BIOENGINEERING HUMAN LIVERS FOR TRANSPLANTATION: WHERE DO WE STAND NOW?

Transcription

1 BIOENGINEERING HUMAN LIVERS FOR TRANSPLANTATION: WHERE DO WE STAND NOW? Pedro M. Baptista, PharmD, PhD Aragon s Health Sciences Research Institute (IIS Aragon), Zaragoza Biomedical Eng. Depart., Carlos III University of Madrid CIBERehd, Spain

2 WIDENING GAP BETWEEN AVAILABLE ORGANS AND PATIENTS WAITING FOR LIVER TRANSPLANT Liver Donation in the US Waiting List Candidates 125,696 as of today at 07:00 (GMT) Liver Waiting List Candidates 14,184 as of today at 07:00 (GMT) Source: The Organ Procurement and Transplantation Network

3 REGENERATIVE MEDICINE: STRATEGY Biopsy Cells Scaffold Tissue CLINICAL TRANSLATION 3

4 USING THIS STRATEGY, WE HAVE BEEN ABLE TO BIOENGINEER AND TRANSPLANT MULTIPLE TISSUES TO HUMANS 4

5 THE LAST DECADES WERE QUITE SUCCESSFUL MAKING THIS TRANSITION, HOWEVER Liver SC Organoid Microfluidic Chip TE Bladder Sources: Meritxel Huch s Lab, Boston University and WFIRM

6 WHOLE HEART DECELLULARIZATION DORIS TAYLOR, UNIVERSITY OF MINNESOTA University of Minnesota scientists create beating heart --and hope for people awaiting organ transplants 6 Ott et al. Nature Medicine 2008

7 WHOLE-LIVER DECELLULARIZATION Triton X NH 4 OH 1cm 1cm Baptista et al. Conf Proc IEEE Eng Med Biol Soc. 2009; Baptista et al. Hepatology, 2011.

8 DECELLULARIZED ORGANS Lungs Pancreas Kidney Intestine Liver Baptista et al. Conf Proc IEEE Eng Med Biol Soc. 2009

9 WHOLE-LIVER BIOENGINEERING Hepatic Cells Vascular Cells Urea (mg/h/total DNA) Seeded Bioscaffo l ds hflcs Days Albumin (ng/h/total DNA) Seeded Bioscaffolds hflcs Days Baptista et al. Hepatology, HALB/CK19/DAPI EpCAM/ASBT/DAPI 25μm

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11 First Bioengineered Animal Liver (rat scaffold and cells) Uygun B, Soto-Gutierrez A. et al., Nature Medicine 2010 First Bioengineered Human Liver (human cells, but ferret scaffold) Baptista PM, Sidiqqi M, et al., Hepatology 2010

12 Simões et al., Scientific Reports 2017 URETHRA RHABDOSPHINCTER BIOENGINEERING DNA (ƞg/mg tissue) 1.6E+4 1.2E+4 8.0E+3 4.0E+3 ** * 0.0E+0 Native 0.5% SDS 1% SDS

13 0.1% SDS + 1% Triton X100 Native PORCINE UTERUS BIOENGINEERING Campo H, Baptista PM et al., Biology of Reproduction 2017

14 Sullivan D. et al., Biomaterials 2012 KIDNEY BIOENGINEERING

15 ORGAN BIOENGINEERING STRATEGY Emma Moran et al. Translational Research 2014

16 Fetal Hematopoiesis Mechano- Biology Cholesterol and Bile Acid Metabolism Drug Metabolism Toxicology Infectious Diseases Transplant Biology and Immunology Developmental Biology Stem Cells ETC

17 Transplantation

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19 SCAFFOLD SEEDING AT DIFFERENT PRESSURES GENERATES DIFFERENT CELL DISTRIBUTION PATTERNS THROUGHOUT THE SCAFFOLDS 1 st day HE DAPI GFP ( P) RFP ( P) GFP higher pressure 25/14 2 nd day dtomato lower pressure 50/25 STOP! 3 rd day 100/50 Unpublished Data.

20 GENERATION OF VASCULAR STRUCTURES LINED WITH ENDOTHELIAL CELLS AND PERICYTES WITH DIFFERENT DIAMETERS Small diameter vessels VEcad; Vimentin Med. diameter vessels Large diameter vessels VEcad; Vimentin VEcad; Vimentin Unpublished Data.

21 PRESENT WORK IN PIGS

22 BIOENGINEERED LIVER TRANSPLANTATION IN PIGS Native Liver Graft Transplant Partial Hepatectomy Portal-Cava Shunt Bioengineered Liver Transplant Unpublished Data.

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24 % o f T o ta l D u c tu la r S tru c tu r e s MINI-LIVER ORGANOIDS AS HUMAN LIVER TISSUE SURROGATES Acellular Scaffold Acellular Liver Disc 3D Liver Organoid Human Liver Cells Heps + Bile Ducts CK19/ALB/DAPI Drug Teratogenesis L D M L D M + D A P T * 0 D u c ta l L a y e r Im m a tu r e D u c t M a tu r e D u c t Baptista et al. Hepatology, 2017.

25 Mouse Duct Development hfetal Liver Liver Discs Ductal Layer 2 nd Ductal Layer CK19/Laminin CK19/Laminin Immature Duct CK19/Laminin CK19/Laminin CK19/Albumin Mature Duct CK19/Laminin CK19/Laminin CK19/Laminin CK19/Laminin Zong et al, Development, 2009

26 SUMMARY -Mechanisms of liver development -Mechanisms of liver disease -Drug discovery and Toxicology -Etc. scaffoldportal vein scaffoldvena cava nativeliver scaffold -Organ Transplantation -Angiogenesis and Vasculogenesis -Vascular Mechanobiology -Etc.

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28 Body parts shop

29 Funding Agencies: Acknowledgments: IIS Aragon, Spain Pilar Sainz Iris Pla Sara Morini Joana Almeida Natalia Sanchez Romero Daniela Rubio Soto Raul Bertol Laura Baeza University Hospital Zurich, CH Daniel Eberli Utrecht University Bart Spee Louis Penning Roos Masereeuw IBB IST, Portugal Irina Neves Manuel Almeida Paulo Vale Claudia Lobato da Silva Joaquim Sampaio Cabral The Wake Forest Institute for Regenerative Medicine, USA Emma Moran Dipen Vyas Abritee Dhal Brandon Gaston Shay Soker Anthony Atala Graça Almeida-Porada Saloomeh Moktari

30 Zaragoza s Liver Team

31 GI and Hepatology Research Group