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Skin injuries pose significant health challenges, with conditions like burns and diabetic, venous, and pressure ulcers presenting complex wound management scenarios. Effective wound care strategies for these injuries encompass a range of interventions, from simple wound dressings to bioactive materials and surgical procedures involving skin substitutes and skin grafting. This review explores the potential of natural polymers, including silk, collagen, gelatin, elastin, cellulose, chitosan, alginate, and hyaluronic acid, in wound management. Natural polymers offer several advantages, including abundance, biodegradability, and compatibility with traditional and modern material fabrication techniques, and have demonstrated safety and efficacy in clinical applications, modulating various facets of the wound healing process. Highlighting preclinical and clinical studies, along with commercial products, this review showcases the versatility and utility of natural polymers in wound management and provides insights into emerging developments, such as 3D bioprinting and stimuli‐responsive materials, which hold promise for personalized wound treatments. Additionally, we discuss the importance of the material format and morphology in engineering the next generation of wound dressings and skin substitutes, offering a pathway to optimize natural polymers for enhanced wound healing outcomes.

Extracellular matrix (ECM) stiffening is a common occurrence during the progression of many diseases, such as breast cancer. To accurately mimic the pathophysiological context of disease within 3D in vitro models, there is high demand for smart biomaterials which replicate the dynamic and temporal mechanical cues of diseased states. This study describes a preclinical disease model, using breast cancer as an example, which replicates the dynamic plasticity of the tumour microenvironment by incorporating temporal (3-week progression) biomechanical cues within a tissue-specific hydrogel microenvironment. The composite hydrogel formulation, integrating adipose-derived decellularised ECM (AdECM) and silk fibroin, was initially crosslinked using a visible light-mediated system, and then progressively stiffened through spontaneous secondary structure interactions inherent between the polymer chains (∼10–15 kPa increase, with a final stiffness of 25 kPa). When encapsulated and cultured in vitro, MCF-7 breast cancer cells initially formed numerous, large spheroids (>1000 μm2 in area), however, with progressive temporal stiffening, cells demonstrated growth arrest and underwent phenotypic changes resulting in intratumoral heterogeneity. Unlike widely-investigated static mechanical models, this stiffening hydrogel allowed for progressive phenotypic changes to be observed, and fostered the development of mature organoid-like spheroids, which mimicked both the organisation and acinar-structures of mature breast epithelium. The spheroids contained a central population of cells which expressed aggressive cellular programs, evidenced by increased fibronectin expression and reduction of E-cadherin. The phenotypic heterogeneity observed using this model is more reflective of physiological tumours, demonstrating the importance of establishing temporal cues within preclinical models in future work. Overall, the developed model demonstrated a novel strategy to uncouple ECM biomechanical properties from the cellular complexities of the disease microenvironment and offers the potential for wide applicability in other 3D in vitro disease models through addition of tissue-specific dECM materials.

The use of tissue adhesives dates to 1940s when surgical glues were introduced for wound closure applications. However, current clinically used tissue adhesives (fibrin and cyanoacrylate glues) have limited adhesion strength and biocompatibility issues which restrict their performance in targeted applications. Due to this unmet clinical challenge, there is a need to develop next‐generation tissue adhesives to expand the current limited available options. Another factor that is often overlooked in the field is the consequence of when these tissue adhesives fail while in use in specific applications. In this review, the complications arising from tissue adhesives that have insufficient adhesion strength are covered, where unintentional loosening and detachment can lead to serious complications depending on both the applications and scenarios in which the adhesives are used. Next, the current methodologies employed to design tissue‐adhesive hydrogels targeting specific applications are also collated. Finally, the different strategies to engineer on‐demand removal property of these tissue‐adhesive hydrogels are consolidated, including some perspectives on current challenges and outlooks in this field.

Abstract With the gradual demographic shift toward an aging and obese society, an increasing number of patients are suffering from bone and cartilage injuries. However, conventional therapies are hindered by the defects of materials, failing to adequately stimulate the necessary cellular response to promote sufficient cartilage regeneration, bone remodeling and osseointegration. In recent years, the rapid development of nanomedicine has initiated a revolution in orthopedics, especially in tissue engineering and regenerative medicine, due to their capacity to effectively stimulate cellular responses on a nanoscale with enhanced drug loading efficiency, targeted capability, increased mechanical properties and improved uptake rate, resulting in an improved therapeutic effect. Therefore, a comprehensive review of advancements in nanomedicine for bone and cartilage diseases is timely and beneficial. This review firstly summarized the wide range of existing nanotechnology applications in the medical field. The progressive development of nano delivery systems in nanomedicine, including nanoparticles and biomimetic techniques, which are lacking in the current literature, is further described. More importantly, we also highlighted the research advancements of nanomedicine in bone and cartilage repair using the latest preclinical and clinical examples, and further discussed the research directions of nano-therapies in future clinical practice. Graphical Abstract

Abstract The paracrine signaling, immunogenic properties and possible applications of mesenchymal stromal cells (MSCs) for cartilage tissue engineering and regenerative medicine therapies have been investigated through numerous in vitro, animal model and clinical studies. The emerging knowledge largely supports the concept of MSCs as signaling and modulatory cells, exerting their influence through trophic and immune mediation rather than as a cell replacement therapy. The virtues of allogeneic cells as a ready‐to‐use product with well‐defined characteristics of cell surface marker expression, proliferative ability, and differentiation capacity are well established. With clinical applications in mind, a greater focus on allogeneic cell sources is evident, and this review summarizes the latest published and upcoming clinical trials focused on cartilage regeneration adopting allogeneic and autologous cell sources. Moreover, we review the current understanding of immune modulatory mechanisms and the role of trophic factors in articular chondrocyte‐MSC interactions that offer feasible targets for evaluating MSC activity in vivo within the intra‐articular environment. Furthermore, bringing labeling and tracking techniques to the clinical setting, while inherently challenging, will be extremely informative as clinicians and researchers seek to bolster the case for the safety and efficacy of allogeneic MSCs. We therefore review multiple promising approaches for cell tracking and labeling, including both chimerism studies and imaging‐based techniques, that have been widely explored in vitro and in animal models. Understanding the distribution and persistence of transplanted MSCs is necessary to fully realize their potential in cartilage regeneration techniques and tissue engineering applications.

Cell cultures of dispersed cells within hydrogels depict the interaction of the cell–extracellular matrix (ECM) in 3D, while the coculture of different cells within spheroids combines both the effects of cell–cell and cell–ECM interactions. In this study, the cell co-spheroids of human bone mesenchymal stem cells/human umbilical vein endothelial cells (HBMSC/HUVECs) are prepared with the assistance of a nanopattern, named colloidal self-assembled patterns (cSAPs), which is superior to low-adhesion surfaces. A phenol-modified gelatin/hyaluronan (Gel-Ph/HA-Ph) hydrogel is used to encapsulate the multicellular spheroids and the constructs are photo-crosslinked using blue light. The results show that Gel-Ph/HA-Ph hydrogels with a 5%-to-0.3% ratio have the best properties. Cells in HBMSC/HUVEC co-spheroids are more favorable for osteogenic differentiation (Runx2, ALP, Col1a1 and OPN) and vascular network formation (CD31+ cells) compared to HBMSC spheroids. In a subcutaneous nude mouse model, the HBMSC/HUVEC co-spheroids showed better performance than HBMSC spheroids in angiogenesis and the development of blood vessels. Overall, this study paves a new way for using nanopatterns, cell coculturing and hydrogel technology for the generation and application of multicellular spheroids.

Abstract While decades of research have enriched the knowledge of how to grow cells into mature tissues, little is yet known about the next phase: fusing of these engineered tissues into larger functional structures. The specific effect of multicellular interfaces on tissue fusion remains largely unexplored. Here, a facile 3D‐bioassembly platform is introduced to primarily study fusion of cartilage–cartilage interfaces using spheroids formed from human mesenchymal stromal cells (hMSCs) and articular chondrocytes (hACs). 3D‐bioassembly of two adjacent hMSCs spheroids displays coordinated migration and noteworthy matrix deposition while the interface between two hAC tissues lacks both cells and type‐II collagen. Cocultures contribute to increased phenotypic stability in the fusion region while close initial contact between hMSCs and hACs (mixed) yields superior hyaline differentiation over more distant, indirect cocultures. This reduced ability of potent hMSCs to fuse with mature hAC tissue further underlines the major clinical challenge that is integration. Together, this data offer the first proof of an in vitro 3D‐model to reliably study lateral fusion mechanisms between multicellular spheroids and mature cartilage tissues. Ultimately, this high‐throughput 3D‐bioassembly model provides a bridge between understanding cellular differentiation and tissue fusion and offers the potential to probe fundamental biological mechanisms that underpin organogenesis.

Biofabrication via light-based 3D printing offers superior resolution and ability to generate free-form architectures, compared to conventional extrusion technologies. While extensive efforts in the design of new hydrogel bioinks lead to major advances in extrusion methods, the accessibility of lithographic bioprinting is still hampered by a limited choice of cell-friendly resins. Herein, we report the development of a novel set of photoresponsive bioresins derived from ichthyic-origin gelatin, designed to print high-resolution hydrogel constructs with embedded convoluted networks of vessel-mimetic channels. Unlike mammalian gelatins, these materials display thermal stability as pre-hydrogel solutions at room temperature, ideal for bioprinting on any easily-accessible lithographic printer. Norbornene- and methacryloyl-modification of the gelatin backbone, combined with a ruthenium-based visible light photoinitiator and new coccine as a cytocompatible photoabsorber, allowed to print structures resolving single-pixel features (∼50 ​μm) with high shape fidelity, even when using low stiffness gels, ideal for cell encapsulation (1–2 ​kPa). Moreover, aqueous two-phase emulsion bioresins allowed to modulate the permeability of the printed hydrogel bulk. Bioprinted mesenchymal stromal cells displayed high functionality over a month of culture, and underwent multi-lineage differentiation while colonizing the bioresin bulk with tissue-specific neo-deposited extracellular matrix. Importantly, printed hydrogels embedding complex channels with perfusable lumen (diameter

Epigenetic approaches using the histone deacetylase 2 and 3 inhibitor-MI192 have been reported to accelerate stem cells to form mineralised tissues. Gelatine methacryloyl (GelMA) hydrogels provide a favourable microenvironment to facilitate cell delivery and support tissue formation. However, their application for bone repair is limited due to their low mechanical strength. This study aimed to investigate a GelMA hydrogel reinforced with a 3D printed scaffold to support MI192-induced human bone marrow stromal cells (hBMSCs) for bone formation. Cell culture: The GelMA (5 wt%) hydrogel supported the proliferation of MI192-pre-treated hBMSCs. MI192-pre-treated hBMSCs within the GelMA in osteogenic culture significantly increased alkaline phosphatase activity (p ≤ 0.001) compared to control. Histology: The MI192-pre-treated group enhanced osteoblast-related extracellular matrix deposition and mineralisation (p ≤ 0.001) compared to control. Mechanical testing: GelMA hydrogels reinforced with 3D printed poly(ethylene glycol)-terephthalate/poly(butylene terephthalate) (PEGT/PBT) scaffolds exhibited a 1000-fold increase in the compressive modulus compared to the GelMA alone. MI192-pre-treated hBMSCs within the GelMA–PEGT/PBT constructs significantly enhanced extracellular matrix collagen production and mineralisation compared to control (p ≤ 0.001). These findings demonstrate that the GelMA–PEGT/PBT construct provides enhanced mechanical strength and facilitates the delivery of epigenetically-activated MSCs for bone augmentation strategies.

Abstract Visible light‐mediated cross‐linking has utility for enhancing the structural capacity and shape fidelity of laboratory‐based polymers. With increased light penetration and cross‐linking speed, there is opportunity to extend future applications into clinical spheres. This study evaluated the utility of a ruthenium/sodium persulfate photocross‐linking system for increasing structural control in heterogeneous living tissues as an example, focusing on unmodified patient‐derived lipoaspirate for soft tissue reconstruction. Freshly‐isolated tissue is photocross‐linked, then the molar abundance of dityrosine bonds is measured using liquid chromatography tandem mass spectrometry and the resulting structural integrity assessed. The cell function and tissue survival of photocross‐linked grafts is evaluated ex vivo and in vivo, with tissue integration and vascularization assessed using histology and microcomputed tomography. The photocross‐linking strategy is tailorable, allowing progressive increases in the structural fidelity of lipoaspirate, as measured by a stepwise reduction in fiber diameter, increased graft porosity and reduced variation in graft resorption. There is an increase in dityrosine bond formation with increasing photoinitiator concentration, and tissue homeostasis is achieved ex vivo, with vascular cell infiltration and vessel formation in vivo. These data demonstrate the capability and applicability of photocrosslinking strategies for improving structural control in clinically‐relevant settings, potentially achieving more desirable patient outcomes using minimal manipulation in surgical procedures.