Keratin biomaterial-based fluid for trauma resuscitation

用于创伤复苏的角蛋白生物材料液体

• 批准号: 7906423
• 负责人: Luke Russell Burnett
• 金额: $ 23.26万
• 依托单位: KERANETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-25 至 2011-05-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906423
• 关键词: Acute; Address; Adverse effects; Aftercare; Age; Animals; Biocompatible; Biocompatible Materials; Biological; Biopolymers; Blood; Blood Circulation; Blood Pressure; Blood Viscosity; Blood Volume; Blood capillaries; Blood flow; Bolus Infusion; Brain; Caliber; Cardiac; Cardiovascular Physiology; Cardiovascular system; Catheters; Cause of Death; Cells; Cessation of life; Characteristics; Chemicals; Chemistry; Chronic; Clinical Trials; Coagulation Process; Colloids; Coupling; Cytolysis; Data; Development; Dialysis procedure; Ensure; Equilibrium; Erythrocytes; Event; Excision; Exposure to; Future; Hair; Health Care Costs; Heart; Hemorrhage; Hemorrhagic Shock; Homeostasis; Hospitals; Human; Hypovolemia; Injury; Keratin; Knowledge; Lead; Left; Left ventricular structure; Life; Liquid substance; Maintenance; Marketing; Measurement; Metabolic; Microscope; Microtomy; Military Personnel; Modeling; Monitor; Multiple Organ Failure; Myocardial; Nature; Organ failure; Outcome; Patients; Performance; Perfusion; Phase; Physiological; Pilot Projects; Preparation; Process; Property; Protein Family; Proteins; Rattus; Recovery; Research Personnel; Resuscitation; Rodent; Safety; Saline; Shock; Smooth Muscle; Sodium Chloride; Solutions; Source; Survival Rate; Techniques; Technology; Temperature; Testing; Thrombosis; Time; Tissues; Trauma; Traumatic Hemorrhage; Universities; Ventricular; Viscosity; Wool; Work; analog; arteriole; base; biomaterial compatibility; capillary; capillary bed; commercialization; crystalloid; density; emergency service responder; flexibility; forest; functional loss; functional restoration; heart function; hemodynamics; improved; injured; instrument; medical schools; mortality; novel; phase 2 study; pre-clinical; pre-clinical research; pressure; programs; public health relevance; response; small molecule; solute; standard of care; technology development; tissue oxygenation; wasting

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：这是一项开发基于角蛋白的复苏液的提案，该液可极大地改善出血治疗后患者的预后。液体复苏技术的不足已导致数万人丧生，并增加了数十亿美元的医疗费用。失血性休克的研究表明，生存主要取决于功能性毛细血管密度（FCD）的维持和随后的组织氧合。传统的复苏液不具备维持 FCD 所需的特性。然而，引入生物相容性粘性生物聚合物（例如角蛋白）可以增加毛细血管跨壁压力，从而逆转严重出血期间引起的毛细血管塌陷。此外，角蛋白的高胶体渗透压可以通过将更多液体带入循环来增强这种效果，而不会在心血管系统、[临床前]血液和组织内引起不良相互作用。由此产生的灌注增加将改善组织氧合并促进代谢废物的清除，从而避免器官衰竭和死亡。 [与非胶体渗透压的传统盐水不同]。 使用人发角蛋白作为胶体可以比传统液体更好地维持 FCD。由于人类角蛋白具有显着的内在生物相容性以及角蛋白家族蛋白质的灵活化学性质，因此可以控制和优化这些材料的物理、化学和生物特性。高效的复苏液可以由易于提取和纯化的角蛋白配制而成，以优化血液相容性和血流动力学特性。我们的初步研究表明，该技术似乎具有生物相容性，不会导致血栓事件或组织损伤。角蛋白类似物的获取成本低廉（角蛋白可以从羊毛或人发中提取，两者的售价均低于每磅 3 美元），可以使用传统技术进行消毒，并且非常坚固；因此它们可以在环境温度（最高 100oF）下储存。这些因素使得基于角蛋白的复苏液有望作为民用或军用复苏液的胶体材料。该项目的主要里程碑是证明使用角蛋白作为复苏液的可行性，其 FCD、左心室功率 (LVP)、心室-动脉耦合 (VAC) 和动脉功能在统计学上显着改善至少 20%。直径，并且]与用常规复苏液治疗的组相比，角蛋白治疗组中至少80％的统计显着存活率。在后续的开发阶段，将进行大型动物试验，以确定最佳角蛋白液体对延迟治疗和长期结果的影响。这些数据将有助于开发临床前数据包，并提交给 FDA 以支持临床试验。 公共卫生相关性：1 至 44 岁人群死亡的一个主要原因是创伤性损伤并伴有出血。不幸的是，目前市场上没有理想的液体来满足外伤性出血和休克的复苏需求。 KeraNetics LLC 是一家初创公司，负责维克森林大学医学院开发的技术，该公司拥有一种新型液体，初步研究表明该液体可以在大鼠失血 40% 后稳定病情。该提案旨在进一步开发这项技术，并通过重点临床前研究计划为人体临床试验和商业化奠定基础。如果成功，这种新型角蛋白复苏液可以被急救人员和医院用来拯救许多因创伤相关的出血和休克的受害者。

项目成果

Hemodynamic recovery after hypovolemic shock with lactated Ringer's and keratin resuscitation fluid (KRF), a novel colloid.

使用乳酸林格氏液和角蛋白复苏液 (KRF)（一种新型胶体）恢复低血容量休克后的血流动力学。

• DOI: 10.3109/21691401.2012.747533
• 发表时间: 2013
• 期刊: Artificial cells, nanomedicine, and biotechnology
• 作者: Nunez,FieskyA;Callahan,MichaelF;Trach,Simon;Burnett,LukeR;Kislukhin,Victor;Smith,ThomasL;VanDyke,Mark
• 通讯作者: VanDyke,Mark