Graduation Semester and Year

2013

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Liping Tang

Abstract

Fibrocytes are circulating connective tissue precursor cells that were first described in 1994 by Bucala et al. as mediators of the innate immune response [1]. Recently the notion of a fibrocyte has not only gained widespread acceptance, but these cells have been identified to participate in a number of disease and pathologic states including aberrant wound repair, fibrosis of organs, cardiovascular disease, and even normal aging. Despite these advancements, little was known about the response of these dynamic cells to biomaterial implants and foreign body reactions. The main focus of my thesis work has therefore focused on investigating fibrocyte-mediate responses, and identifying cellular interactions and the role of fibrocytes during the foreign body response. Our results support that fibrocytes are vital and primary contributors to collagen deposition and expansion of encapsulating fibrotic matrix and scar formation. This thesis summarizes our efforts on the development of several strategies to alleviate fibrocyte driven fibrotic responses.In the first approach macrophage interactions were investigated through the development of a dual, near infrared, imaging probe modality to non-invasively investigate the role of macrophage polarization on implant-associated fibrotic tissue reactions in real time. Two polyethylene glycol based probes were fabricated to detect M1 and M2 macrophages around biomaterial implants and infection. Using antagonistic compounds to block specific cytokine activators, we find that fibrocyte accumulation is linked to macrophages and responsive to transforming growth factor beta (TGF-β) signaling related to alternative macrophage activation. In addition, we found that stabilizing mast cells drastically reduce fibrocyte and fibrocyte-derived collagen production around PLGA implants. Deeper investigation using mast cell depleted and reconstituted mice irrevocably demonstrates that the degree of mast cell activation can dictate subsequent fibrocyte responses.In addition to cellular mediate mechanisms, micropillar implants are used to passively modify fibrocyte activation. Very interestingly fibrocytes were found to be more responsive to topographical changes, specifically spacing and height, of PDMS micropillar implants than fibroblasts or macrophages. The cellular responses were found to correlate with the histological outcomes of fibrosis including granulation tissue formation and collagen production. Lastly, it has recently been shown that fibrocytes possess a multi-potency for several lineages including adipocytes. The potential for differentiation however had not been investigated in vivo. Through the use of mini-osmotic pumps, the potential for directing fibrocyte differentiation in vivo was assessed by delivering specific differentiation agents. The results presented in this thesis provide strong support for novel strategies to resolve or treat complications of the foreign body response and excessive fibrosis to existing medical implants.

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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