20.109(S10):Notebook/T/R Blue Research Proposal/2010/04/25

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Pei and Leanna's Research Proposal Main project page

Topic

Tissue Engineering and Regenerative Medicine using physiologically-relevant mechanical stimuli

(Tentative) Project Idea and Overview

Regeneration or repair of myocardial tissue by pulse vibrations using conditions previously shown to be conducive to skin wound healing.

OVERALL GOAL: We would like to find if mechanical manipulation (with exact parameter values, if we're successful) is capable of reduce natural scarring of damaged myocardial tissue so as to rescue normal function and avoid deterioration natural mechanical and electrical properties of the tissue.

Background

When left untreated, myocardial infarctions ("heart attacks") commonly cause severe damage or even death to the tissue of the myocardium. The typical human bodily response to tissue damage consists of fibroblast proliferation and scarring. While these mechanisms are effective in recovering function and overall viability, the resulting tissue does not always achieve the same level of performance as before. In many cases, scarring can be more detrimental than the original damage. (1)


Previous studies have shown improved success with repair and regeneration of vocal fold tissue, bone tissue, and even teeth accomplished through use of physiologically-relevant mechanical stimulation.(2) Thus, our hypothesis centers around the idea that since the mechanical properties of myocardial tissue play a significant role in proper overall function, perhaps carefully designed mechanical manipulation of damaged myocardial tissue can help improve upon current methods of scar reduction in cardiac tissue healing.


As a starting point, we plan on executing ex vivo studies on myocardial porcine myocardial tissue (**this may change as we further analyze reasonable availability of resources**). We aim to combine physiologically-relevant mechanical stimuli with the presence of TGF-beta that has been shown to have a positive effect on healing (minimal scarring) of skin wounds, and shows potential for being beneficial to treatment of cardiac tissue damage. (1)

References

1. Palatinus JA, Rhett JM, Gourdie RG. Translational lessons from scarless healing of cutaneous wounds and regenerative repair of the myocardium. J Mol Cell Cardio. 2010;48:550-557.

In mammals, the healing response to a wound is scarring; a result of fibroblast proliferation and scar tissue. While this provides a partial restoration of the structure and function of the original tissue, this can generally lead to further harm to the tissue, especially in the heart.

When the heart encounters trauma, it is forced to heal while maintaining function. The heart, relative to other tissues, heals with profound fibrosis and scarring with minimal regeneration. Healing consists of three phases: inflammation, proliferation, and maturation. Inflammation: neutrophil accumulation, macrophage and monocyte infiltration. Proliferation: propogation of cells that have migrated to the wound (epithelial, fibroblasts, endothelial). Maturation: remodeling of collagen to form a scar.

Following myocardial infarction (MI), the most common post-MI cause of death is ventricular arrhythmia. Revascularization of the wound area is of utmost importance, although in some areas of the tissue, neovasculariztion could lead to complications. Growth factors that demonstrate potential in preclinical studes (ex: VEGF-A, FGF-2, PDGF) have yielded disappointling clinical results. TGF-beta is known to reduce scarring, and may even be good for the heart, so this is a possibility in further study. Modulation of the collagen in the scar is another area that needs further study, but would probably help in cardiovascular healing. Little is known about the fibrocyte, but some reports indicate that these cells improve the healing process. The zebrafish is known for its ability to regenerate tissues including the cardiac muscle. The human heart is more susceptible to arrhythmias than newt or fish hearts, however. The MRL mouse has the ability to scarlessly heal ear punch wounds, but too similarly to wt and not in the heart tissue. Diabetics also show a different response to injury.


2. Kutty JK, Webb K. Vibration stimulates vocal mucosa-like matrix expression by hydrogel-encapsulated fibroblasts. J Tissue Eng Regen Med. 2009;4:62-72.

This study investigated the effect of vibratory stimulation on ECM gene expression and synthesis by fibroblasts encapsulated within hyaluronic acid hydrogels that approximate the viscoelastic properties of vocal mucosa. The objective was to find a method for reducing vocal scarring, restoring native matrix composition and improving vocal quality in the event of injury to the vocal fold ECM. Results indicated that vibration is a critical epigenetic factor that regulates vocal fold ECM, and that rapid restoration of the phonatory microenvironment may achieve the stated objective.


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