This proposal addresses the FY21 PRMRP Topic Area of Sustained Release Drug Delivery. More specifically, our proposed project targets Area of Encouragement by providing a platform technology, Hybrid Tissue Engineering Construct (HyTEC), to enable controllable, sustained drug release in tissue repair applications, such as bone regeneration and limb salvage.

Musculoskeletal injuries (MSKI) are endemic among U.S. Military Service Members and significantly strain the Department of Defense’s Military Health System. Severe combat-related MSKI sustained during nearly two decades of conflict in Iraq and Afghanistan have resulted in frequently devastating injuries that challenge acute care capabilities, require extensive rehabilitation, and often result in long-term disability. Today, about 70 percent of war wounds are MSKI and 7 percent of those with major extremity wounds also sustain loss of limbs. On the other hand, noncombat-related MSKI are the leading cause of morbidity and disability in the U.S. Military. Lower extremity injuries, such as segmental bone defects, cause an extensive burden on patients. The inability to bear weight on an extremity drastically reduces mobility. Autogenous or allogenic bone grafting are regarded as the traditional procedures to bridge segmental bone defects. However, these procedures usually require multiple operations, result in patient mobility decline, and are limited to smaller scale defects (< 6 cm) in bone defect reconstruction. Surgical treatments of orthopedic traumas that are larger than 6 cm include vascularized fibular graft, Masquelet technique, and Ilizarov technique.

Among treatments of extremity orthopedic traumas, the Ilizarov technique, or distraction osteogenesis (DO), is a widely accepted surgical procedure for the treatment of large bone defects, bone non-union, persistent bone infection, and limb deformity. Generally, bone transport DO starts with applying external fixation to stabilize the limb, followed by an osteotomy of bone to create a short segment of bone to transport. This segment of bone is moved slowly into the bone defect, slow enough to allow bone to form at the trailing edge while the defect gets smaller at the leading edge, eventually docking and closing the gap. Although many wounded Service Members and civilians have undergone successful limb salvage by DO, there are two known complications: first, the prolonged consolidation at the regenerate site may last for several months to more than 1 year. The long duration of the external frame is poorly tolerated. Second, the high risk of docking site non-union of up to 60% occurs in many patients subjected to bone transport DO and requires a secondary bone grafting procedure to achieve bony union. Evidence from the DO animal model and clinical case studies shows that endogenous bone morphogenetic proteins (BMPs) such as BMP2 are highly expressed in the regenerate site during the distraction phase and gradually diminished during the consolidation phase. BMP2 is among the most potent osteoinductive factors that play a crucial role in bone repair and regeneration. Local injection of recombinant human (rh) BMP2 has been shown to accelerate bone formation in a number of DO models.

Our research question is if we can use a controlled, sustained release of drug delivery approach to maintain an effective BMP2 level to compensate the diminished endogenous BMP2 in the consolidation period to accelerate bone healing in the regenerate site and reduce non-union in the docking site during DO procedure, without secondary grafting, or severe complications. In this project, we propose to develop a BMP2 eluting, poly-caprolactone/beta-tricalcium phosphate (PCL/ß-TCP) biodegradable HyTEC implant as an adjunctive therapy to the DO technique and validate its efficacy in a preclinical large animal sheep DO model for overcoming clinical challenges such as prolonged, insufficient consolidation and high non-union rate in large bone defect healing. PCL- and ß-TCP-based biodegradable materials are U.S. Food and Drug Administration (FDA)-cleared biomaterials for clinical applications. We have extensive experience in fabrication, characterization, and manipulation of PCL/ß-TCP-based biomaterials and controlled growth factor delivery for bone regeneration. We are fully aware of the increasing evidence of side effects when using inappropriately high doses of BMP2, particularly in the spine. We do not expect BMP2 to exhibit such side effects at lower doses, particularly because this novel HyTEC device enables sustained release of BMP2, minimizing unwanted BMP2 release during distraction and reducing the BMP2 dosage required for effective bone healing, which further mitigates the risk of side effects.

The short-term impact is that the development of this device and validation in preclinical large animal model will be a milestone in our long-term efforts for improving the treatment of large bone defects. The long-term impact is that a broad spectrum of HyTEC grafting technology will be developed as alternative to autografts, allografts, and other synthetic bone void fillers for bone reconstruction in large bone defects, bone non-union, persistent bone infection, and limb deformity. The immediate effects would be translated into a reduction in overall Veteran and government costs (more than $23 billion in the past 12 years), as well as improved quality of life for bone injury patients.