Intracavitary Hemostatic Agent for Non-compressible Hemorrhage

不可压缩性出血的腔内止血剂

• 批准号: 8140814
• 负责人: Maja Nowakowski
• 金额: $ 9.37万
• 依托单位: BIOMEDICA MANAGEMENT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140814
• 关键词: Abdomen; Abdominal Cavity; Abdominal Injuries; Accidents; Adherence; Adhesions; Adhesiveness; Age; Animal Model; Animals; Asses; Autoimmune Process; Biocompatible; Blood; Blood flow; Body cavities; Brain; Cause of Death; Cessation of life; Characteristics; Clinical; Coagulants; Coagulation Process; Compartment syndromes; Conflict (Psychology); Data; Devices; Drug Formulations; Edema; Effectiveness; Emergency Situation; Evaluation; Family suidae; Fibrin; Fibrin Tissue Adhesive; Fishes; Foreign Bodies; Gelatin; Goals; Granuloma; Gynecologic Surgical Procedures; Hematoma; Hemorrhage; Hemostatic Agents; Hemostatic function; Hospitals; Hour; Hydrogels; Incidence; Inflammatory; Injury; Investigational New Drug Application; Laceration; Laparoscopic Surgical Procedures; Laparoscopy; Lead; Life; Liver; Measures; Methods; Minimally Invasive Surgical Procedures; Modeling; Modification; Morbidity - disease rate; Movement; Needles; Nonpenetrating Wounds; Operating Rooms; Operative Surgical Procedures; Oryctolagus cuniculus; Paramedical Personnel; Performance; Peritoneal; Phase; Polymers; Prevention; Property; Rattus; Reaction; Refrigeration; Relative (related person); Risk; Safety; Secondary to; Site; Solutions; Speed; Staging; Structural Protein; Surface; Technology; Temperature; Therapeutic; Thrombin; Tissue Adhesives; Tissues; Traffic accidents; Transfusion; Trauma; Violence; Viscosity; arm; base; biomaterial compatibility; body cavity; crosslink; design; improved; in vivo; injured; intraperitoneal; killings; minimally invasive; mortality; novel; novel therapeutics; phase 1 study; phase 2 study; pre-clinical; prevent; public health relevance; scaffold; seal; tool; wound; young adult

DESCRIPTION (provided by applicant): Hemorrhage resulting from traumatic injuries is a major cause of death in accidents, and the primary cause of death on the battlefield. Over 40% of the trauma cases admitted at hospitals in the USA, are due to road traffic accidents. Hemorrhage is the primary cause of death on the battlefield in conventional warfare. The vast majority of these deaths occur before the injured can be transported to a treatment facility. Tissue adhesives and sealants have been developed to control bleeding; but, since all existing haemostatic agents for abdominal intracavitary bleeding are designed to be used in the operating room, not in an emergency at the site of accident or in the battlefield, hemorrhage is often lethal. With early and effective hemorrhage control, more lives can be saved than by any other measure. The goal of the project, is to determine the effectiveness and safety of ClotFoam, a novel gelatin- based fibrin sealant, as a hemostatic agent to stop hemorrhage without compression in cases of severe hemorrhage resulting from intracavitary wound grade III/IV (as measured in the liver), and a novel method of application to be used outside the operating room. The use of this technology can be extended for use in cases of minimally invasive surgery, laparoscopy, brain and gynecological surgery. This technology is based on the physical and coagulation properties of a fibrin sealant embedded in a scaffold, enhanced by pro-coagulants, and delivered as a foam through a C02-propelled delivery device. Phase I studies have provided the "proof of concept" for the use of ClotFoam as non-compressible technology in cases of hemorrhage resulting from very severe trauma (grade 3/grade 4) and in laparoscopic or minimally invasive surgical procedures, by establishing the ability of the agent to adhere to lacerated tissue in a pool of blood. Data obtained from studies in rats, rabbits, and pigs have demonstrated that ClotFoam can generate an adaptable foam that is distributed uniformly; and adheres to the abdominal cavity, even under profuse bleeding, when it is injected intraperitoneally, improving the adhesiveness between lacerated tissue, and initiating a rapid clot formation. Furthermore, Clotfoam's fibrin sealant component has been developed with an advanced technology that overcomes two fundamental problems encountered by fibrin sealants: Shelf life and autoimmune reaction against thrombin. The specific aims of this phase II proposal are to 1) develop a method to sterilize and preserve the agent under ambient conditions, and determine the proteolitic degradation, activity and shelf life of fibrin components maintained under standard refrigeration conditions; 2) Evaluate the material biocompatibility in a subdermal model in the rat. Once it has been determined that the formulation can be sterilized and it is biocompatible, and therefore will not require further modifications, we will 3) develop a standardized animal model (pig) to study the effects of hemostatic agents in cases of non-compressible severe hemorrhage, subsequent to grades III and IV wounds to the liver, resulting from severe traumatic injury; 4) evaluate the ability of ClotFoam to achieve hemostasis in a pig model, following progressively severe hemorrhage secondary to high-flow bleeding caused by grade III, IV liver injury; and assess animal survival at 1 hour, as compared to the control. And finally 5) we will assess safety of the agent through the evaluation of immunological risks, as well as prevention of adhesions, abdominal compartment syndrome, and delayed hematoma and/or edema formation. This data will be used to file for an Investigational New Drug (IND) application and proceed to the clinical stage. PUBLIC HEALTH RELEVANCE: In an age of speed, civil violence and armed conflicts, the incidence of penetrating and blunt injuries to the abdomen has been on the increase. On average, 41.8% of the trauma cases admitted at hospitals, nationwide, are due to road traffic accidents. Also, hemorrhage remains the primary cause of death on the battlefield in conventional warfare. Morbidity and mortality from these abdominal injuries pose a formidable problem, especially in young adults. Early and effective hemorrhage control could theoretically save more lives than any other measure. Unfortunately, all existing haemostatic agents for abdominal intracavitary bleeding day available today are designed to be used in the OPERATING ROOM-not at the locus of injury (i.e. battlefield, car accident, or scene of a shot wound). All available hemostatic agents and sealants require compression, and therefore they cannot be used even in cases of minimally invasive surgery such as laparoscopic surgery. ClotFoam, a novel agent that allows to inject a sealing foam inside a body cavity to seal wounds and stop bleeding has proved to be effective in animal studies. The agent is applied through a mixing needle, similar to a Veress needle-releasing a foam inducer and procoagulants incorporated into gelatin sealants that adhere to injured tissue, compress the wound and stops the bleeding. In this study we to further study the effectiveness and safety, including biocompatibility of ClotFoam in cases of severe hemorrhage caused by grade III and IV traumatic wounds which-if not treated immediately-would lead to exsanguinations. This therapeutic approach will reduce killed in action (KIA) rate, provide new therapeutic tools for paramedics, increase life-saving capability for the medic, offer new t options for laparoscopic and other minimally invasive surgery, and reduce need for surgery and transfusion.

描述（由申请人提供）：外伤导致的出血是事故死亡的主要原因，也是战场上死亡的主要原因。在美国，超过40%的创伤病例是由道路交通事故造成的。在常规战争中，出血是战场上死亡的主要原因。这些死亡绝大多数发生在伤者被送往治疗设施之前。已经开发了组织粘合剂和密封剂来控制出血;但是，由于所有现有的用于腹腔内出血的止血剂都设计用于手术室，而不是在事故现场或战场上的紧急情况下使用，因此出血通常是致命的。通过早期有效的出血控制，可以挽救比任何其他措施更多的生命。该项目的目的是确定ClotFoam（一种新型明胶基纤维蛋白封闭剂）作为止血剂在III/IV级（在肝脏中测量）腔内伤口导致严重出血的情况下止血而无需压迫的有效性和安全性，以及在手术室外使用的新型应用方法。该技术的使用可以扩展到微创手术、腹腔镜手术、脑外科手术和妇科手术。该技术基于包埋在支架中的纤维蛋白密封剂的物理和凝血性质，通过促凝剂增强，并作为泡沫通过CO2推进的递送装置递送。I期研究通过确定ClotFoam粘附在血泊中撕裂组织的能力，为ClotFoam作为不可压缩技术在非常严重创伤（3级/4级）导致出血的情况下以及在腹腔镜或微创外科手术中的使用提供了“概念验证”。从大鼠、家兔和猪的研究中获得的数据表明，ClotFoam可以产生均匀分布的适应性泡沫;当腹腔内注射时，即使在大量出血的情况下，也能粘附在腹腔内，改善撕裂组织之间的粘连，并启动快速凝块形成。此外，Clotfoam的纤维蛋白封闭剂成分采用先进技术开发，克服了纤维蛋白封闭剂遇到的两个基本问题：保质期和对凝血酶的自身免疫反应。本II期提案的具体目的是：1）开发在环境条件下灭菌和保存试剂的方法，并确定在标准冷藏条件下保存的纤维蛋白组分的蛋白水解降解、活性和有效期; 2）在大鼠皮下模型中评价材料的生物相容性。一旦确定该制剂可以灭菌并且是生物相容的，因此将不需要进一步的修改，我们将3）开发标准化动物模型（猪）以研究止血剂在由严重创伤性损伤导致的肝脏III级和IV级创伤后的不可压缩严重出血的情况下的作用; 4）评估ClotFoam在猪模型中实现止血的能力，在由III级、IV级肝损伤引起的高流量出血继发的进行性严重出血之后;并评估与对照相比1小时时的动物存活率。最后5）我们将通过评价免疫风险以及预防粘连、腹腔间隔室综合征和迟发性血肿和/或水肿形成来评估该药物的安全性。这些数据将用于提交研究性新药（IND）申请并进入临床阶段。公共卫生关系：在一个速度、国内暴力和武装冲突的时代，腹部穿透伤和钝伤的发生率一直在增加。平均而言，全国医院收治的创伤病例中有41.8%是由于道路交通事故造成的。此外，出血仍然是常规战争战场上死亡的主要原因。这些腹部损伤的发病率和死亡率构成了一个可怕的问题，特别是在年轻人中。理论上，早期有效的出血控制比任何其他措施都能挽救更多的生命。不幸的是，目前所有用于腹腔内出血的止血剂都是设计用于手术室，而不是用于受伤部位（即战场、车祸或枪伤现场）。所有可用的止血剂和密封剂都需要压缩，因此即使在微创手术（如腹腔镜手术）的情况下也不能使用。ClotFoam是一种新型药剂，可以将密封泡沫注入体腔内以密封伤口并止血，已在动物研究中证明是有效的。该药剂通过混合针施用，类似于Veress针-释放泡沫诱导剂和结合到明胶密封剂中的促凝剂，所述明胶密封剂粘附到受伤的组织上，压缩伤口并止血。在本研究中，我们将进一步研究ClotFoam在III级和IV级创伤性伤口引起严重出血的情况下的有效性和安全性，包括生物相容性，如果不立即治疗，将导致失血。这种治疗方法将降低阵亡率（KIA），为医护人员提供新的治疗工具，提高医护人员的救生能力，为腹腔镜和其他微创手术提供新的选择，并减少手术和输血的需求。