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Organs-on-chips (OoCs) have attracted significant attention because they can be designed to mimic in vivo environments. Beyond constructing a single OoC, recent efforts have tried to integrate multiple OoCs to broaden potential applications such as disease modeling and drug discoveries. However, various challenges remain for integrating OoCs towards in vivo-like operation, such as incorporating various connections for integrating multiple OoCs. We review multiplexed OoCs and challenges they face: scaling, vascularization, and innervation. In our opinion, future OoCs will be constructed to have increased predictive power for in vivo phenomena and will ultimately become a mainstream tool for high quality biomedical and pharmaceutical research. Major considerations for integrating organs-on-chips (OoCs) include scaling and interconnection via vascularization and innervation.Scaling rules are crucial for predicting events that occur in vivo, but so far, there are no optimal scaling rules for microsystems.To develop scaling rules for microsystems, data should be acquired using mesoscale approaches by using in vitro tissues fabricated by bioreactors or 3D printing.Beyond numerous OoC models of vascularization, organ-specific microvasculature and the main connections between each organ part should also be considered for mimicking the in vivo vascular system.There are still few examples of on-chip innervation, but innervated OoCs and neuronal connections between each part in vitro will give new insights into corresponding in vivo behavior.

Challenges in current approaches in diabetes cell therapy highlight the critical need to develop solutions for promoting cell engraftment.Macroencapsulation device with vascularization capacity remains a key limitation in IPC transplantation as it is essential for overcoming hypoxia and nutrient diffusion barriers to ensure cell survival and function.The selection of polymeric biomaterials for different device components, including the frame and hydrogel, directly influences vascularization efficiency.Vascularization devices are constructed using a variety of fabrication approaches tailored to material properties, design complexity, cost, and scalability. These methods enable the production of structural frameworks, porous membranes, and hydrogel-based components, supporting the encapsulation of IPCs for improved transplantation outcomes. Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing cells (IPCs), resulting in disruptions to blood glucose regulation. Cell therapy is an established, FDA-approved treatment for T1D. Incorporating IPCs into vascularized devices provides a promising strategy to enhance therapeutic efficacy. Here, we discuss the challenges of device vascularization and its role in successful IPC transplantation. We explore state-of-the-art engineering strategies used for the efficient vascularization of IPC encapsulation devices, including material selection, design criteria, and fabrication methods for the production and assembly of vascularization device components. In addition, the current state of research and future clinical applications in this field are discussed. Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing cells (IPCs), resulting in disruptions to blood glucose regulation. Cell therapy is an established, FDA-approved treatment for T1D. Incorporating IPCs into vascularized devices provides a promising strategy to enhance therapeutic efficacy. Here, we discuss the challenges of device vascularization and its role in successful IPC transplantation. We explore state-of-the-art engineering strategies used for the efficient vascularization of IPC encapsulation devices, including material selection, design criteria, and fabrication methods for the production and assembly of vascularization device components. In addition, the current state of research and future clinical applications in this field are discussed.

Multiorgan-on-a-chip (multi-OoC) platforms have great potential to redefine the way in which human health research is conducted. After briefly reviewing the need for comprehensive multiorgan models with a systemic dimension, we highlight scenarios in which multiorgan models are advantageous. We next overview existing multi-OoC platforms, including integrated body-on-a-chip devices and modular approaches involving interconnected organ-specific modules. We highlight how multi-OoC models can provide unique information that is not accessible using single-OoC models. Finally, we discuss remaining challenges for the realization of multi-OoC platforms and their worldwide adoption. We anticipate that multi-OoC technology will metamorphose research in biology and medicine by providing holistic and personalized models for understanding and treating multisystem diseases. Multiorgan-on-a-chip (multi-OoC) devices, by supporting cross-organ communication, allow the study of multiorgan processes and modeling of systemic diseases.Multi-OoC approaches provide new insights that would be lost using single-OoC models.Various coupling configurations have been proposed for building multi-OoC platforms, and these present different levels of user-friendliness.Multi-OoC platforms have the potential to transform medical research by opening new avenues for understanding multiorgan diseases and for developing personalized treatments.To further emulate the complexity of the human system in vivo, key elements of the immune, nervous, and vascular systems are being integrated into multi-OoC models.The next generation of multi-OoCs will incorporate multimodal and real-time readouts in the form of on-chip chemical, physical, and molecular sensors, as well as online multiomic analysis.

‘Smart’ bandages based on multimodal wearable devices could enable real-time physiological monitoring and active intervention to promote healing of chronic wounds. However, there has been limited development in incorporation of both sensors and stimulators for the current smart bandage technologies. Additionally, while adhesive electrodes are essential for robust signal transduction, detachment of existing adhesive dressings can lead to secondary damage to delicate wound tissues without switchable adhesion. Here we overcome these issues by developing a flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with skin-interfacing hydrogel electrodes capable of on-demand adhesion and detachment. In mice, we demonstrate that our wound care system can continuously monitor skin impedance and temperature and deliver electrical stimulation in response to the wound environment. Across preclinical wound models, the treatment group healed ~25% more rapidly and with ~50% enhancement in dermal remodeling compared with control. Further, we observed activation of proregenerative genes in monocyte and macrophage cell populations, which may enhance tissue regeneration, neovascularization and dermal recovery. A wireless ‘smart’ bandage stimulates wound healing.

The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.Vascular endothelial growth factor A (VEGFA) is an important regulator of angiogenesis. Increasing knowledge of its role in pathophysiology has culminated in the wide use of anti-VEGFA agents in oncology and in the treatment of neovascular eye disorders, and has opened avenues for promoting tissue vascularization in regenerative medicine.

Vascularization is an important factor in nerve graft survival and function. The specific molecular regulations and patterns of angiogenesis following peripheral nerve injury are in a broad complex of pathways. This review aims to summarize current knowledge on the role of vascularization in nerve regeneration, including the key regulation molecules, and mechanisms and patterns of revascularization after nerve injury. Angiogenesis, the maturation of pre-existing vessels into new areas, is stimulated through angiogenic factors such as vascular endothelial growth factor and precedes the repair of damaged nerves. Vascular endothelial growth factor administration to nerves has demonstrated to increase revascularization after injury in basic science research. In the clinical setting, vascularized nerve grafts could be used in the reconstruction of large segmental peripheral nerve injuries. Vascularized nerve grafts are postulated to accelerate revascularization and enhance nerve regeneration by providing an optimal nutritional environment, especially in scarred beds, and decrease fibroblast infiltration. This could improve functional recovery after nerve grafting, however, conclusive evidence of the superiority of vascularized nerve grafts is lacking in human studies. A well-designed randomized controlled trial comparing vascularized nerve grafts to non-vascularized nerve grafts involving patients with similar injuries, nerve graft repair and follow-up times is necessary to demonstrate the efficacy of vascularized nerve grafts. Due to technical challenges, composite transfer of a nerve graft along with its adipose tissue has been proposed to provide a healthy tissue bed. Basic science research has shown that a vascularized fascial flap containing adipose tissue and a vascular bundle improves revascularization through excreted angiogenic factors, provided by the stem cells in the adipose tissue as well as by the blood supply and environmental support. While it was previously believed that revascularization occurred from both nerve ends, recent studies propose that revascularization occurs primarily from the proximal nerve coaptation. Fascial flaps or vascularized nerve grafts have limited applicability and future directions could lead towards off-the-shelf alternatives to autografting, such as biodegradable nerve scaffolds which include capillary-like networks to enable vascularization and avoid graft necrosis and ischemia.

Tumor vascularization occurs through several distinct biological processes, which not only vary between tumor type and anatomic location, but also occur simultaneously within the same cancer tissue. These processes are orchestrated by a range of secreted factors and signaling pathways and can involve participation of non-endothelial cells, such as progenitors or cancer stem cells. Anti-angiogenic therapies using either antibodies or tyrosine kinase inhibitors have been approved to treat several types of cancer. However, the benefit of treatment has so far been modest, some patients not responding at all and others acquiring resistance. It is becoming increasingly clear that blocking tumors from accessing the circulation is not an easy task to accomplish. Tumor vessel functionality and gene expression often differ vastly when comparing different cancer subtypes, and vessel phenotype can be markedly heterogeneous within a single tumor. Here, we summarize the current understanding of cellular and molecular mechanisms involved in tumor angiogenesis and discuss challenges and opportunities associated with vascular targeting.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats’ eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.