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）：这是开发基于角蛋白的复苏液的提议，该液在出血治疗后大大改善了患者的预后。流体复苏技术不足，导致了数万损失，医疗费用增加了数十万美元。在出血性休克中的研究表明，生存主要取决于功能毛细管密度（FCD）和随后的组织氧合作用。常规复苏液没有维持FCD所需的特征。但是，引入具有生物相容性的粘性生物聚合物（例如角蛋白）会增加毛细血管透壁压力，从而逆转严重出血期间诱发的毛细血管塌陷。此外，角蛋白的高肿瘤压力可以通过将更多的流体带入循环中，而不会煽动心血管系统（临床前]血液和组织中的不良相互作用）来增强这种作用。灌注的增加将改善组织氧合并促进代谢废物的去除，从而避免器官衰竭和死亡。 [，与常规盐水不同，它不是癌症]。 用作胶体的人毛蛋白的使用提供了比传统液体更好地维持FCD的潜力。由于人角蛋白具有显着的内在生物相容性以及角蛋白家族的柔性化学性，因此可以控制和优化这些材料的物理，化学和生物学特性。高效的复苏液可以从角质素中配制，这些角蛋白容易提取和纯化以优化血液兼容性和血液动力学特性。我们的初步研究表明，这项技术似乎是生物相容性的，不会导致血小板事件或组织损伤。角蛋白类似物的价格便宜（可以从羊毛或人的头发中提取角质，两者的售价低于每磅3美元），可以使用常规技术进行灭菌，并且非常强大；因此，它们可以存储在环境温度（高达100OF）下。这些因素使基于角蛋白的复苏液有望成为平民或军事应用中复苏液的胶体材料。 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复苏液。在随后的发展阶段，将进行大型动物试验，以确定基于角蛋白的液体对延迟治疗和长期结局的影响。这些数据将有助于开发临床前数据包，以支持FDA以支持临床试验。 公共卫生相关性：1至44岁的人中的主要死亡原因是与出血同时造成的创伤伤害。不幸的是，当今市场上没有理想的液体来解决创伤性出血和震动复苏的需求。 Keranetics LLC是一家初创公司，负责在Wake Forest University医学院开发的技术开发，具有一种新型的液体，在试点研究中已显示出可在40％的失血后稳定大鼠。该建议旨在通过重点的临床前研究计划进一步开发这项技术，并为人类临床试验和商业化奠定基础。如果成功的话，这种新的角蛋白复苏液可以由急救人员和医院使用，以挽救许多与创伤相关的出血和震惊的受害者。

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