Novel Immunomodulatory Peptide Polymers for VCA Rejection Prevention
Abstract
Military personnel are commonly put in harm’s way when serving their country, and it is the responsibility as a nation to provide them with adequate healthcare solutions to treat any wounds they sustain in the line of duty. The ever-changing nature of combat requires that the medical research community quickly adapt to the needs of active military and Veteran populations. High-energy trauma associated with weapons, such as improvised explosive devices, coupled with better protective armor has led to a significant decrease in torso injuries but has also led to a significant increase in facial and extremity injuries, leading to a rapid rise in the need for face and limb transplantation. While the initial surgical success rate for these large-scale vascularized composite allotransplants (VCAs) has drastically improved over the past several years, patients currently must be given a broad-spectrum, lifelong immunosuppressive drug regimen to prevent rejection. This strategy leaves the patient with limited wound healing and infection-fighting capacity while only having a ~15%-50% first year success rate, so new transplant rejection prevention strategies are a significant unmet clinical need. An emerging alternative strategy is to train the host immune response to become tolerant to the transplant, which aligns with the Fiscal Year 2016 Restorative Transplantation Research Program Focus Area on Immune System Regulation as Specifically Applied to VCA. Recent exciting research has shown that the controlled release of a chemical signal protein recruits a specific cell population that facilitates transplant tolerance. Unfortunately, the protein is very expensive, with a human dose likely to cost more than $100,000. Previously published work has shown that there exists a naturally occurring peptide (i.e., short protein) that is capable of inducing a specific subset of immune cells to produce and secrete the aforementioned protein. Since peptides can be made synthetically instead of requiring bacterial culture-like proteins, they can be commonly produced at less than 10% of the cost, making them a more commercially viable alternative. In order to achieve controlled local peptide delivery, a biomaterial carrier can be employed. While many sacrificial biomaterials exist that can be used to release entrapped payloads, these technologies have limited tailorability, encapsulation efficiency, and overall drug loadings. The enclosed research project proposes the creation of a novel degradable polymer for which the peptide can be directly tethered. It is hypothesized that this peptide-modified polymer will address many of the issues associated with other technologies since material degradation and associated therapeutic peptide delivery can be finely controlled. This novel biomaterial will be assessed by physical and biological characterization techniques to determine the peptide release rate and cell-based protein secretion, respectively. If the peptide-modified polymer functions as expected, then the data generated from this award will be used as preliminary data to secure financial support for more complex cell experiments as well as animal studies to motivate this technology towards clinical translation where it can help military personnel required VCAs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710596
Entities
People
- Bret D Ulery
Organizations
- United States Army
- University of Missouri