Repair of craniofacial bone defects is an important clinical problem with significant socioeconomic impact. Bone that is traumatically injured or diseased often requires surgical repair, but 5-10% of bone fractures fail to heal and failure rates can be even higher when the patient's bone quality is compromised (e.g., osteoporotic). In these cases, stem cell-based therapies have received increasing attention as a method to improve the healing of complex craniofacial defects. The proposed research focuses on mesenchymal stem cell (MSC) therapies because of their extensive use in clinical trials, as well as the major role that MSCs play in musculoskeletal tissue homeostasis and the pathophysiology of osteoporosis. However, in vitro expansion of MSCs to therapeutically relevant numbers reduces their regenerative capacity, and afterwards, direct injection of MSCs alone often leads to low survival. The proposed research addresses this important clinical problem through an innovative materials-based strategy, namely the synthesis and assembly of tunable microgel scaffolds for MSC expansion and delivery. Using efficient ?click? chemistries and by developing photoresponsive materials, we hypothesize that scaffolds can be tuned to: i) prolong the self-renewing and regenerative capacity of MSCs during in vitro expansion and ii) promote the survival and regenerative functions of delivered MSCs that will improve healing of both healthy and osteoporotic bone. Specifically, we propose to:
Aim 1. Develop a hydrogel culture system for MSC expansion and quantify the effects of mechanical cues and passaging history on MSC proliferation, multipotency, secretory properties, and epigenetic landscape;
Aim 2. Process the hydrogel materials into modular microgel units for MSC delivery and tailor their properties to promote MSC survival, retention and regenerative potential;
and Aim 3. Test the influence of MSC expansion conditions and modular microgel delivery systems on MSC survival and bone regeneration in vivo. If successful, this project will have an important impact on public health by providing a powerful new platform for the expansion and site specific delivery of MSCs. Given the versatility of the approach, which can be applied to numerous cell delivery systems, the results will have broader implications that can extend beyond bone regeneration.
Bone that is traumatically injured or diseased often requires surgical repair, but 5-10% of bone fractures fail to heal and for these cases, stem cell-based therapies offer an emerging method to improve healing. However, in vitro expansion of bone marrow derived stem cells to yield therapeutically relevant numbers reduces their reparative capacity, and afterwards, direct injection of the stem cells alone leads to low survival. The proposed research aims to address these limitations by developing innovative biomaterial systems that will: i) prolong the self-renewing and reparative capacity of MSCs during in vitro expansion and ii) promote the survival and regenerative functions of delivered stem cells in vivo. !
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