Date

March 2010

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Science & Engineering

Institution

Oregon Health & Science University

Abstract

Tissue engineering is a promising therapeutic option for injured tissues with deficient endogenous cellular repair such as atherosclerotic lesions of the vascular wall and chondral lesions of the synovial joints. Current cell-based surgical options use autologous tissue that may be of limited supply or the harvest of which can cause donor-site problems. As part of the body’s natural repair process, immature bone marrow-derived cells may be recruited to sites of both diseased vascular wall and damaged articular cartilage. Both vascular engineering with circulating endothelial progenitor cells (EPCs) and cartilage engineering with mesenchymal stem cells (MSCs) are limited by the efficiency and rate of differentiation of these primitive precursors to functional cells resembling endothelial cells and articular chondrocytes. The goal of these studies was to develop tissue engineering platforms that are tailored for the use of bone marrow-derived stem and progenitor cells and that are compatible with existing vascular and chondral interventions. The different natures of these tissues present distinct challenges for cell-based regenerative strategies with regard to geometry, the compartmentalization of the relevant stem/progenitor cells, and environmental factors. For the tissues of interest here, the feasibilities of two different approaches were evaluated based on these challenges and the desire to shorten or eliminate expansion and differentiation times. The proposed strategy for vascular engineering is to avoid isolation altogether by capturing EPCs directly from flow to promote an endothelial monolayer on solid surfaces. In this work, the ability to do so with antibodies directed at the endothelialspecific receptor KDR was investigated and characterized in vitro with model cells. On the other hand, MSCs that are capable of chondrogenesis are physically separated from cartilage, residing in the hypoxic environment of the bone marrow. The proposed strategy for cartilage engineering is to transfer MSCs from bone marrow to cartilage defects following the in vitro formation of three-dimensional aggregates of differentiated MSCs. The goal of this work was to evaluate the effect of culturing MSCs under low oxygen during differentiation in microscopic aggregates designed to overcome mass transport limitations that can exist with culture of larger three-dimensional tissues. These studies answer critical questions about the feasibility of these tissue engineering strategies and lay the foundation for further development towards clinical relevancy.

Identifier

doi:10.6083/M4PV6HBM

Division

Div. of Biomedical Engineering

School

School of Medicine

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