This commentary describes an innovative air-liquid interface (ALI) duodenal organoid system for studying celiac disease (CeD). Derived from patient biopsies, this model uniquely preserves the native tissue microenvironment, including epithelial, stromal, and diverse tissue-resident immune cells, overcoming the limitations of conventional cultures and animal models. When stimulated with gluten peptides, the organoids replicate key pathological features of CeD, such as epithelial cell death mediated by cytotoxic T cells. Research has identified interleukin-7 (IL-7), secreted by mesenchymal cells, as a critical and previously underappreciated mediator of this gluten-induced autoimmune attack. This discovery highlights IL-7 as a promising therapeutic target and establishes the ALI organoid platform as a powerful tool for investigating complex epithelial-immune interactions in other autoimmune and infectious diseases, drug screening, and personalized medicine.

Colorectal cancer (CRC) is one of the most prevalent malignancies globally, characterized by high incidence and mortality rates. Its marked heterogeneity and complex tumor microenvironment (TME) pose considerable challenges to traditional preclinical models. Patient-derived organoids (PDOs) have emerged as pivotal tools for elucidating disease mechanisms, enabling personalized drug screening, and advancing precision medicine, as they faithfully preserve the histological structure, molecular features, and genetic heterogeneity of primary tumors in vitro. However, conventional matrix gel-based culture systems suffer from inherent limitations, including ill-defined composition, significant batch-to-batch variation, and a lack of precise control over mechanical properties, which impede their ability to faithfully recapitulate dynamic intercellular crosstalk and spatiotemporal TME heterogeneity. Recent advances in biomaterials and tissue engineering have provided new opportunities to innovate organoid technologies. This review systematically summarizes the establishment strategies, major applications, and core challenges of CRC organoids, highlighting the potential of modular and programmable biomaterials, particularly hydrogel microspheres, for developing novel construction systems. We propose that hydrogel microspheres, with well-defined chemical composition, tunable mechanical properties, and function as basic building blocks, can be integrated with modular or controllable assembly strategies to construct next-generation CRC organoid models with enhanced biomimetic properties, greater structural complexity, and improved reproducibility. In summary, this review outlines core challenges and future directions, emphasizing that deep integration of engineered culture systems with organoid technology is a critical approach to advancing CRC research toward improved biomimetic recapitulation and greater clinical translational relevance.

Alopecia is globally recognized as a formidable therapeutic challenge, impacting both physiological health and psychological well-being. The crux of effective treatment lies in achieving de novo hair follicle neogenesis, a process that transcends merely stimulating existing follicles. Research into hair follicle organoids (HFOs) is advancing rapidly, transitioning from rudimentary self-assembly models toward high-fidelity, clinical application-driven paradigms. To provide a rigorous synthesis of the current landscape, this review conducted a systematic literature search across the Web of Science, PubMed, and Google Scholar databases. The search strategy utilized combinations of key terms, including “hair follicle organoid,” “alopecia,” “hydrogel,” and “3D bioprinting,” spanning the last 15 years. We comprehensively summarized the design principles and recent breakthroughs in HFO technology. First, the biological foundations of hair follicle development and the specific requirements of its inductive microenvironment were elucidated. Subsequently, we highlighted design strategies for functionalized hydrogels to simulate the hair follicle niche. This included a detailed discussion on modulating physicochemical properties and integrating advanced manufacturing technologies, such as three-dimensional bioprinting. Finally, the potential of HFOs in high-throughput drug screening and complex wound repair was assessed. By serving as a robust, human-relevant in vitro model, HFOs can significantly reduce reliance on animal testing and accelerate the discovery of hair-growth-promoting compounds. By providing both theoretical frameworks and technical insights, this review aims to support the development of high-performance hair follicle regeneration platforms and accelerate their transition from laboratory research to clinical translation.

Skin organoids offer a powerful in vitro platform for modeling human skin physiology, disease mechanisms, and regenerative processes. However, faithfully recapitulating the multilayered architecture of skin, diverse appendages, and integrated vascular- neural networks remains a major challenge. As key extracellular matrix mimetics, hydrogels have emerged as central enablers in advancing skin organoid engineering by complementing passive self-organization with programmable biofabrication strategies. This review summarizes recent progress in hydrogel-assisted skin organoid engineering, highlighting how these systems enable the reconstruction of layered skin architectures, support the morphogenesis of skin appendages, and facilitate the integration of vascular and neural components, thereby progressively improving the structural and functional fidelity of skin organoids. These developments position hydrogel-based platforms as essential tools for advancing next-generation skin organoid models. By enabling more precise control over the microenvironment and tissue organization, hydrogel-assisted strategies are expected to accelerate the development of physiologically relevant skin organoids and expand their applications in regenerative medicine, drug discovery, and the study of complex skin disorders.

Treating critical-sized bone defects is challenging because successful repair relies on proper tissue transitions and timely vascular access, rather than on a single cell fate. Creating fully mature, defect-scale bone grafts in vitro remains constrained by scale, mass transport, and reproducibility, motivating strategies that deliver a programmed starting state and rely on in vivo progression. Organoid systems offer a useful paradigm in this context, as self-organizing microtissues can mimic developmental processes and produce consistent intermediate states. In this developmental engineering framework, callus organoids are cartilage-primed microtissues designed to follow an endochondral callus-to-bone path after implantation. This review synthesizes the mechanisms by which callus organoids are programmed to transition from chondrogenesis to hypertrophy, vascular invasion, ossification, and remodeling. It compares callus organoids to bone organoids and traditional scaffold-based bone tissue engineering, focusing on trajectory control, phase transitions, and timed integration with host transport and vascular systems. Key design variables include the endochondral potential of initial cells, the sequencing of biochemical and mechanical signals, and the timing of maturation and implantation to maintain vascular readiness. The review also discusses bioassembly and biofabrication in relation to diffusion limits and process-compatible potency assessment and quality attributes. Finally, donor variability, mass-transport limitations, incomplete multicellular complexity, and manufacturing standardization are key challenges driving priorities in perfusion and vascularization, architecture-informed fabrication, staged integration of vascular and immune components, and the development of extracellular matrix-based callus-mimetic templates. Overall, the emphasis shifts from building mature bone in vitro to manufacturing standardized callus-like building blocks whose potency is defined by their ability to execute orderly endochondral progression after implantation.

Intervertebral disc degeneration is a complex pathological process driven by multiple factors, involving cellular pathological changes, an imbalance in the inflammatory microenvironment, and oxidative stress mechanisms, and significantly impacts patients’ quality of life. Current treatments lack therapeutic strategies targeting tissue regeneration and repair. With excellent biocompatibility, injectability, tunable mechanical properties, and smart responsive capabilities, hydrogel microspheres serve as ideal carriers for drug, gene, and cell therapies in intervertebral disc degeneration. This paper systematically reviews the preparation techniques and properties of hydrogel microspheres, focusing on their key mechanisms and advantages in gene delivery, drug delivery, and cell-scaffold applications. Subsequently, it summarizes cutting-edge advances in the construction of disc organoids, highlighting the advantages of hydrogel microspheres in mimicking extracellular matrices, constructing 3D biomimetic microenvironments, supporting cell proliferation and differentiation, and recapitulating degenerative microenvironments, thus providing a new platform for disease modeling and personalized therapy. Finally, future directions for hydrogel microsphere-based therapies for disc degeneration are envisioned, including multimodal smart-response design, personalized manufacturing, integrated organoid applications, and non-invasive, precise delivery technologies. This review aims to advance the management of disc degeneration from symptom relief toward functional restoration, thereby promoting clinical translation and the development of precision regenerative medicine.

Repairing critical-sized bone defects remains challenging, and many synthetic fillers trade mechanical stability against bioactivity. In this study, a novel bone tissue-filling material was designed and synthesized. Based on a previously described trabeculae-like biomimetic bone-filling material (TBM), mammoth tusk dentin was incorporated into this material, which endowed it with enhanced mechanical properties. We designated this material as fortified TBM (FTBM). FTBM demonstrated favorable mechanical strength, biocompatibility, and sustained drug-release capacity, thereby improving osteogenesis. In addition, human mesenchymal stem cells were encapsulated within the scaffold, resulting in a cell-laden biomaterial. Its efficacy in repairing bone defects was superior to the original TBM. This high-hardness bone-filling material offers a strategy to enhance the mechanical stability of trabeculae-like fillers, warranting evaluation in load-bearing models.

Liver-bone crosstalk is increasingly recognized as an important regulatory axis in aging-associated diseases, such as metabolic liver disease and osteoporosis. However, conventional two-dimensional co-culture systems and animal models do not adequately capture the multicellular architecture, extracellular matrix context, and bidirectional secretory communication that underlie interorgan senescence propagation. Here, we describe a protocol for constructing a senescent liver- bone organoid platform by integrating a bone matrix-inspired three-dimensional (3D) bioprinted bone organoid system with a mouse duct-derived liver organoid culture system, followed by engineered senescence induction and conditioned-medium exchange. In this protocol, bone marrow-derived mesenchymal stem cells are incorporated into a gelatin/alginate/hydroxyapatite hybrid bioink and printed into porous 3D constructs, whereas liver ductal structures are embedded in Matrigel and expanded into liver organoids before directed differentiation. Senescence is induced in both organoid types using doxorubicin, and systemic aging-related signals are modeled by treating organoids with serum from older mice. Bidirectional communication is then interrogated through reciprocal conditioned-medium transfer assays. This platform enables investigation of interorgan senescence propagation, liver-bone axis dysfunction, and candidate mediators such as 27-hydroxycholesterol in a physiologically relevant 3D setting.