We welcome you to this Special Issue of Advanced Materials entitled “Engineering active materials for biomedical applications”. This special issue focuses on the design and application of biomedical materials that are engineered to be active, in either or both a biological and mechanical context. Current and future biomedical materials at a variety of size scales are highlighted, including their design and screening, with a spectrum of articles describing research ranging from fundamental to translation-application focused.

Historically, biomaterials were designed to be inert in the human body, eliciting no response from the cells and tissues they contacted. Decades of clinical experience and research revealed, though, that implanted biomaterials always generated some response, and the body responses could lead to loss of function or significant inflammatory responses. This appreciation shifted attention in the field to tuning and controlling the body response via the design of specific mechanisms of engagement of biomaterials with the cells and tissues in the body, in order to generate favorable outcomes and maintain the functionality of the implanted materials. This approach has generated many successes, but the initial biomaterials designed from this perspective tended to be passive, with pre-designed features and functions, and little ability to dynamically interface or respond to the body, from either a biological or physical perspective. In contrast, many researchers are currently designing active biomaterials that directly interface in specific manners with the body, and actively direct biological processes over time. In this special issue, we highlight four areas in which this concept is currently being explored – mechanically active biomaterials, materials that actively direct the host immune response (immunomaterials), materials designed to promote tissue repair and regeneration, and dynamic materials. Each of these sub-topics is briefly reviewed in the following sections.

Mechanically Active Materials

Biomedical applications for mechanically active materials include “sense and respond” functions, muscle assist, controlled drug delivery, long-term monitoring of physiological parameters, and enhanced in vitro testbeds for cell culture. Nie et al. (adma.202205609) provide a review on using such materials for bio-interfaced sensors for continuous monitoring. Examples include sensors for measuring pressure at the skin interface, on the cardiac surface and for internal body processes. They describe future applications for materials that are highly sensitive, stable, and have a wide dynamic range, systems for noise reduction and for decoupling types of mechanical loads. Modifications of these mechanically active materials could have applications in soft robotics and human–machine interfaces. Pirozzi et al. (adma.202210713) review another class of mechanically active materials — artificial muscles — with a specific use case of cardiac assistance. Design requirements for this application are comprehensively outlined in addition to the key advantages of this approach over currently available mechanical circulatory support devices, specifically the ability to provide pulsatile support without contacting blood. They review pneumatic, magnetic, dielectric elastomers and electrohydraulic actuators for this application and contrast the benefits and challenges of each approach for the treatment of heart failure. Roy et al. (adma.202300017) describe a bilayer hydrogel folding system that can generate folding patterns, similar to the mucosal tissue in the epithelium of the upper respiratory airways. The hydrogel is composed of a double network of alginate and polyacrylamide. Cells can be encapsulated into the patterned hydrogels and programable, on-demand folding is enabled by incorporating magnetic microparticles to provide a dynamic culture system to study the influence of folding patterns on cellular function. Finally, mechanically active materials can be implanted in the body and deliver therapeutics on demand. Mendez et al. (adma.202303301) describe a hybrid hydrogel actuator that can elicit tunable mechanoresponsive release of drug from a hydrogel layer through pneumatic actuation. Dosing can be controlled by magnitude, frequency, and duration of actuation. The device can adhere to tissue with a flexible adhesive and in the future can be integrated with mechanical assist technologies for a mechanotherapeutic effect.

Immunomaterials

The past two decades has witnessed a roaring development of new material systems for orchestrating immune cells and the immune system toward favoring the treatment of diseases including cancer, autoimmune disorders, inflammatory diseases, and tissue injury. These immunomaterials can provide physicochemical and mechanical cues to control the activation status and phenotypes of immune cells, release immunomodulatory agents in a spatiotemporally controllable manner, and actively attract and modulate immune cells in situ.

In this special issue, Park et al. (adma.202311505) report the ability of tumor cells to utilize the mineralization of collagen in the extracellular matrix to evade the attack of natural killer cells. Using a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and selective manipulation of tumor cell glycan patterns, they demonstrated that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increases their glycocalyx thickness while enhancing resistance to attack by natural killer cells. Han et al. (adma.202209778) provide a comprehensive review of the design principles of bioresponsive immunotherapeutic materials that can release immunoactive agents in a controllable manner to recruit, house, and manipulate immune cells. These immunomaterials can respond to pH, temperature, redox species, ATP, enzymes, hypoxia, and platelets by releasing various types of immunoactive agents to regulate the properties and functions of dendritic cells, T cells, neutrophils, macrophages, and B cells. Further, Bo et al. (adma.202210452) discuss how immunomaterials have enabled one to skip the time-consuming and costly process of identifying tumor-specific antigens, by facilitating the generation of antigens from tumor cells in situ and making the best use of the in situ generated antigens to provoke potent effector T cell response. A step further to their accumulating understanding of immune responses associated with regenerative biomaterials, Han et al. (adma.202310476) now find that the signatures of inflammation and interleukin-17 signaling (sign of type-3 immune activation) increase with injury and treatment both locally and regionally in aged animals. Their results indicate that age-associated senescent-T cell communication promotes type-3 immunity in T cells, and local administration of IL17-neutralizing antibodies results in improved healing and muscle repair in older animals.

Materials for Tissue Repair and Regeneration

Wound healing and tissue regeneration are complex, multi-step, processes that involve signaling activities between cell populations and their surrounding environment that vary in space and time. Biomaterials are often utilized to provide a physical space in which these processes can be engineered while providing and organizing key signals to interacting cells to enhance therapeutic outcomes. The chemistry of these materials, along with their physical properties, can be crucial both to the biological outcome, and to the practicality of strategies to promote healing and regeneration.

In this special issue, a number of papers demonstrate the potency of appropriately designed biomaterials in orchestrating biological processes to promote desirable outcomes. From the perspective of materials chemistry, Latif et al. (adma.202208364) have screened 315 polymer surfaces for those that regulate fibroblast function, as these connective tissue cells are key players in the wound healing process. They identified chemistries that promoted regeneration-relevant cell processes, and subsequently fabricated the promising chemistries into microparticles that enable ready application to diabetic skin wounds. Pro-regenerative chemistries identified in the screen were demonstrated to enhance wound closure with a single application, indicating exciting potential for the treatment of chronic wounds. Mammalian cells utilize specific cell-surface receptors to bind and interact with the surfaces of materials, and many of the ligands for these receptors have been identified and can be incorporated into materials to provide highly specific regulation over cell engagement and function. Here, Rijns et al. (adma.202300873), exploit hydrogels fabricated from dynamic supramolecular fibers to decouple the impact of the ligand density from local gel mechanical properties on the ability of epithelial cells to orient appropriately. Epithelial cell orientation, or polarity, is key to formation of organoids and cysts, which are widely used as models of development and disease, and increasingly to serve as a test-bed for therapy testing. Their findings demonstrate an interplay between gel mechanics and ligand presentation in controlling appropriately polarized epithelial cysts. In addition to their utility in cell culture models of tissue, transplantation of cells into patients is an increasingly approach to therapy in many disease settings. While biomaterials are often utilized as vehicles for cell therapy, recent efforts have demonstrated that the cells themselves can be used as a delivery vehicle for materials into the body – these biomaterials may be used to control the behavior of the transplanted cells, and/or engage with host cells with which the transferred cells interface. Adebowale et al. (adma.202210059) provide a review of recently developed strategies to decorate the surfaces of various cell types with polymer coatings or particles at varying size scales (nm to micron). Studies to date have demonstrated that this strategy can enhance the function of the cell carrying the material, be utilized to deliver particles to specific anatomic sites and cell types in the body, and provide novel drug delivery strategies. Cardiovascular disease, particularly heart failure, impacts many patients, and the development of biomaterials that can enhance tissue repair and regeneration has been an active area of research for decades. However, delivery of the materials without inducing additional tissue damage can be a challenge, and Chen et al. (adma.202300603) provide an overview of recent approaches to develop materials that can be delivered to the heart via the bloodstream – minimizing the invasiveness of the delivery procedure and allowing rapid treatment. Important aspects in the design of these materials include enhancing their localization to the heart, and making them responsive to local environmental conditions.

Dynamic Materials

The integration of materials into the human body has shaped medicine in general. In the past decades, researchers have acknowledged the importance of this integration by mimicking biological materials in all aspects, e.g., from their mechanical properties to how they present bioactive signals to cells, and by designing interactive materials that react on biological stimuli. In nature, tissues are formed by complex, intricate molecular compositions held together by both covalent and directed non-covalent interactions. These molecular interactions give tissues their dynamic behavior. Building these dynamics into biomaterials, as well as introducing interactivity, are emerging approaches to make materials for biomedical applications such as regenerative medicine, tissue engineering, and cell therapy.

Ma et al. (adma.202306358) describe the importance of the design of enzyme-activatable polymers for both diagnosis and therapy. They review how to design and synthesize different polymers and materials that can react to enzymes, and show the perspective of the field to introduce multiple activatable groups, as well as revolutionary ideas for novel design concepts for the future. Furthermore, Nelson et al. (adma.202211209) showed the use of dynamic covalent bonds to make adaptable hydrogels. They applied 1,2-dithiolanes as dynamic covalent photocrosslinkers. In this way hydrogels could be made for multiple photoinduced dynamic processes, such as the tuning of mechanical properties such as stress relaxation and stress stiffening, as well as the introduction of bioactivity through network functionalization. Rijns et al. (adma.202300873) applied supramolecular chemistry to make dynamic supramolecular hydrogels as synthetic extracellular matrices that could be applied to study cyst formation of epithelial cells. Using a modular approach, the ligand concentration steering cell adhesion and concomitant polarization of the cysts could be controlled. They found that the effective ligand concentration is the determining factor in steering epithelial polarity. Fernández-Galiana et al. (adma.202210807) reviewed the use of Raman-based techniques to design and develop biomedical materials. They showed the many aspects of Raman measurements, such as spatial mapping of biomolecular species in bioactive materials and the occurrence of solid-to-solid phase transitions. They also highlight studies that used Raman spectroscopy to characterize both natural and synthetic materials.

中文翻译：

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用于生物医学应用的工程活性材料

我们欢迎您阅读本期题为“用于生物医学应用的工程活性材料”的先进材料特刊。本期特刊侧重于生物医学材料的设计和应用，这些材料在生物和机械环境中具有活性或两者兼而有之。重点介绍了各种尺寸尺度的当前和未来生物医学材料，包括它们的设计和筛选，并发表了一系列文章，描述了从基础到以转化应用为重点的研究。

从历史上看，生物材料被设计为在人体中呈惰性，它们接触的细胞和组织不会引起任何反应。然而，数十年的临床经验和研究表明，植入的生物材料总是会产生一些反应，而身体反应可能导致功能丧失或严重的炎症反应。这种认识将该领域的注意力转移到通过设计生物材料与体内细胞和组织结合的特定机制来调整和控制身体反应，以产生有利的结果并保持植入材料的功能。这种方法取得了许多成功，但从这个角度设计的初始生物材料往往是被动的，具有预先设计的特性和功能，并且从生物或物理角度来看，几乎没有动态接口或响应身体的能力。相比之下，许多研究人员目前正在设计活性生物材料，这些材料以特定方式直接与身体接触，并随着时间的推移积极指导生物过程。在本期特刊中，我们重点介绍了目前正在探索这一概念的四个领域——机械活性生物材料、主动指导宿主免疫反应的材料（免疫材料）、旨在促进组织修复和再生的材料以及动态材料。以下各节将简要回顾这些子主题中的每一个。

机械活性材料

机械活性材料的生物医学应用包括“感知和响应”功能、肌肉辅助、受控药物输送、生理参数的长期监测以及用于细胞培养的增强型体外测试台。Nie 等人 （adma.202205609） 对使用此类材料进行生物接口传感器进行连续监测进行了综述。例如，用于测量皮肤界面、心脏表面和体内过程压力的传感器。它们描述了高灵敏度、稳定和宽动态范围材料的未来应用，以及用于降噪和机械负载解耦类型的系统。这些机械活性材料的改性可能在软机器人和人机界面中得到应用。Pirozzi 等人 （adma.202210713） 回顾了另一类机械活性材料 — 人造肌肉 — 具有心脏辅助的特定用例。除了这种方法相对于目前可用的机械循环支持设备的主要优势外，还全面概述了此应用的设计要求，特别是能够在不接触血液的情况下提供脉动支持。他们回顾了用于此应用的气动、磁性、介电弹性体和电液致动器，并对比了每种治疗心力衰竭的方法的优势和挑战。Roy 等人 （adma.202300017） 描述了一种双层水凝胶折叠系统，该系统可以产生折叠图案，类似于上呼吸道上皮中的粘膜组织。水凝胶由海藻酸盐和聚丙烯酰胺的双网络组成。 细胞可以封装到图案化的水凝胶中，并通过掺入磁性微粒来实现可编程的按需折叠，以提供动态培养系统来研究折叠模式对细胞功能的影响。最后，机械活性材料可以植入体内并按需提供治疗。Mendez 等人 （adma.202303301） 描述了一种混合水凝胶致动器，它可以通过气动致动从水凝胶层中引发药物的可调机械响应性释放。剂量可以通过启动的幅度、频率和持续时间来控制。该设备可以用柔性粘合剂粘附在组织上，将来可以与机械辅助技术相结合，以达到机械治疗效果。

 免疫材料

在过去的二十年里，见证了用于协调免疫细胞和免疫系统的新材料系统的飞速发展，有利于治疗癌症、自身免疫性疾病、炎症性疾病和组织损伤等疾病。这些免疫材料可以提供物理化学和机械线索来控制免疫细胞的激活状态和表型，以时空可控的方式释放免疫调节剂，并在原位主动吸引和调节免疫细胞。

在本期特刊中，Park 等人 （adma.202311505） 报道了肿瘤细胞利用细胞外基质中胶原蛋白的矿化来逃避自然杀伤细胞攻击的能力。通过将具有受控矿物质含量的合成骨基质模型、纳米级光学成像和肿瘤细胞聚糖模式的选择性操作相结合，他们证明胶原蛋白矿化上调了肿瘤细胞的粘蛋白型 O-糖基化和唾液酸化，从而增加了它们的糖萼厚度，同时增强了对自然杀伤细胞攻击的抵抗力。Han 等人 （adma.202209778） 全面回顾了生物响应性免疫治疗材料的设计原理，这些材料可以以可控的方式释放免疫活性剂来募集、容纳和操纵免疫细胞。这些免疫材料可以通过释放各种类型的免疫活性剂来调节树突状细胞、T 细胞、中性粒细胞、巨噬细胞和 B 细胞的性质和功能，从而对 pH 值、温度、氧化还原物质、ATP、酶、缺氧和血小板做出反应。此外，Bo 等人 （adma.202210452） 讨论了免疫材料如何通过促进原位肿瘤细胞产生抗原并充分利用原位产生的抗原来激发有效的效应 T 细胞反应，从而使人们能够跳过耗时且昂贵的鉴定肿瘤特异性抗原的过程。Han 等人 （adma.202310476） 进一步积累了对与再生生物材料相关的免疫反应的理解，现在发现炎症和白细胞介素 17 信号传导（3 型免疫激活的标志）的特征在老年动物中随着局部和局部的损伤和治疗而增加。 他们的结果表明，与年龄相关的衰老 T 细胞通讯可促进 T 细胞中的 3 型免疫，并且局部施用 IL17 中和抗体可改善老年动物的愈合和肌肉修复。

组织修复和再生材料

伤口愈合和组织再生是复杂的多步骤过程，涉及细胞群与其周围环境之间的信号活动，这些活动在空间和时间上各不相同。生物材料通常用于提供一个物理空间，在该空间中可以设计这些过程，同时为相互作用的细胞提供和组织关键信号以增强治疗效果。这些材料的化学性质及其物理特性对生物结果以及促进愈合和再生的策略的实用性都至关重要。

在本期特刊中，许多论文展示了适当设计的生物材料在协调生物过程以促进理想结果方面的潜力。从材料化学的角度来看，Latif 等人 （adma.202208364） 已经筛选了 315 种聚合物表面，用于调节成纤维细胞功能的聚合物表面，因为这些结缔组织细胞是伤口愈合过程中的关键参与者。他们确定了促进再生相关细胞过程的化学物质，随后将有前途的化学物质制成微粒，以便随时应用于糖尿病皮肤伤口。筛选中鉴定的促再生化学成分被证明可以通过单次应用增强伤口闭合，这表明治疗慢性伤口具有令人兴奋的潜力。哺乳动物细胞利用特定的细胞表面受体结合材料表面并与之相互作用，这些受体的许多配体已被鉴定出来，并且可以掺入材料中，以提供对细胞参与和功能的高度特异性调节。在这里，Rijns 等人 （adma.202300873） 利用由动态超分子纤维制成的水凝胶来解耦配体密度与局部凝胶机械特性对上皮细胞适当定向能力的影响。上皮细胞取向或极性是类器官和囊肿形成的关键，类器官和囊肿被广泛用作发育和疾病的模型，并越来越多地用作治疗测试的试验台。他们的研究结果表明，凝胶力学和配体呈递在控制适当极化的上皮囊肿方面存在相互作用。 除了在组织细胞培养模型中的实用性外，在许多疾病环境中，将细胞移植到患者体内也是一种越来越重要的治疗方法。虽然生物材料通常被用作细胞治疗的载体，但最近的研究表明，细胞本身可以用作材料进入体内的输送载体——这些生物材料可用于控制移植细胞的行为，和/或与转移细胞接触的宿主细胞结合。Adebowale 等人 （adma.202210059） 回顾了最近开发的策略，这些策略用不同尺寸尺度（nm 到微米）的聚合物涂层或颗粒装饰各种细胞类型的表面。迄今为止的研究表明，这种策略可以增强携带材料的细胞的功能，用于将颗粒输送到体内的特定解剖部位和细胞类型，并提供新的药物输送策略。心血管疾病，尤其是心力衰竭，影响着许多患者，几十年来，开发可以增强组织修复和再生的生物材料一直是一个活跃的研究领域。然而，在不诱导额外组织损伤的情况下输送材料可能是一个挑战，Chen 等人 （adma.202300603） 概述了开发可通过血流输送到心脏的材料的最新方法——最大限度地减少输送过程的侵入性并允许快速治疗。这些材料设计的重要方面包括增强它们对心脏的定位，并使它们对当地环境条件做出反应。

 动态材质

材料与人体的整合总体上塑造了医学。在过去的几十年里，研究人员通过在各个方面模仿生物材料，例如从它们的机械特性到它们如何向细胞传递生物活性信号，以及通过设计对生物刺激做出反应的交互式材料，已经认识到这种集成的重要性。在自然界中，组织是由复杂、错综复杂的分子组成形成的，这些分子组成通过共价和定向非共价相互作用结合在一起。这些分子相互作用赋予组织动态行为。将这些动态构建到生物材料中，并引入交互性，是为再生医学、组织工程和细胞疗法等生物医学应用制造材料的新兴方法。

马 et al. （adma.202306358） 描述了酶活化聚合物设计对诊断和治疗的重要性。他们回顾了如何设计和合成可以与酶反应的不同聚合物和材料，并展示了该领域的视角，介绍了多个可激活的基团，以及未来新颖设计概念的革命性想法。此外，Nelson 等人 （adma.202211209） 展示了使用动态共价键来制造适应性强的水凝胶。他们应用 1,2-二硫环作为动态共价光交联剂。通过这种方式，可以制造水凝胶用于多种光诱导动力学过程，例如调整应力松弛和应力硬化等机械性能，以及通过网络功能化引入生物活性。Rijns 等人 （adma.202300873） 应用超分子化学制造动态超分子水凝胶作为合成的细胞外基质，可用于研究上皮细胞的囊肿形成。使用模块化方法，可以控制配体浓度、引导细胞粘附和伴随的囊肿极化。他们发现，有效配体浓度是控制上皮极性的决定因素。Fernández-Galiana 等人 （adma.202210807） 回顾了使用基于拉曼的技术来设计和开发生物医学材料。他们展示了拉曼测量的许多方面，例如生物活性材料中生物分子种类的空间映射以及固到固相变的发生。他们还重点介绍了使用拉曼光谱来表征天然和合成材料的研究。