Bioactive Poly(Ethylene Glycol) Hydrogel Composites for Recapitulating the Form and Function of Engineered Musculoskeletal Tissues

Schoonraad, Sarah Angela Monica

Graduate Thesis Or Dissertation

Bioactive Poly(Ethylene Glycol) Hydrogel Composites for Recapitulating the Form and Function of Engineered Musculoskeletal Tissues Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/0z708z02c

Abstract

When damage to tissues of the musculoskeletal system occurs, the native repair mechanisms can be limiting. As an example, in cartilaginous regions like the physis (or growth plate), healing can result in the formation of a bony bar that can limit or prevent a child’s normal longitudinal growth. Current treatment approaches for damage to musculoskeletal tissues often rely on autograft or allograft transplant, which run risks of donor site morbidity or disease transmission, respectively, or rely on the use of materials that cannot integrate or regenerate the native tissue. Therefore, alternative approaches to treatment are needed. Tissue engineering seeks to develop regenerative platforms that can overcome these limitations and restore the native tissue. The pursuit of restorative treatments requires the development of systems that can not only recapitulate the tissue form, but also the function. This can prove challenging when engineering systems for the treatment of load-bearing tissues, like cartilage and bone. These challenges arise due to the conflicting needs of the cellular environment, which is well-supported by a soft cellular niche that supports nutrient transport, cellular differentiation, and extracellular matrix (ECM) deposition, while simultaneously providing a mechanically robust scaffold capable of supporting the physiological demands of the system. Looking to the native tissue as a cue, we see that these needs are met in the form of biological composites. Both cartilage and bone are composed of aqueous cellular environments housed within structurally competent fibrous networks. This begs the questions as to whether a composite material that incorporates a soft tissue biomimetic hydrogel, within an independently designed, stiff 3D-printed structure, may be able to simultaneously meet those demands. The overall goal of this dissertation was to investigate a bioactive PEG hydrogel composite, as a platform for musculoskeletal tissue engineering applications. Towards this goal, this dissertation first tests that growth factors, covalently tethered to a soft biomimetic PEG hydrogel niche, can more robustly guided mesenchymal stem cell (MSC) differentiation. Herein the effects of two osteoinductive bone morphogenetic proteins (BMPs) BMP-2 and BMP-9, on directing MSCs towards osteogenesis, are investigated. Additionally, the simultaneous presentation of tethered TGF-β3 and IGF-1 on the ability to initiate chondrogenesis of MSCs for physeal cartilage repair is evaluated. Finally, this work addresses the structural niche of encapsulated MSCs by assessing a composite biomaterial composed of a stiff 3D printed structure infilled with these soft bioactive PEG hydrogels, which better meets the mechanical demands of musculoskeletal system.

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