Ultrathin dissolvable antibiofilm wound contact dressing with silver and gallium

整个研究计划包含Embed Biosciences要求不得向个人发布的专有/特权信息 政府以外的，但为审查和评估的目的除外。 ! 总结 在美国，与治疗慢性伤口相关的医疗保健费用每年超过250亿美元。 生物膜被认为是延迟愈合的关键因素。许多伤口表面复杂 并且清创术可能具有挑战性，留下的生物膜碎片仍然对抗菌治疗具有抗性， 作为生物膜复发的病灶。没有市售的局部制剂有效地用于 伤口中生物膜的分散。由NIH和私募股权投资资助的嵌入式生物科学公司的研究， 已经导致了具有独特形状因子的无创接触矩阵的发展。MicroLyte®基质 是一种20-25 μ m厚的可溶性聚合物多层膜，可无痛放置在伤口中， 经过设计可以在几天内溶解。该矩阵密切符合基本轮廓， 伤口床以提供生物活性分子的局部和长期释放。最近获得FDA 基于该平台的MicroLyte® Ag缠绕基质的清除率，其中基质浸渍有银 纳米粒子在原位形成。它已被成功地用于治疗数千名患者的慢性伤口， 美国它在体外和小鼠感染伤口模型中可有效杀灭广谱细菌。然而，在这方面， 它不能有效地杀死包裹在生物膜中的细菌。在我们最近发表的研究中， 银和镓（Ga 3+）离子在消除生物膜中的作用。基于这些科学发现和成功的临床 在医院采用MicroLyte® Ag基质微球形状因子，该SBIR项目的目标是开发一种 经济、易于放置、可溶解的伤口接触基质，其可以在一个或多个表面上部署银和镓的协同作用。 伤口表面，以消除生物膜。第1阶段可行性研究的结果记录了MicroLyte Matrix，当 在聚合物多层膜中战略性地浸渍有无毒的银纳米颗粒和镓， 能够在体外将>4 log 10 CFU的细菌分散在混合物种生物膜中。在延迟伤口愈合模型中， 在小鼠中，这种基质在治疗的3天内消除了预先建立的坚固生物膜中>90%的细菌。 这些结果证明了我们的科学前提，放大协同配对镓和银离子对生物膜 将它们呈现在微尺度基质中。第1阶段结果为开展第2阶段研究提供了有力支持。 2项研究旨在优化MicroLyte Matrix设计，以更快地消除伤口床中的生物膜。 第2阶段研究的目标是：（1）定制MicroLyte基质，以实现更高的载量和延长银的释放 （2）筛选基质中银和镓的生物相容性限度;（3）筛选剂量反应 （4）优化负载以分散生物膜在小鼠骨折伤口中 模型，和（5）评估对感染生物膜的猪伤口模型中的愈合的影响。在这个项目中， 已经组建了一个在生物材料方面具有丰富专业知识的研究人员团队（Agarwal，Pranami，Dalsin， Abbott）、微生物学（Czuprynski）、动物伤口模型（McAnvillage）和临床伤口护理（McAnvillage和 Schurr）。第2阶段研究的成功完成将产生一种储存稳定的MicroLyte Ag/Ga基质， 安全性和有效性数据，可以很容易地转化为FDA批准的人体临床研究。 !

The entire Research Plan contains proprietary/privileged information that Imbed Biosciences requests not be released to persons outside the Government, except for purposes of review and evaluation.! ! SUMMARY The health care costs associated with treatment of chronic wounds exceeds $25 billion annually in the U.S. Biofilms are implicated as a key factor responsible for delayed healing. Many wounds have complex surfaces and debridement can be challenging, leaving biofilm fragments that remain resistant to antimicrobial therapy and act as a nidus for recrudescence of biofilms. There is no commercially available topical formulation effective in dispersal of biofilms in wounds. Research at Imbed Biosciences, funded by NIH and private equity investments, has resulted in the development of an ultrathin wound contact matrix with a unique form factor. MicroLyte® Matrix is a 20-25 µm-thick dissolvable polymeric multilayer film that allows painless placement in wounds and can be engineered to dissolve over several days. The ultrathin matrix conforms intimately to the underlying contours of a wound bed to provide localized and long-term release of bioactive molecules. Imbed recently obtained FDA clearance for MicroLyte® Ag wound matrix based on that platform, where the matrix was impregnated with silver nanoparticles formed in situ. It has been used successfully to heal chronic wounds in thousands of patients in U.S. It is effective in killing a broad spectrum of bacteria in vitro and in infected wound models in mice. However, it is not effective in killing bacteria encased in biofilms. In our recently published study, we demonstrated synergy of silver and gallium (Ga3+) ions in eliminating biofilms. Based on those scientific findings and successful clinical adoption of MicroLyte® Ag matrix ultrathin form factor in hospitals, objective of this SBIR project is to develop an economic, easy to place, dissolvable wound contact matrix that can deploy synergy of silver and gallium on a wound surface to eliminate biofilms. Results of Phase 1 feasibility study documented that MicroLyte Matrix, when strategically impregnated with non-toxic loadings of silver nanoparticles and gallium in polymeric multilayers, is able to disperse >4 log10 CFUs of bacteria in a mixed species biofilm in vitro. In a delayed wound healing model in mice, such a matrix eliminated >90% of bacteria in a pre-established robust biofilm within 3 days of treatment. These results proved our scientific premise of amplifying synergy in pairing gallium and silver ions against biofilm bacteria by presenting them in a microscale matrix. Phase 1 results provide strong support for pursuing a Phase 2 study to optimize the MicroLyte Matrix design that can obtain faster elimination of biofilms in the wound bed. The goals of Phase 2 research are: (1) Tailor MicroLyte Matrix for higher loadings and extended release of silver and gallium, (2) Screen biocompatibility limits of silver and gallium in the matrix, (3) Screen dose response against mixed species biofilms in vitro, (4) Optimize loadings for dispersal of biofilms in a murine splinted-wound model, and (5) Evaluate effect on healing in a porcine wound model infected with biofilms. For this project, Imbed has assembled a team of researchers with substantial expertise in biomaterials (Agarwal, Pranami, Dalsin, and Abbott), microbiology (Czuprynski), animal wound models (McAnulty) and clinical wound care (McAnulty and Schurr). Successful completion of Phase 2 research will result in a shelf-stable MicroLyte Ag/Ga matrix with safety and efficacy data that can be readily translated into human clinical studies for FDA clearance. !