Layer-by-Layer Nano Matrix for Growth Plate Regeneration

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Abstract Growth plate fracture in children represents a significant problem in clinics. Although only 15-30% of all childhood fractures are growth plate fractures, because a growth plate determines the length and shape of a mature bone, this type of fracture may result in severe growth abnormalities in patients. It is known that ~1.4% of growth plate fractures result in some type of growth arrest, which can be angular deformities caused by peripheral disturbances or longitudinal shortening when centrally located lesions occur. Growth plate fractures that extend into the blood supply of the epiphysis enable the transport of bone marrow and mesenchymal stem cells (MSCs) into the metaphyseal growth plate leading to the formation of a bony bridge and growth arrest. Therefore, the key challenge to repairing a growth plate injury is how to mediate MSC differentiation spatially at the injury site and restoring a growth and development that temporally matches the surrounding uninjured cartilaginous growth plate. Currently, there is no clinically-approved tissue engineering therapy to treat growth plate fractures. Surgery is the only available treatment, and is only offered after a bony bridge has formed. It includes removing the bony bridge and inserting autologous fat or cartilage tissue into the empty space to discourage bony bridge reformation. However, this surgical procedure is very invasive and has an unsatisfactory success rate. To overcome these limitations, the objective of this proposal is to develop an injectable nano-matrix to place cartilage-regenerating factors directly into the fracture, with multiple functional layers to control the timing of drug delivery. Our central hypothesis is that we can develop a layer-by-layer nano-matrix (LbL-NM) to achieve spatially and temporally controlled SDF1 and TGF-β1 delivery for growth plate regeneration. The rationale that underlies the proposal is that once this injectable LbL-NM is developed to spatially and temporally mediate MSC differentiation in mice, it can be further developed as a minimally invasive and highly effective tissue engineering approach to treat growth plate fracture in a larger animal model. We will test our central hypothesis by pursuing two specific aims: 1) Develop an LbL-NM to spatially control the delivery of TGF-β1 and SDF1 in vitro and evaluate its treatment outcomes for growth plate regeneration in vivo, and 2) Develop an LbL-NM to control the duration of TGF-β1 supply in the LbL-NM in vitro and evaluate its treatment outcomes for growth plate regeneration in vivo. With the completion of this study, we expect to realize an LbL- NM to achieve spatially and temporally controlled TGF-β1 and SDF1 delivery to mediate MSC differentiation in an injured growth plate. This outcome would have an important positive impact on developing the first tissue engineering approach to growth plate healing.