Whole Organ Bioengineering Science & Sensibility. Doris A. Taylor, PhD, FAHA, FACC Director, Regenerative Medicine Research Texas Heart Institute

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1 Whole Organ Bioengineering Science & Sensibility Doris A. Taylor, PhD, FAHA, FACC Director, Regenerative Medicine Research Texas Heart Institute

2 Disclosure Founder/Consultant/shareholder Miromatrix Medical Inc Dr. Taylor holds a financial interest in Miromatrix Medical, Inc. She is entitled to sales royalty through the University of Minnesota for products related to research.

3 Number of People The goal is not cells The unmet need is for organs Transplants Deceased Donors Dr. Cooley s House Source: OPTN: Organ Procurement and Transplantation Network 3

4 Engineering complex organs & tissues Cell therapy field emerges s (acceptance of biologic therapies) Stem cell biology matures ( s) Perfusion decellularization generates vascularizable ECM scaffolds (2008) ipsc technology enables personalized organs created by ECM recellularization (2010s)

5 Strategies For Meeting an Unmet Need Either: Build it or Use what already exists

6 Build It

7 Use What Exists Give Nature the tools and get out of the way

8 Lessons learned in building a TAMH Size matters So does anti-coagulation Need a power source Wear and tear on parts = poor durability Must reconcile the interdependency of left and right sides of the organ Need Actuation mechanism Need Drive line

9 Using What Exists for a Bioartificial Heart Size matters Need for anti-coagulation Wear and tear on parts/poor durability Inability to reconcile the interdependency of left and right sides of the organ External actuation mechanism Externalized drive line Need for a power source

10 Lessons learned from TAMH Size Anti-coagulation matters Wear and tear on parts = poor durability Inability to reconcile the interdependency of left and right sides of the organ External actuation mechanism Externalized drive line Need for a power source

11 Use Nature s Conduits Sanchez PL, Taylor DA, Fernandez-Aviles F. (2015) Acellular Human Heart Matrix: A Critical Step Toward Whole Heart Grafts. Biomaterials August; 61: PMID: Sanchez PL, Fernandez-Santos ME, Taylor DA, Fernandez-Aviles F. (2016) Data from acellular human heart matrix. Data Brief May 18;8: doe: /j.dib ecollection PMID:

12 Di-O Di-I DAPI CMFDA enos Repopulate with autologous cells Vasculature Cells proliferate Endocardium vessels lined Nonthrombogenic Circulatory circuit Robertson MJ, Dries-Devlin JL, Kren SM, Burchfield JS, Taylor DA. (2014) Optimizing Recellularization of Whole Decellularized Heart Extracellular Matrix. PLoS One Feb 27;9(2):e PMID:

13 Building a Bioartificial Heart Large size Need for anti-coagulation Wear and tear on parts = poor durability Inability to reconcile the interdependency of left and right sides of the organ External actuation mechanism Externalized drive line Need for a power source

14 BTT not DT

15 Harnessing 2 natural tools Stem cells healthy ECM

16 16

17 The solution may be a biomechanical combination CARMAT Biological valves Mechanical pump

18 Lessons learned from TAMH Size Anti-coagulation matters Wear and tear on parts = poor durability Reconcile the inter-dependency of left and right sides of the organ External actuation mechanism Externalized drive line Need for a power source

19 A unique biomechanical combination Heterotopic transplantation of a partially re-cellularized heart with bi-ventricular mechanical support

20 Let Nature Do Some of the Work Reconcile the inter-dependency of left and right sides

21 Let Nature Do Some of the Work Macroscopically Cells are recruited into ECM Cell localize appropriately Taylor et al THI unpublished data

22 Let Nature Do Some of the Work Microscopically Neo-vessels are found in the implant α-sma CD31 α-sma After 60 days 50 mm Taylor et al THI unpublished data

23 βmhc- H&E Let Nature Do Some of the Work Microscopically Neo-muscle is found in the implanted heart 1000 μm 50 μm 200 μm Taylor et al THI unpublished data

24 Generating enough cardiomyocyte cells is the major rate limiting step in cardiac regenerative medicine Reliable approvable matrix sources porcine or human Organ complexity Bioreactors that maintain integrity of construct over time Technical hurdles Adult human heart: ~2 billion myocytes requires ~80L of medium monthly to survive in vitro Piece of heart tissue 1.5x1.5x2cm: ~10 M myocytes Requires ~400mL of medium monthly to survive in vitro

25 Use What Already Exists Automated cells factories Clinical grade extracorporeal system 25

26 Given all the hurdles.

27 This is about more than heart Organs Limb Thorax Abdomen Perfusion Decellularization Developed in Taylor lab 2008

28 We ve got that covered too Liver Robertson Taylor (2018) PLoS ONE 13(1): e

29 Conclusions The unmet need is organs for transplant Door is open for human solid organ engineering decm provides optimal advantages as a scaffold Mechanical devices are improving Biology can augment devices Mechanical/ biologic combinations may be the best solution 29

30 Deep in the Heart of Texas National Institutes of Health/NHLBI AHA DeHaan Foundation EU SABIO Project UT School of Public Health

31 REAL Conclusion But most of all have FUN (Flash mob for Stephen Hawking) We spend as much time at work as at home - enjoy it