Designing bio-instructive materials for translation ready medical devices

医疗保健依赖于医疗设备，但这些设备往往有很大的感染和故障风险。据估计，医疗器械市场的规模不到5000亿美元，而每年用于治疗慢性伤口的支出为250亿美元。随着我们人口的老龄化，我们的医疗系统也受到多重抗生素耐药性和病毒爆发的压力。例如，新冠肺炎最初死亡的50%是由于继发性细菌感染[周等人]。《柳叶刀》，2020]。医疗器械故障率高达20%，通过以器械为中心的感染、免疫排斥或两者兼而有之，给我们的医疗服务带来了不成比例的负担。设备和外部伤口护理产品所用的生物材料显著影响免疫和愈合反应，并影响感染的结局。在EPSRC计划资助的“下一代生物材料发现”中，发现物理表面图案(拓扑图)与新型聚合物相结合，在临床前感染模型中既减少了细菌生物膜的形成，又提高了材料在体外和体内的免疫接受性。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通过生物指令进行拓扑图案化，以改善愈合和接受度。要利用这些发现，需要针对特定的医疗设备环境，并阐明行业翻译的作用机制。该项目将利用3D打印来制造包含1000多个聚合物化学-地形组合的ChemoTopChips，这些组合允许使用对宿主免疫细胞和感染病原体相互作用的半自动体外测量来有效地探索和绘制可能的设计空间。这些ChemoTopChips将允许从分泌到培养介质(分泌组)中的生物分子、吸附在表面(生物界面)的生物分子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。同样的制造方法将被用于制造用于临床前测试的设备；体内信息将通过对感染和愈合的微创监测以及对外植体的详细分析来最大化。这些信息流将使用人工智能(特别是机器学习)合并，以建立有效的性能模型并提供机械洞察力，从而允许设计准备在该项目之外转换为医疗设备的材料。在咨询了广泛的临床医生后，我们选择了以下两种设备：-用于慢性/不可愈合伤口的伤口护理产品：减少感染的敷料，诱导免疫动态平衡并促进慢性伤口的愈合，这些伤口每年导致英国7000例糖尿病相关截肢，并花费NHS每年10亿英镑的管理费用。-需要组织整合但容易发生纤维化/粘连和生物膜相关感染的植入物：用于修复腹股沟或盆腔器官脱垂的外科网状物，通常在分娩后困扰女性。NHS每年进行10万次这样的手术，感染率高达10%，外加异物反应并发症。为利用这一机会而组建的团队在生物材料、人工智能、添加剂制造以及对生物材料的免疫和细菌反应的体外和体内测量领域拥有独特的经验。这些设施包括最近开放的GB 100M诺丁汉生物发现研究所、最近资助的EPSRC GB 1M高分辨率/高通量3D打印机套件，以及独特的GB 2.5M 3DOrbiSIMS Cat2冷冻设施。在诺丁汉的这些投资使这里成为世界上唯一有能力进行这一项目的地点。由临床医生、行业合作伙伴和领先学者组成的咨询委员会将每年举行会议，为该项目提供意见。

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.