Engineering immunomodulatory materials for regenerative medicine

目前的生物医学和组织工程策略旨在提供能够改善或恢复受损或疾病组织功能的技术，这些组织具有功能和部位合适的新组织。生物材料在植入式医疗器械行业发挥了核心作用，改善了全球数百万人的生活。然而，生物材料是异物，因此对生物材料的不良免疫反应是一个根本性的挑战，可能会影响和降低患者的生活质量。这些不良反应经常被认为干扰愈合，导致立即出现的急性后果，如巨大的疼痛、过度的炎症、组织破坏，甚至医疗器械的隔离和排斥。缺乏对生物材料-免疫系统相互作用的详细了解，导致微环境发生重大病理变化，是开发有效的基于生物材料的治疗和组织工程方法的主要障碍。最近，人们已经认识到，决定临床结果的最重要的因素是宿主对生物材料的反应，即免疫介导的组织对异物存在的反应。具有良好免疫调节特性的生物材料可以将对异物植入的默认反应(即疤痕组织形成或纤维包裹)转变为组织整合和功能重建。设计调节免疫反应的材料需要了解免疫系统在正常生理过程中的作用，包括伤口修复、发育和组织动态平衡，以及免疫系统通过与常驻干细胞/祖细胞的串扰对组织重建的贡献。水凝胶(高水合聚合物基质)由于其独特的物理化学性质(如载药量、生物相容性和生物降解性)在再生医学中具有很好的免疫调节应用前景。在这个高度跨学科的项目中，将通过探索天然和合成材料来开发能够缓解异物反应和促进组织再生的新生物材料。用于评估新型生物材料的标准体外测试协议通常遵循国际标准化组织(ISO)用于医疗器械的生物评估的协议。然而，最近一项欧洲生物材料评估的多中心分析得出结论，生物材料的体外评估不适合预测体内的接受性，并强调了改进当前的体外评估方案和开发更相关的体外测试的作用。修复和设计新组织的尝试需要一套完善的方法工具包来测试和评估对这些材料的免疫反应。为此，拟议的研究将开发创新的方法和解决方案，使之能够验证更广泛的生物材料相互作用，它们的再生潜力，以及通过标准化测试控制免疫反应的能力。具体目标包括：O1。开发一种新的方法工具包来测试和评估材料的免疫反应，以标准化所需的方法。开发量身定制的免疫调节生物材料和方法，以指导组织再生中的免疫反应和环境。设计的生物材料的物理化学和生物学特性(例如，体外细胞存活、细胞外基质的产生、炎症反应)将通过利用开发的方法工具包来评估，以确定其用于再生医学应用的免疫调节潜力。03利用3D生物打印来处理开发的免疫调节材料以促进免疫耐受，并通过使用标准化方法工具包来评估制造的结构用于再生医学应用的潜力。

Current biomedical and tissue engineering strategies aim to provide technologies capable of improving or restoring the function of damaged or diseased tissues with functional and site-appropriate neo-tissue. Biomaterials have played a central role in the implantable medical device industry and have improved the lives of millions of people worldwide. However, biomaterials are foreign bodies, thus adverse immune reactions to biomaterials represents a fundamental challenge which can impact and reduce the quality of life for patients. These adverse reactions are often seen to interfere with healing, leading to immediate acute outcomes such as immense pain, excessive inflammation, tissue destruction, or even isolation and rejection of medical devices. The lack of detailed understanding of biomaterial-immune system interactions, resulting in significant pathological changes in the microenvironment, is a major barrier to developing effective biomaterial-based therapies and tissue engineering approaches. Recently, it has been recognized that the most important determinant of successful clinical outcomes is the host response to the biomaterial, i.e., the immune-mediated tissue reaction to the presence of the foreign body. Biomaterials that have favourable immunomodulatory properties can shift the default response to a foreign body implant (i.e., scar tissue formation or fibrous encapsulation) towards one of tissue integration and functional remodelling.Designing materials to modulate the immune response requires an understanding of the role of the immune system in normal physiologic processes including wound repair, development, and tissue homeostasis as well as an understanding of the immune system contribution to tissue remodelling through crosstalk with resident stem/progenitor cells. Hydrogels (highly hydrated polymeric matrices) are promising materials for immunomodulatory application in regenerative medicine due to their unique physicochemical properties (e.g., drug loading capacity, biocompatibility, and biodegradability). Within this highly interdisciplinary project, new biomaterials that can mitigate the foreign-body response and promote tissue regeneration will be developed by exploring natural and synthetic materials. The standard in vitro testing protocols for assessing novel biomaterials generally follow the International Organisation of Standardisation (ISO) protocols for the biological evaluation of medical devices. However, a recent European multicentre analysis of biomaterial assessments concluded that in vitro evaluations of biomaterials are not suitable to predict in vivo acceptance and highlights the role for improving current in vitro assessment protocols and developing more relevant in vitro assays. Attempts to repair and engineer new tissues requires a well-established toolkit of methods to test and evaluate the immune response to these materials. For this, the proposed research will develop innovative approaches and solutions that enable to validate the broader biomaterials interactions, their regenerative potential and ability to control the immune response with the standardised tests. Specific objectives include:O1. To develop a new toolkit of methods to test and evaluate the immune response of materials to standardise methods required.O2. To develop tailored immunomodulatory biomaterials and approaches to direct immune response and environments in tissue regeneration. The physicochemical and biological properties (e.g., in vitro cell viability, ECM production, inflammatory response) of designed biomaterials will be assessed by exploiting the developed toolkit of methods to establish their immunomodulatory potential for regenerative medicine applications.O3 To process developed immunomodulatory materials using 3D bioprinting to promote immune tolerance, and to assess the potential of manufactured structures for regenerative medicine applications by using the standardised toolkit of methods.