Exosome-mediated Craniofacial Bone Tissue Engineering by Controlled Release

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Abstract Healthy bone is critically important to systemic health. Of relevance to the craniofacial complex, dental implants require that empty sockets are filled with bone prior to implant placement and restoring dentition. Bone quality and bone amount are strongly correlated with both the short- and long-term success of dental implants. Biomaterials-based bone regeneration is promising to circumvent shortcomings of bone grafting. These biomaterials can be functionalized with instructive components which guide tissue regeneration. Exosomes, thought to be nature's endogenous biomolecule delivery platform, are particularly interesting because of their innate biocompatibility and capacity to communicate with cells to modulate their phenotype. Recent in vitro data suggests that exosomes derived from mineralizing MC3T3 pre-osteoblasts are able to induce mineralization in naive bone marrow stromal cells. However, engineering a means for their efficient therapeutic delivery in vivo, in a clinically and biologically relevant manner is a challenge in exosome-mediated therapy. The overall therapeutic goal of this project is to exploit the regenerative capacity of endogenous mesenchymal stem cells by mimicking the natural secretion of exosomes with a polymeric tissue engineering construct. My preliminary data suggests that polymeric self-assembly via a tunable biodegradable copolymer can encapsulate exosomes, which are released in a sustained fashion over time. My central hypothesis is that controlled release of osteogenic exosomes from a polymer matrix will promote craniofacial bone healing. The specific aims are to 1) develop a well-controlled fabrication method which allows incorporation of an exosome-releasing modality into a three-dimensional tissue engineering construct; 2) evaluate the integrity of the bioactive exosome contents during encapsulation and release, and their ability to cause phenotype changes in downstream cells; and 3) validate the technology invented herein in two in vivo models of craniofacial bone regeneration. The outcomes of the proposed experiments will demonstrate a means for the encapsulation and controlled delivery of exosomes from a polymer matrix, causing craniofacial bone regeneration without stem cell transplantation. Effective exosome encapsulation and release strategies, which preserve their biologic activity, are critical to advancing the field of exosome-mediated clinical therapies, which can be applied to the regeneration of many tissue types.