CARDIAC TISSUE

ENGINEERING

BY

MARYAM IDRIS MUSA (20142926)

Overview

Introduction

Biomaterials

Cells

Biomolecule

TE product requirements

Heart valves

Blood vessels

Myocardium

Introduction

Heart disease is the leading cause of death and disability all over the world accounting for

approximately 40% of all human mortality

Treatment limitations:

Cardiomyocytes cannot divide to replace injured cells

Restricted intrinsic capacity of the heart

Lack of organs for transplantation and

Complications associated with immune suppressive treatments

The main targets for tissue engineering

Blood vessels

Heart muscles- myocardium and

Heart valve

Biomaterials

Most commonly used biomaterials for

cardiovascular tissue engineering are

Biodegradable Polymeric scaffolds (Polyglycolic acid PGA)

Hydrogels(seeded with collagen,

fibrin, alginate)

Decellularized tissue

(composed of natural ECM proteins:

collagen, fibronectin etc.)

Biomaterials-Scaffolds

Scaffold provides structure for

cells/tissue to grow and deliver

biomolecules (growth factors,

cytokines, etc.)

Properties (chemical, mechanical,

biological) should be adjusted to

provide appropriate performance.

Cells

Cell types most commonly used for cardiac tissue engineering (smart 2008)

Embryonic stem cells

Bone marrow- derived mesenchymal stem cells

Skeletal myoblasts

Induced pluripotent stem cells

Multipotient adult germline stem cells

Endothelial progenitor stem cells

Very small embryonic-like stem cells

Endogenous cardiac stem cells

Mesenchymal Stem Cells

Found in many tissues and organs

Are multipotent and possess

extensive proliferation potential

Bone marrow-derived adult stem

cells can be differentiated to many

cell types like cartilage bone and

adipose fat

Use of adult stem cells allows

autologous cell transplantation

Embryonic Stem Cells

Collected at the blastocyst stage (day 6) of embryogenesis

Can differentiate into cells from all three germ layers of the body ( endoderm, endoderm, mesoderm)

Capable of self-renewaland undifferentiated proliferation in culture for extended time.

BIOMOLECULES

Angiogenic Factors

Vasculogenic Factors

Growth Factors

Differentiation Factors

TE Product Requirements

Biocompatible

Should not elicit immune or inflammatory response

Functional

Adequate mechanical and hemodynamic function, mature ECM, durability

Living

Growth and remodelling capabilities of the construct should mimic the native heart

valve, blood vessel or myocardium structure

Continued

Blood Vessels

Must be able to withstand high-pressure fluid dynamics, turbulence

Biocompatible, functional, living

Valves

Must be able to operate in a very dynamic and severe environment

Open and close at 1Hz, exposed to mechanical stresses, high pressure fluid dynamics, turbulence etc.

Myocardium Patch

High vascularity is critical

Mechanical and electrical anisotropy

High metabolic demand

Overview

Tissue engineered

construct

Cells

Scaffolds Signals

Autologous

Allogeneic

Xenogeneic

Stem

Growth factors

Cytokines

Mechanical

stimulation

Differentiation factorsNatural

Synthetic

Tissue Engineered Heart Valves

The heart consists of four chambers two atria

9upper chamber), two ventricles(lower ventricles)

Valves are flaps that are located on each end of

the two ventricle (lower chamber) of the heart

Valves prevent backward flow of blood

As the heart muscle contracts and releases, the

valves open and shut, letting blood flow into the

ventricles and atria at alternate times

What's being used for TEHV:

Cells

Vascular cells

Valvular cells

Stem cells

Scaffolds

Synthetic (PLA, PLGA)

Natural (collagen, HA, fibrin)

Decellularised biological matrices

Mechanical stimulation

Pulsatile flow systems

Cyclic flexure bioreactors

Tissue Engineered Blood Vessels

TEBV has become necessary because

Atherosclerosis, in the form of coronary artery

disease results in over 515,000 coronary arterybypass graft procedures a year in the United

States alone

Many patients do not have suitable

vessels due to age, disease, or previoususe

Synthetic coronary bypass vessels have not

performed adequately to be employed to any

significant degree

What is being used for TEBV:

Cells

Endothelial cells

Smooth muscle cells

Fibroblasts and Myofibroblasts

Genetically modified cells

Stem cells (MSCs ESCs)

Scaffolds

Synthetic(PET, ePTFE, PGA, PLA, PUs)

Natural (collagen)

Decellularized biological matrices

Mechanical StimulationPulsatile Flow Systems

Cyclic longitudinal strain

Signalling FactorsGrowth Factors (bFGF, PDGF, VEGF)

Cytokines

Bypass Vascular Grafts

Graft fabrication requires designs of a suitable mold

Walls are cellularized with smooth muscle cells

Lumen is cellularized with endothelial cells

Tissue Engineered Myocardium

Overview: Myocardial Infarction

One or more regions of the

heart muscle experience a

severe and prolonged

decrease in oxygen supply

because of insufficient

coronary blood flow

The affected muscle tissue

subsequently becomes

necrotic

Myocardial Patch

Cells

Cardiocytes

Cardiac progenitor cells

Skeletal muscle cells

Smooth muscle cells

Stem cells (MSCs ESCs)

Scaffolds

Synthetic (PEG 3d MMP- responsive hydrogel)

Natural

(collagen, ECM proteins, alginate)

Cell sheets

Mechanical StimulationPulsatile Flow Systems

Rotational seeding

Cyclic mechanical strain

Signalling Factors

Growth Factors(Insulin, transferrin, PDGF,5-azacytidine)

Cytokines

Conditioned media

Co-culture

Recent Developments

Researchers at the Brigham and Women's Hospital and Harvard Medical School in

Boston and the University of Sydney in Australia were able to combine a novel elastic

hydrogel with micro scale technologies to create an artificial cardiac tissue that

mimics the mechanical and biological properties of the native heart. Which can be

used to address the challenge of engineering complex 3D- tissues as in heart tissues.

Harvard scientists have merged stem cell and “organ-on-a-chip” technologies to

grow, for the first time, functioning human heart tissue carrying an inherited

cardiovascular disease.

Previous studies have shown that cardiomyocytes can grow on porous scaffolds

such as gels made from alginate or gelatin. However, these materials are poor

conductors. To make a conductive scaffold, Khademhosseini and his colleagues,

including Xiaowu (Shirley) Tang of the University of Waterloo,

Continued…

in Ontario, enveloped carbon

nanotubes in a crosslinked gelatin film.

The team coated the nanotubes with

gelatin modified with methacrylate

monomers. They then shone light on the

nanotubes to crosslink the

methacrylate, producing a hydrogel.

The nanotubes formed a fibrous

network that connected pores of the

gel. These nanotube strands mimic

conductive fibers in heart muscle called

Purkinje fibers

Heart ScaffoldCarbon nanotubes (thin strands) form fibrous networks in a porous hydrogel. Researchers used this material to grow cardiac tissue in the lab.

Credit: ACS Nano

Conclusion

Despite all the work being carried out for decades, a lot still need to be done in Taking these tissue engineered constructs from benchtop to bedside

Better understanding the human body and how to manipulate cells

References

www.sciencedirect.com

An introduction to Biomaterials. Ramaswami, P and Wagner, WR. 2005

www.seas.Harvard.edu

Roger, v et al. heart disease and stroke statistics.2011. update: a report

from the American Heart association. Circulation. 2011

www.sciencedaily.com Building heart tissue that beats: Engineered tissue

closely mimics natural heart muscle March 12, 2014