Developing an Angiogenic Therapy to Enhance and Accelerate Repair of Traumatic Bone Defects
Abstract
The number and severity of long bone defects sustained by Soldiers in combat is increasing largely due to the development of improvised explosive devices (IEDs). Furthermore, due to improvements in armor technology, more Soldiers are surviving initial blast wounds, but are left with devastating trauma to exposed skeletal regions. These high-energy injuries include complex fractures and large bone defects with compromised blood supply. Currently, injured Service personnel spend weeks to months in the hospital undergoing intricate operations to reconstruct the injured skeleton. These dreadful injuries and their subsequent treatment lead to substantial medical costs and loss of manpower and place an enormous biomedical burden on the military and society as a whole. The reconstruction and regeneration of bone after battlefield injury is therefore an immediate high-priority clinical challenge. This project herein outlines the development of a therapeutic strategy that combines blood vessel forming therapy with nanotechnologies designed to optimize the effect of the drug at sites of bone injury. Following bone injury, the initial healing response is highly dependent on functional blood vessels. These blood vessels are necessary in order to supply the injured bones with the necessary molecular and cellular substrates required for successful healing. Explosive device injuries disrupt the normal function of blood vessels convoluting the process of bone healing, which can result in complications such as infection, delayed healing, or even complete failure of bone healing. For this reason, research involving the interface between blood vessel development and bone healing is critical. Cutting-edge research now reveals that it is possible to trigger blood vessel formation within large bone defects with the introduction of a small molecule called deferoxamine (DFO), an iron-binding agent currently FDA approved for the treatment of patients with excess iron in their bloodstream. DFO also works to increase the presence of a potent mediator of blood vessel formation called HIF 1-alpha, which stimulates angiogenesis (new blood vessel growth). Since blood vessel formation is required for bone healing, we have utilized this mechanism to accelerate bone regeneration and healing. In our preliminary animal studies, we have demonstrated the ability to use multiple local injections of DFO to regenerate bone in an accelerated manner and achieve complete healing in scenarios where bones normally do not heal due to blood vessel injury. Although these results are promising, the method of DFO delivery to a bone defect site is a cumbersome process that may preclude its use in the clinical setting. Currently, DFO is delivered via localized injections that are administered directly into a bone defect site through the overlying skin. Typically, multiple injections are required over a prolonged period of time to achieve the expected result. Inherent drawbacks to the use of multiple localized DFO injections include (1) multiple injections are morbid and would be unpleasant clinically; (2) the injected dose is mostly cleared systemically within a few hours of injection, so there is very little drug retained at the injury site where it potentially could have the most efficacy; (3) administering multiple injections into a bone defect site through the skin has the potential to introduce infection into the wound bed; and (4) with the recent understanding of the timing and distribution of vascular growth at a bone injury site, drug delivery could be improved to coincide with maximal angiogenic stimulation. In an effort to remove the need for repeated injections and simplify the delivery strategy, we have collaborated with biochemists to produce a technology that couples tiny, resorbable-biocompatible microparticles to DFO. This coupling is optimal because it allows for improved healing patterns and is easier for the patient and the surgeo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210449
Entities
People
- Steven Buchman
Organizations
- United States Army
- University of Michigan