Organoids represent miniaturized in vitro models of native tissues and organs that have become enormously popular in modern life science research and promise exciting advances in basic science, drug development, personalized medicine, and cell therapy. However, despite an increasing variety of protocols for deriving organoids from different cell types, many approaches lack robustness and physiological relevance, resulting in organoids of highly variable morphology, size, cell‐type composition, and function. These limitations complicate the seamless implementation of organoid technology in many real‐world applications.

A major challenge in organoid culture is the complete dependence of organoid “development” on stem cell or mature cell self‐organization, the process by which initially homogeneous cell populations spontaneously break symmetry and undergo in vivo‐like pattern formation and morphogenesis. This self‐assembly process is responsible for the impressive functionality level that can be achieved with organoid culture compared to more conventional cell culture approaches. At the same time, complete dependence on self‐organization is its main weakness: the innate developmental programs that drive organoid formation are largely stochastic, resulting in high phenotypic noise, as well as the absence of specific architectural and functional features. A significant challenge is further imposed by the pathological transformation of tissues into cancer, rewriting the microenvironment structure, and impacting its components.

By providing an optimal permissive environment and by adding critical missing instructive cues and cellular or structural components, advanced functional materials have the potential to improve organoid culture towards rationally designed multicellular systems with increased robustness and physiological relevance. In this special section, we asked leading experts in the field of biomaterials, microfabrication, organ‐on‐a‐chip technology, and tissue engineering to report on their recent developments in this emerging field and outline their vision for the future.

Sangeeta Bhatia and colleagues report a new method, entitled CAMEO (Controlled Apoptosis in Multicellular tissues for Engineered Organogenesis), which enables the noninvasive triggering of controlled apoptosis in genetically engineered cells (article number 1910442). They used the technique to study stromal cells and primary human hepatocytes in 3D hepatic microtissues. In another study, Christopher Chen and colleagues utilized the CAMEO and engineering‐by‐elimination approach to study fibroblasts’ contributions in the initial and late‐stage morphogenesis of endothelial cells (article number 2003777).

Breaking the conventional barriers of using xenogenic Matrigel in organoids, Kerstin Schneeberger and colleagues report a hydrogel platform based on polyisocyanopeptides and laminin‐111 for human liver organoid cultures (article number 2000893). The organoid platforms have applications in various pre‐clinical and clinical studies, including cell therapy and tissue engineering. Mathias Lutolf and colleagues developed an alternative to Matrigel with low‐defect thiol‐Michael addition hydrogels based on novel building blocks designed toward minimizing structural defects (article number 2000761). These hydrogels overcome previously reported structural defects due to diluted bifunctional components that form polymeric loops, compromising Michael‐addition hydrogels’ biophysical properties.

Three articles in this themed section focus on the role of the tumor microenvironment and their impact on cancer progression and/or response to therapeutics. Claudia Fischbach‐Teschl and colleagues report multicellular breast cancer spheroids embedded in collagen scaffolds to study how obesity‐mediated changes in adipose stromal cells impact cancer cell migration and invasion (article number 1910650). Roger Kamm and colleagues report a 3D vascularized tumor on‐chip to demonstrate that vascular and stromal contributions influence drug delivery and anti‐cancer efficacy of Taxols, currently not captured by simpler models (article number 2002444). A step more advanced, Milica Radisic and colleagues developed 3D vascularized pancreatic adenocarcinoma tissue, micro‐engineered in a tri‐culture system composed of patient‐derived pancreatic organoids, fibroblasts, and the endothelial cells on a perfusable platform, situated in a 96‐well plate. The approach enables understanding of the dynamic, synergistic relationship between the multiple components of the tumor microenvironment. It may further lead to a better understanding of how the multicellular cross talk impacts tumors and drug efficacy (article number 2000545).

Organoids in immunological research are few. This special section also covers the development of primary and secondary lymphoid tissues as organoids. Martin Ehrbar and colleagues report bone marrow organoids using a transglutaminase crosslinked system based on hybrid hydrogels of poly(ethylene glycol) and hyaluronic acid (article number 1910282). The bone marrow organoid maintains, expands, and differentiates human bone marrow‐derived stromal cells and human hematopoietic stem and progenitor cells in vitro. In contrast to the bone marrow niche, Ankur Singh and colleagues developed a synthetic lymphoid organoid that recapitulates selective lymph node aspects and the spleen (article number 2001232). Using single‐cell RNA sequencing of lymph node stromal cells, microenvironment factors in B‐cell follicles are identified and applied to develop biologically inspired ex vivo immune organoids from poly(ethylene glycol) hydrogels with varying endpoint chemistry. These organoids can regulate differentiation and epigenetics of young and aged primary B‐cells in response to bacterial antigens from a clinical isolate of antibiotic‐resistant strains, demonstrating the potential for developing antigen‐specific antibodies against infectious diseases.

Three review articles discuss the development in the field of organotypic and organoid cultures. Carsten Werner and colleagues discuss the advantages and limitations of decellularized and reconstituted biopolymeric matrices and biohybrid and fully synthetic polymer hydrogel systems for organotypic and organoid cultures (article number 2000097). The other two review articles have specific organ system focus. David Schaffer and colleagues discuss and opine on the central nervous system, addressing approaches to overcome roadblocks in constructing advanced organoid models and developing effective stem cell therapy (article number 2002931). They also discuss the regulatory aspects of organoid and cell therapies. On the other hand, Andres Garcia and colleagues focus on discussing the diverse array of biomaterials used to enhance the in vitro and in vivo function and maturation of insulin‐secreting β‐cell organoids (article number 2000134).

Finally, the special section includes a unique approach to overcome the limitations of polydimethylsiloxane (PDMS) microfluidic cultures, which remain the cornerstone for building microphysiological systems. PDMS's structure and hydrophobicity restrict its use with lipophilic molecules, posing hurdles in biological applications. Kevin Healy, Phillip Messersmith, and colleagues report PDMS coating with catechol‐functionalized calix‐4‐arene based macrocyclic polyphenols (article number 2001274). Such coatings show potential for an increase in the hydrophilicity of PDMS and reduced absorption of hydrophobic therapeutics, while preserving high oxygen permeability, cell viability, and function. We expect that such coatings will find tremendous use in the development of microphysiological organotypic and organoid cultures.

We believe that this collection of research articles and reviews serves as a testimony to the enormous promise of organoids and advanced functional materials and as a foundation for understanding the challenges and barriers for making these organotypic cultures a reality. Our sincere hope is that the next generation of bioengineers, material scientists, developmental and cancer biologists, and immunologists will find inspiration from this collection and contribute transformative new ideas to advance this field further.

类器官代表了微型的天然组织和器官的体外模型，这些模型已在现代生命科学研究中广受欢迎，并有望在基础科学，药物开发，个性化药物和细胞疗法方面取得令人振奋的进步。然而，尽管从不同细胞类型获得类器官的协议种类繁多，但许多方法仍缺乏鲁棒性和生理相关性，导致类器官的形态，大小，细胞类型组成和功能高度可变。这些限制使类器官技术在许多实际应用中的无缝实现变得复杂。

类器官培养的主要挑战是类器官“发育”完全依赖于干细胞或成熟细胞的自组织，这一过程使最初的同质细胞群体自发地打破对称性并在体内进行样样形成和形态发生。与更常规的细胞培养方法相比，这种自组装过程可为类器官培养提供令人印象深刻的功能水平。同时，完全依赖自组织是其主要弱点：驱动类器官形成的先天发育程序在很大程度上是随机的，从而导致较高的表型噪声，以及缺乏特定的结构和功能特征。组织从病理学转变成癌症，重写微环境结构并影响其组成部分，进一步带来了重大挑战。

通过提供最佳的允许环境并添加关键的缺少指导性提示和细胞或结构成分，先进的功能材料具有改善类器官培养的潜力，朝着合理设计的多细胞系统发展，具有增强的鲁棒性和生理相关性。在本节中，我们请生物材料，微细加工，芯片上的器官技术和组织工程领域的领先专家汇报他们在该新兴领域的最新发展，并概述他们对未来的愿景。

桑吉塔巴蒂亚及其同事报告的新方法，题为CAMEO（ç ontrolled甲在凋亡的影响中号为ulticellular组织Ë ngineered ö rganogenesis），这使得在无创基因工程细胞凋亡控制（文章编号1910442）的触发。他们使用该技术研究了3D肝微组织中的基质细胞和原代人肝细胞。在另一项研究中，克里斯托弗·陈（Christopher Chen）及其同事利用CAMEO和消除工程学方法研究了成纤维细胞在内皮细胞的初始和晚期形态发生中的作用（货号2003777）。

Kerstin Schneeberger和同事报告说，打破异种基质胶在类器官中使用的常规障碍，他报道了一种基于聚异氰肽和层粘连蛋白111的水凝胶平台，用于人类肝脏类器官培养（文章编号2000893）。类器官平台可用于各种临床前和临床研究，包括细胞疗法和组织工程。Mathias Lutolf及其同事开发了一种低缺陷的硫醇-Michael加成水凝胶替代Matrigel，该凝胶基于旨在减少结构缺陷的新型结构单元（商品编号2000761）。这些水凝胶克服了先前报道的由于稀释的双功能成分形成聚合物环而导致的结构缺陷，从而损害了迈克尔加成水凝胶的生物物理特性。

本主题部分中的三篇文章重点介绍了肿瘤微环境的作用及其对癌症进展和/或对治疗反应的影响。Claudia Fischbach‐Teschl及其同事报道了胶原蛋白支架中嵌入的多细胞乳腺癌球状体，以研究肥胖介导的脂肪基质细胞变化如何影响癌细胞的迁移和侵袭（文献编号1910650）。Roger Kamm及其同事报告了3D血管化肿瘤芯片，以证明血管和基质的作用影响了紫杉醇的药物递送和抗癌功效，目前尚无法通过较简单的模型获得（文章编号2002444）。迈进了一步，Milica Radisic及其同事开发了3D血管化胰腺腺癌组织，该组织在由患者衍生的胰腺类器官组成的三培养系统中进行了微工程处理，成纤维细胞和位于可灌注平台上的内皮细胞，位于96孔板中。该方法能够理解肿瘤微环境的多个组成部分之间的动态，协同关系。它可能进一步导致人们更好地了解多细胞串扰如何影响肿瘤和药物功效（文章编号2000545）。

免疫学研究中的类器官很少。这个特殊的部分还涉及原发性和继发性淋巴组织作为类器官的发育。Martin Ehrbar及其同事报告了一种基于转谷氨酰胺酶交联系统的骨髓类器官，该系统基于聚乙二醇和透明质酸的混合水凝胶（货号1910282）。骨髓类器官在体外可以维持，扩展和分化人骨髓来源的基质细胞以及人造血干细胞和祖细胞。与骨髓生境相反，Ankur Singh及其同事开发了一种合成的类淋巴类器官，该类器官可概括选择性淋巴结方面和脾脏（商品编号2001232）。使用淋巴结间质细胞的单细胞RNA测序，确定了B细胞卵泡中的微环境因子，并将其用于从具有不同终点化学性质的聚乙二醇水凝胶中开发生物启发的离体免疫类器官。这些类器官可以响应来自临床耐药菌菌株的细菌抗原，调节年轻和老年原代B细胞的分化和表观遗传学，证明了开发针对传染病的抗原特异性抗体的潜力。

三篇评论文章讨论了器官型和类器官文化领域的发展。卡斯滕·沃纳（Carsten Werner）及其同事讨论了用于有机型和类器官培养的脱细胞和重组生物聚合物基质以及生物混合和完全合成的聚合物水凝胶系统的优势和局限性（商品编号2000097）。其他两篇评论文章有特定的器官系统重点。David Schaffer及其同事讨论并认为中枢神经系统，解决在构建先进的类器官模型和开发有效的干细胞疗法中克服障碍的方法（文章编号2002931）。他们还讨论了类器官和细胞疗法的监管方面。另一方面，

最后，该特殊部分提供了一种独特的方法来克服聚二甲基硅氧烷（PDMS）微流体培养的局限性，而后者仍然是构建微生理系统的基石。PDMS的结构和疏水性限制了其与亲脂性分子一起使用，在生物学应用中构成障碍。凯文·希利（Kevin Healy），菲利普·梅瑟史密斯（Phillip Messersmith）及其同事报道了以邻苯二酚官能化的杯芳烃-4-芳烃为基的大环多酚的PDMS涂层（货号2001274）。这样的涂层显示出增加PDMS的亲水性和减少疏水性治疗剂的吸收的潜力，同时保留了高的透氧性，细胞活力和功能。我们期望这样的涂层将在微生理器官型和类器官培养的发展中找到巨大的用途。

我们相信，这些研究文章和评论集可证明类器官和先进功能材料的巨大前景，并成为理解使这些有机型文化成为现实的挑战和障碍的基础。我们的真诚希望是，下一代生物工程师，材料科学家，发育和癌症生物学家以及免疫学家将从该系列中寻找灵感，并贡献出创新性的新思想来进一步推动该领域的发展。