SBIR-STTR Award

This is a proposal to develop a keratin based resuscitation fluid that greatly improves outcomes for patients following treatment of hemorrhage. Inadequate fluid resuscitation technology has contributed to tens of thousands of lives lost and billions of dollars of increased healthcare costs. Studies in hemorrhagic shock show that survival is primarily determined by the maintenance of functional capillary density (FCD) and subsequent tissue oxygenation. Conventional resuscitation fluids do not possess the characteristics necessary to maintain FCD. Introduction of a biocompatible, viscous biopolymer such as keratin, however, can increase capillary transmural pressure, thereby reversing capillary collapse induced during severe hemorrhage. Moreover, the high oncotic pressure of keratins can reinforce this effect by bringing more fluid into the circulation without instigating adverse interactions within the cardiovascular system, [Preclinical] blood and tissues. The resulting increase in perfusion will improve tissue oxygenation and facilitate the removal of metabolic waste, thereby averting organ failure and death. [, unlike conventional saline which is not oncotic]. The use of human hair keratin proteins as colloids offers the potential to maintain FCD better than conventional fluids. Because of the remarkable intrinsic biocompatibility of human keratins and the flexible chemistry of the keratin family of proteins, the physical, chemical, and biological properties of these materials can be controlled and optimized. Highly effective resuscitation fluids can be formulated from keratins that are easily extracted and purified to optimize blood compatibility and hemodynamic properties. Our preliminary studies show that this technology appears to be biocompatible and does not lead to thrombotic events or tissue damage. The keratin analogs are inexpensive to obtain (keratins can be extracted from either wool or human hair, both of which sell for less than $3 per pound), can be sterilized using conventional techniques, and are incredibly robust; therefore they can be stored at ambient temperatures (up to 100oF). These factors make keratin-based resuscitation fluids promising as colloidal materials for resuscitation fluid in either civilian or military applications. The major milestone for this project is demonstration of the feasibility of using keratin as a resuscitation fluid by showing a statistically significant improvement of at least 20% in FCD, [left ventricular power (LVP), ventricular-arteriol coupling (VAC), and arterial diameter, and] a statistically significant survival rate of at least 80% in the keratin treated groups compared to groups treated with conventional resuscitation fluids. In subsequent phases of development, large animal trials will be conducted to determine the effect of optimal keratin-based fluids on delayed treatment and long-term outcomes. These data will be instrumental in developing a preclinical data package to be submitted to the FDA in support of clinical trials.

Public Health Relevance:
A major cause of death among people ages 1 to 44 years is traumatic injury with concomitant hemorrhage. Unfortunately there is no ideal fluid available on the market today to address the need for resuscitation from traumatic hemorrhage and shock. KeraNetics LLC, a startup company tasked with development of technology developed at the Wake Forest University School of Medicine, has a novel fluid that has been shown in pilot studies to stabilize rats after as much as a 40% blood loss. This proposal seeks to further develop this technology and lay the ground work for human clinical trials and commercialization through a focused program of preclinical research. If successful, this new keratin resuscitation fluid can be used by first responders and hospitals to save many victims of trauma-related hemorrhage and shock.

Thesaurus Terms:
Abscission; Acute; Address; Adverse Effects; After Care; After-Treatment; Aftercare; Age; Animals; Armed Forces Personnel; Arterioles; Autoregulation; Biocompatible; Biocompatible Materials; Biological; Biomaterials; Biopolymers; Bleeding; Blood; Blood Circulation; Blood Pressure; Blood Viscosity; Blood Volume; Blood Capillaries; Blood Erythrocyte; Blood Flow; Blood Normocyte; Bloodstream; Body Tissues; Bolus; Bolus Infusion; Brain; Caliber; Capillaries; Capillary; Capillary, Unspecified; Cardiac; Cardiovascular; Cardiovascular Body System; Cardiovascular Physiology; Cardiovascular System; Cardiovascular System (All Sites); Catheters; Cause Of Death; Cells; Cessation Of Life; Characteristics; Chemicals; Chemistry; Chronic; Circulation; Circulatory Collapse; Clinical Trials; Clinical Trials, Unspecified; Clotting; Coagulation; Coagulation Process; Colloids; Common Rat Strains; Coupling; Cytolysis; Data; Death; Development; Dialysis; Dialysis Procedure; Diameter; Encephalon; Encephalons; Ensure; Equilibrium; Erythrocytes; Erythrocytic; Event; Excision; Exposure To; Extirpation; Future; Hosp; Hair; Health Care Costs; Health Costs; Healthcare Costs; Heart; Hemorrhage; Hemorrhagic Shock; Homeostasis; Hospitals; Human; Human, General; Hypovolemia; Injury; Investigators; Keratin; Knowledge; Lead; Left; Left Ventricles; Left Ventricular Structure; Life; Liquid Substance; Lysis; Mof Syndrome; Maintenance; Maintenances; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marketing; Marrow Erythrocyte; Measurement; Metabolic; Methods And Techniques; Methods, Other; Microscope; Microtomy; Military; Military Personnel; Modeling; Monitor; Mortality; Mortality Vital Statistics; Multiple Organ Failure; Muscle, Involuntary; Muscle, Smooth; Myocardial; Nature; Nervous System, Brain; Organ Dysfunction Syndrome, Multiple; Organ System, Cardiovascular; Organ Failure; Outcome; Patients; Pb Element; Performance; Perfusion; Phase; Physiologic; Physiological; Physiological Homeostasis; Pilot Projects; Preparation; Pressure; Pressure- Physical Agent; Process; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Protein Family; Proteins; Rat; Rattus; Recovery; Red Blood Cells; Red Cell; Red Blood Corpuscule; Red Cell Of Marrow; Removal; Research Personnel; Researchers; Resuscitation; Reticuloendothelial System, Blood; Reticuloendothelial System, Erythrocytes; Rodent; Rodentia; Rodentias; Safety; Saline; Saline Solution; Science Of Chemistry; Shock; Smooth Muscle (Tissue); Sodium Chloride; Sodium Chloride (Nacl); Solutions; Source; Structure Of Arteriole; Surgical Removal; Survival Rate; Techniques; Technology; Temperature; Testing; Thin Sectioning; Thin Sectionings; Thrombosis; Time; Tissues; Trauma; Traumatic Hemorrhage; Treatment Side Effects; Universities; Vascular, Heart; Ventricular; Viscosity; Wool; Work; Analog; Arteriole; Balance; Balance Function; Base; Biocompatibility; Biomaterial Compatibility; Blood Corpuscles; Blood Loss; Capillary; Capillary Bed; Cardiovascular Function; Circulatory Shock; Circulatory System; Clinical Investigation; Commercialization; Crystalloid; Density; Dialysis Therapy; Emergency Service Personnel; Emergency Service Responder; Emergency Service/First Responder; First Responder; Flexibility; Fluid; Forest; Functional Loss; Functional Restoration; Gene Product; Heart Function; Heavy Metal Pb; Heavy Metal Lead; Hemodynamics; Improved; Injured; Instrument; Liquid; Medical Schools; Multiple Organ System Failure; Novel; Phase 2 Study; Pilot Study; Pre-Clinical; Pre-Clinical Research; Preclinical; Preclinical Research; Pressure; Programs; Public Health Relevance; Resection; Response; Restore Function; Restore Functionality; Restore Lost Function; Salt; Side Effect; Small Molecule; Solute; Standard Of Care; Technology Development; Therapy Adverse Effect; Tissue Oxygen Saturation; Tissue Oxygenation; Treatment Adverse Effect; Wasting

Although numerous advances have been made in the treatment of severe hemorrhage, current blood plasma substitutes do not address new insights in resuscitation medicine. Research in fluid technologies and vascular response following significant pre-hospital hemorrhage has identified several important characteristics that an optimal resuscitation fluid would possess. These include the ability to restore plasma volume, microcirculation, and oxygen delivery as well as practical items such as a low cost, low to no side effects, easy transportation, and storage. Conventional resuscitation fluids possess one or more limitations when compared to these ideal characteristics. The biocompatible, viscous, and oncotic biopolymer keratin is a potential solution to restore plasma volume while actually improving tissue oxygenation by recruitment of fluid into the vasculature and maintaining/improving hemodynamic parameters of microcirculation. The use of keratin in resuscitation fluids offers the potential to optimize a fluid that is compatible to the human circulatory microenvironment. Because of the flexible chemistry of keratin family of proteins, the physical, chemical, and biological properties of these materials can be controlled and optimized. By using chemical extraction techniques to preserve molecular weight and by formulating fluids to specific viscosities and oncotic pressures, optimal resuscitation fluids can be obtained. Purification strategies of these keratin fluids developed at the Wake Forest School of Medicine and licensed to KeraNetics have resulted in a fluid technology that, in rodent models, has solved many of the challenges with alternative resuscitation fluids. This fluid is based on a biocompatible keratin-based system that can be tuned to the hemodynamic needs of victims of severe hemorrhage/shock without the potential for thrombotic events or tissue damage. The keratin analogs are inexpensive to obtain (keratins can be extracted from human hair, which can be acquired for less than $3 per pound), can be sterilized using conventional techniques, and are shelf and temperature stable. Therefore, they can be stored at ambient temperatures (up to 50 degrees Celsius). Thus, keratin-based resuscitation fluids are potentially an ideal colloidal-based fluid for use by first responders. Data from the Phase I project determined that a specially formulated resuscitation fluid now called by the trade- name KeraStat"" is optimal and that this fluid has positive influence on hemodynamic recovery after hemorrhage/shock. Based on this data, we will test the hypothesis that KeraStat can restore normal cardiovascular performance and provide improved outcomes after hemorrhage/shock. This project will first examine the optimal keratin resuscitation fluid dosage/administration protocol in a rodent model. Using this protocol, we will then examine the effect of KeraStat on delayed treatment and long-term outcomes in a porcine model of trauma/hemorrhage/shock. These data will be instrumental in developing a preclinical data package to be submitted to the US Food and Drug Administration in support of clinical trials.

Public Health Relevance:
Despite the fact that traumatic injuries represent the fifth overall leading cause of death in the United States, there is no ideal fluid available on the market to address the need for resuscitation from traumatic hemorrhage and shock. In a Phase I SBIR project, KeraNetics developed a novel keratin-based resuscitation fluid that was shown to hemodynamically stabilize rats after as much as a 40% blood loss while overcoming many of the limitations of conventional resuscitation fluids. This proposal seeks to further develop a keratin resuscitation fluid, KeraStat"", and lay the groundwork for human clinical trials and commercialization of a potentially transformational technology through a focused program of preclinical research.