Designing bio-instructive materials for translation ready medical devices

医疗保健依赖于医疗设备，但这些设备通常具有感染和故障的重大风险。据估计，医疗器械市场规模不到5000亿美元，而每年用于治疗慢性伤口的费用为250亿美元。随着我们的人口老龄化，我们的医疗保健系统也受到多种抗生素耐药性和病毒爆发的压力。例如，50%的初始COVID-19死亡是由于继发性细菌感染[Zhou et al. The Lancet，2020]。高达20%的医疗设备故障率通过以设备为中心的感染、免疫排斥或两者兼而有之，给我们的卫生服务带来了不成比例的负担。在EPSRC计划资助“下一代生物材料发现”中，发现了物理表面图案（形貌）与新型聚合物的结合，既减少了细菌生物膜的形成，又增加了材料在体外和体内临床前感染模型中的免疫接受性。这为用作植入物和伤口护理产品的生物材料提供了一种新的范例，其中新型聚合物可以使用生物指令进行形貌图案化以改善愈合和接受。为了利用这些发现，需要针对特定的医疗器械环境，并阐明其作用机制，以便由行业进行翻译。该项目将利用3D打印来制造包含一千多种聚合物化学-形貌组合的ChemoTopoChips，从而可以使用半自动化的在线技术有效地探索和映射可能的设计空间。体外测量宿主免疫细胞和感染病原体单独和共培养的相互作用。这些ChemoTopoChips将允许从分泌到培养基中的生物分子（分泌组）、吸附到表面的生物分子（生物界面）以及它们对宿主细胞和细菌的影响中提取非常高含量的分子信息。将使用相同的制造方法来制造用于临床前试验的器械;将使用随时间推移的感染和愈合的微创监测以及对外植体的详细分析来最大限度地利用体内信息。这些信息流将使用人工智能进行合并（特别是机器学习）来构建有效的性能模型，并提供机械洞察力，从而设计出可在本项目之外转化为医疗器械的材料。在咨询了广泛的临床医生后，我们选择了以下两种器械：-用于慢性/不愈合伤口的伤口护理产品：敷料，以减少感染，诱导免疫稳态和促进慢性伤口愈合，导致7000糖尿病相关截肢在英国每年花费NHS £ 10亿管理。需要组织整合但易于发生纤维化/粘连和生物膜相关感染的植入物：用于修补疝或盆腔器官脱垂的外科补片，这些疾病通常困扰分娩后的女性。NHS每年进行10万例此类手术，感染率高达10%，加上异物反应并发症。为利用这一机会而组建的团队在生物材料，人工智能，增材制造以及生物材料免疫和细菌反应的体外和体内测量领域拥有独特的经验。设施包括最近开放的1亿英镑的诺丁汉生物发现研究所，最近资助的EPSRC 100万英镑的高分辨率/高吞吐量3D打印机套件和独特的250万英镑的3DOrbiSIMS Cat 2低温设施。在诺丁汉的这些投资使这里成为世界上唯一有能力开展这一项目的地方。由临床医生、工业合作伙伴和领先学者组成的咨询委员会将每年举行一次会议，为该项目提供投入。

Healthcare relies on medical devices, yet often these have significant risk of infection and failure. The medical device market is estimated to be just under US$500 billion, while US$25 billion is spent annually on treatment of chronic wounds. As our populations becomes older, our healthcare systems are also becoming stressed by multi-antibiotic resistance and viral outbreaks. For example, 50% of initial COVID-19 fatalities were due to secondary bacterial infections [Zhou et al. The Lancet, 2020]. Medical device failure rates of up to 20% burden our health service disproportionately through device centred infection, immune rejection, or both. The biomaterials that devices and external wound care products are made from significantly influence immune and healing responses and affect the outcome of infection.In the EPSRC Programme Grant "Next Generation Biomaterials Discovery", physical surface patterns (topographies) combined with novel polymers were found which both reduce bacterial biofilm formation and increase the immune acceptance of materials in vitro and in vivo in preclinical infection models. This provides a new paradigm for biomaterials used as implants and wound care products, where novel polymers can be topographically patterned to improved healing and acceptance using bio-instruction. To exploit these findings requires targeting to specific medical device environments and elucidation of the mechanism of action for translation by industry.This project will utilise 3D printing to manufacture ChemoTopoChips containing over a thousand polymer chemistry-topography combinations that allow the possible design space to be efficiently explored and mapped using semi-automated in-vitro measurements of host immune cell and infecting pathogen interactions individually and in co-culture. These ChemoTopoChips will allow a very high content of molecular information to be extracted from biomolecules secreted into the culture media (the secretome), those adsorbed to the surface (the biointerface) and their impact on both host cells and bacteria. The same fabrication approaches will be used to make devices for preclinical testing; in vivo information will be maximised using minimally invasive monitoring of infection and healing over time and detailed analysis of explants. These information streams will be merged using artificial intelligence (specifically machine learning) to build effective models of performance and provide mechanistic insight, allowing design of materials ready for translation as medical devices outside this project.After consultation with a wide range of clinicians we have chosen to target the following two devices: -Wound care products for chronic/non-healing wounds: dressings to reduce infection, induce immune-homeostasis and promote healing in chronic wounds that result in 7000 diabetes related amputations in the UK per year and cost the NHS £1bn a year to manage.-Implants requiring tissue integration but prone to fibrosis/adhesion and biofilm-associated infection: surgical meshes used for repair of hernias or pelvic organ prolapse commonly afflicting women after childbirth. The NHS undertakes 100k such operation each year with infection rates of up to 10%, plus foreign body response complications.The team assembled to exploit this opportunity has unique experience in the areas of biomaterials, artificial intelligence, additive manufacturing and in vitro and in vivo measurements of immune and bacterial responses to biomaterials. Facilities including the recently opened £100m Nottingham Biodiscovery Institute, the recently funded EPSRC £1m suite of high resolution/high throughput 3D printers and the unique £2.5m 3DOrbiSIMS Cat2 cryo-facility. These investments in Nottingham make this the only location in the world that is capable of undertaking this project.An Advisory Board of clinicians, industrial partners and leading academics will meet annually to provide input to the project.