Date of Graduation

8-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Engineering (PhD)

Degree Level

Graduate

Department

Biomedical Engineering

Advisor/Mentor

Jeffrey Wolchok

Committee Member

Kartik Balachandran

Second Committee Member

Nicholas P Greene

Third Committee Member

Young H Song

Keywords

Cytokines;ECM;Immunomodulation;Inflammatory injury;Injectable therapeutics;Skeletal muscle

Abstract

Although skeletal muscle displays an astonishing regenerative capacity, injuries or diseases that resulted in bedridden or chronic muscle wasting can overwhelm this intrinsic feature of skeletal muscle and lead to functional deficit (range of motion and/or strength) and overall reduction in quality of life. Microenvironmental cues within injured skeletal muscle dictate regenerative and repair process which are tightly coordinated interplay among resident cells, cells recruitment and immune response following an assault in the muscle extracellular matrix (ECM). The successful regeneration of functional tissues requires both appropriate modulation of the inflammatory response, and activation of a variety of cell populations. Biomaterials offer unique opportunities to spatiotemporally control cytokine delivery and may provide significant benefits in the modulation of immune cells and muscle-immune micro-environment (MIME) to promote regeneration. The aim of this dissertation is to create injectable therapeutics that are capable of both modulating the inflammatory response and directly promoting muscle regeneration. In aim 1, we investigated the safety and therapeutic potential of human muscle derived decellularized ECM to promote muscle regeneration in mouse disuse and reloading hindlimb injury model and rabbit chronic rotator cuff tear muscle degenerative injury model. In aim 2, we investigated the therapeutic potential of delayed delivery of IL-10 to boost muscle regeneration when combined with progenitor cells repair (mined muscle grafts) in rat volumetric muscle loss injury model. Together, the findings of these two aims further our understanding of the role that pro-regenerative immune cells play in promoting endogenous mechanisms of tissue repair after muscle injury and present potential therapeutic avenues to modulate the MIME in aiding muscle repair and recovery.

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