Affinity-Controlled Co-Delivery of Immunomodulatory and Osteogenic Proteins to Enhance Bone Repair
Abstract
Musculoskeletal injuries to the extremities account for nearly half of all traumatic injuries experienced by military Service Members and civilians and can cause substantial disability. Many of these injuries involve severe bone fractures that don’t heal properly on their own. When bone repair proceeds normally, it involves a carefully orchestrated series of events involving numerous cells and proteins from surrounding tissues. However, this process is often disrupted in complex musculoskeletal injuries in which a severe bone fracture is accompanied by significant damage to surrounding soft tissue and prolonged inflammation. Current treatment strategies for severe bone injury involve surgical reconstruction of damaged tissue or delivery of the potent bone-forming protein, bone morphogenetic protein-2 (BMP-2). Yet, neither of these strategies can fully restore limb function. While BMP-2 delivery is promising because it stimulates the growth of new bone within the injury, high BMP-2 doses can cause side effects such as abnormal bone overgrowth and excessive inflammation. The need for high BMP-2 doses in the clinic is partly due to fact that BMP-2 is delivered using collagen sponges, which cannot adequately trap the protein; this results in rapid BMP-2 release into the surrounding tissue, further exacerbating side effects. This project seeks to transform current clinical practices for treating severe bone injuries by developing a strategy to better localize proteins within injury sites to enable the use of lower, safe protein doses. By confronting critical drawbacks of current treatments for bone injury, this project addresses the Topic Area of sustained release drug delivery and the Area of Encouragement of techniques to provide sustained release of drugs in tissue repair applications, such as bone. Our goal is to develop a strategy that can precisely deliver multiple proteins involved in different aspects of the bone healing process and that can be easily incorporated into clinical collagen sponges. Since prolonged inflammation has been implicated in poor bone healing, we will specifically focus on creating a biomaterial that delivers the anti-inflammatory protein interleukin-4 (IL-4) with BMP-2 to carefully control both the immune response and bone formation following injury. We will incorporate small protein binding partners into the clinical collagen sponge that can trap and slowly release either IL-4 or BMP-2. We will employ an innovative directed evolution approach to identify specific binding partners for each therapeutic protein. Directed evolution is a process by which proteins with specific qualities can be selected or evolved from a large library of yeast displaying millions of proteins. Directed evolution will be used in the context of this project to identify protein binding partners that bind to IL-4 or BMP-2 with different strengths. Once protein binding partners are identified from yeast libraries, they can be generated in large quantities and attached to collagen sponges. By controlling the strength of the interactions between therapeutic proteins and their binding partners, the timing and extent of protein release from a collagen sponge can be fine-tuned. We will test the hypothesis that gradual release of IL-4 will regulate inflammation, while local retention of BMP-2 will stimulate bone formation within the injury site, resulted in better tissue repair overall. This is the first time that directed evolution has been used to identify specific protein binding partners to control protein release from a biomaterial. Since the release of each protein will only be controlled by its designated binding partner, it is expected that this approach will enable significantly better control over protein delivery in the body than other strategies available in the clinic. This new class of biomaterials that can fine-tune protein delivery will enable, for the first time, the thorough investigation of the role of in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210700
Entities
People
- Marian H Hettiaratchi
Organizations
- United States Army
- University of Oregon