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: 8394296
• 负责人: Luke Russell Burnett
• 金额: $ 37.44万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394296
• 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; 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. 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.

描述（由申请人提供）：尽管在严重出血的治疗方面已经取得了许多进展，但目前的血浆替代品并没有解决复苏医学的新见解。对院前严重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备的几个重要特征。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、低甚至无副作用、易于运输和储存等实用项目。与这些理想特性相比，传统的复苏液具有一个或多个局限性。生物相容性、粘性和胶体生物聚合物角蛋白是恢复血浆容量的潜在解决方案，同时通过将液体补充到脉管系统中并维持/改善微循环的血流动力学参数来实际上改善组织氧合。在复苏液中使用角蛋白可以优化与人体循环微环境相容的液体。由于角蛋白家族蛋白质的灵活化学性质，这些材料的物理、化学和生物特性可以得到控制和优化。通过使用化学提取技术来保持分子量，并将液体配制到特定的粘度和胶体渗透压，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产生了一种液体技术，该技术在啮齿动物模型中解决了替代复苏液面临的许多挑战。这种液体基于生物相容性角蛋白系统，可以根据严重出血/休克受害者的血流动力学需求进行调整，而不会发生血栓事件或组织损伤。角蛋白类似物的获得成本低廉（角蛋白可以从人的头发中提取，每磅的价格不到 3 美元），可以使用传统技术进行灭菌，并且在货架和温度上稳定。因此，它们可以在环境温度（最高 50 摄氏度）下储存。因此，基于角蛋白的复苏液可能是急救人员使用的理想的基于胶体的液体。第一阶段项目的数据确定，一种现在被称为“KeraStat”的特殊配制的复苏液是最佳的，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。根据这些数据，我们将检验以下假设： KeraStat 可以恢复正常的心血管功能，并在出血/休克后提供改善的结果。该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，然后我们将使用该方案检查其效果。 KeraStat 对猪创伤/出血/休克模型的延迟治疗和长期结果进行了研究。这些数据将有助于开发临床前数据包，并将其提交给美国食品和药物管理局以支持临床试验。 公共健康相关性：尽管事实上外伤是美国第五大死因，但市场上没有理想的液体来满足外伤出血和休克的复苏需求。在 I 期 SBIR 项目中，KeraNetics 开发了一种新型的基于角蛋白的复苏液，该液能够在失血量高达 40% 后稳定大鼠的血流动力学，同时克服了传统复苏液的许多局限性。该提案旨在进一步开发角蛋白复苏液 KeraStat”，并通过重点临床前研究计划为人体临床试验和潜在转化技术的商业化奠定基础。