Regenerative Medicine: Current Concepts and Changing Trends


>>GOOD AFTERNOON. IT GIVES ME GREAT HONOR AND PLEASURE TO INTRODUCE YOU TO TODAY’S SPEAKER, DR. ANTHONY ATALA, THE DIRECTOR OF WAKE FOREST INSTITUTE FOR REGENITIVE MEDICINE AND A PROFESSOR AND CHAIR AT THE DEPARTMENT OF UROLOGY, WAKE FOREST UNIVERSITY SCHOOL OF ç MEDICINE. DR. AT LA RECEIVED HIS MD DEGREE AT UNIVERSITY OF LOUISVILLE AND RESIDENCY AT THE SAME INSTITUTION. AFTER HIS FELLOWSHIP IN UROLOGY AND WORK AT HARVARD MEDICAL SCHOOL, HE MOVED TO WAKE FOREST UNIVERSITY IN 2004. DR. ATALA IS A PRACTICING SURGEON, UROLOGIST AND A RESEARCHER IN THE AREA REGENITIVE MEDICINE. HIS CURRENT WORK FOCUSES ON GROWING HUMAN CELLS, TISSUES AND ORGANS. DR. ATALA IS A RECIPIENT OF MANY AWARDS, INCLUDING THE CRYSTFUR COLUMBUS FOUNDATION AWARD AND THE ROGUE TEG NOLOGY AWARD IN HEALTH AND MEDICINE N2011, HE WAS ELECTED TO THE INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMY OF SCIENCES. OKAY. IF TRANSPLANTATION COULD BE THE SOLUTION FOR INJURED OR DECEASED ORGANS, THEN WE PROBABLY WOULDN’T HAVE DR. ATALA GIVING US THIS TALK TODAY. HE HAS BEEN A PIONEER IN REGENITIVE MEDICINE AND GROWING ORGANS. DR. ATALA ENGINEERED BLADDERS AND FOUND CLINICAL APPLICATIONS AND HELPED THE LIVES OF OTHERWISE INCURABLE PATIENTS. I AM ABSOLUTELY SURE THAT HIS INNOVATIVE THINKING AND INSPIRING LECTURE TODAY WILL BE STIMULATING TO THE GREATER BIOMEDICAL RESEARCH COMMUNITY. (APPLAUSE) SO AGAIN, THANKS FOR HAVING ME. I’D LIKE TO THANK ALL OF THE INDIVIDUALS WHO HOSTED ME TODAY AND I HAD VISITS WITH, INCLUDING NIDDK, AS WELL AS ROB AND THEIR STAFF FROM NID IMPLEMENT AND A LOT OF OTHER COLLEAGUES AND FRIENDS. IT’S GREAT TO BE HERE TODAY TALKING WITH YOU TODAY ABOUT REGENITIVE MEDICINE. SO, REGENITIVE MEDICINE ACTUALLY DATES ITS HISTORY BACK TO THE ORGAN TRANSPLANTATION. IF YOU THINK BACK TO THE FIRST TRANSPLANT, OCCURRED BACK IN BOSTON IN 19 FOUR, THIS SHOWS A PAINTING — 1954 — OF THE FIRST TRANSPLANT EVER WITH JOE IN THE FRONT GETTING THE PATIENT READY FOR THE TRANSPLANT WHILE IN THE BACK ROOM, THE CHIEF OF UROLOGY AND THE BRIGHAM AND WOMEN’S HOSPITAL IN BOSTON RETRIEVING THE ORGAN, A KIDNEY, MANY ADVANCES SINCE THAT TIME. SO MANY LIVES HAVE BEEN SAVED. BUT STILL, WE ARE FACING A LOT OF THE SAME CHALLENGES IN TERMS OF ORGAN REJECTION AND ORGAN SHORTAGE. AND THAT IS WHAT WE TRY TO SOLVE BY THIS FIELD THAT WE CALORIE GENITIVE MEDICINE, WHICH REALLY INVOLVES MANY DIFFERENT AREAS. EITHER USING SCAFFOLDS ALONE OR CELLS ALONE OR BOTH TOGETHER. OR ENABLING TECHNOLOGY SO LIKE SMALL MOLECULES AND WAYS TO ENHANCE TISSUE REGENERATION. AS I MENTIONED, THIS GOES BACK A LONG TIME AND ACTUALLY GOES BACK FURTHER THAN THE AGE OF TRANSPLANTATION. THIS IS A BOOK THAT WAS PUBLISHED IN THE 1930s TITLED, “THE CULTURE OF ORGANS.” I WANT YOU TO KNOW ONE OF CO-AUTHORS OF THIS BOOK AND CHARLES LINBURG. THE SAME CHARLES LINBURG WHO FLEW ACROSS THE ATLANTIC IN THE 1920s. HE SPENT THE REST OF HIS LIFE WORKING AT THE ROCKEFELLER INSTITUTE IN NEW YORK WITH ALEXIS CORREL WHO WENT ON TO DO MAJOR THINGS FOR THE FIELD OF ORGAN REGENERATION. THE FIRST ACTUAL PATIENT EXPERIENCE WHERE A PATIENT ACTUALLY RECEIVED THEIR OWN CELLS FOR THERAPY, JUST PRIMARY, NORMAL CELLS FOR THERAPY, DATES BACK TO THE 1981 WHERE AT THE MASS GENERAL HOSPITAL IN BOSTON, A BURN PATIENT HAD A VERY SMALL PIECE OF HER SKIN TAKEN, THE CELLS WERE KNOWN AND EXPANDED AND PLACED ON A DRESSING AND THIS WAS PLACED OVER THE BURN WOUND. NOW IT DID NOT GENERATE NEW SKIN, BUT THEY DID SHOW THAT THEY WERE ABLE TO ENHANCE ç SKIN REGENERATION AND WOUND HEALING. THAT MARKED THE VERY FIRST TIME THAT THE PATIENT’S OWN PRIMARY CELLS WERE ACTUALLY USED FOR THERAPY. SO THE FIELD HAS BEEN AROUND FOR SO LONG, WHY SO FEW CLINICAL ADVANCES? REALLY, IF I WERE TO POINT TO EXTREME MAJOR AREAS WHICH WERE CHALLENGING, I WOULD LIST THOSE HERE. FIRST AN ABILITY TO GROW NORMAL PRIMARY CELLS OUTSIDE OF THE BODY IN LARGE QUANTITIES. JUST A FEW DECADES AGO, WE COULD NOT GET MOST PRIMARY CELLS TO GROW OUTSIDE OF THE BODY. THE SECOND CHALLENGE WAS INADEQUATE BIOMATERIALS, ALLOWING THE CORRECT MATERIALS THAT ARE BIOCOMPATIBLE TO BE USED INSIDE THE BODY AND THE THIRD IS, INADEQUATE VASC LATERY AND WE’LL TALK BRIEFLY BEEACH OF THESE 3. THE FIRST ONE, GETTING THE CELLS TO GROW. OVER THE LAST THREE DECADES, MAJOR ADVANCES, SOME OF THE WORK THAT WE PERSONALLY DID AT THE INSTITUTE FOR REGENITIVE MEDICINE INVOLVES LOOKING AT PRIMARY CELLS AND HOW TO GET THEM TO GROW AND MANY SCIENTISTS OVER THE WORLD WORKING ON THE SAME CHALLENGES FOR THE LAST SEVERAL DECADES. REALLY, THIS ACTUALLY SHOWS A PIECE OF BLADDER TISSUE. AND JUST 20 YEARS AGO, YOU COULD NOT REALLY GET THESE CELLS TO EXPAND IN VERY LARGE QUANTITIES OUTSIDE OF THE BODY. WE REALLY HAD TO DO WITH WHERE ARE THESE PROGENITOR ç CELLS LOCATED? BACK THEN WE DIDN’T KNOW WHERE THESE CELLS WERE ACTUALLY PLACED AND IT TURNS OUT THAT THESE PROGENITOR CELLS ARE KEY TO BE ABLE TO BE HARVESTED AND GROWN AND EXPANDED OUTSIDE OF THE BODY. IF YOU’RE ABLE TO TARGET THESE CELLS AND USING THE RIGHT GROWTH FACTORS, WE COULD THEN GET THESE CELLS TO GROW. WE COULD TAKE THESE CELLS THAT WE COULDN’T EXPAND A FEW DECADES AGO AND BY USING A VERY SIMPLE STRATEGY, TO TAKE A VERY SMALL PIECE OF TISSUE, LESS THAN HALF A SIZE OF A POSTAGE STAMP AND BY 60, YOU COULD HAVE ENOUGH CELLS TO COVER A FOOTBALL FIELD. THIS OPENED THE DOORS FOR MANY OTHER APPROACHES IN THE FIELD OF REGENITIVE MEDICINE. IF WE COULD TAKE TARGETED PROGENITOR CELLS AND EXPAND THEM, WE COULD THEN USE THOSE SAME CELLS IN THE SAME PATIENT WITH OUR RE– WITHOUT REJECTION. NOW SEVERAL DECADES LATER, MANY SCIENTISTS HAVE WORKED IN THIS FIELD AND MOST CELL TYPES CAN IN FACT BE GROWN AND EXPANDED OUTSIDE OF THE BODY. EVEN NOW WITH ALL THE MAJOR ADVANCE THAT IS WE HAD IN THE FIELD OF CELL BIOLOGY, THERE ARE STILL SEVERAL CELL TYPES THAT WE CANNOT EXPAND OUTSIDE OF THE BODY. THAT INCLUDES THE LIVER, NERVE AND PANCREAS, FOR EXAMPLE. THESE ARE CRITICAL TISSUES BUT WE STILL CAN’T GET THE CELLS TO BE EXPANDED OUTSIDE OF THE BODY. FOR THOSE WE DO NEED STEM CELL POPULATIONS WHICH WE WILL COVER LATER DURING IT TALK. THE SECOND CHALLENGE WAS BIOMATERIALS. AND REALLY WE FOLLOWED A LOT OF THE SAME PRINCIPALS THAT YOU WOULD EXPECT. YOU WANTED YOUR BIOMATERIALS TO BE COMPATIBLE, ALLOW FOR CELL VIABILITY AND EXPANSION TO OCCUR. REALLY THE ONE MAJOR PRINCE PA PEL WE FOLLOWED IS THE SCAFFOLD SHOULD REPLICATE THE BIOMECHANICAL AND STRUCTURAL PROPERTIES OF THE TISSUE BEING REPLACED. VERY SIMPLE. TRYING TO REPLACE A PIECE OF BONE, YOU’RE GOING TO USE A VERY DIFFERENT BIOLOGICAL MATERIAL OR BIOMATERIAL THAT YOU WOULD IF YOU’RE GOING TO TRY TO REPLACE A BLOOD VESS EM. EL. ONE IS STRONG AND STUDY AND NEEDS TO WITH STAND LARGE AMOUNTS OF PRESSURE AND THE OTHER IS ELASTIC AND COMPLIANT. SO TOTALLY DIFFERENT BIOMATERIALS THAT YOU’LL NEED FOR YOUR CONSTRUCTS. BACK IN 1973, A SIMPLE PRINCIPAL WAS CELLS OR TISSUES CANNOT BE IMPLANTED IN VOLUMES GREATER THAN 3 MILLIMETER TUBE WITHOUT VASC LATERY. HE MADE GREAT STRIDES AND ADVANCES IN THE FIELD OF ANGIOGENESIS AND THE PRINCIPLES HE DESCRIBED IN THE 70s, ARE BASICALLY THE SAME PRINCIPLES WE ARE STILL USING TODAY TO MAKE SURE WE HAVE ADEQUATE VASC LATERY FOR THE CONSTRUCTS THAT ARE ENGINEERED. HOW DOES NATURE SOLVE THIS PROBLEM? AILINGY YOU MAY SEE AT THE BOTTOM OF THE OCEAN FLOOR — ALGAE OR A LEAF STRUCTURE, THE TREE, THE WHOLE HUMAN BODY, BRANCHING BRANCHING IS A SOLUTION TO NUTRIENT DIFFUSION. THAT’S WHY MANY INVESTIGATORS START WORKING ON THE SCAFFOLD SYSTEMS THAT UNDER THE NAKED EYE LOOK LIKE A PIECE OF YOUR BLOUSE OR SHIRT BUT UNDER THE MICROSCOPE, IT HAS A BRANCHING PATTERN ç WHICH ALLOWS THE CELLS TO LAY DOWN IN A SHORT FORM BUT DOES ALLOW FOR THE BRANCHING TO BE PRESENT AND THE PEROSSITY FOR MOST NEOVASCULAR STATION AND NEOANGIOGENESIS. THIS ACTUALLY SHOWS THAT THE SCAFFOLD ALONE IS NOT SUFFICIENT. THIS IS WORK THAT WE DID BACK IN A FEW YEARS AGO SHOWING THAT ç
IF WE IMPLANTED MUSCLE CELLS ALONE IN THE BACK OF A MOUSE, THESE ARE HUMAN MUSCLE CELLS, IF WE IMPLANT THOSE IN THE BACK OF A MOUSE, NOT MUCH HAPPENS. IF WE ADD ENDOTHELIAL CELLS, WE HAVE A LITTLE BIT OF VASCULARITY, IF WE ADD VEGF, THE STRONGEST GROWTH FACTOR FOR VASCULARITY, YOU HAVE MUCH BETTER FORMATION OF VESSELS BUT IF WE ADD THE MUSCLE CELLS AND THE GROWTH FACTOR AND THE ENDOTHELIAL CELLS, YOU HAD THE BEST VOLUME FORMATION OF THE CELLS THAT WERE FORMING TISSUE AND THE BEST TISSUE ARCHITECTURE. THIS GOES TO SHOW IF YOU’RE TRYING TO ENGINEER STRUCTURES, YOU REAL DOE NEED TO HAVE ALL THE COMPONENTS NECESSARY FOR ADEQUATE VASCULARITY. ONE OF THE FIRST TARGETS THAT WE WENT AFTER WAS THE YOUR RETHRA, THE CHANNEL THAT CONNECTS THE BLADDER TO THE OUTSIDE OF THE BODY. AND VERY EARLY STUDIES IN THE EARLY 1990s, WE WERE ABLE TO SHOW THAT IF WE USED A BLADDER SSL OR MATRIX, ECM DERIVED FROM TISSUE, SO WE TAKE BASICALLY A PIECE OF BLADDER AND WE THEN USE VERY MILD DETERGENT WISH THE CELLS AWAY AND WE WERE LEFT JUST WITH THE EXTRACELLULAR MATRIX. IF WE USE THESE TYPE OF MATRIX TO REPLACE A URETHRAL DEFECT IN A RABBIT, YOU COULD SEE HERE THAT ONE CENTIMETER WAS THE MAXIMUM DISTANCE BY WHICH THIS TISSUE WAS FORMED WITHOUT MAJOR SCAR FORMATION. IF YOU DID NOT USE ANY CELLS. IF HOWEVER, WE ADDED THE CELLS TO THE CONSTRUCT, TO THE SCAFFOLD, AND THEN REPLACED THAT SEGMENT, IT FORMED NORMAL URETHRAL TISSUE. AND THIS WAS THROUGHLY CONSISTENT REGARDLESS OF THE TISSUE TYPE WE WERE TARGETING. HALF CENTIMETER FOR MANY EDGE. SO HERE ARE SOME PATIENTS WHO PRESENTED TO US WITH A URETHRAL INJURY AND YOU CAN SEE HERE ABOUT A 6 CENTIMETER DEFECT. HERE IS NORTH URETHRA, DEFECTIVE AREA AFTER THE INJURY. SO HOW WOULD WE TAKE ADVANTAGE OF THIS ONE CENTIMETER RULE OR HALF CENTIMETER FROM ANY EDGE? WELL, IF WE DO HAVE THE NATIVE ORGAN HERE, AND WE PRESERVE THAT, AND WE REPLACE JUST THE TOP PORTION, WHICH IS THE ONE THAT IS INJURED, SO LET ME GO BACK ONE SLIDE TO SHOW YOU THE BOTTOM WAS OKAY WITH THE TOP PORTION, WHICH WAS DEFECTIVE. SO WE WILL PRESERVE THE BOTTOM PORTION, WHICH IS NORMAL AND ONLY REPLACE THE TOP PORTION WITH THE MATRIX ALONE WITHOUT THE CELLS. WE THEN ARE ABLE TO OBSERVE THIS RULE OF A HALF CENTIMETER FROM ANY ONE EDGE. AND BY USING THESE SCAFFOLDS ALONE, WE WOULD ENABLE TO REPAIR THESE PATIENTS USING THESE TECHNIQUES WHERE WE BROUGHT THE PATIENTS TO THE OPERATING ROOM SUITE AND REPLACED THE TOP PORTION AND HERE IS AN X-RAY OF THAT PATIENT SIX MONTHS AFTER REPAIR. WE LOOK AT THE HISTOLOGY, YOU CAN SEAT ELEMENTS THAT BASICALLY IS NORMAL TISSUE OVER THIS MATRIX. AND WE LOOK AT THE ENDSCOPIC PICTURE, THIS SHOWS THE PATIENT’S URETHRA, YOU CAN SEE THE AREA OF THE NARROWING PRIOR TO SURGERY SHOWING YOU SIX MONTHS LATER THE REGENERATED AREA RIGHT HERE FULLY CREATED BY THE USE OF THE PATIENT’S OWN CELLS AND EXTRACELLULAR MATRIX. NOW, WHAT HAPPENS, HOWEVER, IF WE HAVE A PATIENT WHO HAS A FULL DEFECT? AND YOU CAN NOT USE THIS RULE? SO HERE IS A PATIENT WHO PRESENTED WITH A MAJOR INJURY. HERE IS THE BLADDER, PROSTATE AND HERE IS THE MAJOR DEFECT. NO NORMAL URETHRA IS LEFT BEHIND. ç YOU REALLY HAVE TO REPLACE THE ENTIRE SEGMENT FROM HERE TO HERE IN A TUBULAR MANNER. WHAT DID WE DO? HERE YOU ABSOLUTELY NEED THE CELLS. YOU CAN’T GET AROUND IT. SO WE TOOK THE SCAFFOLD, WE TOOK THE URETHRAL CELLS AND PLACED ONE CELL TYPE ON THE UNITED STATES AND THE OTHER CELL TYPE ON THE INSIDE, TUBULARIDES IT AND YOU CAN SEE HERE THE TUBULAR SEGMENT BEING IMPLANTELç SURGICALLY. HERE IS THE X-RAY OF THAT PATIENT SHOWING YOU FULL URETHRAL REGENERATION AND WE PUBLISHED THAT PAPER JUST LESS THAN A YEAR AGO IN THE LANCIT. THIS ACTUALLY SHOWS THE PATIENT’S — LOOKING AT FIVE PATIENTS SHOWING THE INJURIES AT THE TIME OF PRESENTATION. THE FIRST X-RAYS USUALLY THREE MONTHS AFTER SURGERY AND THEN THE LATEST X-RAYS UP TO SIX YEARS LATER SHOWING THE URETHRAS CONTINUE TO DO WELL LONG TERM AND THEY DO THE SAME FUNCTIONALLY. THEY WERE ABLE TO FUNCTION WELL OVER TIME. SO WE HAVE A 14-YEAR FOLLOW-UP USING SCAFFOLDS ALONE WITHOUT THE CELLS FOR PARTIAL SIR COMPANYRENTIAL REPLACEMENT AND OVER A 7 YEAR FOLLOW-UP WITH THE CELLS FOR A MORE COMPLEX REPAIR SHOWING YOU DIFFERENT STRATEGIES OF REGENERATION DEPENDING ON THE PATIENT’S PRESENTATION. WE FOLLOWED SOME OF THE SAME STRATEGIES FOR BLOOD VESSELS. THESE ARE NANOFIBERS WE USE. WE USED BASICALLY THESE NANOFIBE TOURS CREATE THE STRUCTURES INSTEAD OF A CELLULARRIZED SEGMENT. WE USED THESE MANUFACTURER SCAFFOLDS AND THEN WE COAT THE OUTSIDE WITH MUSCLE CELLS, THE INSIDE WITH ENDOTHELIAL CELLS AND WE END UP WITH A TRILAYER, BLOOD VESSEL STRUCTURE. THIS SHOWS THE BIOREACTOR AND THE BIOREACTOR — OKAY. IT’S NOT WORKING. SO, ACTUALLY UNDER NORMAL CONDITIONS, YOU WILL SEE THIS BIOREACTOR WITH A BLOOD VESSEL PUMPING AWAY AND ACTUALLY THAT REPLACES VESSELS FROM THE BIOREACTOR SO THEY CAN ACTUALLY FUNCTION OVER TIME. THIS IS A CAROTID ARTERY REPLACED USING THESE TECHNIQUES BECAUSE IT’S A CAROTID ARTERY 6 MONTHS AFTER — APPROXIMATELY 5-6 MONTHS AFTER IMPLANTATION SHOWING PATENCY OF THE BLOOD VESSEL AND THIS IS THE PAPER PUBLISHED SHING THE BLOOD VESS TOLLS FUNCTION LONG TERM. SAME THING WITH HARD VALVES HERE. THIS IS ENGINEERED HARD VALVE AGAIN. THIS IS UNDER NORMAL CIRCUMSTANCES. THE IF THE SLIDES WERE WORKING WELL, YOU WOULD SEE THE BIOREACTOR BASICALLY GLOWING AND YOU WOULD SEE THE BIOREACTOR PUMPING AWAY AND SHOWING YOU THE HARD VALVES OPENING AND CLOSING. THIS IS SOME OF THE SAME STRATEGIES WE USE TO ENGINEER THE STRUCTURES. NOW THE ADVANTAGE OF THESE BIOREACTORS IS THAT WITH THESE BIORACKETTORS IS THAT WHEN WE USE THEM, THEY ACTUALLY ALLOW FOR THE ENDOTHELIAL CELLS TO LAY DOWN AND — THE SLIDES ARE NOW NOT MOVING. LET ME SEE IF I CAN DO THIS. MORE TECHNICAL DIFFICULTIES. I THOUGHT YOU GUYS WOULD HAVE A BETTER SYSTEM THAN WE DID. HERE IT IS, ACTUALLY. SO BASICALLY WHAT YOU SEE HERE IS AFTER THESE CELLS ARE IN A BIOREACTOR, THEY ACTUALLY, THE FLOW ALLOWS THESE ENDOTHELIAL CELLS TO LAY DOWN IN AN ORGANIZED MANNER SO WHEN YOU IMPLANT THESE STRUCTURES, THE FLOW FROM THE PATIENT IS NOT GOING TO DISRUPT ENDOTHELIAL CELLS OR?X(áQPáE ANY TYPE OF ABNORMAL FLOW THAT WOULD EFFECT THE LONG-TERM FUNCTIONALITY OF THE HARD VALVE. NOW I’LL TALK TO YOU ABOUT FLAT STRUCTURES, SUCH AS SKIN, THE SIMPLEST TO CREATE. THEY ARE COMPLEX BUT IN TERMS OF ORGANIZATIONAL STRUCTURE OF ORGANS, WE CONSIDER LEVEL ONE. THEY ARE ONE CELL TYPE AND FLAT STRUCTURE AND ç EASIER TO CREATE ARCHITECTURALLY. WE TALKED ABOUT TUBULAR STRUCTURES LIKE BLOOD VESSELS FOR EXAMPLE. MORE COMPLEX, TUBULAR, SO ARCHITECT REALLY THEY ARE COMPLEX. TWO DIFFERENT CELL TYPES BUT THEY ARE ACTING AS A CONDUIT ALLOWING AIR OR FLUID TO GO THROUGH IT. A STEADY STATE WITHIN A DEFINED PHYSIOLOGICAL RANGE. STILL COMPLEX BUT NOT AS COMPLEX AS NONTUBULAR ORGANS, THE THIRD LEVEL OF COMPLEXITY. THESE ORGANS WHICH ARE HALLOW AND NONTUBULAR HAVE TO ACT ON DEMAND. THEY USUAL VE MORE THAN TWO DIFFERENT CELL TYPES OR TWO CELL TYPES ARE MORE COMPLEX. IN ADDITION, THE STRUCTURE IS MORE COMPLEX. SO LET’S TALK ABOUT ONE OF THESE ORGANS HERE. SAME STRATEGY AS WITH THE OTHER STRUCTURES THAT WE CREATED. IT’S VERY IMPORTANT TO HAVE THE RIGHT CELLS AND TO HAVE THE RIGHT CELL BIOLOGY TO BE ABLE TO GROW AND EXPAND THESE CELLS OUTSIDE THE BODY IN LARGE QUANTITIES. THEN I’M GOING TO SHOW YOU WHAT THE STRATEGY IS THAT WE HAVE USED TIME AND AGAIN. WE ALWAYS START THE CELL BIOLOGY USING HUMAN CELLS BECAUSE THE HUMAN CELLS ARE THE CELLS THAT WE WILL EVENTUALLY USE CLINICALLY. WE THEN, ONCE WE KNOW THAT THERE WAS EXPANDED CELLS RELIABLY AND WE GET THE SAME CELL TYPE TIME AND AGAIN, WE THEN ARE ABLE TO START OUR IN VIVO STUDIES WHERE WE START TO PLACE THESE CELLS INTO SPECIFIC BIOMATERIALS AND WE START TO TEST THESE BIOMATERIALS TO SEE WHICH ONE WOULD BE BEST AND THEN TESTING THESE CELLS WITH THE BIOMATERIALS IN A THYMIC MICE TO AVOID REJECTION. AND THIS SHOWS WHAT HAPPENS INSIDE THE BODY. REMEMBER, THIS IS VERY POROUS. SO AT FIRST, EVEN HOPE WE LAYER THE CELLS WITH THE EPITHELIAL CELLS ON ONE SIDE AND THE MUSCLE CELLS ON THE OTHER, IN FACT, THE CENTER HAS BOTH CELL TYPES BY ONE WEEK. BY TWO WEEKS YOU START TO SEE THE LAYERING. BY THREE WEEKS CONTINUED LAYERING AND BY FOUR WEEKS THE LAYERING IS COMPLETE. BY THEN, ALMOST ALL THE EPITHELIAL CELLS ARE ON ONE SIDE AND ALMOST ALL THE MUSCLE CELLS ARE ON THIS SIDE. NOW YOU CAN SEE THE VASCULARITY AS WELL. YOU CAN SEE EARLY ON BY THE WAY WITHIN 48 HOURS. ONCE WE KNOW WHAT TO EXPECT IN A MOUSE MODEL, WE THEN GO TO A RABBIT MODEL AND NOW WE WILL DO OR ACTUALLY CONDUCT THE STUDIES IN RABBITS LIKE WE WOULD DO IN A HUMAN. BASICALLY WE TAKE A SMALL BIOPSY FROM THE RABBIT. WE THEN EXPAND THOSE CELLS OUTSIDE THE BODY. WE THEN CREATE THE CONSTRUCT AND WE DO A PARTIAL REPLACEMENT ONLY AND WE DO THIS BECAUSE WE WANT TO DEFINE WHAT THE CONTRIBUTION WILL BE FROM THE ASSESSMENT OF PERIPHERY AS OPPOSED TO THE CELLS THAT WE ARE IMPLANTING. YOU CAN SEE HERE WE, AFTER TAGGING THE CELLS, IT TURNS OUT THAT OVER 99% OF THE CELLS THAT ARE CREATED, THAT FORM THE TISSUE, ACTUALLY COME FROM THE CELLS THAT WE PUT IN. ONLY ABOUT 1% COMES FROM THE PERIPHERY IF WE PRELOAD THE SCAFFOLD. WE THEN CREATE A TOTAL REPLACEMENT MODEL WHERE WE GO IN AND TAKE A SMALL BIOPSY AND GROW AND EXPAND THE CELL AND DO A TOTAL REPLACEMENT. NOW WE KNOW THAT THE ENTIRE ORGAN WILL COME ONLY FROM THE CELLS AND THE SCAFFOLD THAT WE PUT IN. AND WE NOW USE THESE FANCY BIOREACTORS THAT HAVE ALL KINDS OF FEEDBACK MECHANISMS THAT TELLS US WHAT IS GOING ON WITH THE TISSUE. AND THIS SHOWS A SCAFFOLD ALONG WITHOUT THE CELLS HERE. HERE IS THE SCAFFOLD FULLY SEEDED WITH MUSCLE ON THE OUTSIDE. EPITHELIAL CELLS ON THE INSIDE AND HERE ARE THE X-RAYS SHOWING YOU THAT IF YOU DON’T USE THE CELL AS EXPECTED, THIS WILL FIBROSIS AND COLLAPSE.
%Q CENTIMETER FROM ANY ONE EDGE. IF WE USE THE CELLS, YOU DO HAVE NORMAL TISSUE CONSTRUCTION OVER TIME AT LEAST GEOGRAPHICALLY. WE ARE LOOKING AT GROWTH. YOU CAN SEE WHAT IS GOING ON. BY ONE MONTH YOU CAN SEE RIGHT THROUGH THE MUSCLE TISSUE THAT IS BEING FORMED BUT YOU STILL SEE THIN AREAS WHICH ARE NOT YET FULLY FORMED. SO YOU’RE SEEING ç A THIN MUSCLE HERE AND YOU CAN SEE THE SCAFFOLD RIGHT THROUGH THAT. BY THREE MONTHS, THE TISSUE IS FULLY DEVELOPED AND BY NOW THE SCAFFOLD IS ALMOST ALL GONE AND BY SIX MONTHS YOU’RE LEFT JUST WITH THE ORGAN ITSELF. IF YOU DON’T SEED IT WITH CELLS, IT’S GOING TO RESOC AND FIBROSIS OVER TIME. LOOK AT THE COLLAGEN CONTENT AND WE LOOK AT THE EPITHELIAL PHENOTYPE WITH A1A3 AND SMOOTH MUSCLE PHENOTYPE AND PROXIMATES NORMAL ORGANS BY SIX MONTHS. WHEN WE LOOK AT THE MOLECULAR MARKERS, LOOKING AT REGULATORY GENES AND PROTEINS, IT PROXIMATES THE NORMAL ORGAN BY SIX MONTHS. WE LOOK AT THE COLLAGEN DECISION AND LOOKING AT COLLAGEN 1, 2, 3, AND THE ELAST IN AND AGAIN PROXIMATES THE NORMAL ORGAN BY SIX MONTHS. WHEN WE LOOK AT THE BIOMECHANICAL PROPERTY, THE ABILITY OF ORGANS TO HAVE ELASTICITY AND COLLAPSE AND AGAIN PROXIMATES THE NORMAL ORGAN BY SIX MONTHS. WHEN WE LOOK AT THE INTERIVATION, IT PROXIMATES THE NORMAL ORGAN BY SIX MONTHS. YOU CAN IMAGINE, NERVOUS COMING IN CRITICALLY IMPORTANT TO THE LONG-TERM VIE BELTY OF TREES STRUCTURES. WE DO TWO TESTS THAT THESE ARE INNOVATIVE JUST LIKE THEY ARE VASCULARIZED. WE TAKE VERY SMALL PIECES OF THE ENGINEERED TISSUE AND DO ORGAN VAT STUDIES AND LOOKING AT THE ORGAN VAT STUDIES WE THEN TEST WITH AGONIST AND ANTAGONISTS AS WELL AS ELECTROFILL STIMULATION, WE ARE ABLE TO SHOW THAT IN FACT, THESE ORGANS APPROXIMATE THE NORMAL INTERIVATION BY SIX MONTHS. AND THIS LED US TO OUR PLANS NOW IN TERMS OF CLINICAL TRIAL GOALS. AND BASICALLY THE FIRST INDICATION IS THAT WE HAVE TARGETED IS PATIENTS WITH WHO PRESENTED WITH A GENESIS OF THE ORGAN. THESE ARE PATIENTS WHO ARE BORN WITH THIS CONGENITAL DEFECT WHERE THEY DON’T HAVE THE ORGAN PRESENT. BUT THEY HAVE A RUDIMENTARY STRUCTURE. WE CAN THEN GO IN, TAKE A SMALL BIOPSY OF THAT STRUCTURE AND GROW THE CELL AND CREATE CONSTRUCT AND IMPLANT IT. THAT’S ACTUALLY IN PROGRESS NOW. ANOTHER AREA THAT WE HAVE LAUNCHED IN THE CLINIC IS THE USE OF THE OTHER ORGANS WHICH IS BASICALLY THE BLADDER. NOW THE BLADDER IS AGAIN ANOTHER TYPE OF COMPLEX HALLOW, NONTUBULAR ORGAN, SAME STRATEGY HERE. WE TAKE A SMALL BIOPSY OF THE TISSUE, COMPOSED OF TWO DIFFERENT CELL TYPES, MUSCLE AND UTHILLIA. WE EXPAND CELLS OUTSIDE OF THE BODY AND 30 DAYS LATER WE HAVE ENOUGH CELLS FOR A CONSTRUCT AND THEN WE CREATE IN THE SHAPE OF THE ORGAN AND COAT THE INSIDE WITH THESE CELLS, AND THE OUTSIDE WITH THE ç MUSCLE CELLS AND THEN WE ARE ABLE TO GO BACK AND PLACES IN AN OVEN-LIKE DEVICE AND INCUBATOR, WHICH HAS THE SAME CONDITIONS AS THE HUMAN BODY AND THEN WE IMPLANT THAT BACK INTO THE PATIENT. WE PUBLISHED OUR PRECLINICAL STUDIES IN 1999. AND WE ACTUALLY START OUR CLINICAL EXPERIENCE AROUND WANT SAME TIME. THESE WERE PATIENTS WITH HIGH-PRESSURE, LOW-CAPACITY BLADDERS, ALL MEDICAL THERAPY AND CONSIDERED CANDIDATES FOR BLADDER RECONSTRUCTION AND FOR SOME OF THE PATIENTS, WE BROUGHT THEM IN AND DID THREE DCT SCANS AT THE TIME WE TOOK THE BIOPSY SO WE COULD DEFINED WHAT THE BLADDER SHAPE SHOULD LOOK LIKE. WE USED THESE 3D RECONSTRUCTION SOFTWARES THAT WE WERE ABLE TO USE TO DEFINE THE CONSTRUCT. AND WE THEN CONSTRUCTED THESE BLADDER SHAPES SPECIFICALLY FOR EACH PATIENT AND WE THEN IMPLANTED THAT INTO THE PATIENTS WITH, WHO HAD SPINE BIFIDA AND WE THEN, YOU CAN SEE HERE, WHAT WAS USED TO COVER THAT CONSTRUCT. AND THIS ACTUALLY SHOWS THE RESULTS. WE HAD THREE DIFFERENT PATIENT SERIES WITHIN THE INITIAL STUDY. AND IT TURNED SOUTH THAT THE PATIENTS IN THE LAST SERIES WERE THE ONES WHO DID THE BEST. PATIENTS WHO HAD THE COLLAGEN, SCAFFOLDS WITH A POLYGLYCOLIC AND THEN COVERAGE. YOU CAN SEE ç HERE, PRE-OPERABLY WHAT THE BLADDER LOOKS LIKE, HERE IS THE BLADDER AFTER THE ENGINEERED CONSTRUCT HAS BEEN PLACED. AND THIS SHOWS THE TRACING, THE BLADDER PRESSURE OF THESE PATIENTS. NOW THE MAIN REASON THAT WE DID SOME OF THESE PATIENTS WAS BECAUSE THEIR BLADDER PRESSURES WERE SO HIGH. AS YOU KNOW, BLADDER PRESSURES GET ABOUT 40 SENT PETER’S AND THEY ACTUALLY ARE AT RISK OF KIDNEY DAMAGE. AND THAT’S WHAT YOU SEE HERE WITH THIS PATIENT. CLEARLY OR 40 CENTIMETERS AND THEN POSTOPERATIVELY THE PRESSURES ARE DOWN WHERE THEY SHOULD BE WITH A RISING PRESSURE WHEN THEY ARE READY TO VOID OR EMPTY. AND THEN ALAN REDDICK WHO HAS A SURGEON AND CHIEF AT CHILDREN’S HOSPITAL BOSTON AND HARVARD MEDICAL SCHOOL ACTUALLY ABOUT A YEAR AND A HALF AGO, SHOWED THE LONG-TERM RESULTS OF THESE PATIENTS SHOWING THAT THEY CONTINUE TO HAVE INCREASED CAPACITY. DECREASED PLAIDER PRESSURES. AND INCREASED ELASTICITY OR COMPLIANCE LONG-TERM. SHOWING THAT THESE CONSTRUCTS CONTINUE TO DO WELL AS THESE PATIENTS GET OLDER. IN OTHER WORDS, THE BLADDERS ARE GROWING WITH THESE YOUNG PATIENTS THAT WERE IMPLANTED. WE PUBLISHED OUR INITIAL RESULTS IN THIS JOURNAL BACK IN 2006. THE PHASE I TRIALS WERE COMPLETED AND REPORTED IN THIS ARTICLE, PHASE II TRIALS HAVE NOW ALSO BEEN COMPLETED. THEY ARE UNDER FOLLOW UP AND NOW WE HAVE OVER A 12-YEAR FOLLOW UP WITH THESE STUDIES. THIS WORK IS STILL IN PROGRESS TRYING TO MOVE IT FORWARD. WE TALKED ABOUT FLAT STRUCTURES, LEVEL 1, TUBULAR STRUCTURES LEVEL TWO, HALLOW NONTUBULAR LEVELS 3 AND THE SOLID ORGANS ARE THE MOST COMPLEX. THESE ARE THE LEVEL 4. BY FAR THE MOST COMPLEX BECAUSE OF THE MASSIVE NEED OF VAC LATERY BECAUSE THERE ARE SO MANY MORE CELLS PERCENT METER THAN ANY OTHER STRUCTURE. SO BASICALLY — PERCENT METER — THIS SHOWS WHERE WE ARE WITH THIS WORK SHOWING YOU THESE ARE COMPLEX ORGANS. WE DID THE CELL BIOLOGY AND THEN MOUSE STUDIES AND PARABLE REPLACEMENT AND THEN THE FULL REPLACEMENT WHERE WE ARE REPLACING ENTIRE ORGANS AND THEN WE RETRIEVED THOSE OVER TIME FOR ANALYSIS. YOU CAN SEE HERE THAT HERE IS THE NATIVE ORGAN SHOWING YOU ADDED VASCULARITY, THAT’S WHEN THIS STUDY SHOWS, VASCULARITY OF THE ORGAN. HERE IS THE ENGINEERED ORGAN. AND OF COURSE A CONTROL THAT DID NOT DO WELL. WHEN WE LOOK AT THE PRESSURE, THE PRESSURE ACHIEVED, THEY WERE APPROXIMATED NORMAL ORGAN AGAIN BY SIX MONTHS. AND THESE PRESSURES WERE SUFFICIENT FOR PENETRATION, COPALATION AND EJACKALATION AND WE WERE ABLE TO OBTAIN SPERM FROM THE VAGINAL BULBS OF THE PARTNERS AND WE WERE ABLE TO SHOW THAT THESE IN FACT LED TO POSITIVE PREGNANCY. AND THIS STUDY WAS PUBLISHED IN TNAS IN 2010. OTHER STRATEGIES, SAME AS WE USED FOR THAT WE STARTED USING IN THE EARLY 1990s FOR LIVER. AGAIN, WHAT WE DO IS THE CONCEPT HERE IS TO HAVE THESE ORGANS WHICH ARE NOT USED FOR TRANSPLANTATION, SO WE CAN TAKE THESE ORGANS, WHICH ARE DISCARDED LIKE THE LIVER, WE BRING THESE ORGANS IN AND WE USE VERY MILD DETERGENT WASH THE CELLS AWAY AND THEN WE PRESERVE THE VASCULAR ç TREE. THIS ACTUALLY ON THE LEFT SIDE YOU WILL SEE — YOU WON’T SEE IT AGAIN. THE VIDEO IS NOT WORKING. BUT BASICALLY, WHAT YOU WOULD HAVE SEEN IS ACTUALLY A FLUOROSCOPY OF HOW THIS VASCULAR TREE IS PRESERVED EVEN THOUGH THE CELLS ARE GONE. AND WHAT WE THEN DO IS WE THEN ARE ABLE ç TO BASICALLY SEEK
THESE LIVER CELLS ON TO THE ORGAN. WE PRO FUSE WITH THE LIVER CELLS AND THE VASCULATURE WITH ENDOTHELIAL CELLS AND END UP WITH THESE MINIATURE LIVER ORGAN THAT IS ARE ABLE TO SECRETE UIA AND METABOLIZE DRUGS AND PRODUCE ALBUMEN. AND THAT’S WHAT YOU SEE HERE. AND THEN ANOTHER STRATEGY IS BIOPRINTING. SO WE STARTED THIS A WHILE BACK. THIS IS ONE OF OUR FIRST ATTEMPTS AT THIS BY CREATING TWO CHAMBER HEARTS. AND THESE WERE DONE ONE LAYER AT A TIME. AND WHAT YOU SEE HERE IS WE USED YOUR TYPICAL DESKTOP INK JET PRINTER AND YOU SEE THIS PRINTER GOING BACK AND FORTH PRINTINGTH SCAFFOLD ONE LAYER AT A TIME. THIS IS YOUR TYPICAL DESKTOP INK JET PRINTER BUT THE CARTRIDGE HAS CELLS INSTEAD OF INK. AND WHAT YOU SEE, YOU SEE THE STRUCTURE BEATING A FEW HOURS LATER AND 4-6 HOURS LATER, YOU ACTUALLY SEE THE CARDIOMYOSITES BEATING TOGETHER AS WELL. AND ANOTHER STRATEGY THAT WE USED FOR SOLID ORG AGAINST IS TO CREATE A WAIFER. IN REALITY YOU MAY NOT NEED TO REPLACE AN ENTIRE ORGAN. AS YOU KNOW, YOU DON’T GET INTO ORGAN FAILURE REGARDLESS OF THE ORGAN USUALLY UNTIL OVER 90% OF THE ORGAN IS GONE. RIGHT? SO YOU STILL HAVE A HUGE RESERVE IN YOUR ORGANS. IF YOU COULD JUST BOOST THAT 10% TO 20%, YOU MAY BE ABLE TO TAKE THAT PATIENT OFF DIALYSIS, FOR EXAMPLE. SO THE CHALLENGE OR THE GOAL HERE IS TO CREATE THESE WAIVERS YOU CAN INSERT INTO THE ORGAN AND SO, THIS ACTUALLY SHOWS ONE OF OUR SYSTEMS TO CREATE THESE CELLS. WE THEN CREATE THESE WAIVERS YOU SEE HERE. WE THEN PACK THESE WITH THE CELLS AND WE PLACE SMALL DRAINAGE TUBES INTO THE SILICONE RESERVOIRS AND IMPLANT THESE INTO COWS AND STEER. AND YOU CAN SEE HERE THAT THREE MONTHS LATER, WE ARE ABLE TO RETRIEVE THESE STRUCTURES, WHICH ARE MAKING THIS YELLOW FLUID, WHICH IS CONSISTENT WITH URINE. AND OF COURSE IF WE DON’T USE ANY CELLS, NOTHING HAPPENS. YOU CAN SEE HERE THE CAPSULE, PROXIMAL DISTAL TUBUALS, ALL PRESENT WITHIN THE STRUCTURES. IF WE DON’T USE THE CELLS, OF COURSE, ç NOTHING HAPPENS. LOOKING AT VITAMIN D3 LEVELS CONSISTENT WITH KIDNEY, WHEN WE LOOK AT THE MOLECULAR MARKERS LOOKING AT BOTH REGULATORY GENES AND PROTEINS, AGAIN THEY ARE CONSISTENT WITH KIDNEY. AND WE WERE ABLE TO SHOW THIS STUDY BACK SUCCESSFUL TRANSPLANTATION OF CLONED CELLS BECAUSE WE USED CLONE CELLS TO CREATE THESE CONSTRUCTS BUT WE WERE ABLE TO DO THIS AS WELL WITH ADULT CELLS. AND YET ANOTHER STRATEGY. AND A FOURTH STRATEGY THAT WE HAVE USED, WE HAVE FIVE STRATEGIES FOR SOLID ORGANS. THE FOURTH IS JUST USE CELL THERAPY. NOW, FOR CELL THERAPY, WE USE MANY DIFFERENT CELL TYPES. AND SO FOR THIS, WE ALSO TARGET STEM CELLS AND AS KNOW, AND JUST UNTIL RECENTLY, THERE WERE ONLY THREE RETROVIRAL PROVEN CLONAL POPULATIONS OF STEM CELLS THAT WOULD GIVE RISE TO ALL THREE GERM LAYERS. THAT IS THEY WERE CONSIDERED PLURIPOTENT OR HIGHLY MULTIPOTENT AND THAT INCLUDES STEM CELLS AND THE IPS CELLS AS WELL AS ADULT BONE MARROW STEM CELLS AND BOTH HAVE THEIR PLUSES AND MINUSES. THE PLUS IS THAT THEY REPLICATE WITH A GREAT POTENTIAL. THEY GROW VERY RAPIDLY. BUT AS YOU KNOW, SOME OF THE ç DOWNSIDE IS THEY MAY FORM PAIR TOME AS AND MAY HAVE ISSUES WITH REJECTIONS. FOR ADULT BONE MARROW STEM CELLS, THEY DON’T FORM TUMORS AND DO NOT REJECT, ESPECIALLY IF YOU USE THEM IN AN APOL GUS MANNER. BUT THE CHALLENGE THERE, THE DOWNSIDE IS THEY DON’T HAVE AN ACTIVE REPRESENTATIVE TERB FOR THE CELLS TYPES WE NEED FOR SURGERY, FOR THERAPY, ECHO DERM AND ENDODERM. THEY ARE VERY GOOD CELL TYPES WITH PLUSES AND MINUSES. NO PERFECT CELL. SO APPROXIMATELY, 11 YEARS AGO, OR 12 YEARS AGO, WE STARTED LOOKING AT ALTERNATE SOURCES OF TEMCELLS AND LOOKING AT THE AMNIOTIC FLUID AND PLACENTA AS SOURCES. AND WE WERE ABLE TO OBTAIN AMNIOTIC FLUID AT 14 WEEKS OF GESTATION AND SAMPLE ELFING OR PLACENTAL TISSUES AS EARLY AS 12 WEEKS OF GESTATION AND WE WERE THEN ABLE TO ISOLATE THE SPECIFIC CELLS. I HAD BEEN KNOWN FOR DECADES THAT THESE SOURCES HAD THREE GERM LAYERS. WE WERE NOT LOOKING FOR DIFFERENT SHADED CELLS. WE WERE LOOKING FOR A TRUE STEM CELL POPULATION. SO WE ENDED UP IN FACT, STARTED A SEARCH AND FOUND AS STEM CELL POPULATION BY SELECTING FOR C KIT AND THESE STEM CELLS ENDED UP HAVING A POTENTIAL TO GO INTO ALL THREE GERM LAYERS. WE SHOWED THESE CELLS GO INTO FAT, BONE, MUSCLE INCLUDING CARDIAC, BLOOD VESSELS, LIVER AND OTHER TISSUES. AND WE WERE ABLE TO SHOW THROUGH A SOUTHERN — THIS STUDY SHOWING A SOUTHERN BLOT, WITH A RETROVIRAL INSERT SHOWING THAT ALL THE CELLS CAME FROM ONE CELL THAT. IS THE CELLS WERE CLONAL. ONE CELL AND ONE CELL ALONE WAS ABLE TO GIVE RISE TO ALL THREE GERM LAYERS. THE CELLS HAD MARKERS CONSISTENT WITH HUMAN EMBYRONIC STEM CELLS INCLUDING — BUT THEY ALSO HAD MARKERS CONSISTENT WITH ADULT STEM CELLS. THAT’S WHEN WE KNEW WE HAD SOMETHING DIFFERENT. IN FACT, WE STARTED DOING EXPRESSION PROFILE ANALYSIS OF THE STEM GENES AND IF YOU CAN PICTURE THAT HUMAN EMBYRONIC STEM CELLS HERE AND IPS CELLS ARE SOMEWHERE HERE, AND BONE MARROW STEM CELLS ARE SOMEWHERE HERE IN TERMS OF THEIR ABILITY TO GO INTO DIFFERENT GERM LAYERS, THE AMNIOTIC FLUIDS WERE IT WERE AROUND HERE. SO VERY CLOSELY RELATED TO IPS AND HES CELLS. IN THEIR STEMNESS GENES. THEY HAD WOULD DOUBLE IN NUMBER EVERY 36 TO 48 HOURS. BUT THIS IS WHERE THE MAIN DIFFERENCE OCCURRED. THE CELLS WERE MORE DEVELOPED, SLIGHTLY MORE DEVELOPED SO THEY WOULDN’T FORM IN THE PAIR TOME AS WHEN INJECTED IN VIVO. THAT’S A MAJOR DIFFERENT WITH THESE CELLS. AND THE REASON FOR THAT IS BECAUSE THEY ARE NOT ADDS PRIMITIVE AS THE HES OR IPS. THEY ARE ONE STEP FORWARD FROM THAT. INTERESTINGLY, WE ARE ALSO ABLE TO GET THESE CELLS TO FORM AMBROYD BODIES USING THREE DIFFERENT TECHNIQUES AS WELL AS DIFFERENT MEDIA. AND THE CELLS WERE ABLE TO EXPRESS THESE EMBROYD BODIES AND ABLE TO EXPRESS ALL THREE GERM LAYERS WITH DOWN REGULATION OF THE GENES THAT YOU WOULD EXPECT TO BE DOWN REGULATED WITH THE FORMATION OF THE AMBROYD BODY. AND AGAIN, SHOWING ALL THREE GERM LAYERS TO BE PRESENT WITH THESE AMBROYD BODIES. SO BASICALLY WE HAD A CELL POPULATION THAT WE COULD MAYBE USE FOR THERAPEUTIC APPLICATIONS. NOW THERE ARE TWO WAYSES TO USE THE CELLS. THEY COULD BE USING THEM ç IN AN APOL GUS MANNER AVOIDING REJECTION LIKE OTHER STEM CELLS OR APPROXIMATELY 100 UNIQUE SPECIMENS COULD SUPPLY 99% OF THE US POPULATION WITH A PERFECT GENETIC MATCH WITH TRANSPLANTATION. SO TWO WAYS TO USE THESE CELLS. AND TRYING TO GET THESE CELLS BASICALLY OR ABOUT 4 1/2 MILLION BIRTHS PER YEAR ç SO TAKE IT
FROM A DISCARDED PLACENTA, THE AFTER BIRTH AND CREATE YOUR BAG VERY READILY. SO WE WERE ABLE TO SHOW THE CELLS GOING INTO FAT WITH UPREGULATION OF A TYPICAL FAT GENES. THE CELLS WOULD GO INTO BONE, THIS IS A PRINTED 3D BONE THAT THAT WAS CREATED WITH A PRINTER. BIOPRINTER. AND WE SHOWED THESE CELLS GO INTO CARDIAC PHENOTYPE AND IT’S INTERESTING. YOU CAN SEE HERE SOK2. AND YOU CAN SEE WHAT HAPPENS WHEN WE START TO SHADE THE CELLS. IT ACTUALLY WHEN A 10-DAY PERIOD, SOKX2 GOES DOWN TO ZERO WHILE AT THE SAME TIME, CARDIAC T GOES UP 1200 FOLD. AND NOW YOU CAN SEE THAT TYPICAL STRETCH FIBERS PRESENT IN THE CARDIOMYOSITE. SO YOU CAN SEE WHAT HAPPENS AS
CELLS TOWARDS THE CORRECT PHENOTYPE. ALSO, WE WERE ABLE TO SHOWS THESE CELLS GOING INTO THE ENDOTHELIAL PATHWAY SHOWING UPREGULATION OF GENE CONSISTENT WITH ENDOTHELIAL CELLS. AS WELL AS LIVER TISSUE, SHOWING CELLS COULD SECRETE URA. FOR A SELL TO SECRETE UREA, THAT’S SIMILAR TO PANCREATIC CELLS CREATING INSULIN OR NERVE CELLS CREATING DOPAMINE. AND THEN WE STARTED TO SHIFT THESE CELLS ALL OVER THE COUNTRY AND OUTSIDE TO THE U.S. AND ALSO PEOPLE MAKING THEIR OWN CELL TYPES AND THIS IS FOR EXAMPLE, A PAPER THAT CAME OUT OF GEORGIA TECH, THE FIRST PAPER, OUTSIDE OF OUR GROUP TA CAME OUT OF GEORGIA TECH SHOWING THESE CELLS GO INTO CARTILAGE AND PUBLISHED NOW MANY PAPERS SINCE SHOWING THEY COULD GO INTO BONE AND OTHER STRUCTURES. THIS SAY PAPER OUT OF CALIFORNIA SHOWING THESE CELLS GOING INTO LUNG, INTO A LUNG PHENOTYPE AND RESCUE LUNG INJURY. THIS IS A PAPER SHOWING THE CELLS COULD GO INTO THE KIDNEY AND CAUSE OR BE INCORPORATED INTO THE KIDNEY DURING HEALING. AND THIS IS YET ANOTHER PAPER ALSO IN THE KIDNEY SHOWING THAT RESCUE OF A NEPHRITEIS IN A MOUSE MODEL. BUT PROBABLY THE MOST EXCITING PAPER WE SEEN TO DATE IS THIS ONE WHICH CAME OUT OF PARIS, OUT OF THE PAS TOUR INSTITUTE AND THE UNIVERSITY OF PARIS, SHOWING CELLS COULD GO INTO A HEMATOPOIETIC PATH. THEY ACTUALLY USED THE NAG NEGATIVE MOUSE MODEL, KNACK NEGATIVE MOUSE MODEL WHICH IS BONE MARROW DEPLETED AND THEY INJECTED THE AMNIOTIC FLUID STEM CELLS IN THIS BONE MARROW-DEPLETED MODEL AND THEY SHOWED THE BONE MARROW WAS REPOPULATED WITH ALL THREE TYPES OF HEMATOPOIETIC CELLS. MYELOID, ARITHROID AND LUKOID. AT OUR INSTITUTE, WE DID WORK WITH THE VERY PIONEERING PROJECT OF NIBIB, THE QUANTUM PROJECT, BASICALLY AUTHORING THESE TYPES OF GRANTS THAT WOULD FUNDED AT A LARGER LEVEL SHOWING THAT THESE CELLS MAY BE USEFUL SOME DAY FOR SOME SORT OF DIABETES THERAPY BY BRINGING THESE CELLS, THEY DO INCORPORATE AND DO GO INTO A PANCREATIC INSUFFICIENCY MODEL AND ABLE TO TAKE UP RESIDENCE THERE AND SHOW SOME OF THE PROPERTIES OF BETA CELLS. BUT AGAIN, THIS CELL IS DEFINITELY NOT A PERFECT CELL EITHER. NO CELL IS PERFECT. NEITHER IS THIS ONE. SO, BASICALLY THE WEAKNESS WITH THIS CELL IS THAT YOU DO HAVE TO WORK HARDER TO GET THIS CELL TO DIFFERENT SHADES. SO FOR EXAMPLE, WITH AN HESL, WITHIN A WEEK, YOU CAN GET NERVE 4Z GET LIVER CELLS OR THIS CELL TYPE FOR US TO GET LIVER CELLS WE SHOWED YOU, IT TAKES ABOUT 20 DAYS AND YOU HAVE TO GO THROUGH A VERY LABOR-INTENSIVE PROCESS IN TERMS OF GROWTH FACTOR TO GET THEM THERE. THEY JUST WANT TO EASILY GO INTO A SPECIFIC PATH. BUT THAT’S ALSO THE SAME PROPERTY THEY DOES NOT ç ALLOW
THE CELLS TO FORM IN THE SAY TOME A IT’S GIVE-AND-TAKE IN TERMS OF WHAT YOU WANT OUT OF THIS CELL. BUT BASICALLY, ALL OF THESE CELLS ARE GOOD CELLS. IT JUST DEPENDS ON HOW THE PATIENT WILL PRESENT IN TERMS OF WHAT PATIENT YOU MAY WANT TO USE IN THE FUTURE. AND THIS PAPER WAS HIGHLIGHTED IN THE JOURNAL FROM THE WOMAN. SO BASICALLY, WHAT I TRIED TO DO FOR YOU TODAY IS REALLY GIVE YOU AN OVERVIEW OF WHERE WE THINK THIS FIELD IS WHERE WE CAN USE SCAFFOLDS ALONE AND WE CAN USUALLY DO THIS FOR SMALL — USING SCAFFOLDS AND CELLS TOGETHER TO ENGINEER STRUCTURES, OR WE CAN USE CELLS ALONE. AND WHEN WE LOOK AT CELLS, IT’S IMPORTANT TO REALIZE THAT THE BEST CELL WILL BE THE CELL THAT BENEFITS THE PATIENT THE BEST. AND FOR EXAMPLE, LET’S TAKE THE HEART CELL. NOW IT TURNS SOUTH. IN THE LAST FIVE YEARS, ONLY HAS IT BEEN FIGURED OUT HOW TO GET THEM TO EXPAND OUTSIDE THE BODY. SO NOW THESE CELLS ARE EXPANDABLE OUTSIDE OF THE BODY. FIVE YEARS AGO YOU COULDN’T GET THEM TO EXPAND OUTSIDE OF THE BODY. LET ME ASK YOU THIS. IF A PATIENT PRESENTS WITH END-STAGE HEART DISEASE, ARE YOU WILLING TO GO AND PICK A SMALL PIECE OF THAT HEART TISSUE AND PUT THAT PATIENT TO THE PROCEDURE? PROBABLY NOT. SO EVEN IF YOU CAN GET THOSE CELLS, CHANCES ARE YOU’RE NOT GOING TO USE THAT SPECIFIC CELL STORAGE. SO WHAT I MEAN BY THAT IS THE CELL YOU CHOOSE, WILL DEPEND ON THE CELL PROPERTIES AND ALSO ON THE PATIENT AND HOW THEY PRESENT. AND IT’S INTERESTING BECAUSE THIS YEAR, THIS MONTH, IN FACT, IT IS — YOU CAN SEE THE NEW INITIATIVE, A GREAT INITIATIVE, THAT WAS ACTUALLY CREATED BY FRANCIS COLLINS WITH THE CREATION OF A NEW INTRAMURAL CENTER AT THE NIH AND THIS IS ACTUALLY A PAPER, ONE OF THE OPENING PAPERS FOR THE NEW JOURNAL, STEM CELL TRANSLATIONAL MEDICINE, AN INTERESTING STORY OF ITSELF. THE JOURNAL STEM CELLS WAS ACTUALLY FIRST PUBLISHED 30 YEARS AGO. THE FIRST JOURNAL ON THE FIELD BEFORE MOST ANYONE HAD EVEN HEARD OF THE TERM, PIONEERING EFFORT. 30 YEARS LATER, EXACTLY THIS MONTH, NOW THIS MONTH IS ACTUALLY THE LAUNCH OF THIS NEW JOURNAL, STEM CELL TRANSLATIONAL MEDICINE ALSO BY THE SAME PUBLISHER. PIONEERING EFFORTS TO SHOW WHERE THE FIELD IS TODAY. SO 30 YEARS AGO, THE RESEARCH WAS IN THE CELL’S BIOLOGY. THIRSTY YEARS LATER TODAY, WE ARE DEALING WITH — 30 YEARS — THE TRANSLATIONAL ASPECTS OF THE CELLS AND NOTHING MORE FITTING THAN HAVING AN OPENING ARTICLE IF THIS NEW JOURNAL BY THE LEADER OF YOUR NIH. ONE OF THE THINGS I DO WANT TO MENTION TO YOU IS THAT IT IS VERY EASY TO WATCH A PRESENTATION LIKE THIS AND SAY, WOW, THIS IS SO EASY. EVERYTHING WORKS. AND YOU KNOW — NOTHING COULD BE FURTHER FROM THE TRUTH. I WANT YOU TO REALIZE THAT SOME OF THE WORK IN THIS PRESENTATION WAS PERFORMED BY MORE THAN 1000 RESEARCHERS AT OUR INSTITUTE OVER A 20-YEAR TIME SPAN. AND IT DOES REQUIRE A MULTIDISCIPLINARY APPROACH. MOLECULAR BIOLOGIST, CELL BIOLOGISTS, MATERIAL SCIENTISTS, BIOENGINEERS, WORKING TOGETHER TO BRING YOU TECHNOLOGIES TO THE BENCH TO THE BEST SIDE. IT’S A MULTIDISCIPLINARY THE SAME PROBABLE AT THE SAME TIME. AND THESE TECHNOLOGIES ARE NOT EASY. IT TAKES ENORMOUS AMOUNT OF BELABOR TO GET THE RIGHT CELL,S RIGHT BIOMATERIALS, AND GET THE RIGHT BIOLOGY TO WORK AND ALSO TO MAKE SURE THAT THE STRUCTURES REMAIN FUNCTIONAL AND SAFE LONG-TERM. WE ARE VERY FORT NOT HAVE TRULY A REMARKABLE INVESTIGATORS AND SCIENTISTS AT OUR INSTITUTE. OVER 300 FACULTY AND STAFF OF THIS INSTITUTE WHICH IS NOT VIRTUAL. BASICALLY OVER 270 OF THESE FOLKS WORK FULL-TIME FOR THE INSTITUTE WHERE THEIR PRIMARY APPOINTMENT IS IS AT THE
INSTITUTE WORKING TOGETHER TO BRING THESE TECHNOLOGIES TO PATIENTS. THIS MULTIDISCIPLINARY APPROACH HAS PROVEN TO BE VERY FRUITFUL. AND ANOTHER MULTIDISCIPLINARY EFFORT, FOR EXAMPLE, IS NOW CURRENTLY ACTIVE WITH THE FORMATION OF THE ARMED FORCES IN REGENITIVE MEDICINE, AN EFFORT FROM THE ARMY, THE NAVY, MARINES, AIR FORCE, NIH, AND THE VA, ALL TOGETHER FUNDING THIS MULTIINSTITUTIONAL EFFORT TO BRING THESE TECHNOLOGIES TO OUR WOUNDED WARRIORS. AND BASICALLY, THIS WAS LAUNCHED IN 2008. AND THIS ACTUALLY IS FOCUSED IN FOUR AREAS. BURNS, EXTREMITY INJURIES, CRANIOFACIAL INJURIES AND SCARLESS WOUND HEALING. AND THIS IS BASICALLY 27 UNIVERSITIES WORKING TOGETHER AND THE GOAL OF A FIRM WAS TO HAVE ONE TECHNOLOGY PLAN TO ENTER A CLINICAL TRIAL IN A PATIENT BEFORE THE FIVE YEARS WERE OUT. WE ARE NOW 2.5 YEARS OR ALMOST 3 YEARS INTO THIS PROGRAM, NATIONAL PROGRAM. AND WE HAVE OVER 8 CLINICAL TRIALS WHICH ARE CURRENTLY ACTIVE IN THESE AREAS. SO JUST SHOWS THE POWER OF BRINGING A MULTIDISCIPLINARY APPROACH TOGETHER. I ALWAYS LIKE TO SHOW THIS CARTOON, AND HERE IS THE STAGECOACH DRIVER. HE GOES, A, B, C, D, E, F AND THEN FINALLY STOPS. THESE ARE USUALLY THE SCIENTISTS AND THESE ARE USUALLY THE SURGEONS RIGHT HERE. AND AS YOU KNOW, I’M A SURGEON ACTUALLY BUT WHEN IT COMES TO RESEARCH AND GETTING THESE THINGS TO THE CLINIC, WE REALLY DO WANT TO MAKE SURE WE HAVE SERVED METHOD 1, A METHODICAL MANNER OF GETTING THESE TECHNOLOGIES TO PATIENTS. WHICH MEANS ANY TIME THAT WE HAVE LAUNCHED ANY TECHNOLOGIES TO PATIENTS, WE MADE ABSOLUTELY SURE THAT WE KNOW EVERYTHING WE CAN ABOUT THE CELL BIOLOGY, THAT WE DO EVERYTHING WE CAN IN THE LABORATORY, THAT THE RESULTS ARE REPRODUCIBLE TIME AND TIME AGAIN. AND WE THEN HAVE TREATED THE PATIENT SLOWLY, CAREFULLY, AND WITH A LONG TERM FOLLOW-UP AND WE USUALLY DO NOT COME OUT WITH OUR PUBLISHED RESULTS UNTIL WE HAVE ABOUT A 5-YEAR FOLLOW-UP IN A SET NUMBER OF PATIENTS. AND WE DO THAT BECAUSE WE WANT TO MAKE SURE THAT WE DO IT CAREFULLY AND SLOWLY. NOW, WE ARE NOW OVER 14 YEARS SOUTH SINCE WE PLANTED OUR FIRST STRUCTURES IN PATIENTS. NOW WE CAN START TO THE LOOK FORWARD TO ACCELERATE THIS PROCESS. AND WE WILL. BUT NEVER FORGETTING THAT SAFETY OF THE PATIENT IS OUR NUMBER 1 PRIORITY. HISTORICALLY, I JUST LIKE TO POINT OUT THAT THINGS CHANGE ALL THE TIME. THIS IS A HISTORICAL PERSPECTIVE PUT TOGETHER BY “SCIENCE” MAGAZINE AND HERE THEY SHOW THE IRON LUNG. HOW MANY PEOPLE IN THIS AUDIENCE, REMEMBER THE IRON LUNG? I SEE A FEW HANDS UP. AS KNOW, WHEN THIS WAS INTRODUCED IT WAS SUPPOSED TO BE THE PROMISE FOR MEDICINE. AND THE ONLY PLACE WILL YOU SEE THESE NOW IS IN MUSEUMS. MEDICAL MUSEUMS. HERE IS ENGINEER BLADDER. I CAN ASSURE THAT YOU 50 YEARS FROM NOW, PEOPLE WILL LOOK BACK AT THIS TECHNOLOGY AND SAY, WOW. WASN’T THAT ç PRIMITIVE? AND THAT IS WHY WE ARE HERE TO DO. THAT’S WHAT WE ARE CHARGED TO DO. TO CONTINUOUSLY IMPROVE THE TECHNOLOGIES THAT WE HAVE AND TO MAKE OUR OWN TECHNOLOGIES OBSOLETE SO WE CAN ADVANCE THE SCIENCE AND GET THESE TECHNOLOGIES TO OUR PATIENTS IN THE FASTEST MANNER POSSIBLE WITH SAFETY. AT THIS TIME, I’D LIKE ACKNOWLEDGE SOME OF THE ç
SOURCES WHICH HAVE MADE THIS WORK POSSIBLE FOR US. AND FINALLY, TO THANK YOU ALL ONCE AGAIN AND JUST LIKE I THOUGHT, THIS VIDEO DOES NOT WORK AGAIN. BUT BASICALLY THIS WAS LUKE, WHO IS NOW OVER 10 YEARS OUT IN RECEIVING HIS ENGINEERED ORGAN. I HAD THE PLEASURE OF SEEING HIM LESS THAN A YEAR AGO FOR THE FIRST TIME AFTER 10 YEARS. HE IS NOW IN COLLEGE AND REALLY DOING VERY WELL. AND FOR US, THE PROMISE OF REGENITIVE MEDICINE IS NOT ABOUT THE CELL TYPE WE USE, OR THE BIOMATERIALS WE CHOOSE. IT’S ALL ABOUT MAKING OUR PATIENTS BETTER. THANK YOU FOR YOUR ATTENTION TODAY. (APPLAUSE)>>THANK YOU VERY MUCH, TONY. I THINK WE HAVE NO TIME FOR QUESTIONS. AND THERE WILL BE NO RECEPTION. BUT DR. ATALA WILL TAKE QUESTIONS OVER THERE. THANK YOU.

13 thoughts on “Regenerative Medicine: Current Concepts and Changing Trends

  1. Dr Atala is a lying scumbag who is typical of some MD's who fail to credit the hard work of the numerous life scientists who developed many of the techniques he is promoting in the name of Medicine.

  2. Yes, really. Developemental Biologists have grown vertebrate organs in growth factor solution since the early 90s. Molecular Biologists have been using stem cell biologists in Italy have been researching. ECM was used to grow cartilage tissue others were grown in eptithelial cells in engineered mice. More importantly biologists have been studying regeneration of functioning tissues such as limbs in amphibians revealing ECM was necessary for tissue developement.

  3. All the tissues Atala is describing simple organs made up of a few layers of epithelial cells. Ask him to grow a fully functioning heart or complete limb as has been observed in the Zebra fish and amphibians. Molecular Biologists have already elucidated the signaling pathway that allows a severely damaged heart to regenerated in the body known as the delta Notch pathway. I myself grew spleen tissue in dishes utilizing coated plastics and fetal bovine serum over a decade ago.

  4. The use of beta-Catenin can induce the Wnt signaling pathway that promotes the growth of hair follicles, unfortunately it can also induce the expression of some oncogenes which potentially result in melanomas. I'm confident that within a few years, Biologists will fine tune the temporal application of growth factors to induce hair follicular growth while simultaneously suppressing the expression of oncogenes.

  5. I think individuals with this condition will most likely have a number of choices that will be tailored to their unique gene expression profiles. The art of inducing signaling pathways with respect to follicular growth is at it's infancy, however encouraging.

  6. Yeah especially for women because when they lose their hair its worse than it is for men! I only liked Atala probably because of my ignorance of the field of biotechnology – I just thought that talk he did at TED (a conference I utterly loathe) outlined some great technologies – but im sure there are a load of smaller biotech professionals working on some amazing stuff that simply havent had the limelight he has been given.

  7. My problem with Atala is he misleads the public, his heart is nothing more than cardiomyocytes that beat simultaneously. A true fully functioning heart is complicated with thick ventricle walls with nerves, vessels, and fibers that strengthen the heart. A true fully functioning heart opens calcium channels in wave pulses across the ventricle walls. Other transmembrane channels must coordinate along with the CNS to beat normally allowing for a successful transplant.

  8. Regenerative medicine also includes the possibility of growing tissues and organs in the laboratory and implanting them when the body cannot heal itself. Read More @ http://bit.ly/2RAzQmV

    For instance, according to National Cancer Institute in 2018, approximately 1,735,350 new cases of cancer will be diagnosed in the United States and 609,640 people will die from the disease.

Leave a Reply

Your email address will not be published. Required fields are marked *