Evaluating the Effects of Synthetic Nanoparticle Antibodies Used for Treating Traumatic Musculoskeletal Injuries

Severe traumatic bone injuries remain the leading cause of death among patients below the age of forty-five. The current clinical standard for treating severe bone injuries is autografting; however, this process is limited by poor integration between graft and host tissue, donor site pain, and limited tissue availability that prevent ideal healing outcomes. Systemic immune dysregulation and immunosuppression have been cited to be integral to poor healing outcomes; however, neither of these conditions have been fully studied nor characterized with musculoskeletal injuries in mind. The systemic immunosuppressive environment leads to an overproduction of myeloid derived suppressor cells (MDSCs), which are known for downregulating immune effector cells necessary for successful bone regeneration, thus causing an imbalance in immune response. Current treatment options fail to address the direct targeting of MDSCs and systemic immune dysregulation. Developing a novel therapeutic capable of directly targeting and depleting excessive MDSCs could restore immune homeostasis, promote successful musculoskeletal healing, and enhance current treatment methods for musculoskeletal injuries.

To target MDSCs and potentially restore immune homeostasis in a preclinical animal model, synthetic nanoparticle antibodies (SNAbs) were fabricated to mimic the cell-targeting functionality of monoclonal antibodies (mAbs), which possess financial and manufacturing limitations. Rats underwent a composite muscle and femoral defect, in which 8mm of the mid-diaphysis was segmented and volumetric muscle loss was induced. The injured rats went eight weeks without treatment to allow the systemic immunosuppressive environment to manifest. At eight weeks, the rats were treated with either local delivery of bone morphogenetic protein-2 (BMP-2), or local BMP-2 and intravenously-delivered SNAbs. Tail-vein blood draws were taken to characterize relevant immune cell populations pre- and post- treatment. The immune cell populations were quantified via flow cytometry. The bone defects were imaged using Faxitron x-rays and total bone volume was measured using microcomputed tomography (μCT) at various timepoints.