Biomaterials as Stem Cell Niches for Cardiac

Cell Therapy

Rashedul Islam

M Sc. Student

Dept. of

Biotechnology and Genetic Engineering

Jahangirnagar University, Savar, Dhaka

Bangladesh.

• Cardiac cell therapy

• Possible cells for cardiac cell therapy

• Delivery methods of stem cells

• Limitations

• Biomaterials as scaffold for cardiac cell therapy

• Conclusion

Outline of the presentation

Therapy for myocardial infarction and heart failure.

Aims to restore the functionality of the diseased or injured

myocardium using stem/progenitor cells.

The key elements are:

the choice of donor cell, the strategy of delivery and the

understanding of the mechanisms.

Issues with human embryonic stem cells:

Immunogenicity

Tumorigenesis

Ethical challenges

Cardiac Cell Therapy

A variety of cell types have been tested for acute myocardial

infarction and chronic heart failure.

Autologous cell sources: Adult bone marrow derived stem

cells and skeletal-muscle derived myoblasts.

Skeletal-muscle derived myoblasts?

Reported with ventricular arrhythmias.

Bone marrow-derived stem cells?

Significantly increase global or regional ejection fraction

Reduce infarct size and end systolic volumes in patients with

acute myocardial infarction

Autologous, thus eliminates the need for immunosuppression

Circulating endothelial progenitor cells, or tissue-residing stem

cells improved neovascularization and cardiac function.

What types of cells could be used?

1. Intramyocardial injection

2. Intracoronary injection

3. Intravenous injection and

4. Chemotactic mobilization

Delivery Strategies for Cardiac Cell Therapy

• Direct injection of stem cells in myocardium.

• Injections are most frequently made into the left ventricle by direct

epicardial approach or using a catheter-based transendocardial

approach.

A. Epicardial injection:

• Injection process is simple and considered as the most reliable

delivery method.

Advantages:

• Higher cell retention within the myocardium.

• Requires fewer cells to achieve engraftment compared with

intracoronary or intravenous injection.

Disadvantage:

• This invasive delivery is associated with intraoperative and

postoperative risks.

• Increase the risk of cardiac arrhythmias or require the use of anti

arrhythmic agents

1. Intramyocardial injection

B. Transendocardial injection:

• An improved approach for intramyocardial injection is to

implant stem cells.

• Utilizes a percutaneous catheter-based approach.

• For example, NOGATM system uses a percutaneous catheter

guided by left ventricular electromechanical mapping to implant

stem cells.

Advantages

• This system allows for injection with high precision into

nonviable areas of the myocardium with an injection-needle

catheter, which offers an advantage over the more invasive

surgical approach and its associated risks.

• Can be repeated if needed.

1. Intramyocardial injection

• A percutaneous transluminal coronary catheter used for

intracoronary delivery of bone marrow-derived stem cells after

myocardial infarction.

Advantages:

• It can deliver the maximum concentration of cells to the site of

infarct and peri-infarct tissue.

• Allows the stem cells to ‘‘home to’’ and incorporate in the

areas bordering the infarct zone in a homogenous manner.

• Thus no ‘islands’ of cells in the infarcted myocardium.

Disadvantage:

• May lead to decreased blood flow which could cause ischemia

leading to arrhythmia.

2. Intracoronary injection

• Intravenous injection obviates the need for cardiac surgery or

cardiac catheterization.

• Heavily depends on homing signal and homing mechanisms.

• It is thought that, micro-environmental factors, expression of

matrix and adhesion molecules by injured tissue, homing

receptors and various factors relating to migration are involved

in the homing process of stem cells.

Advantages:

• Least invasive

Disadvantages:

• Due to long circulation time, cells could be lost by extraction

towards non-cardiac organs and fail to home to the area of

infarct.

• Consequently, a large dose of stem cells may be needed to get

enough cells reach to the heart compared with other delivery

routes.

3. Intravenous injection

Bodo E. Strauer, and Ran Kornowski Circulation.

2003;107:929-934

Copyright © American Heart Association, Inc. All rights reserved.

Delivery options for stem cell transfer modalities

to the heart.

• The homing of stem cells has beenperformed via local delivery of various chemotacticfactors

• Homing factor, stromal derived factor 1 alpha (SDF-1α)demonstrated enhanced recruitment of c-kit+ stem cellsto myocardium in a mouse infarct model.

• It was correlated with increased ejection fraction andfractional shortening determined by echocardiography.

4. Chemotactic Mobilization

doi: 10.1161/01.ATV.0000073832.49290.B5

Regardless the application methods, other limitations are-

• Majority of transplanted cells die within the first dayspost-transplantation and the long term engraftment rateis very low.

• The main factor contributing to cell death is that theareas where stem cells are transplanted to are ischemicregions.

Solution:

• Biomaterial scaffolds for cardiac cell therapy .

Limitations

• A tissue-engineering approach to achieve myocardial

regeneration by implanting cells into a scaffold onto the surface

of the heart.

• The scaffold served as a temporary stem cell niche to maintain

the proliferation and differentiation of the transplanted stem cells.

• A fibrin patch with porcine mesenchymal stem cells to the LV

anterior wall of swine LV myocardial infarction models were

transplanted.

• The results indicated this fibrin-MSC patch may prevent LV wall

thinning and rescue myocardial function.

• Another novel approach is PEGylated fibrin biomatrix using a

dysfunctional, amine reactive PEG.

• This system was designed to realize a combination strategy

which aims to facilitate myocardium regeneration after

myocardial infarction by delivering both stem cells and growth

factors to the injured myocardium.

Biomaterial scaffolds for cardiac cell therapy

• Although stem cell therapy is reported as efficacious, the

underlying mechanism remains unclear and there is significant

opportunity to improve clinical outcomes.

• Stem cells may improve cardiac function by trans-

differentiating into endothelial cells or cardiomyocytes, by

promoting angiogenesis and improving myocardial blood flow,

or by paracrine effects.

• More efficient delivery method and localization are strongly

required.

• Engineering appropriate interaction between biomaterials and

cells can increase both delivery efficiency and appropriate

localization to the injured sites, thus reducing high dose

requirements and improving the cells functions.

Conclusion

Thank you