRUGGLE WITH PICKING THE RIGHT PATIENT AND CONTROLLING THE PATIENT VARIABILITY. WE HAVE NO CONTROL OVER PATIENT VARIABILITY. BUT ALL OUR PATIENTS PRESENT WITH NOT JUST ARTHRITIS IN ONE JOINT, IT COULD BE MEDIAL LATERAL SIDE, FEMORAL IN CASE OF KNEE AND NOT INVOLVE MEDIAL LATERAL SIZE, THOSE ARE DIFFERENT PROBABILITIES OF FAILURE ALREADY, WE KNOW THAT FEMORAL DISEASE AT LEAST IN OUR PRACTICE IS A NON-RESPONDER NO REASON TO OFFER SOMEBODY WITH PRIMARY FEMORAL DISEASE PRP INJECTION WE HAVEN'T SEEN RESPONSES IN THOSE PATIENTS. BUT PATIENTS PRESENT WITH OBESITY OR NOT SYSTEMIC INFLAMMATORY MARKERS ARE NOT OSTEOPOROSIS ARE NOT, WE ARE NOT COMPARTMENTALIZING THOSE PATIENTS OR CATEGORIZING OR EVEN COLLECTING DATA IN A WAY SYSTEMATICALLY ALLOWS US TO DO RETROSPECTIVE ANALYSIS IF THERE IS A COHORT OF PATIENTS WE ARE PARTICULARLY GOOD OR BAD AT ALREADY. OR VITAMIN D DEFICIENT OR NOT, THIRD OF MY PATIENTS UNDERGOING THE ARTHROPLASTY WHEN WE SCREEN THEM OR VITAMIN B DEFICIENT BEFORE WE COME IN AND WE HAVE TO CORRECT THAT BEFORE SURGERY. SO WE HAVEN'T TAKEN THE SYSTEMIC APPROACH, AS ONE JOINT AT A TIME APPROACH, THAT IS A MISTAKE. >>RIGHT ON. >>GEORGE YOU HAVE THE DATA AT THE CLEVELAND CLINIC. YOU HAVE BEEN DOING THIS SINCE I WAS THERE. ALL THIS DATA IS RIGHT THERE. YOU CAN DO THIS RETROSPECTIVE ANALYSIS, YOU HAVE EVERY PATIENT THERE WITH ALL THAT DATA. >>IT IS DESIGNED WELL, THERE IS PLACE WHERE PATIENTS ENTER DATA, PLACE WHERE PHYSICIANS ENTER DATA WE CAN CAPTURE THAT DATA BUT HALF THE PATIENTS DON'T COME BACK. WE DON'T HAVE A HIGH QUALITY STUDY WE GET MORE PATIENTS TO COME BACK AND PROVIDE OUTCOMES SO WE CAN REPORT ON PATIENTS THAT DO COME BACK BUT THERE ARE PATIENTS THAT DON'T COME BACK IN THE SYSTEM. WE DON'T NECESSARILY COMPARTMENTALIZE INFLAMMATORY MARKERS OR WE HAVE MEASURES OF OBESITY. WE KNOW IF THEY HAVE ONE OR BOTH THESE INVOLVED BUT WE DON'T HAVE NECESSARILY SYSTEMATIC INFORMATION ON ALL THOSE, ALL THOSE OTHER PARSING PHENOMENON BUT WE ARE TRYING, I THINK THAT IS THE POINT. WE DO THAT DATA, I HAVE DATA CONNIE HAS DATA. WE ALSO HAVE A GOOD WAY TO SYSTEMATICALLY MERGE DATA INTO SOMETHING WHERE WE COULD MAKE IT MORE POWERFUL. >>BUT THAT WOULD BE IMPORTANT. IT REALLY LOOKING AT THE SYSTEMIC ASPECTS, THAT MAJOR THING TO HIGHLIGHT FROM OUR DISCUSSION HERE DANIEL WHITE HAS HID HAND UP FOR A WHILE. >>THANK YOU. ANDREAS AS WELL. >>FROM MY PERSPECTIVE AS PHYSICAL THERAPIST EMERGING LITERATURE ABOUT UNDERLOADING BEING A RISK FACTOR FOR THE DEVELOPMENT OF OSTEOARTHRITIS AND PATELLA FROM OSTEOARTHRITIS AND THAT HIGHLIGHTS THE NEED FOR PAYING ATTENTION TO THE LOADING ENVIRONMENT AND HOW IMPORTANT THAT IS. ALL MAJOR MEDICAL ASSOCIATIONS RECOMMEND SORT OF STANDARD EXERCISE AND BEING PHYSICALLY ACTIVE FOR KNEE OA. I THINK AN IMPORTANT AREA TO CONSIDER ARE INTERVENTIONS YOU TALK ABOUT CAN BE DONE IN CONJUNCTION WITH AN EXERCISE PROGRAM SO THAT YOU ARE LEVERAGING THE BENEFITS OF BOTH EMERGING THERAPY AS WELL AS TRIED AND TRUE OPTIMIZE PATIENTS SORT OF HEALTH STATUS. GIVING THE FAR REACHING BENEFITS OF EXERCISE AND PHYSICAL ACTIVITY FROM EVERYTHING FROM MOOD AND PSYCHOSOCIAL STATUS TO PAIN AND HEALTH RELATED QUALITY OF LIFE, WHY NOT LEVERAGE THAT IN ADDITION TO MERGING APPROACHES AND COOL APPROACHES THAT FARSHID WAS TALKING ABOUT WITH THE TRIED AND TRUE. MY THOUGHTS USING A MULTI-MODAL APPROACH FOR INVESTIGATING USE IN THOSE AREAS. >>GOOD POINTS. ANY THOUGHTS HOW THIS DATA CAN BE COLLECTED IN A SYSTEMATIC AND FASHION EASY TO USE? >>FROM GENERAL ACTIVITY LEVEL, OBJECTIVE MONITORS USED WELL ESTABLISHED TO RECORD PEOPLE'S PHYSICAL ACTIVITY AS WELL AS A BIG EMERGING AREA IS SEDENTARY BEHAVIOR. MOST OF US ARE SITTING RIGHT NOW AND HOW MUCH SITTING WE ARE DOING AND HOW THAT -- WHAT THE RATIO OF SITTING TO WALKING TO STANDING ARE. USING RESEARCH GRADE MONITORS WELL ESTABLISHED PROTOCOLS ARE SIMPLE WAY THEY CAN BE INCORPORATED AT A MINIMUM AS OUTCOME MEASURE INTO ANY STUDY. HOPE THAT ANSWERS YOUR QUESTION. >>THANK YOU. ANDREAS. I THINK MAYBE ALSO BRIEFLY INTRODUCE YOURSELF. >>ANDREAS, HHS, I'M A CLINICIAN -- I >>I KNOW YOU I WANTED TO MAKE SURE EVERYBODY HAD A CHANCE TO HEAR YOU. >>WE HAVE KNOWN EACH OTHER FOR 20 YEARS. I THINK WHAT CONFUSES ME AS A CLINICIAN THE MOST, THIS IS PICKING UP A POINT GEORGE MADE IN TERMS OF HOW IT DOESN'T RESPOND TO PRP INJECTIONS. I SEE PATELLA FEMORAL ISSUES AFTER A ACL. TEN YEARS AGO HAD ACL BUT NOW A LESION. DOESN'T MAKE SENSE BUT PICKS UP ON WHAT DANIEL SAID IN TERMS OF MAYBE CHANGES IN QUAD STRENGTH, MAYBE PEOPLE BECOME MORE HAMSTRING, THAT LEADS TO ARTHRITIS. BUT ARTHRITIS IN PEOPLE WHETHER PLAYED BASKETBALL SINCE THEY WERE FOUR SO THAT'S REPETITIVE MICROTRAUMA AND I SEE THAT IN PEOPLE WITH PAT LA ALL THE TIME, -- PATELLA ALL THE TIME AND DON'T MECHANICALLY HAVE GOOD TRACK AND THEN I SEE TIP OF ICEBERG IN PATIENTS WHO HAVE JOINT DISEASE. ON X-RAY THEY MIGHT LOOK THE SAME AND WE ALL THEM ARTHRITIS BUT THEY HAVE DIFFERENT CHALLENGES AND AS LONG AS WE THROW EVERYONE IN THE SAME POT, SAY LET'S TREAT THIS ARTHRITIS PATIENT THE RESULTS AND THAT IS WHAT WE HAVE, ARE VERY CONFUSING. AS CLINICIAN NOT CALL PEOPLE ARTHRITIS BUT GET SUBCATEGORIES AND GET BETTER, I THIS I THEN OUR TRIALS WOULD BE BETTER. >>WE TALKED THE NEED TO PHENOTYPE PATIENTS AND TREMENDOUS HETEROGENEITY IN PATIENT PHENOTYPE. >>MULTI-DISCIPLINARY MODELING OF THE DIFFERENT OA SUB TYPES. SO WE WILL DEFINITELY HIGHLIGHT THOSE ARE AREAS OF -- THANK YOU, ANDREAS. SHALL WE MOVE TO THE NEXT TOPIC? >>LARISSA'S POINT WEIGH IN ON THIS FROM THE REGULATORY. >>I JUST WANTED TO COME BACK TO THE COMMENTS ABOUT THE IMPORTANCE OF HAVING A STANDARD DEFINING HOW YOU MAKE THESE PRODUCTS WHETHER PRP CELL THERAPY, STEM CELLS, MESENCHYMAL STEM CELLS, MEDICINAL SIGNALING CELLS, WHAT ARE ARE WE TALKING ABOUT HOW ARE WE MAKING THEM, THERE HAVE TO BE MORE OR LESS DEFINED APPROACH. BEFORE WE GO INTO CLINICAL TRIALS WE HAVE TO LOOK AT THE QUALITY AND CONSISTENCY HOW THESE TREATMENTS ARE MADE. MAYBE AS A GROUP MAYBE ONE OUTCOME OF THIS DISCUSSION WE COULD FIND WAYS TO TRY TO CONTRIBUTE TO DEVELOPMENT OF STANDARDS HOW THESE PRODUCTS COULD BE POTENTIALLY MADE BEFORE THEY TRIED. THAT IS ONE COMMENT. THE OTHER IT WAS STRIKING TO SEE IN THE PRESENTATIONS, HOW SOMEBODY LOOKED AT CLINICALTRIALS.GOV AND DIFFERENT TYPES OF THERAPIES WHEN THEY START WITH THOUSANDS OF TRIALS AND WHEN PRODUCT GO INTO PHASE 3 THERE ARE FEW LEFT. I WANTED TO MAKE A POINT THERE'S PROBABLY A REASON FOR WHY THERE ARE FEW LEFT. BECAUSE IF THEY WERE PROPERLY INVESTIGATED, THEY DIDN'T WORK. SO THAT IS ANOTHER CONTEXT FOR OUR BELIEFS IN THINGS WE ARE TRYING TO BUY OURSELVES INTO. AGAIN IT IS REALLY IMPORTANT TO HAVE QUALITY INVESTIGATIONS DONE WITH THESE PRODUCTS AND BE A LITTLE MORE SKEPTICAL BEFORE WE JUMP INTO BELIEVING THINGS WILL WORK. >>I HAD TO SUMMARIZE ONE THING THAT'S COME OUT OF SIX HOURS, PRIORITIES FOR MOVING FORWARD CONTACTIZATION. STANDARDIZATION AND CHARACTERIZATION VARIOUS WAYS GEORGE MENTIONED WITH PRP. RECOGNIZE LIMITATIONS BUT CLEARLY EVERYTHING STARTS THERE. A ROT STARTS TH LOT OF IT STAR >>YES. >>GO TO NUMBER 3, CHALLENGES AND GAPS, LOT OF THIS COME OUT. >>BACK TO AMYE, THE QUESTION I ASKED AT THE VERY BEGINNING AND YOU ANSWERED NICELY, THE BARRIERS TO CLINICAL TRIALS.MENT SO SAY WE HAVE A PREPARATION WE CAN STANDARDIZE. WE CAN CHARACTERIZE IT. WE RUN A CLINICAL TRIAL IN A REALISTIC FASHION, HOW DO WE DO MULTI-CENTRIC TRIALS. RHETORICAL QUESTION CHALLENGE BUT THESE ARE THE CHALLENGES. >>I HAD ADDRESS TO ONE OF THE QUESTIONS THAT WAS SUBMITTED TO ME WAS HOW TO ATTRACT MORE PEOPLE AND CONSISTENTLY IN PEOPLE MORE THAN SEVERAL TIMES WHERE PEOPLE START OUT IN CLINICAL TRIALS BUT CHOOSE NOT TO FURTHER PARTICIPATE. IT WAS VERY CLEAR, I WAS SURPRISED THAT THERE IS EVEN A CHOICE BECAUSE IT WASN'T DEFINED CLEARLY ENOUGH PATIENT IN TERMS OF THAT CHOICE OR AT LEAST OPPORTUNITY FOR FURTHER EDUCATION AND EXPLANATION MAYBE SOME WIGGLE ROOM, CAN'T DO TOO MUCH BUT I THINK THAT PARTICULARLY IN AREA OF CARTILAGE ANYTHING ABOUT CARTILAGE HERE IS MY QUESTION TO THE ILLUSTRIOUS PANEL FOR THOSE THAT CONDUCTED STUDIES, WHAT NOT, HOW DO YOU EXPLAIN IT TO A PATIENT? THEY GET THE IDEA IT IS CARTILAGE, I USED EDUCATIONAL PATIENT LECTURERS, I USE THE CHICKEN BONE AS A PERFECT EXAMPLE. ARE YOU STILL DOING THAT? SEEMS HIGHLY EFFECTIVE. EVEN VEGANS KNOW WHAT A CHICKEN BONE WITHOUT THE MEAT LOOKS LIKE. AND THAT'S A GREAT START. YOU HAVE TO GIVE THE PATIENT A LEAP OF FAITH TO OKAY THAT IS WHAT THE CARTILAGE IS, WHAT WE ARE DOING OUR STUDY ON. NOW WE WANT TO TEST YOURS OUT. SO THEN ALL THE FEAR, ARE YOU GOING TO HURT ME, PUT SOMETHING UNUSUAL IN ME THAT I'M NOT GOING TO CONTROL. THERE'S ALL THE QUESTIONS AND IF YOU DON'T ANSWER UP FRONT WILL ABSOLUTELY FILTER UP, MAYBE NOT DURING THEIR -- YOUR SESSION WITH THEM OR YOUR NURSE PRACTITIONER SESSION SESSION WITH THE PATIENT BUT CERTAINLY WILL FILTER UP, HAVING SOME SESSIONS IN SOME WAY COLLECTIVELY SUPPORTED CONVENED BY THE FDA BY LARISSA MIGHT BE HELPFUL IN AREAS WHERE CLINICAL TRIALS HAVE TO BE DONE ON PARTS OF PEOPLE'S BODIES THAT JUST SCARE THE HOLY BEJESUS OUT OF THEM, THAT IS MY QUESTION TO YOU HOW SUCCESSFUL HAS IT BEEN, REPEAT SCENARIO WHAT IS YOUR EXPERIENCE AND SHARING WHAT WORKS. SHARING WHAT DOES DID NOT WORK IS VALUABLE TOO. >>CLINICAL TRIALS ARE HARD BECAUSE PATIENTS COME IN BELIEVING THE STUFF ALL WORKS AND DON'T WANT RANDOMIZE, THEY WANT THE ACTIVE TREATMENT, IT IS AN AREA WE AS PHYSICIANS NEED, PATIENTS THINK ITAS. THAT IS ONE MORE -- IT DOES. THAT IS ONE MORE CHALLENGE especially relevant to regenerative medicine due to aggressive marketing and everything out there. >>DANIEL, I DON'T KNOW IF YOU CAN SEE ME I HAD TO MOVE TO MY CAR FROM MY OFFICE I'M SORRY. I'M QUITE COMFORTABLE ADDRESSING SOME OF THOSE QUESTIONS BECAUSE YOU AND OTHERS PROBABLY KNOW WE HAVE DONE A COUPLE OF TRIALS THAT LED TO THE REGISTRATION OF THESE PROJECTS AND I EVEN HAD TO TALK TO PATIENTS TO RANDOMIZE AGAINST MICROFRACTURE FOR THE SECOND TIME IN A SECOND MULTI-CENTER TRIAL AND IT COMES DOWN TO BEING HONEST AND TRANSPARENT ABOUT WHAT WE KNOW AND WHAT WE DON'T KNOW. AND IT COMES DOWN TO THE PATIENT DOCTOR TRUST AND IF THEY TRUST YOU THEY WILL TRUST YOU ARE DOING THE TRIAL FOR A GOOD REASON. CONTRARY WHAT I HEAR PEOPLE SAY I HAVE NOT FOUND A SINGLE PROBLEM WITH RANDOMIZATION OF THE PATIENTS. UNLESS THEY GET THE IDEA THEY ARE USED FOR MARKETING PURPOSES. THOSE STUDIES DON'T DO WELL, BUT IF THERE IS REAL SURGICAL EQUIPOISE OR SCIENTIFIC UNCERTAINTY PATIENT WILL FOLLOW WHAT DOCTOR EXPLAINS TO THEM, IF THEY EXPLAIN IT UNDERSTANDABLE TERMS THAT IS MY EXPERIENCE. >>FARSH. >>I HAVE A QUESTION ABOUT THE CLINICAL TRIALS ISSUE. LACK OF GOOD CONTROL GROUP, THERE IS A HUGE PLACEBO EFFECT IN OA STUDIES PARTICULARLY IF THE KNEE HAS INJECTION IN IT OR ANY INJECTION OCCURS, 20 TO 40% PLACEBO EFFECT. IF YOU HAVE A TRIAL WITHOUT THAT IT IS NOT GOING TO BE MEANINGFUL. YOU SEE AN EFFECT. THE OTHER IS I HAVE BEEN REVIEWING CLINICAL TRIALS ON MSC AND I WOULD SAY A GOOD NUMBER ARE NOT TRIALS, THEY ARE JUST REGISTERED WITH NUMBER OF PATIENTS FOR VARIOUS OF THESE FLY BY NIGHT CLINICS TO SAY WE HAVE A TRIAL ONGOING. THEREFORE NEVER REPORTED. ANOTHER GROUP NOT REPORTED BECAUSE THEY HAVE NEGATIVE FINDINGS OR INCONCLUSIVE FINDINGS, BECAUSE OF THAT THERE IS INCREDIBLE STATISTICAL BURDEN ON THE TRIALS THAT ARE RUN PROPERLY. SO THINK IF AS A LABORATORY YOU JUST TOSSED 50% OF YOUR DATA BECAUSE IT WASN'T SIGNIFICANT, AND YOU JUST REPORTED THE POSITIVE SIDE WHAT DOES THAT MEAN? TERMS OF THE STATS FOR YOUR POSITIVE FINDINGS? AS A FIELD WE HAVE DONE THAT. SO IF WE HAVE CLINICAL TRIALS NOW WE HAVE A BETTER FINDING FOR IT TO BE MEANINGFUL BECAUSE HALF THE BATTLE IS THROWN OUT WHETHER YOU THROW IT OR NOT, IT IS A BIG STATISTICAL PICTURE OF WHERE WE ARE AS A FIELD. BETTER OVERSIGHT ON THIS AND THE REPORTING. IT IS A BRAIN DUMP AND WE NEED BETTER CLINICAL TRIALS, NOT JUST MORE CLINICAL TRIALS. >>AGREED. ALSO TO SPECIFY AHEAD OF TIME THE PRIMARY OUTCOME WE TALKED THROUGH THIS MEETING ABOUT HOW STRUCTURAL OUTCOMES DO NOT RELATE TO PAIN OR SYMPTOMS OR EVEN FUNCTION UNTIL LATE IN THE DISEASE IF SOMETHING IS SPECIFICALLY TO REPAIR THE CARTILAGE I WOULD SUBMIT PRIMARY OUTCOME SHOULD NOT BE PATIENT REPORTED PAIN, THAT IS STILL AN IMPORTANT OUTCOME BUT IF YOUR THERAPY IS GEARED TOWARDS REPAIRING AND REGENERATIVE CARTILAGE, IT IS ALSO VERY IMPORTANT TO HAVE A STRUCTURAL OUTCOME HOW LONG IT DID THA THA. NOT SAYING TO IGNORE PATIENT REPORTED OUTCOME BECAUSE AS WE TALKED ABOUT THAT'S THE MAIN REASON THE PATIENT SEEKS TREATMENT BUT SYMPTOMS MAY AS WE KNOW SYMPTOMS IN OA DEVELOP LATER, TYPICALLY LATER THAN STRUCTURAL DISEASE SO IF WE ARE TRYING TO OPT FOR EARLY TREATMENT,S THE CARTILAGE REPAIR PROCEDURES ARE TO ALTER PRESUMABLY IMPROVE STRETCHER SO THERE NEEDS TO BE MORE ACCEPTANCE IN THE CLINICAL TRIALS, WHAT STAGE OF OA ARE WE TALKING ABOUT AND WHAT ARE THE IMPORTANT OUTCOMES FOR THAT STAGE. END STAGE DISEASE YES AS JOHNNY AND OTHERS MENTIONED. IF YOU ARE TRYING TO GET PEOPLE TO HAVE LESS PAIN SO THAT THEY CAN FUNCTION BETTER AND STAVE OFF THE JOINT REPLACEMENT, THEN THAT IS ANOTHER OUTCOME BUT EARLY ON I DON'T THINK THAT CAN BE THE PRIMARY OUTCOME LIKE TO ASK CAROLYN LUTZKO. >>YOU MAY RECALL, SO MY INTEREST IS IN DEVELOPMENT AND MANUFACTURING OF CELL BASED THERAPIES. SO IN LISTENING THROUGH THE DISCUSSION, MOST OF MY WORK IS BLOOD AND GENETICS RELATED. THE MOVEMENT TOWARDS ALLO TRANSPLANTS OR ALLO THERAPIES IS GOING TO HELP THAT REALLY GETTING AT THE QUESTION BECAUSE YOU CAN CENTRALIZE YOUR MANUFACTURING AND IF YOU HAVE MORE LIKE INVESTIGATIONAL PHARMACY AT MANY SITES, ENROLLMENT MAYBE DIFFERENT AT LEAST YOU CAN TACKLE THAT, WHETHER IT'S MSCs, EVEN PRP, IT WOULD BE FROZEN,NA IPS ARE GREAT WAY TO DO THAT. I THINK IT COULD -- YOU CAN GET IT SOME OF THESE DIFFERENTLY AS WE -- IF WE CAN AND AS WE MOVE TO ALLO THERAPIES. >>THANK YOU. >>GEORGE MUSCHLER. >>I WAS GOING TO COME BACK TO COMMENT MADE IN ADDITION TO BEING ABLE TO SELECT PATIENTS TO BE PARTICIPANTS IN THESE STUDIES GETTING THEM TO COME BACK FOR FOLLOW-UP AND REMAIN YOU MADE THE STATEMENT YOU CAN'T BELIEVE THAT IS AN OPTION TO NOT FOLLOW-UP. SO THAT IS -- WE FEEL THAT WAY TOO BUT THE ONLY POWER THAT CLINICIANS HAVE IS TO BUILD TRUST AS SHANE MENTIONED AND DANIEL MENTIONED AND TO SHOW THE PATIENT YOU CARE ABOUT THEM COMING BACK. CLINICAL COORDINATORS ARE ESSENTIAL IN THAT PROCESS. TO THIS DAY BUT STILL PATIENTS HAVE OPTIONS. AND ONE OF THE LEVERS THAT HAS NOT BEEN APPLIED TO THESE STUDIES AND THERE MAYBE AN OPPORTUNITY TO DO THAT IS TO PARTNER WITH PAYERS BECAUSE YOU CAN IMAGINE A PATIENT WHO WOULD LIKE TO HAVE ACCESS TO THESE THERAPIES AND LIKE TO BE PARTICIPANT IN A STUDY, A PAYER WHO WOULD LIKE KNEE REPLACEMENTS AND HAVE CHEAPER OPTION BUT WOULD REIMBURSE A PATIENT ONLY IF THEY CAME BACK TO FOLLOW-UP. AS PART OF THE STUDY. THERE IS AN OPPORTUNITY THERE. WE GOT A LITTLE WAY DOWN THE ROAD WITH MEDICAL ABOUT SIX OR EIGHT YEARS AGO AND SOME LEADERSHIP CHANGED BUT THERE IS AN OPTION WHERE FOR ANY OF US WHO LIVE IN AN ENVIRONMENT WITH COLLABORATIVE PAYER TO IMPROVE PATIENT PARTICIPATION. >>THANK YOU. I THINK DAN'S COMMENT HIGHLIGHTED THE IMPORTANCE OF BUILDING TRUST IN TRANSPARENCY AND IF YOU HAVE THE PAYERS INVOLVED ARE YOU CONCERNED GEORGE, THERE MAYBE EFFECT ON HOW PATIENT VIEWS THEIR TREATMENT? >>HOPEFULLY NOT, HOPEFULLY THEY -- IN OUR CASE WHERE OUR OPINION IS THAT WE USE SIX MONTH FOLLOW-UP AS WINDOW SO NOT A LONG FOLLOW UP, WE KNOW IT IS WITHIN A YEAR PATIENTS ARE THINKING OF US, THEY HAVEN'T CHANGED THEIR ADDRESS OR PHONE NUMBER. NOT CHANGED JOBS SO IT IS POSSIBLE TO REACH THEM. THEY STILL HAVE THE SAME PAYER DURING THAT TIME. THERE IS NO REASON TO MAKE THIS CO-WE ARESIVE, WE WANT TO KNOW, ARE YOU BETTER, WORSE, DO YOU CLIMB STAIRS, NOT CLIMB STAIRS B ARE YOU STILL WORKING, STILL PLAY SPORTS, THERE IS A LIMITED NUMBER OF QUESTIONS AND WE DON'T HAVE TO DESIGN IT IN A WAY TO PHYSICALLY COME BACK UNLESS WE HAVE IMAGING TO DO OR INFLAMMATORY MARKERS TO DO OTHER THINGS BUT WE CAN MAKE IT EASY ENOUGH TO PATIENTS TO DO IT. I THINK IT IS -- THERE IS NO REASON WE SHOULDN'T HAVE 80 TO 90% FOLLOW-UP ON THESE STUDIES IF WE CAN ALIGN PROCESS AND MAKE EASY FOR PATIENTS TO COMMUNICATE WELL BUT ALSO MOTIVATE THEM SO THEY ARE NOT INCLINED IF THEY ARE UNCERTAIN ABOUT OUTCOME OR ANOTHER SHINEC OBJECT SHOWS UP ON COMPUTER SCREEN AND THEY WANT WANT THE TRY SOMETHING ELSE, THEY FEEL GUILTY BECAUSE THEY DID SOMETHING ELSE, WE DON'T WANT THEM TO FEEL GUILTY ABOUT THAT. THERE IS HOPE IN COMMUNICATING BUT I DON'T PRETEND IT IS EASY BUT ONE EXTRA LEVER. I DON'T THINK IT WOULD COME, WE ARE NOT ASKING THEM -- NOT PUTTING THEM AT RISK. >>WE COULD ALWAYS CONSIDER PCORI WAY WHICH IS PCORI BASICALLY SAYS YOU WILL PAY PATIENTS FOR THEIR PARTICIPATION, YOU WILL PAY PATIENTS WHO ARE SITTING ON YOUR INVESTIGATION COMMITTEE. YOU WILL PAY THE PATIENT OR TWO SITTING ON EXECUTIVE PROJECT COMMITTEE. THE PAYMENT IS VERY -- IT IS UNDER $50. L IN SOME CASES WE HAVE SEEN WHERE PROBABLY OUT OF $50 PER PERSON MAX OVER THE TIME -- NUMBERS OF RESPONSES THAT THEY WILL NEED TO GIVE, THEY WILL GIVE THEM A LITTLE BIT MORE UP FRONT AND FOLLOW-UP WITH A BIG HIT AT THE END IF YOU WILL. YOU ARE TALKING $35. >>THIS IS DANIEL SORRY TO INTERRUPT BUT I THINK THAT THE ROLE OF THE CRC, STUDY COORDINATOR OR DESK ATTENDANT FIRST POINT OF CONTACT IS IMPERATIVE. ALSO THE FIRST DISCUSSION THAT WE HAVE HAD WITH PATIENTS IN ALL THESE TRIALS IS IS -- WE DON'T HAVE GOOD DATA WE REALLY DON'T HAVE GOOD TRIALS, THIS COULD BE A GOOD TRIAL BUT WE NEED EVERYBODY TO PARTICIPATE IN THE WHOLE TRAJECTORY SO THEY ARE NOT JUST A SUBJECT, THEY ARE A TEAM MEMBER. THE MOMENT THE PATIENT UNDERSTANDS THEY ARE PART OF THE TEAM DOING THE TRIAL NOT JUST PART OF THE SUBJECTS STUDIED, THE ENGAGEMENT IS MUCH DIFFERENT. WE EVEN HAD PEOPLE ASK TO CONTINUE TO FIVE AND TEN YEARS AND HAVE A SURGICAL ARTHROSCOPY, THESE ARE NOT CRAZY PEOPLE, PEOPLE TRYING TO CONTRIBUTE. THAT IS WHY U YOU HAVE 98 AND 100% FOLLOW-UP IF PATIENTS ARE ENGAGED IN RESEARCH QUESTION, THEY ALSO IF THEY DROP OUT IF THEY DON'T SEND IN THEIR QUESTIONNAIRES ANY MORE, THE STUDY WILL BE AT RISK AND SHARE RESPONSIBILITY AND THAT IS ONE ASPECT. AND THE OTHER ASPECT THAT IS BENEFICIAL NOW IS THAT THROUGH TELEHEALTH OPPORTUNITIES HAVE EXPANDED THROUGH COVID REGULATION, WE ARE ABLE TO DO MORE FOLLOW-UPS THROUGH VIRTUAL CONSULTATION AND NOT EVERY TIME DO I NEED TO TOUCH THE PATIENT MYSELF OR DO A KNEE EXAM MYSELF, IF THE IMAGING PROTOCOL IS WELL ESTABLISHED THEY CAN HAVE IMAGING PROTOCOLS DONE LOCALLY IN SCANNERS VALIDATED WITHIN THE TRIAL. AND YOU CAN DO FOLLOW-UP THROUGH QUESTIONNAIRES AND VIRTUAL CONSULTATION WHICH LIMITS THE TRAVEL RISK AND THE DROP OUT SO EVOLVING TECHNOLOGIES ARE TO OUR BENEFIT I THINK. HIGH QUALITY FOLLOW-UP IS IMPERATIVE FOR THE TRIAL. IF YOU DROP BELOW 90% THE CHILD IS AT RISK. >>THANK YOU. SO WE ARE NOW AT 5:20. SO WE ARE SCHEDULED TO HEAR FROM LINDSEY AND BOB CARTER. >>YES, THANK YOU. SO MUCH. I WILL ASK BOB TO OFFER COMMENTS FIRST THEN FOLLOW AFTER THAT. >>THANK YOU. >>THIS HAS BEEN A FANTASTIC MEETING. REALLY APPRECIATE THOUGHTFUL INPUTS FROM AND THE TALKS WAROR WERE SUPERB. SO THANKFUL FOR YOUR TIME AND EFFORT. I DO THINK REGENERATIVE MEDICINE IS FUTURE. I DO THINK WE SOME DAY YOU CAN IMAGINE WE WILL HAVE A THERAPY OR COMBINATION OF THERAPIES THAT IN SOME PEOPLE ARE GOING TO LEAD TO HEALING OF CARTILAGE AND ABEYANCE OF OTHER FACTORS THAT LEAD TO REPETSIVE DEGENERATION INFLAMMATORY CHANGES. SO WE ARE AT THE VERY EARLY STAGE OF THIS. WE ARE WORKING THROUGH THE LOOKING GLASS TRYING TO FIGURE HOW TO GET ON THE OTHER SIDE OF IT. SO I DO THINK WE NEED A WIN I THINK ALL THIS STUFF GOING ON IN SOCIETY, FOCUS ON WHAT IS IT GOING TO TAKE TO HAVE A DEMONSTRATION THAT WE CAN IMPROVE THINGS? WE ACTUALLY HAVE GOOD DATA WE CAN REGROW CARTILAGE WITH FGF 18, IT DID REGROW IT ON LATERAL SIDE, DIDN'T REDUCE PAIN SO PROGRAM WAS STOPPED. WE DO KNOW FROM THAT AND THE DISTRACTION STUDIES THAT WE CAN LEAD TO REGROWTH OF CARTILAGE IN PATIENTS WITH ACTIVE OA IN HUMANS. HUMANS. SOE STARTING POINTS REASONABLE TO BELIEF WILL WORK BUT WE HAVE TO GET A WIN TO SAY HERE IS A PLACE WHERE IT WORKS. TO GEORGE'S POINT, NOT ONLY HAVE TO BE DEFINED IN TERMS OF INTERVENTION, ALSO DEFINED ON WHO THE SUBJECTS ARE. PARTICIPANTS. PARTNERS IN THE STUDY. DEFINING THE PEOPLE YOU THINK MOST LIKELY TO RESPOND DEFINING THE THERAPY IN TERMS OF ALL THINGS YOU SAID IN TERMS OF HOW TO CHARACTERIZE IT AND FINDING A WAY TO GET A WIN, THIS ACTUALLY WORKS WHETHER PRP OR EXOSOMES OR CELLS. I DID GO BACK ORS TALK TALK ABOUT THEIR VERSION OF THE MEAN, DEGREE OF REVERSION TO MEAN IN PATIENTS WITH PAIN IS ASTOUNDING. IF THE STUDIES ARE NOT WELL CONTROLLED, THE REVERSION OF THE MEAN NOT TO MENTION PLACEBO EFFECT, THE VERSION OF THE MEAN IS OFTEN MUCH GREATER. WE WHERE OVERWHELM ANY SIGNALING WE HAVE SO WE HAVE DEAL WITH THAT. ONCE WE HAVE THE BIN WELCOME CHARACTERIZE JOHNNY'S PART OF THIS, HIS CELLS ARE SENT TO CENTER WHERE THEY WILL DO IN DEPTH CELL CHARACTER CAUTIONS AS PART OF REGENERATIVE MEDICINE INNOVATION PROJECT, WE DO NEED TO UNDERSTAND WHAT IS GOING ON, I THINK TO THE POINT DR. BARRY MADE ABOUT CURRENT STANDARDS ARE NOT SUFFICIENT. ONCE WE HAVE A WIN WE CAN START INVESTIGATING MECHANISMS IN HUMAN AND BROADENING OUT -- THIS IS THE POPULATION WE SEE -- WE CAN BELIEVE. WHAT IS MORE GENERAL YOU KNOW THIS IS A WIN, PEOPLE WANT TO BE REIMBURSED BUT AS SCIENTIST, OUR JOB IS TO FIGURE OUT WHO RESPONDS TO WHICH PREPARATIONS. I DON'T KNOW NIAMS CAN FUND THE TRIAL WE NEED. IT MAY LEAD TO BIG IN THE CELL PREPS IF THAT IS WHERE WE GOING, MAYBE TOO EXPENSIVE FOR US. WE HAVE TO FIGURE HOW TO GET THAT DONE AND IT MAY NOT BE ONE AND DONE. THIS IS EXPENSIVE PATH. WITH THAT, I THINK THERE IS HONEHOPE. WE WILL GET THERE, MAE TAKE FIVE YEARS, 50, A HUNDRED BUT THIS IS THE FUTURE, WE ARE JUST STARTING COULDN'T THE PATH, WE ARE EXPLORE -- DOWN THE PATH. WE WANT TO FIGURE HOW TO MAKE THAT PATH STRAIGHT AS POSSIBLE. THANK YOU FOR THE PARTICIPATION. HAVING SAID THAT, I DON'T HAVE TO PAY FOR IT, I'M GOING TO TURN IT OVER TO LINDSEY. >>SKIP THAT QUESTION NUMBER 4 WHAT DO WE NEED BESIDES MONEY, RIGHT? >>YEAH. NO. BOY, AM I GRATEFUL TO THE EFFORT DEVOTED TO ORGANIZING THIS AND TO ALL OF YOU WHO SPENT SO MANY HOURS WITH US, IT WAS A FASCINATING DISCUSSION, I LEARNED A TREMENDOUS AMOUNT, I WAS WRITING DOWN HIGH LEVEL THEMES AS WE REMEMBER GOING ALONG, BOB TOUCHED UPON SO MANY OF THEM, JUST CRITICAL IMPORTANCE OF STUDY DESIGN, CHARACTERIZATION AND STANDARDIZATION OF THE PRODUCT, AND PROCESSES. T THE HETEROGENEITY OF THE PATIENTS FROM MINOR STRUCTURAL DEFECTS TO GENERALIZED OSTEOARTHRITIS OF DECADES AND DURATION AND THE IMPORTANCE OF BETTER UNDERSTANDING THE MECHANISMS. I LOVED WHO WAS IT THAT SAID I'M FORGETTING OFF THE TOP OF MY HEAD, ONE OF OUR PARTICIPANTS PERHAPS A GOAL TREESIS ON MOVING FORWARD, BOY THAT WOULD BE FANTASTIC, IF WE COULD GET TO A WIN THAT WOULD BE AMAZING. HOW TO GET THERE IS NOT CLEAR BUT REALLY APPRECIATED THE THOUGHTFUL DISCUSSION AND IN TERMS OF THE NEW OPPORTUNITIES MANY OF YOU TALKED ABOUT FUTURE IN WHICH COMBINATION THERAPIES ARE BEING APPLIED AND EXAMINED IN RIGOROUS WAYS WE HAVE A LOT OF WORK TO DO TO GET THERE. THE COMMENTS ABOUT IPSCs WERE INTERESTING AND I THOUGHT THAT COMMENTS ABOUT SOME OF THE NOVEL GENE THERAPY EDITING APPROACHES WERE REALLY EXCITING. SYNTHETIC GENE CIRCUITS, SO WE ARE ALREADY SEEING REALLY EXCITING INNOVATIVE APPROACHES IN THIS AREA. THANK YOU AMYE FOR BRINGING US BACK TO CENTER OF THE UNIVERSE. PATIENT HERE. SO IMPORTANCE OF PATIENT ENGAGEMENT, GOOD PATIENT COMMUNICATION CHARACTERIZED BY TRANSPARENCY, THAT WAS CRITICALLY IMPORTANT. LASTLY TOO I WANT TO SAY HOW FORTUNATE WE WERE TO HAVE LARISSA HERE FROM THE FDA. I LEARNED A LOT FROM THAT ONE PRESENTATION, HOPEFULLY Y'ALL FOUND THAT HELPFUL AS WELL. I DON'T KNOW WHAT ELSE TO SAY EXCEPT THANK YOU, THANK YOU THIS WAS REALLY GREAT DISCUSSION ABOUT IMPORTANT COMPLICATED TOPIC. SO THEN PERHAPS ONNA NOTE, I DON'T KNOW WHETHER JONELLE OR TED WERE PLANNING ON LAST WORDS BUT REALLY ENJOYED THIS. >>JUST WANT TO THANK LEADERSHIP FOR THE SUPPORT AND LONG TIME SUPPORT ONE AND A HALF YEARS TO MAKE THIS HAPPEN. THANKS TO PARTICIPANTS TO FOR YOUR CONTRIBUTIONS AND YOUR COMPROMISE, YOU ARE WILLING TO TAKE OUR ASSIGNMENT. AND I APPRECIATE IT. I THINK THIS IS A VERY GOOD ROUND TABLE DISCUSSION. THANK YOU ALL. >>THANK YOU, TED. >>THANKS TO CONNIE AND SCOTT. >>ABSOLUTELY. THANK YOU. >>I THINK WHAT WE SHOULD DO MOVING FORWARD IS TAKE A DAY OR TWO A WEEK OR MONTH AND THINK ON THIS AND COMMUNICATE VIA EMAIL M IF SOMETHING DOES COME OUT OF THIS PUT YOUR THOUGHTS DOWN AND EMAIL TO THE GROUP. IF YOU HAVE RANDOM THOUGHTS HOW WE MIGHT -- WHAT CONCLUSION REACHED HERE AND IMPORTANTLY ACTION ITEMS, WHAT ARE THE REAL PRIORITIES MOVING FORWARD. WE TALKED ABOUT SOME BUT ANY IDEAS THAT COME UP PLEASE SHARE WITH US. >>THANK YOU JONELLE. >>THANK YOU TO EVERYBODY. I'M SORRY, I CUT YOU OFF, DR. CHU. >>DAVID AND EVERYONE, THANK YOU SO MUCH. >>I WAS JUST GOING TO SAY MEETING IS ADJOURNED, HOPE EVERYTHING HAS A PLEASANT EVENING DEPENDING ON WHAT TIME ZONE YOU ARE IN. >>WE WILL SEND PICTURES. >>THANKS FOR TECHNICAL SUPPORT OF DAVID. >>GOOD NIGHT. EVERYBODY.