An Injectable Synthetic Agent to Stop Internal Bleeding
Abstract
Around the world, almost 14,000 people die every day because of uncontrolled bleeding. The sources of hemorrhage are very diverse, ranging from road traffic injuries in civilian settings to gunshot wound in military battlefield, making it a major cause of death for all ages, contributing to 10% of mortalities. Moreover, hemorrhage is highly time-dependent, since one can bleed out within minutes. Hence, a majority of hemorrhage-related deaths occur before patients reach a hospital. If an immediate, point-of-injury treatment is provided, 60-90% of these prehospital mortalities can be potentially avoided. Currently available on-site bleeding interventions largely rely on the use of tourniquets, pressure dressings, and other topical hemostatic agents, which can only treat extremity-related hemorrhagic conditions that are visible and accessible. For internal, non-compressible bleeding, there are no prehospital treatments available to staunch the blood loss, and surgical intervention is generally required. Thus, there is an unmet need to develop hemostats that can promote rapid clot formation and stop bleeding at inaccessible, non-compressible injury sites. One promising approach toward that end is the fabrication of synthetic platelet substitutes that can be administered intravenously and can augment the natural hemostasis process to rapidly stop bleeding. Although several particulate hemostatic agents have been reported, their potential adverse reactions through complement activation and complex manufacturing process pose a challenge toward their clinical translation. So far, no clinically approved formulations of synthetic injectable hemostats exist. Here, we propose to address this unmet need by developing a hyaluronic acid-based formulation. Hyaluronic acid is a natural biomacromolecule that is widely used as an active cosmetic ingredient and clinically approved for treat various diseases. By conjugating two peptides to hyaluronic acid, we generated a novel agent that we named as a Hemostatic Agent via Polymer Peptide Interfusion (HAPPI). HAPPI is the first polymer-peptide conjugate of its kind, a conjugate of hyaluronic acid with multiple copies of von Willebrand factor-binding and collagen-binding peptides. HAPPI is dry-storable for months, highly selective, and injectable in the blood by simple reconstitution when needed. The rationale for the design of HAPPI is that, after intravenous injection, the presentation of peptides in HAPPI will target them to the vascular injury sites and recruit activated platelets and promote their adhesion to the injury site, thereby promoting the formation of a vascular plug and induce hemostasis. We have validated the safety and hemostatic efficacy in rodent models. HAPPI induced more than 90% reduction in blood loss in mice and improved survival in rats after liver resection injury. Encouraged by these preliminary results, we propose to validate the effectiveness of HAPPI for treating non-compressible traumatic hemorrhage in pig using a liver injury model. We posit that HAPPI will be an effective treatment strategy with high translational feasibility for treating life-threatening, non-compressible traumatic injuries. At the end of this project, we expect to have obtained a detailed evaluation of key parameters of the technology in a relevant trauma model as well as key therapeutic parameters including pharmacokinetics, dose response, efficacy, and tolerance. Alignment with Focus Area: Innovative and novel technologies that can stop life-threatening bleeding in the torso region of patients who are delayed in receiving definitive surgical care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210113
Entities
People
- Samir Mitragotri
Organizations
- President and Fellows of Harvard College
- United States Army