Preclinical Development of an Absorbable Antibacterial Bone Hemostatic Agent

可吸收抗菌骨止血剂的临床前开发

基本信息

批准号：
7612540
负责人：
TIMOTHY C FISHER
金额：
$ 9.97万
依托单位：
CEREMED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-03 至 2011-08-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612540
关键词：
Address Adhesives Adverse effects Aging Animals Anti-Bacterial Agents Anti-Infective Agents Antibiotic Prophylaxis Antibiotics Australia Avitene Bacterial Adhesion Biocompatible Bone Surface Buffers Cardiac Cardiac Surgery procedures Cessation of life Clinical Clinical Research Collagen Complication Country Defect Development Drug Formulations Drug Kinetics Dyes Evaluation Femur Gentamicins Goals Health Care Costs Hemorrhage Hemostatic Agents Hemostatic function Hour Immunoassay Implant In Vitro Incidence Infection Infection prevention Inflammation Inflammatory Inpatients Kinetics Measurement Measures Mechanics Mediastinitis Microscopic Modeling Monitor Morbidity - disease rate Muscle Netherlands Operative Surgical Procedures Oryctolagus cuniculus Osteogenesis Osteomyelitis Particle Size Performance Phase Polymers Porifera Postoperative Period Prevention Process Property Rattus Reporting Research Design Research Personnel Rest Risk Sampling Site Staging Sterilization for infection control Sternotomy Structure Surface Sweden Temperature Testing Time Toxic effect Treatment Cost Validation Viscosity Water Wound Infection base beeswax biomaterial compatibility bone bone wax carcinogenicity cost cytotoxicity disability genotoxicity implantation in vivo manufacturing process meetings mortality pre-clinical preclinical study prevent public health relevance reproductive stability testing subcutaneous wound

项目摘要

DESCRIPTION (provided by applicant): OsteneTM is a soft moldable adhesive material that sticks well to bleeding bone surfaces. It was invented by researchers at USC and CHLA as a replacement for standard bone wax, a beeswax-based material that causes local inflammation and is known to increase the risk of infection after surgery. In contrast, Ostene is a combination of biocompatible water-soluble polymers which is absorbed completely within 2-3 days of implantation; it is non-inflammatory and also has an intrinsic anti-infective effect due to its ability to prevent bacterial adhesion to surfaces. This combination of properties makes Ostene an ideal material for delivery of antibiotics directly to the wound during any surgical procedure that involves the cutting of bone. The objective of this project is to develop a formulation of Ostene with Gentamicin which retains its hemostatic properties but also releases gentamicin during the immediate post-operative period to prevent infection of the bone (osteomyelitis) or the rest of the wound. This application describes the initial formulation development, in vitro validations, biocompatibility testing and in vivo animal pharmacokinetic studies. These pre-clinical studies will form the basis for a 510(k) / IND submission, to be followed by a clinical study in phase II, which will examine whether the interoperative use of Ostene+Gentamicin in cardiothoracic surgery can reduce the incidence of sternal wound infections (SWIs). SWIs are relatively common (6-9%), cause significant morbidity and mortality (1-2%) and have a high cost of treatment (average >$20,000 per case). By extension from previous studies, successful development and deployment of Ostene+Gentamicin could potentially reduce the incidence of SWIs by 50%, which would have a major impact on SWI related deaths, disability and treatment costs. PUBLIC HEALTH RELEVANCE: Sternal wound infections (SWIs) are a relatively common complication of cardiac surgery. In recent studies, the reported incidence of SWI after sternotomy was 6-9%, of which about two- thirds were classified as superficial, and one-third of (2-3% in total) as deep SWI or mediastinitis, which are associated with significant morbidity, often require prolonged inpatient treatment, and have a mortality rate between 10 and 20%. In the US, cost estimates for treatment of an SWI range from $20,000 to $40,000. These numbers are consistent with studies from other countries, e.g., $16,600 in the Netherlands, $18,500 (Sweden) and $23,250 (Australia). Assuming a current average treatment cost of one SWI in the US to be $25,000, with 646,000 cardiac operations per year and an SWI incidence of 5%, the total additional health care cost due to this one potentially preventable complication amounts to $800,000,000 annually. Local delivery of Gentamicin to the surgical site via a collagen sponge implant has been shown to reduce the incidence of SWI by about 50%. The product to be developed under this proposal Ostene+Gentamicin, is expected to be at least as effective for prevention of SWI as the collagen-based implant, but will also be considerably less expensive and much easier to use during surgery. Ostene is fully resorbed within 1-3 days, a more appropriate time frame for antibiotic prophylaxis compared to the collagen sponge, which remains at the site for 2-3 weeks. Ostene is increasingly used for hemostasis in cardiac surgery as a preferred alternative to bonewax or other hemostatic materials (e.g., Avitene). Thus, once developed, the Ostene+ Gentamicin combination would be not expected to meet any major barrier to acceptance.

描述（由申请人提供）：ostenetm是一种柔软的可塑性材料，非常粘在骨表面出血。它是由USC和CHLA的研究人员发明的，作为标准骨蜡的替代，这是一种基于蜂蜡的材料，可引起局部炎症，众所周知会增加手术后感染的风险。相比之下，ostene是生物相容性水溶性聚合物的组合，在植入后的2-3天内完全吸收了水溶性聚合物。它是非炎症性的，并且由于其能够防止细菌粘附到表面的能力，因此具有内在的抗感染作用。这种特性的组合使奥蛋白成为在任何涉及切割骨骼的手术过程中直接输送抗生素向伤口传递的理想材料。该项目的目的是用庆大霉素开发ostene的表述，该表达保留其止血特性，但在术后直接术中也会释放庆大霉素，以防止骨骼感染（骨髓炎）或伤口的其余部分。该应用描述了初始配方的发展，体外验证，生物相容性测试和体内动物药代动力学研究。这些临床前的研究将构成510（k） / IND提交的基础，然后在第二阶段进行临床研究，该研究将检查在心胸外科手术中互操作使用术的互操作使用可以降低胸骨伤口感染的发生率（SWIS）。 SWIS相对普遍（6-9％），引起明显的发病率和死亡率（1-2％），并且治疗成本很高（平均> 20,000美元）。从以前的研究中扩展，成功开发和部署Ostene+庆大霉素可能会使SWIS的发生率降低50％，这将对与SWI相关的死亡，残疾和治疗成本产生重大影响。公共卫生相关性：胸骨伤口感染（SWIS）是心脏手术的相对常见并发症。在最近的研究中，据报道，胸骨切开术后SWI的发生率为6-9％，其中约三分之二被归类为表面，其中三分之一（总计2-3％）为深SWI或纵隔炎，这与大量发病率有关，通常需要长时间的患病治疗，并且具有10％和20％的死亡率。在美国，SWI治疗的成本估算范围从20,000美元到40,000美元不等。这些数字与其他国家的研究一致，例如荷兰的16,600美元，$ 18,500（瑞典）和23,250美元（澳大利亚）。假设美国目前的平均治疗费用在美国为25,000美元，每年为646,000个心脏手术，SWI发病率为5％，由于这一可能可预防的并发症的总额外医疗保健费用每年为800万美元。已证明，通过胶原蛋白海绵植入物将庆大霉素的局部输送到手术部位可将SWI的发生率降低约50％。根据该提案Ostene+庆大霉素开发的产品，预计至少在防止SWI的植入物中与基于胶原蛋白的植入物一样有效，但在手术过程中也将较便宜，并且更易于使用。与胶原蛋白海绵相比，Ostene在1-3天内完全放映了抗生素预防的时间范围，该胶原海绵在现场持续了2-3周。在心脏手术中，奥蛋白越来越多地用于止血，作为骨膜或其他止血物质的首选替代品（例如Avitene）。因此，一旦开发，Ostene+庆大霉素组合就不会遇到任何主要的接受障碍。