Date of Graduation

8-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Cell & Molecular Biology (PhD)

Degree Level

Graduate

Department

Cell & Molecular Biology

Advisor/Mentor

Hestekin, Jamie A.

Committee Member

Balachandran, Kartik

Second Committee Member

Wolchok, Jeffrey C.

Third Committee Member

Beitle, Robert R. Jr.

Keywords

Extracellular matrix; Membrane; Muscle regeneration; Scaffold; Tissue engineering; Volumetric muscle loss

Abstract

Volumetric muscle loss overwhelms skeletal muscle’s ordinarily capable regenerative machinery, resulting in fibrosis and severe functional deficits which have defied clinical repair strategies. My work spans the design and preclinical evaluation of implants intended to drive the cell community of injured muscle toward a regenerative state, as well as the development of an understanding of the molecular responses of this cell community to biomaterial interventions. I demonstrate a new class of biomaterial by leveraging the productive capacity of sacrificial hollow fiber membrane cell culture; I show specifically that unique threads of whole extracellular matrix can be isolated by solvent degradation of cultured hollow fiber systems and that this matrix exhibits composition and structure appropriate for wound healing applications. I additionally demonstrate the application of an emerging pore characterization technique and contribute a new open source software for evaluation of mesoporous pore diameter distribution and surface area, key properties governing the performance of sacrificial cell culture materials. Toward a better understanding of the biomolecular systems mediating implant efficacy, I demonstrate the first transcriptomic investigation of a specific promising combinatorial cell-scaffold implant in a rat model of volumetric muscle loss, showing an expedited recovery of muscle contractile force concurrent with a coordinated upregulation of peripheral neuroregenerative signaling. Together, these findings establish a new scalable approach for the production of biomimetic implant materials in vitro as well as molecular targets informing the design of promising muscle regenerative biomaterials.

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