SBIR-STTR Award

Hemorrhage resulting from traumatic injuries is a major cause of death in accidents, and the primary cause of death on the battlefield. Early and effective hemorrhage control can save more lives than any other measure. Tissue adhesives and sealants have been developed to control bleeding; but, currently, all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the operating room--not in an emergency at the site of accident or in the battlefield. The goal of the proposed project is to develop an intracavitary hemostatic agent --Hemostatic Adhesive Foam (HAF) --that promotes hemostasis in cases of severe bleeding that would otherwise lead to exsanguination. This approach is based on the physical and coagulation properties of a mixture of Teleostan Gelatin type A, Polyvinylpyrrolidone, Sucrose and Fibrinogen, with a water-soluble foam inducer; the addition of thrombin and P-selectin inmunoglobin chimera, and on its form of application. The cross- linked compound forms an adhesive matrix over damaged, lacerated tissue following abdominal or other intracavitary trauma. In preliminary studies, it was demonstrated that HAF can generate adaptable foam that is distributed uniformly, and adheres to the abdominal cavity, even under profuse bleeding, when it is injected intraperitoneally through a Verres disposable needle. Our hypothesis is that once HAF is injected in the peritoneal cavity, it distributes and adheres evenly to the walls, improving the adhesiveness between lacerated tissues and potentiating clot formation through the up-regulation of P-selectin. Our specific aims are to demonstrate in two ex vivo models: a) that the upregulation of P-selectin enhances the adhesive, physical, and coagulation properties of HAF, and to determine the extent to which this agent promotes adhesiveness between tissue and damaged surfaces in the presence of profuse bleeding; b) its effects on clot formation; c) to determine if the addition of other thrombin and fibrin like agents and P-selectin-immunoglobulin chimera -that specifically stimulate P-selectin, will enhance clot formation and clot strength effects of this agent, and; d) evaluate restoration of vital functions and survival. Phase I proposed studies could provide the "proof of concept" for the use HAF as an intracavitary hemostatic agent in cases of non-compressible hemorrhage. Phase II studies will define the adhesive and coagulation properties of the compound in an intracavitary hemorrhage military-relevant animal model (pig), study tissue distribution, pharmacokinetics, reabsorption and toxicity of HAF. Upon completion of the phase II effort, phase III studies will involve extended pharmacokinetic studies for filing an Investigative New Drug (IND) application to start studies in human volunteers. In an age of speed, civil violence and armed conflicts, the incidence of penetrating and blunt injuries to the abdomen has been on the increase. On average, nationwide 41.8% of the trauma cases admitted at hospitals are due to road traffic accidents. Also, hemorrhage remains the primary cause of death on the battlefield in conventional warfare. Although, the morbidity and mortality from these injuries are gradually decreasing, abdominal injuries still pose a formidable problem, especially in young adults, Early and effective hemorrhage control could theoretically save more lives than any other measure; however, the best strategy to achieve this goal outside of the operating room and particularly in austere and hostile field situations is not clear. Currently, all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the OPERATING ROOM not at the site of injury (i.e. battlefield, car accident, shot wound). A novel form of application through a Verres needle and the utilization of novel procoagulants compounds such as P-selectin immunoglobulin chimera incorporated to gelatin sealants could provide the adhesion strength and coagulatory properties necessary to stop bleeding in the site of injury We propose to develop an intracavitary hemostatic agent --Hemostatic Adhesive Foam (HAF)--that forms an adhesive matrix over damaged, lacerated tissue following abdominal or other intracavitary trauma to promote hemostasis in cases of severe bleeding which, if not treated immediately, would lead to exsanguinations. The proposed study provides an opportunity to demonstrate HAF efficacy as an intracavity hemostatic agent. This therapeutic approach will reduce killed in action (KIA) rate, increased life saving capability for the medic, and reduce need for surgery and transfusion.

Thesaurus Terms:
blood coagulation, drug delivery system, drug design /synthesis /production, drug screening /evaluation, emergency care, hemostatic animal mortality, blood pressure, gelatin, nonhuman therapy evaluation, selectin, thrombin, trauma, wound healing laboratory rat

Hemorrhage resulting from traumatic injuries is a major cause of death in accidents, and the primary cause of death on the battlefield. Over 40% of the trauma cases admitted at hospitals in the USA, are due to road traffic accidents. Hemorrhage is the primary cause of death on the battlefield in conventional warfare. The vast majority of these deaths occur before the injured can be transported to a treatment facility. Tissue adhesives and sealants have been developed to control bleeding; but, since all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the operating room, not in an emergency at the site of accident or in the battlefield, hemorrhage is often lethal. With early and effective hemorrhage control, more lives can be saved than by any other measure. The goal of the project, is to determine the effectiveness and safety of ClotFoam, a novel gelatin- based fibrin sealant, as a hemostatic agent to stop hemorrhage without compression in cases of severe hemorrhage resulting from intracavitary wound grade III/IV (as measured in the liver), and a novel method of application to be used outside the operating room. The use of this technology can be extended for use in cases of minimally invasive surgery, laparoscopy, brain and gynecological surgery. This technology is based on the physical and coagulation properties of a fibrin sealant embedded in a scaffold, enhanced by pro-coagulants, and delivered as a foam through a C02-propelled delivery device. Phase I studies have provided the "proof of concept" for the use of ClotFoam as non-compressible technology in cases of hemorrhage resulting from very severe trauma (grade 3/grade 4) and in laparoscopic or minimally invasive surgical procedures, by establishing the ability of the agent to adhere to lacerated tissue in a pool of blood. Data obtained from studies in rats, rabbits, and pigs have demonstrated that ClotFoam can generate an adaptable foam that is distributed uniformly; and adheres to the abdominal cavity, even under profuse bleeding, when it is injected intraperitoneally, improving the adhesiveness between lacerated tissue, and initiating a rapid clot formation. Furthermore, Clotfoam's fibrin sealant component has been developed with an advanced technology that overcomes two fundamental problems encountered by fibrin sealants: Shelf life and autoimmune reaction against thrombin. The specific aims of this phase II proposal are to 1) develop a method to sterilize and preserve the agent under ambient conditions, and determine the proteolitic degradation, activity and shelf life of fibrin components maintained under standard refrigeration conditions; 2) Evaluate the material biocompatibility in a subdermal model in the rat. Once it has been determined that the formulation can be sterilized and it is biocompatible, and therefore will not require further modifications, we will 3) develop a standardized animal model (pig) to study the effects of hemostatic agents in cases of non-compressible severe hemorrhage, subsequent to grades III and IV wounds to the liver, resulting from severe traumatic injury; 4) evaluate the ability of ClotFoam to achieve hemostasis in a pig model, following progressively severe hemorrhage secondary to high-flow bleeding caused by grade III, IV liver injury; and assess animal survival at 1 hour, as compared to the control. And finally 5) we will assess safety of the agent through the evaluation of immunological risks, as well as prevention of adhesions, abdominal compartment syndrome, and delayed hematoma and/or edema formation. This data will be used to file for an Investigational New Drug (IND) application and proceed to the clinical stage.

Public Health Relevance:
In an age of speed, civil violence and armed conflicts, the incidence of penetrating and blunt injuries to the abdomen has been on the increase. On average, 41.8% of the trauma cases admitted at hospitals, nationwide, are due to road traffic accidents. Also, hemorrhage remains the primary cause of death on the battlefield in conventional warfare. Morbidity and mortality from these abdominal injuries pose a formidable problem, especially in young adults. Early and effective hemorrhage control could theoretically save more lives than any other measure. Unfortunately, all existing haemostatic agents for abdominal intracavitary bleeding day available today are designed to be used in the OPERATING ROOM-not at the locus of injury (i.e. battlefield, car accident, or scene of a shot wound). All available hemostatic agents and sealants require compression, and therefore they cannot be used even in cases of minimally invasive surgery such as laparoscopic surgery. ClotFoam, a novel agent that allows to inject a sealing foam inside a body cavity to seal wounds and stop bleeding has proved to be effective in animal studies. The agent is applied through a mixing needle, similar to a Veress needle-releasing a foam inducer and procoagulants incorporated into gelatin sealants that adhere to injured tissue, compress the wound and stops the bleeding. In this study we to further study the effectiveness and safety, including biocompatibility of ClotFoam in cases of severe hemorrhage caused by grade III and IV traumatic wounds which-if not treated immediately-would lead to exsanguinations. This therapeutic approach will reduce killed in action (KIA) rate, provide new therapeutic tools for paramedics, increase life-saving capability for the medic, offer new t options for laparoscopic and other minimally invasive surgery, and reduce need for surgery and transfusion.

Public Health Relevance Statement:
Narrative In an age of speed, civil violence and armed conflicts, the incidence of penetrating and blunt injuries to the abdomen has been on the increase. On average, 41.8% of the trauma cases admitted at hospitals, nationwide, are due to road traffic accidents. Also, hemorrhage remains the primary cause of death on the battlefield in conventional warfare. Morbidity and mortality from these abdominal injuries pose a formidable problem, especially in young adults. Early and effective hemorrhage control could theoretically save more lives than any other measure. Unfortunately, all existing haemostatic agents for abdominal intracavitary bleeding day available today are designed to be used in the OPERATING ROOM-not at the locus of injury (i.e. battlefield, car accident, or scene of a shot wound). All available hemostatic agents and sealants require compression, and therefore they cannot be used even in cases of minimally invasive surgery such as laparoscopic surgery. ClotFoam, a novel agent that allows to inject a sealing foam inside a body cavity to seal wounds aznd stop bleeding has proved to be effective in animal studies. The agent is applied through a mixing needle, similar to a Veress needle-releasing a foam inducer and procoagulants incorporated into gelatin sealants that adhere to injured tissue, compress the wound and stops the bleeding. In this study we to further study the effectiveness and safety, including biocompatibility of ClotFoam in cases of severe hemorrhage caused by grade III and IV traumatic wounds which-if not treated immediately-would lead to exsanguinations. This therapeutic approach will reduce killed in action (KIA) rate, provide new therapeutic tools for paramedics, increase life-saving capability for the medic, offer new t options for laparoscopic and other minimally invasive surgery, and reduce need for surgery and transfusion.

NIH Spending Category:
Bioengineering; Hematology; Injury (total) Accidents/Adverse Effects

Project Terms:
Abdomen; Abdominal; Abdominal Cavity; Abdominal Injuries; Accidents; Adherence; Adherence (attribute); Adhesions; Adhesiveness; Age; Animal Model; Animal Models and Related Studies; Animals; Arm; Asses; Autoimmune; Autoimmune Process; Autologous Fibrin Tissue Adhesive; Biocompatible; Bleeding; Blood; Blood flow; Blunt Injuries; Body Tissues; Body cavities; Body cavity structure; Brain; Cause of Death; Cavitas abdominis; Celioscopy; Cessation of life; Characteristics; Clinical; Clinical Trials, Phase I; Clinical Trials, Phase II; Clotting; Coagulants; Coagulation; Coagulation Process; Common Rat Strains; Compartment syndromes; Conflict; Conflict (Psychology); Data; Death; Devices; Diagnostic Laparoscopy; Donkey; Dropsy; Drug Formulations; Early-Stage Clinical Trials; Edema; Effectiveness; Emergencies; Emergency Situation; Encephalon; Encephalons; Equus asinus; Evaluation; Family suidae; Fibrin; Fibrin Adhesive; Fibrin Glue; Fibrin Sealant; Fibrin Sealant System; Fibrin Tissue Adhesive; Fibrinogen Adhesive; Fishes; Foreign Bodies; Formulation; Formulations, Drug; Gelatin; Goals; Granuloma; Granulomatous Lesion; Gynecologic Surgery; Gynecologic Surgical Procedures; Gynecological Surgical Procedure; HOSP; Hematoma; Hemorrhage; Hemostasis; Hemostatic Agents; Hemostatic function; Hemostatics; Hospitals; Hour; Hydrogels; Hydrops; Incidence; Inflammatory; Injuries, Nonpenetrating; Injury; Investigational New Drug Application; Killings; Laceration; Laparoscopic Surgery; Laparoscopic Surgical Procedures; Laparoscopy; Lead; Life; Liver; Mammals, Rabbits; Mammals, Rats; Measures; Methods; Minimal Access Surgical Procedures; Minimal Surgical Procedures; Minimally Invasive Surgical Procedures; Modeling; Modification; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Movement; Needles; Nervous System, Brain; Nonpenetrating Wounds; Operating Rooms; Operation; Operative Procedures; Operative Surgical Procedures; Oryctolagus cuniculus; Paramedic; Paramedical Personnel; Pb element; Performance; Peritoneal; Peritoneoscopy; Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Pigs; Polymers; Prevention; Property; Property, LOINC Axis 2; Rabbit, Domestic; Rabbits; Rat; Rattus; Reaction; Refrigeration; Relative; Relative (related person); Reticuloendothelial System, Blood; Risk; Safety; Secondary to; Site; Solutions; Speed; Speed (motion); Staging; Structural Protein; Suidae; Surface; Surgery, Gynecological; Surgical; Surgical Interventions; Surgical Procedure; Surgical Procedures, Minimally Invasive; Swine; TRNSF; Technology; Temperature; Therapeutic; Thrombase; Thrombin; Tissel; Tissue Adhesives; Tissues; Traffic accidents; Transfusion; Trauma; Upper arm; Violence; Viscosity; adult youth; base; biocompatibility; biomaterial compatibility; blood loss; body cavity; body movement; body system, hepatic; cross-link; crosslink; design; designing; fibrinogenase; heavy metal Pb; heavy metal lead; improved; in vivo; injured; intraperitoneal; laparoscopy-assisted surgery; minimally invasive; model organism; new therapeutics; next generation therapeutics; novel; novel therapeutics; organ system, hepatic; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase I trial; phase II trial; porcine; pre-clinical; preclinical; prevent; preventing; protocol, phase I; protocol, phase II; public health relevance; scaffold; scaffolding; seal; study, phase II; suid; surgery; tisseel; tool; violent; violent behavior; wound; young adult