Magnetically Actuated Therapy for Bone Regeneration

The objective of this study is explore radiofrequency (RF) sensitive nanotherapeutics as tools to control stem cell function and differentiation for the improved regeneration and reconstruction of large non-healing bone defects. This proposal addresses the Nanomaterials for Bone Regeneration area described in the Peer Reviewed Medical Research Program Discovery Award program announcement. Blast wounds represent a constellation of polytraumatic injuries including extremity amputations, open pelvic fractures, upper extremity, and often-craniofacial injuries. Increasing survival of blast-injured patients has left many Service members with segmental bone defects and amputations. In total, 27% of battlefield injuries include injuries of the head and neck, 22% include of the upper extremity, and 32% involve the lower extremity. The lack of success with current methodologies of vascularized bone transport (limited donor sites), bone grafting (commonly resorbs), distraction osteogenesis (impractical for craniofacial), and stem cell-based therapies (lacking reliable directed differentiation in vivo) are the major technical challenges of segmental bone reconstruction. This study seeks to address this issue through the development of a spatiotemporally selective magnetic nanoparticle system delivering osteogenic and proliferation inducing miRNA to non-healing bone defects resulting in enhanced healing. We call this system the Targeted Inducible Gene Regulation System (TIGeRS). Modulation of gene expression with microRNA (miRNA) is a promising technique for improving control of wound healing and tissue repair processes. miRNAs are short, non-coding RNA's involved in gene regulation. The use of miRNA's to control the differentiation of progenitor stem cells is attractive as a potential therapy for the reconstruction or regeneration of damaged tissues. Directing the differentiation of regenerating tissue toward bone or vasculature is of particular interest in the design of therapies for bone defects, spinal fusion, and skeletal reconstruction, which are often associated with trauma, cancer, or infection. This technology represents a paradigm shift from current methods of delivering bone-inducing compounds such as diffusible bone morphogenic protein (BMP) or viral-based BMP gene delivery where there is little spatial or temporal control of expression. The use of uncontrolled differentiation factors in the reconstruction of bone defects often results in heterotopic ossification, or abnormal bone growth in soft tissue, a side effect, which is very detrimental for the patient and costly for healthcare providers to resolve. Using the antibody-targeted TIGeRS to control the expression of miRNA mimics provides a new and powerful tool to direct the differentiation of endogenous stem cells during the repair of deep tissue defects. The combination of antibody targeting and RF sensitive miRNA mimic activation in the TIGeRS platform enables a means to control, spatially and temporally, selective bone repair via a minimally invasive technique. As this technique targets the patient's own mesenchymal stromal cells (MSC) and progenitors, those cells already present and involved in wound repair, it is attractive clinically. As single doses of the miRNA have demonstrated efficacy in bone repair in vivo, this technique could require minimal treatments for the patient. This substantially simplifies the clinical and regulatory paradigm reducing cost and improving patient access. Further development of this platform and technique will result in improved reconstructed tissue with minimal side effects, such as heterotopic ossification often associated with state-of-the-art surgical methods.