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: 8531331
• 负责人: Luke Russell Burnett
• 金额: $ 40.36万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531331
• 关键词: Accidents; Acute; Address; Advanced Development; Adverse effects; Age; Animal Experiments; Animal Model; Animals; Biocompatible; Biocompatible Materials; Biological; Biopolymers; Blood; Blood Coagulation Disorders; Blood Plasma Volume; Blood Vessels; Blood Volume; Cardiac; Cardiovascular system; Cause of Death; Characteristics; Chemicals; Chemistry; Chronic; Clinical; Clinical Trials; Conscious; Data; Dose; Drug Formulations; Drug Kinetics; Evaluation; Event; Family suidae; Guns; Hair; Hemorrhage; Hemorrhagic Shock; Histology; Hospitals; Hour; Human; Hypovolemic Shock; Injury; Keratin; Lactated Ringer' s Solution; Licensing; Liquid substance; Marketing; Measures; Medicine; Methodology; Microcirculation; Modeling; Molecular Weight; Names; Organ; Outcome; Oxygen; Performance; Perfusion; Pharmaceutical Preparations; Phase; Plasma; Property; Protein Family; Proteins; Protocols documentation; Radial; Radiolabeled; Rattus; Recovery; Research; Research Contracts; Resuscitation; Rodent; Rodent Model; Shock; Simulate; Small Business Innovation Research Grant; Solutions; System; Techniques; Technology; Temperature; Testing; Tissues; Translations; Transportation; Trauma; Traumatic Hemorrhage; Traumatic Shock; Treatment Protocols; Tritium; United States; United States Food and Drug Administration; Viscosity; Whole Blood; Work; analog; arm; base; biomaterial compatibility; clinically relevant; commercialization; cost; cost effective; crystalloid; dosage; emergency service responder; flexibility; forest; hemodynamics; improved; insight; instrument; man; medical schools; novel; pre-clinical; pre-clinical research; preclinical study; pressure; programs; prototype; public health relevance; radiotracer; research study; response; safety study; standard of care; tissue oxygenation

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：尽管在严重出血的治疗方面取得了许多进展，但目前的血浆替代品并未解决复苏医学的新见解。对院前大出血后的液体技术和血管反应的研究已经确定了最佳复苏液体应具有的几个重要特征。这些包括恢复血浆容量、微循环和氧气输送的能力，以及低成本、低副作用或无副作用、易于运输和储存等实用项目。当与这些理想特性相比时，常规复苏流体具有一个或多个限制。生物相容性、粘性和粘附性生物聚合物角蛋白是恢复血浆容量的潜在解决方案，同时通过将流体募集到脉管系统中并维持/改善微循环的血液动力学参数来实际改善组织氧合。在复苏液中使用角蛋白提供了优化与人体循环微环境相容的液体的潜力。由于角蛋白家族蛋白质的灵活化学性质，这些材料的物理、化学和生物学性质可以被控制和优化。通过使用化学提取技术来保持分子量，并通过将液体配制成特定的粘度和压力，可以获得最佳的复苏液体。维克森林医学院开发并授权给KeraNetics的这些角蛋白液体的纯化策略导致了一种液体技术，该技术在啮齿动物模型中解决了替代复苏液体的许多挑战。该液体基于生物相容性角蛋白系统，可根据严重出血/休克患者的血液动力学需求进行调整，而不会发生血栓形成事件或组织损伤。角蛋白类似物的获得成本低廉（角蛋白可以从人发中提取，每磅价格低于3美元），可以使用传统技术灭菌，并且保质期和温度稳定。因此，它们可以在环境温度下储存（高达50摄氏度）。因此，基于角蛋白的复苏流体可能是供第一响应者使用的理想的基于胶体的流体。来自I期项目的数据确定了一种特殊配制的复苏液（现在称为商品名KeraStat）是最佳的，并且该液体对出血/休克后的血流动力学恢复具有积极影响。基于这些数据，我们将检验KeraStat可以恢复正常心血管功能并改善出血/休克后结局的假设。本项目将首先在啮齿动物模型中检查最佳角蛋白复苏液剂量/给药方案。使用该方案，我们将在猪创伤/出血/休克模型中检查KeraStat对延迟治疗和长期结局的影响。这些数据将有助于开发一个临床前数据包，提交给美国食品和药物管理局，以支持临床试验。