Clinical Constraints Associated With Myocardial Infarction Biology Essay

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There is increasing need for medical therapeutics to treat ailments and diseases compromising the normal functions of the human body, or even for aesthetic purposes. This need will escalate as the human population continues to increase. Heart diseases continue to be the primary cause of death in the USA, UK and Canada killing one person every 34 seconds in the USA [1]. Patients suffering from acute myocardial infarction are at a higher risk of stroke and heart failure and have increased mortality rates compared to the general population [2]. Myocardial infarction (MI) results in heart wall thinning, myocyte slippage and ventricular wall dilation. Following myocardial infarction, the ability of the myocardial tissue to regenerate is lost eventually resulting in heart failure. This limited regenerative capability of infarcted myocardium [3] has provoked the research of potential therapies [4] focusing on improvement of myocardial function by administering bio-molecules [5], acellular materials [6], cells [7] or engineered tissue [8], to myocardial tissue. However each technique has its own disadvantages attributed to, degradation of biomolecule [9], loss of cells from the injection site [10,11], growth of scar tissue between engineered and native myocardium [12] and mechanical properties not similar to that of heart muscle. Current therapies could only retard the progression of disease and hence tissue engineering strategies are required to facilitate engineering of a suitable biomaterial for myocardial infarction. The recent advances in the areas of nanotechnology, stem cell biology and tissue engineering have facilitated scientists with potential tools to develop new strategies for myocardial regeneration.

Clinical constraints associated with Myocardial Infarction

In ischemic myocardium, transplanted cells can hardly stay and survive in the infarcted region. This appears to be the major issue affecting therapeutic effects of MI by cellular cardiomyopathy. Additionally clinical success is also thwarted by maximum cell loss presumptively due to physical stress, absence of survival factors, and disruption of cellâ€"to-cell interactions in the transplanted heart [13,14]. One promising approach to prevent the increase of heart failure after myocardial infarction is the implantation of engineered cardiac patch at the site of infarction which has mechanical properties comparable to that of native tissue, capable of integrating with host tissue and favor homing of stem cells at the site of infarction. Thus, in addition to having enough elasticity for mechanical support, an ideal cardiac patch material must provide an excellent milieu for cell survival. Furthermore, the ideal biomaterial should be capable of being safely replaced by newly formed tissue and also degrade at an appropriate time period without producing any toxic products [15]. Thus the choice of biomaterials is a critical step for developing cardiac patch for MI. Three essential selection criteria include: (i) elasticity; (ii) biodegradation; (iii) the ability to retain and deliver cells. Investigative therapies for myocardial infarction commonly use naturally derived materials as one element of a treatment in combination with synthetic materials for mechanical support. Naturally derived materials used in experimental or clinical treatment of infarcts include tumor-derived basement membrane matrix gel (Matrigel) [16], alginate [17], collagen [18], laminin [19], fibrin [20] and decellularized extracellular matrix (ECM) [21], all of which can enhance cell and tissue function in the myocardial region. They provide a natural substrate for cellular attachment, proliferation, and differentiation in its native state. However natural polymers have very poor mechanical properties and hence are used in combination with synthetic polymers like PLLA, PCL, PLGA and PLA, for improving their mechanical properties and degradability. Despite several advantages such as safety and improved functioning, the recently developed cell based and biomaterial strategies fail to answer many important clinical aspects such as homing of cells and integration of construct to the infarcted heart for cardiac tissue regeneration.

Hypothesis and Objectives

1.3.1 Hypothesis

In native tissue, cell growth and structural development is supported by the ECM. Failure to regenerate the myocardial tissue was attributed to cell death occurring after engraftment of the cells within the host myocardium. Lack of an appropriate microenvironment in scarred myocardium might be a plausible reason for colossal loss and ineffective homing of injected cells. Moreover, the site of MI is a poor environment for cell proliferation and differentiation. Hence, in order to increase cell viability some factors to improve such an infertile environment are desirable. We have applied an alternative approach, by the encapsulation of cells onto the elastomeric PGS as the core material which has mechanical properties comparable to that of the native heart; with natural polymers such as Gelatin, Collagen and Fibrinogen as the shell materials to assist in cellular processes. We hypothesized that guided by nanotopographical cues provided by the underlying random core/shell nanofibrous scaffolds, and mechanical support provided by PGS, the tissue constructs may display anisotropic re-arrangement of cells, provide homing of therapeutic cells and improve the functionality of infarcted myocardium.

1.3.2 Objectives

The aim of the current research study is to develop a cardiac biomaterial which is biocompatible and possesses mechanical properties comparable to that of the native myocardium. The aim of the tissue engineered cardiac patch is to deliver healthy cells onto the infarct region and provide left ventricular restrain i.e. mechanical support to the left ventricle. We aim to achieve the above objective by the following research strategy

Identification of a suitable biomaterial that has favorable mechanical properties comparable to that of native myocardium

Fabrication of nanofiber constructs using core/shell electrospinning technique, with PGS as the core polymer and natural polymer as the shell material

Material characterization of electrospun constructs by FESEM to analyze the fiber morphology, FTIR to analyze the functional groups and contact angle for testing hydrophilicity of the scaffolds

In vitro tests to analyze the biocompatibility of the isolated cardiomyocytes and MSCs on the electrospun constructs and also to analyze the ability of PGS scaffolds to induce cardiogenic differentiation of MSCs.

Test the cardiac protein expression by immunocytochemistry analysis using cardiac specific marker proteins like actinin, troponin, myosin heavy chain and connexin 43. The cardiogenic differentiation of MSCs was further confirmed by performing dual immunocytochemistry using MSC marker proteins and cardiac marker proteins.

Inclusion of angiogenic and anti-apoptotic growth factors and cytokines like VEGF and IGF-1 on the site of infarction and testing its ability for homing and differentiation of MSCs in vivo.

In vivo evaluation of PGS nanofibrous constructs by improving the ejection fraction, wall motion, contractibility and regeneration of the infarcted myocardium in an in vivo porcine model for confirming the potentials of PGS biomaterial to serve as a suitable cardiac patch for cardiac tissue engineering applications.

Significance of the project

The success of cardiac biomaterials will profoundly depend on the use of an apropos biomaterial like PGS nanofibers which are capable of providing mechanical strength as well as the biological cues necessary for functional tissue formation. In this study, we hypothesized that a combinatorial approach of PGS/natural polymer core/shell fibrous patch material and stem cell therapy is of potential interest for the treatment of heart failure rather than either strategy alone. Our approach takes advantage of the ability of an elastomeric biomaterial sheet comprising of PGS/natural polymer core/shell fibers to act as a flexible patch; with this approach, (i) cells would remain adhered to the nanofibrous patch preventing cell loss and providing a more site-directed repair mechanism. It is increasingly accepted that physical cues play a key role in cell growth and tissue assembly [22,23]. These signals are important in stem cells (SCs) during self-renewal, proliferation, and differentiation. (ii) A elastomeric substrate and the ability to tune the mechanical properties within a given range could be advantageous as cell differentiation was shown to be affected by substrate stiffness [24]. (iii) Additionally, it has been estimated that a cell number on the order of one billion would need to be replaced in patients with heart failure [25]. The present study proposed PGS/natural polymer core/shell fibrous scaffolds comparable to cardiac ECM like topography, which promotes in situ regeneration and homing of cells; thereby reducing the number of requisite cells, is desirable for cardiac tissue engineering. Figure 1 indicates the various milestones of the project for achieving a suitable construct for Myocardial tissue engineering.

Biomaterials for Cardiac Tissue Engineering (Cardiac Patch)

PGS/Collagen core/shell fibers

PGS/Gelatin core/shell fibers

PGS/Fibrinogen core/shell fibers

In Vitro studies using MSCs/cardiomyocytes co-culture to confirm ability of PGS scaffolds to induce cardiogenic differentiation of MSCs

In Vitro studies using cardiomyocytes to confirm the ability of PGS scaffolds to maintain the functionality of cardiomyocytes

In Vivo studies on a Porcine infarct model

Figure 1.1 Milestones of the project for achieving a suitable cardiac construct having mechanical property comparable to that of native myocardium with the ability to retain the functional activity of cardiomyocytes and induce cardiogenic differentiation of MSCs.

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