A HyTEC Implantable Device That Enables Personalized, Sustained Release of Bioagent for Large Bone Defect Reconstruction and Limb Salvage
Abstract
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 def
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210189
Entities
People
- Yunzhi Peter Yang
Organizations
- Stanford University
- United States Army