An antimicrobial-eluting bioresorbable bone filler for orthopaedic application

描述（由申请人提供）：Carmell Therapeutics的长期目标是开发一种基于血浆的生物材料骨填充产品，该产品将洗脱抗菌药物以抑制感染。48-68%的开放性伤口和100%的严重开放性伤口围手术期存在细菌污染。在美国，每年约有123,000例开放性胫骨骨折受到污染，需要额外的患者治疗费用为29,000美元。额外的间接成本（工伤赔偿、工资损失、生产力损失等）是巨大的，但很难量化。目前的护理标准包括全身抗生素，早期清创，以及经浸渍的聚甲基丙烯酸甲酯（PMMA）微球局部预防性使用抗生素，这些微球具有未知的释放动力学，必须在骨复位手术之前从缺损处去除。临床医生需要一种既能增强骨修复，又能通过局部抗生素输送控制感染的产品。Carmell认为，将抗菌药物与血浆生物材料（PBMs）（在降解过程中洗脱再生因子）相结合，有可能满足这一需求。第一阶段的假设是，这种名为REPAIR Plus“骨腻子”的产品可以在局部输送抗菌剂来控制感染。为了验证这一假设，将把抗菌剂纳入PBMs，并使用基于磁盘扩散的体外试验验证其释放和活性。然后使用代谢测定和电子显微镜在体外建立产物的生物活性和生物相容性。该产品对铜绿假单胞菌和金黄色葡萄球菌及其生物膜的抗菌活性将在体外使用3D荧光染色和细胞培养技术进行验证。最后，利用大鼠胫骨模型建立体内清除金黄色葡萄球菌感染的试点可行性研究，其中添加细菌

DESCRIPTION (provided by applicant): The long-term goal of Carmell Therapeutics for this proposal is to develop a blood plasma-based biomaterial bone filler product that will elute antimicrobials to inhibit infection. Bacterial contamination is present perioperatively in 48-68% o all open wounds and 100% of severe open injuries. Per year in the U.S. ~ 123,000 open tibia fractures are contaminated, requiring an added patient treatment cost of $29,000. Additional indirect costs (Worker's Compensation, lost wages, productivity, etc.) are enormous but harder to quantify. Current standard of care involves systemic antibiotics, early debridement, and the off-label, prophylactic use of local antibiotic delivery via impregnated poly(methyl methacrylate) (PMMA) beads, which have unknown release kinetics and must be removed from the defect prior to bone reduction procedures. Clinicians need a product that enhances bone repair as well as controls infection through local antibiotic delivery. Carmell believes that combining antimicrobial delivery with its blood plasma-based biomaterials (PBMs) (which elute regenerative factors as they degrade) have the potential to meet this need. The Phase I hypothesis is that the product, the REPAIR Plus" Bone Putty, can locally deliver antimicrobials to control infection. To test the hypothesis antimicrobials will be incorporated into PBMs and their release and activity will be verified using disk diffusion-based in vitro assays. The products biological activity and biocompatibility will then be established in vitro using a metabolic assay and electron microscopy. The product's antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus and their biofilms will be demonstrated in vitro using 3D fluorescence staining and cell culture techniques. Finally, clearance of S. aureus infection in vivo in a pilot feasibility study using a rat tibia model will be established, where bacteria added to a bone defect will be challenged with the product to determine the product's ability to clear the bacteria over 14 days. Following the demonstration of feasibility in Phase I, Phase II will build on the infection control data to examine enhanced bone repair (with infection control) in vivo as well as conduct regulatory-focused studies to demonstrate biocompatibility and safety, all to prepare for a first-in-man clinical study. Carmell will additionally recruit an antibiotic supplier as a partner for supply and regulatory documentation as well as for potential licensing opportunities. Overall, an effective, off-the-shelf, and easy to use product that could improve patient outcome and reduce treatment complications as well as costs will have enormous marketing potential for the treatment of open tibia fractures and other open bone fracture applications.