Multi-Cellular And Multi-Scale Approaches For Cartilage Repair

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Doctor of Philosophy (PhD)
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Cartilage repair
Mesenchymal stem cells
Tissue engineering
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To date, there are no surgical interventions that can fully restore damaged cartilage. While the field of tissue engineering has emerged as a potential solution, there exist numerous shortcomings in existing technologies. This thesis addresses some of these shortcomings by developing multi-cellular and multi-scale approaches to advance technologies for cartilage repair. For instance, co-culture systems have recently been introduced as a novel tissue engineering strategy for cartilage repair. We show here that a small pool of young/healthy chondrocytes (CH) can rejuvenate a larger pool of older/infirm mesenchymal stem cells (MSC), improving matrix deposition while suppressing MSC hypertrophic conversion. This resolves the deficiency of CH supply as well as phenotypic instability and age-related decline in potential of MSCs. Biomimetic design in cartilage tissue engineering is yet another challenge, given the complexity of the native tissue. While articular cartilage is a highly stratified tissue with depth-dependent properties, most cell-laden cartilage constructs described in the literature simply recapitulate bulk functional properties without morphologic recapitulation. Here, we develop a layer-by-layer fabrication strategy to promote depth dependent tissue formation and function. We also introduce a novel method to properly transport nutrients and wastes into/out of engineered constructs. Finally, another equally important aspect in designing engineered cartilage tissue is clinical translation. In this, the simplicity of application, including ease of handling and preparation, and methods for implantation in situ, are required for clinical translation. To address this, we developed a micro-scale co-culture system that can be easily fabricated and delivered into cartilage defects in the context of current clinical cartilage repair procedures. Collectively, the thesis advances our understanding of the chondrogenic capacity of MSCs, introduces various methods to improve MSC chondrogenesis (using chemical and natural factors), and identifies some of the underlying mechanisms regulating this process. Further, this work introduces novel methods to fabricate engineered cartilage to mimic the structure of native tissue as well as clinical relevant methods to couple tissue engineering efforts with current clinical practice. These innovative approaches may aid the many patients who suffer from cartilage disease by enhancing cartilage tissue engineering strategies and reducing them to clinical practice.

Robert L. Mauck
Jason A. Burdick
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