Enhancement of spatially-controlled MSC responses in a multi-compartment CG scaffold for tendon-bone junction regeneration

Tendon-bone junction;Tissue engineering;Bioreactor;Cyclic tensile strain;Collagen-glycosaminoglycan (CG) scaffold;Mechanotransduction;Extracellular matrix (ECM);Beta-cyclodextrin;Mesenchymal stem cell;Guest-host interactions

Grier, William Kane

关键词: Tendon-bone junction;    Tissue engineering;    Bioreactor;    Cyclic tensile strain;    Collagen-glycosaminoglycan (CG) scaffold;    Mechanotransduction;    Extracellular matrix (ECM);    Beta-cyclodextrin;    Mesenchymal stem cell;    Guest-host interactions;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/99090/GRIER-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

There have been many advancements in the field of tissue engineering for the repair or regeneration of single tissues. However, orthopedic injuries often occur at the interface between soft tissues and bone. The tendon-bone junction (TBJ) is a classic example of such an interface, containing overlapping patterns of growth factors, extracellular matrix (ECM) proteins and structure, and mineral content that serve to dissipate stress concentrations and effectively transfer force between contracting muscles and bone for locomotion. Current clinical strategies to treat common TBJ injuries, such as in the rotator cuff, prioritize mechanical reattachment, forsaking biological reintegration and recapitulation of the native structure. As a result, TBJ repairs are plagued by high failure rates, and new tissue engineering solutions are necessary for improved patient outcomes. Modern efforts in tissue engineering have focused on the design of new instructive biomaterials that present combinations of compositional, microstructural, mechanical, and biochemical cues, with the potential to control stem cell fate decisions and promote enhanced tissue regeneration. This thesis describes a series of studies undertaken to better comprehend the impact of biomaterial cues and mechanical stimulation on cell bioactivity and the application of this knowledge to the design of spatially-graded biomaterials and culture techniques for engineering the TBJ. The studies herein utilize collagen-glycosaminoglycan (CG) scaffolds, a set of regulatory compliant analogs of the native ECM that have been previously applied to the regeneration of dermis, peripheral nerves, and osteochondral tissues. Here, we show how scaffold microstructure and mechanical properties are critical regulators of the maintenance of tenocyte phenotype and bioactivity in in vitro culture. We also describe the design and fabrication of a custom cyclic tensile strain (CTS) bioreactor system for the examination of the effects of mechanical stimulation on cell-material interactions and stem cell differentiation for tendon regeneration.The knowledge gained in this study was then applied to a spatially graded scaffold to selectively bias stem cell differentiation for TBJ applications. These results represent the first application of CTS across a spatially graded material with variations in microstructural alignment, mineral content, and mechanical properties. Finally, we adapt the CG scaffold system to selectively sequester and display growth factor content through the promotion of guest-host interactions. The growth factors presented by the scaffolds are sufficient to drive enhanced stem cell responses. Together, these studies present the framework for designing instructive biomaterials to regulate stem cell fate in a spatially-dependent manner in the context of musculoskeletal interface repair.