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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

Image-guided volumetric bioprinting allows for the adaptive fabrication of complex structures for tissue engineering. Seminal work by Florczak et al. introduces Generative, Adaptive, Context-Aware 3D Printing, a workflow that uses computer vision to automatically generate functional, vascular-like networks that conform to living cells within hydrogels, improving their functionality. Image-guided volumetric bioprinting allows for the adaptive fabrication of complex structures for tissue engineering. Seminal work by Florczak et al. introduces Generative, Adaptive, Context-Aware 3D Printing, a workflow that uses computer vision to automatically generate functional, vascular-like networks that conform to living cells within hydrogels, improving their functionality.

Lithography bioprinting can fabricate constructs with high resolution for potential use in tissue engineering applications. Seminal work by Grigoryan and colleagues developed bioresins with precise control over the x, y, and z-planes during lithography bioprinting and applied this technique to fabricating physiologically biomimetic alveolar lung models.

Microchannels are simple, perfusable architectural features engineered into biomaterials to promote mass transport of solutes to cells, effective cell seeding and compartmentalisation for tissue engineering applications, control over spatiotemporal distribution of molecules and ligands, and survival, integration, and vascularisation of engineered tissue analogues in vivo. Advances in biofabrication have led to better control over microchannel fabrication in 3D scaffolds, enabling sophisticated designs that drive the development of complex tissue structures. This review addresses the importance of microchannel structures in biomaterial design and regenerative medicine, and discusses their function, fabrication methods, and proposed mechanisms underlying their effects. Microchannels are effective means of improving the functional performance and survival of engineered tissue analogues for regenerative medicine applications.Microchannels enhance mass transport of solutes to cells, allow control over cell and ligand distribution, and enhance integration of the implanted constructs with the host tissue through improved tissue and vascular ingrowth.Biofabrication techniques are driving advances in microchannel design, performance and access to sophisticated biomaterial scaffolds and tissue designs.

Autologous fat grafting offers significant promise for the repair of soft tissue deformities; however, high resorption rates indicate that engineered solutions are required to improve adipose tissue (AT) survival. Advances in material development and biofabrication have laid the foundation for the generation of functional AT constructs; however, a balance needs to be struck between clinically feasible delivery and improved structural integrity of the grafts. A new approach combining the objectives from both the clinical and research communities will assist in developing morphologically and genetically mature AT constructs, with controlled spatial arrangement and increased potential for neovascularization. In a rapidly progressing field, this review addresses research in both the preclinical and bioengineering domains and assesses their ability to resolve functional challenges. The current and emerging adipose tissue regeneration strategies are somewhat misaligned, without a clear focus on the appropriate structural and functional demands required in vivo.The development of biomimetic materials has been rigorous, but these materials now need to be unified with established biofabrication strategies to meet the clinical design challenges.Efforts to prevascularize adipose tissue constructs have been significant; however, scalability and surgical feasibility remain an issue.Generating mature adipose tissue constructs is a major challenge in the field; however, refined culture strategies and adjuvant factors have made headway, laying the foundation for future clinical relevance.There is a clear trade-off between minimally invasive delivery and architectural control in vivo. Striking a balance between these will be key to fast-tracking engineered adipose tissue grafting.

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. Recognized for actively modulating wound healing, natural polymers offer safe and effective options for designing wound dressings and skin substitutes. This review explores natural polymers in both commercial and emerging wound dressings, focusing on preclinical and clinical studies. It also provides insights into emerging developments, such as 3D bioprinting and stimuli‐responsive materials, which hold promise for personalized wound treatments.

Isolated cardiac trabeculae are small heart muscle tissue preparations, which have been widely used in in vitro studies of mechanics and energetics function of cardiac muscle. Current instruments for such experimentation often (1) involve delicate mounting of the muscle, (2) constrain investigations to one muscle at a time, and thus (3) limit experimental throughput. Here, we present a novel device that allows trabeculae to be secured by a visible‐light photo‐crosslinked hydrogel, manipulated via a robust motor‐driven stainless steel cantilever, and their shortening and force production to be measured and controlled using feedback from real‐time imaging. The device has multiple wells, making it amenable to high‐throughput testing of muscle. We use our robust, accurate image registration techniques to measure cantilever and gel deformation during trabecula contraction and thereby provide a measure of trabecula shortening and force production during twitches. We apply methods to allow the trabecula to contract either isometrically or isotonically. The methods used in this device can be widely applied to the study of the mechanics of cardiac muscle samples in laboratories with available light microscopic systems. What is the central question of this study? Existing devices for trabecula experimentation are challenging to use as they require manually attaching the muscle at each end to sutures/hooks/clamps/pins, and usually involve the direct manipulation, using forceps, of the delicate tissues: can a better device be constructed? What is the main finding and its importance? Methods were developed for constraining cardiac trabeculae with hydrogel and applying feedback‐control during contractions. These methods are applicable across many available light microscope systems, and may in future allow parallelized study of cardiac trabeculae.

Osteoarthritis (OA), the commonest arthritis, is characterized by the progressive destruction of cartilage, leading to disability. The Current early clinical treatment strategy for OA often centers on anti‐inflammatory or analgesia medication, weight loss, improved muscular function and articular cartilage repair. Although these treatments can relieve symptoms, OA tends to be progressive, and most patients require arthroplasty at the terminal stages of OA. Recent studies have shown a close correlation between joint pain, inflammation, cartilage destruction and synovial cells. Consequently, understanding the potential mechanisms associated with the action of synovial cells in OA could be beneficial for the clinical management of OA. Therefore, this review comprehensively describes the biological functions of synovial cells, the synovium, together with the pathological changes of synovial cells in OA, and the interaction between the cartilage and synovium, which is lacking in the present literature. Additionally, therapeutic approaches based on synovial cells for OA treatment are further discussed from a clinical perspective, highlighting a new direction in the treatment of OA.

The current limitations of commercial microcarriers for mesenchymal stromal cell (MSC) expansion are driving the demand for novel tuneable microcarriers.Novel microcarriers are effective in improving MSC expansion under static and dynamic culture conditions without compromising their stemness and differentiation potential.Integrating microcarrier-based cultures within dynamic bioreactors provides an effective scalable approach for MSC expansion and harvest for downstream clinical translation.The development of good manufacturing practice (GMP)-grade systems, non-xenogenic culture media, and optimised bioreactors, which are compatible with novel microcarriers, is essential to improve cell yield and reproducibility. Microcarrier expansion systems show exciting potential to revolutionise mesenchymal stromal cell (MSC)-based clinical therapies by providing an opportunity for economical large-scale expansion of donor- and patient-derived cells. The poor reproducibility and efficiency of cell expansion on commercial polystyrene microcarriers have driven the development of novel microcarriers with tuneable physical, mechanical, and cell-instructive properties. These new microcarriers show innovation toward improving cell expansion outcomes, although their limited biological characterisation and compatibility with dynamic culture systems suggest the need to realign the microcarrier design pathway. Clear headway has been made toward developing infrastructure necessary for scaling up these technologies; however, key challenges remain in characterising the wholistic effects of microcarrier properties on the biological fate and function of expanded MSCs. Microcarrier expansion systems show exciting potential to revolutionise mesenchymal stromal cell (MSC)-based clinical therapies by providing an opportunity for economical large-scale expansion of donor- and patient-derived cells. The poor reproducibility and efficiency of cell expansion on commercial polystyrene microcarriers have driven the development of novel microcarriers with tuneable physical, mechanical, and cell-instructive properties. These new microcarriers show innovation toward improving cell expansion outcomes, although their limited biological characterisation and compatibility with dynamic culture systems suggest the need to realign the microcarrier design pathway. Clear headway has been made toward developing infrastructure necessary for scaling up these technologies; however, key challenges remain in characterising the wholistic effects of microcarrier properties on the biological fate and function of expanded MSCs.

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. We summarize 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 trophic factors regulating mesenchymal stromal cell (MSC) activity in vivo, as well as multiple approaches for cell tracking and labeling in vitro and in vivo. Understanding the distribution and persistence of MSCs is necessary to fully realize potential cartilage regeneration techniques and tissue engineering applications.