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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.
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
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