Engineering Skeletal Muscle with Biodegradable Hydrogels

Harvard University, Cambridge MA

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Abstract

DESCRIPTION (provided by applicant): Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application. Skeletal muscle tissue is often required in reconstructive craniofacial surgery, and the long-term goal of the applicants'research is to regenerate functional craniofacial skeletal muscle. The parent grant has the goal is combining localized presentation of specific growth factors with cell transplantation using biodegradable polymer vehicles that serve to control the availability of the factors to host and transplanted cells, control the activation and migration of the transplanted cells to repopulate and regenerate damaged host tissue, and regulate muscle vascularization and reinnervation. Many of the patients who could benefit from this therapy are older, but the parent grant addresses skeletal muscle regeneration in young animals. Aging is associated with a loss of regenerative ability in skeletal muscle, diminishing angiogenic response, and loss of reinnervation potential following injury. This revision addresses the relevance of our approach in the context of aging. More specifically, a new aim has been added to the project (Aim 4), in which we will determine how sustained satellite cell and growth factor delivery-induced muscle regeneration is altered in middle age (10 months) and old (20 months) animals. This aim is based on the new sub-hypothesis that aged animals will demonstrate an impaired intrinsic regenerative capacity, emphasizing the importance of the active strategy developed in this project. In addition, local and sustained IGF-1 delivery will be examined for its ability to enhance the intrinsic regenerative ability of skeletal muscle in aged mice. This addition to the experimental approach is based on our new Preliminary Data that demonstrates localized and sustained IGF-1 delivery from the materials enhances regeneration in young mice. The proposed studies will improve the current understanding of the roles of VEGF and IGF-1 signaling, and satellite cell activation in regeneration of damaged muscle, particularly in the context of aging. The use of aged animals in pre-clinical studies is expected to more closely mimic human patients than the young animals typically used in tissue engineering and regeneration studies. PUBLIC HEALTH RELEVANCE: The proposed studies will improve the current understanding of the roles of VEGF and IGF-1 signaling, and satellite cell activation in regeneration of damaged muscle, particularly in the context of aging. The use of aged animals in pre-clinical studies is expected to more closely mimic human patients than the young animals typically used in tissue engineering and regeneration studies.