Using this template set

Building New Hearts: Regenerative Medicine Becomes a RealityTexas Heart Institute Regenerative Medicine ResearchDoris A. Taylor, Ph.D., D.Sc. (hon), FAHA, FACCVancouver, British ColumbiaOctober 5, 2015

Worldwide Burden of Cardiovascular Diseases

Repair isnt enough; the unmet need is organs for transplant

Patch

874,000 people die each year from heart disease2,600 patients wait for approximately 2,300 hearts each year

The unmet need for organs4Source: OPTN: Organ Procurement and Transplantation Network Number of People

#

If it were easy, someone else would have done it

What does it take to build a complex solid organ?

#

Biologic matrices (Eschenhagen) DEVICESPrometheusFrenesius Bioprinting

Decellularized cadaveric organs

Scaffold Options

#

Building ScaffoldsUtilizing xenogeneic or non-transplantable organs as scaffolds for re-building tissues with stem cells

Cadaveric heart

Use detergent to remove cellsDecellularized heart(extracellular matrix only)

#

Why decellularized ECM instead of devices or bioprinting?14 days3 days

#

Human organs are not suitable for transplant

Day 0Day 3

#

Human-sized organ scaffolds: Porcine

#

Structure is retained after removal of all cells

SABIO Sanchez, AvilesTaylor

#

Acellular vessels retain blood

SABIO Sanchez, AvilesTaylor

#

Complex ECM with GFs, sugars & mechanical properties

Composition is a major advantage

#

Stem Cell SourcesiPS cells Reprogrammed skin/blood cells Cord blood cells/Amniotic fluid cellsTissue-derived stem cells:BloodBone marrowFatMuscle Revitalized bone marrow or fat stem cells

#

dECM + cardiac derived cells

dECMdECM + CMs

#

What can we build?

#

Cardiovascular Regeneration involves making heart valves (A), ventricular patches (B), or coronary vessels (C). Whole hearts can be generated from decellurized matrices (D) and rebuilt using stem cells (E).18

Cardiac valves: scaffold intact

#

Acellular valves are competent

#

Valves can be engineered

#

Creating a Beating Heart in the Lab

Step 1. Cardiac Patches as a tool for repair or deliveryStep 2. Bio-Artificial Hearts for Transplantd-ECM patch applied day 3 post MIvs. sham treatment

Decell rat heart LV or RV

#

22

Edge of patch suggests integration, vascularization & cell recruitment

#

Creating a Beating Heart in the Lab

+/- Cells

Step 1. Cardiac Patches as a tool for repair or delivery (porcine)Step 2. Bio-Artificial Hearts for Transplant

#

24

Veins and trabeculae

Vascularized heart is an unmet need

Acellular vessels are patent

#

Creating a Beating Heart in the Lab

+ Stem cells+ Cells

Step 1. Cardiac Patches as a tool for repair or delivery (porcine)Step 2. Revascularized bio-artificial hearts

Coronary arteries

Whole heart - labeled cells perfused into artery and veins

#

26

Coronary arteries

Veins and trabeculae

Whole heart - labeled cells perfused into artery and veins

Recellularization of acellular coronary vessels via infusion of cells

#

PLoS One.2014;9(2): e90406.Published online Feb 27, 2014.doi:10.1371/journal.pone.0090406

Large & small diameter vessels re-lined throughout the heart

#

CMFDA eNOSCMFDA vWFCMFDA PCNADi-O Di-I DAPIPLoS One.2014;9(2): e90406. Published online Feb. 27, 2014. doi: 10.1371/journal.pone.0090406Vascular cells proliferate & function

DecellularizationRecellularization

Technology to create cardiac scaffold from any speciesTechnology for stem cells to repopulate scaffold into beating heart+=

Creating a Beating Heart in the LabA BEATING HEART

#

30

Steps of creating a beating heart in the lab

Heterotopic Transplant+/- Cells

Step 2. Revascularized heartsStep 3. Bio-Artificial Hearts for Transplant

#

31

Creating a Beating Heart in the Lab

Heterotopic Transplant+/- Cells

Step 2. Revascularized heartsStep 3. Bio-Artificial Hearts for Transplant

#

32

HurdlesOrgan complexity

Atria, Ventricle, Pacemaker, Neurons, Fibroblasts, Stem cellsBillions of cells at an affordable costOnce we have cells organ potency Longevity years and yearsEndogenous responsively/repairPhysiologic response

Progenitor cells

Cardiac stem cells

Endothelial cardiomyocytes Smooth muscle cells Numbers

Types

#

Potential Therapies

0Drug TestingTherapeuticsNew CellsMarket Size$200M$$$B$2BOrgan in a dishMatrix + CellsOrgans for TransplantMatrix + CellsCardiacPatch123Liver Assist Device

Liver

Heart

Kidney

Pancreas

Lung

Time

#

Tools and testing applications are a natural byproduct of early R&D work on therapeuticsRevenues from tools for research and testing will provide non-dilutive funds to clinical programPOC in liver or cardio drug testing validates technology for all therapeutic organs and tissues

ConclusionsThe unmet need is organs for transplantdECM provides optimal advantages as a scaffold The door is open for complex human organ engineeringRegenerative medicine is coming of age

The rate-limiting step is CELLS

#

And then theres this

Weve got that covered too

Liver

#

37

human hepatocytes live for a month

#

And then when you want to get rid of that drink

Decellularized Porcine kidney

#

THANK YOUI WISH I WERE THERE

First they ignore you, then they laugh at you, then they fight you, then you win.

Mahatma Gandhi

National Institutes of Health/NHLBI AHA DeHaan Foundation EU SABIO Project UT School of Public HealthTexas Heart Institute

Deep in the Heart of Texas