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Mechanical stimuli have fundamental roles in articular cartilage during health and disease. Chondrocytes respond to the physical properties of the cartilage extracellular matrix (ECM) and the mechanical forces exerted on them during joint loading. In osteoarthritis (OA), catabolic processes degrade the functional ECM and the composition and viscoelastic properties of the ECM produced by chondrocytes are altered. The abnormal loading environment created by these alterations propagates cell dysfunction and inflammation. Chondrocytes sense their physical environment via an array of mechanosensitive receptors and channels that activate a complex network of downstream signalling pathways to regulate several cell processes central to OA pathology. Advances in understanding the complex roles of specific mechanosignalling mechanisms in healthy and OA cartilage have highlighted molecular processes that can be therapeutically targeted to interrupt pathological feedback loops. The potential for combining these mechanosignalling targets with the rapidly expanding field of smart mechanoresponsive biomaterials and delivery systems is an emerging paradigm in OA treatment. The continued advances in this field have the potential to enable restoration of healthy mechanical microenvironments and signalling through the development of precision therapeutics, mechanoregulated biomaterials and drug systems in the near future.The pathways involved in sensing and responding to mechanical stimuli have important roles in maintaining cartilage health, and can contribute to disease when dysregulated. This Review discusses cartilage mechanosignalling pathways and how they can be targeted to treat osteoarthritis.

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes. Pancreatic islets derived from stem cells are benchmarked against primary cells.

Osteoarthritis (OA) is a disabling condition that affects billions of people worldwide and places a considerable burden on patients and on society owing to its prevalence and economic cost. As cartilage injuries are generally associated with the progressive onset of OA, robustly effective approaches for cartilage regeneration are necessary. Despite extensive research, technical development and clinical experimentation, no current surgery-based, material-based, cell-based or drug-based treatment can reliably restore the structure and function of hyaline cartilage. This paucity of effective treatment is partly caused by a lack of fundamental understanding of why articular cartilage fails to spontaneously regenerate. Thus, research studies that investigate the mechanisms behind the cartilage regeneration processes and the failure of these processes are critical to instruct decisions about patient treatment or to support the development of next-generation therapies for cartilage repair and OA prevention. This Review provides a synoptic and structured analysis of the current hypotheses about failure in cartilage regeneration, and the accompanying therapeutic strategies to overcome these hurdles, including some current or potential approaches to OA therapy.Cartilage defects often fail to heal, which can lead to degenerative changes and ultimately to osteoarthritis. This Review discusses various hypotheses for why articular cartilage fails to regenerate and accompanying potential therapeutic solutions.

The early treatment and rapid closure of acute or chronic wounds is essential for normal healing and prevention of hypertrophic scarring. The use of split thickness autografts is often limited by the availability of a suitable area of healthy donor skin to harvest. Cellular and non-cellular biological skin-equivalents are commonly used as an alternative treatment option for these patients, however these treatments usually involve multiple surgical procedures and associated with high costs of production and repeated wound treatment. Here we describe a novel design and a proof-of-concept validation of a mobile skin bioprinting system that provides rapid on-site management of extensive wounds. Integrated imaging technology facilitated the precise delivery of either autologous or allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area, replicating the layered skin structure. Excisional wounds bioprinted with layered autologous dermal fibroblasts and epidermal keratinocytes in a hydrogel carrier showed rapid wound closure, reduced contraction and accelerated re-epithelialization. These regenerated tissues had a dermal structure and composition similar to healthy skin, with extensive collagen deposition arranged in large, organized fibers, extensive mature vascular formation and proliferating keratinocytes.

Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.In this Review, Murry and colleagues describe the hallmarks of cardiomyocyte maturation and the current approaches to mature stem cell-derived cardiomyocytes, highlighting challenges and future directions to generate cardiomyocytes with an optimal maturation state for use in research and regenerative medicine.

Insufficient intracellular anabolism is a crucial factor involved in many pathological processes in the body 1 , 2 . The anabolism of intracellular substances requires the consumption of sufficient intracellular energy and the production of reducing equivalents. ATP acts as an ‘energy currency’ for biological processes in cells 3 , 4 , and the reduced form of NADPH is a key electron donor that provides reducing power for anabolism 5 . Under pathological conditions, it is difficult to correct impaired anabolism and to increase insufficient levels of ATP and NADPH to optimum concentrations 1 , 4 , 6 – 8 . Here we develop an independent and controllable nanosized plant-derived photosynthetic system based on nanothylakoid units (NTUs). To enable cross-species applications, we use a specific mature cell membrane (the chondrocyte membrane (CM)) for camouflage encapsulation. As proof of concept, we demonstrate that these CM-NTUs enter chondrocytes through membrane fusion, avoid lysosome degradation and achieve rapid penetration. Moreover, the CM-NTUs increase intracellular ATP and NADPH levels in situ following exposure to light and improve anabolism in degenerated chondrocytes. They can also systemically correct energy imbalance and restore cellular metabolism to improve cartilage homeostasis and protect against pathological progression of osteoarthritis. Our therapeutic strategy for degenerative diseases is based on a natural photosynthetic system that can controllably enhance cell anabolism by independently providing key energy and metabolic carriers. This study also provides an enhanced understanding of the preparation and application of bioorganisms and composite biomaterials for the treatment of disease. Proof of concept of the viability of a plant-derived photosynthetic system based on nanothylakoid units encapsulated in a chondrocyte membrane to enhance cell anabolism in chondrocytes is demonstrated.

Individuals with spinal cord injury (SCI) can face decades with permanent disabilities. Advances in clinical management have decreased morbidity and improved outcomes, but no randomized clinical trial has demonstrated the efficacy of a repair strategy for improving recovery from SCI. Here, we summarize recent advances in biological and engineering strategies to augment neuroplasticity and/or functional recovery in animal models of SCI that are pushing toward clinical translation.Advances in cellular regeneration and technical approaches to spinal cord repair are on the verge of being translated into clinical trials.

Microporous annealed particle (MAP) scaffolds are flowable, in situ crosslinked, microporous scaffolds composed of microgel building blocks and were previously shown to accelerate wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow MAP degradation by switching the chirality of the crosslinking peptides from l - to d -amino acids. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, d -peptide crosslinked MAP hydrogel ( d -MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. MAP scaffolds recruit IL-33 type 2 myeloid cells, which is amplified in the presence of d -peptides. Remarkably, d -MAP elicited significant antigen-specific immunity against the d -chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation. Microporous annealed-particle degradable scaffolds have been developed and shown to induce type 2 innate and adaptive immune response that facilitated skin wound healing.

Many forms of blindness result from the dysfunction or loss of retinal photoreceptors. Induced pluripotent stem cells (iPSCs) hold great potential for the modelling of these diseases or as potential therapeutic agents. However, to fulfill this promise, a remaining challenge is to induce human iPSC to recreate in vitro key structural and functional features of the native retina, in particular the presence of photoreceptors with outer-segment discs and light sensitivity. Here we report that hiPSC can, in a highly autonomous manner, recapitulate spatiotemporally each of the main steps of retinal development observed in vivo and form three-dimensional retinal cups that contain all major retinal cell types arranged in their proper layers. Moreover, the photoreceptors in our hiPSC-derived retinal tissue achieve advanced maturation, showing the beginning of outer-segment disc formation and photosensitivity. This success brings us one step closer to the anticipated use of hiPSC for disease modelling and open possibilities for future therapies. Induced pluripotent stem cells (iPSCs) hold great potential for modelling human developmental processes and diseases. Here the authors induce human iPSCs to spontaneously form fully laminated three-dimensional retinal tissue containing functional photoreceptor cells.

Stroke is the primary cause of disability due to the brain's limited ability to regenerate damaged tissue. After stroke, an increased inflammatory and immune response coupled with severely limited angiogenesis and neuronal growth results in a stroke cavity devoid of normal brain tissue. In the adult, therapeutic angiogenic materials have been used to repair ischaemic tissues through the formation of vascular networks. However, whether a therapeutic angiogenic material can regenerate brain tissue and promote neural repair is poorly understood. Here we show that the delivery of an engineered immune-modulating angiogenic biomaterial directly to the stroke cavity promotes tissue formation de novo, and results in axonal networks along thee generated blood vessels. This regenerated tissue produces functional recovery through the established axonal networks. Thus, this biomaterials approach generates a vascularized network of regenerated functional neuronal connections within previously dead tissue and lays the groundwork for the use of angiogenic materials to repair other neurologically diseased tissues.