Continuous bleeding, bacterial infection, oxidative stress, and vascular damage within a diabetic wound microenvironment necessitate the development of multifunctional dressings that match the complex physiological process of skin healing. Herein, copper–tannic acid (CuTA) nanosheets were first synthesized by chelating copper ions with tannic acid (TA). These nanosheets were subsequently integrated into an injectable self-healing hydrogel comprising methacrylic anhydride-modified gelatin (GelMA), cationic guar gum (CG), and borax. Through free-radical polymerization as well as hydrogen and borate ester bonds formation, we fabricated an acidic and highly reactive oxygen species (ROS)-responsive composite hydrogel named GGB-CT, which exhibited remarkable hemostasis and adhesion. With responsive decomposition of GGB-CT, the released CuTA efficiently scavenged excess ROS as well as effectively killed bacteria by inhibiting arginine synthesis, blocking the tricarboxylic acid cycle and inducing cuproptosis-like death in the tested microbes. In the later stages of wound healing, the composite hydrogel substantially promoted macrophage polarization and angiogenesis, thus accelerating the re-epithelialization of the wound area. Overall, this study proposes an innovative hydrogel for treating infected diabetic wounds and may inspire new thinking of high-performance hydrogels for biomedical applications. 

Incorporating copper-based nanosheets into an injectable self-healing hydrogel enables superb repair of infected diabetic wound

Setting time as the fourth dimension, 4D printing allows us to construct dynamic structures that can change their shape, property, or functionality over time under stimuli, leading to a wave of innovations in various fields. Recently, 4D printing of smart biomaterials, biological components, and living cells into dynamic living 3D constructs with 4D effects has led to an exciting field of 4D bioprinting. 4D bioprinting has gained increasing attention and is being applied to create programmed and dynamic cell-laden constructs such as bone, cartilage, and vasculature. This review presents an overview on 4D bioprinting for engineering dynamic tissues and organs, followed by a discussion on the approaches, bioprinting technologies, smart biomaterials and smart design, bioink requirements, and applications. While much progress has been achieved, 4D bioprinting as a complex process is facing challenges that need to be addressed by transdisciplinary strategies to unleash the full potential of this advanced biofabrication technology. Finally, we present future perspectives on the rapidly evolving field of 4D bioprinting, in view of its potential, increasingly important roles in the development of advanced dynamic tissues for basic research, pharmaceutics, and regenerative medicine. 

4D bioprinting of programmed dynamic tissues

Peripheral nerve injuries (PNIs) frequently occur due to various factors, including mechanical trauma such as accidents or tool-related incidents, as well as complications arising from diseases like tumor resection. These injuries frequently result in persistent numbness, impaired motor and sensory functions, neuropathic pain, or even paralysis, which can impose a significant financial burden on patients due to outcomes that often fall short of expectations. The most frequently employed clinical treatment for PNIs involves either direct sutures of the severed ends or bridging the proximal and distal stumps using autologous nerve grafts. However, autologous nerve transplantation may result in sensory and motor functional loss at the donor site, as well as neuroma formation and scarring. Transplantation of Schwann cells/Schwann cell-like cells has emerged as a promising cellular therapy to reconstruct the microenvironment and facilitate peripheral nerve regeneration. In this review, we summarize the role of Schwann cells and recent advances in Schwann cell therapy in peripheral nerve regeneration. We summarize current techniques used in cell therapy, including cell injection, 3D-printed scaffolds for cell delivery, cell encapsulation techniques, as well as the cell types employed in experiments, experimental models, and research findings. At the end of the paper, we summarize the challenges and advantages of various cells (including ESCs, iPSCs, and BMSCs) in clinical cell therapy. Our goal is to provide the theoretical and experimental basis for future treatments targeting peripheral nerves, highlighting the potential of cell therapy and tissue engineering as invaluable resources for promoting nerve regeneration. 

Advances of Schwann cells in peripheral nerve regeneration: From mechanism to cell therapy.

Implantable hydrogel-based bioelectronics (IHB) can precisely monitor human health and diagnose diseases. However, achieving biodegradability, biocompatibility, and high conformality with soft tissues poses significant challenges for IHB. Gelatin is the most suitable candidate for IHB since it is a collagen hydrolysate and a substantial part of the extracellular matrix found naturally in most tissues. This study used 3D printing ultrafine fiber networks with metamaterial design to embed into ultra-low elastic modulus hydrogel to create a novel gelatin-based conductive film (GCF) with mechanical programmability. The regulation of GCF nearly covers soft tissue mechanics, an elastic modulus from 20 to 420 kPa, and a Poisson's ratio from - 0.25 to 0.52. The negative Poisson's ratio promotes conformality with soft tissues to improve the efficiency of biological interfaces. The GCF can monitor heartbeat signals and respiratory rate by determining cardiac deformation due to its high conformability. Notably, the gelatin characteristics of the biodegradable GCF enable the sensor to monitor and support tissue restoration. The GCF metamaterial design offers a unique idea for bioelectronics to develop implantable sensors that integrate monitoring and tissue repair and a customized method for endowing implanted sensors to be highly conformal with soft tissues. 

Gelatin-Based Metamaterial Hydrogel Films with High Conformality for Ultra-Soft Tissue Monitoring

3D bioprinting technology is widely used to fabricate various tissue structures. However, the absence of vessels hampers the ability of bioprinted tissues to receive oxygen and nutrients as well as to remove wastes, leading to a significant reduction in their survival rate. Despite the advancements in bioinks and bioprinting technologies, bioprinted vascular structures continue to be unsuitable for transplantation compared to natural blood vessels. In addition, a complete assessment index system for evaluating the structure and function of bioprinted vessels in vitro has not yet been established. Therefore, in this review, we firstly highlight the significance of selecting suitable bioinks and bioprinting techniques as they two synergize with each other. Subsequently, focusing on both vascular-associated cells and vascular tissues, we provide a relatively thorough assessment of the functions of bioprinted vascular tissue based on the physiological functions that natural blood vessels possess. We end with a review of the applications of vascular models, such as vessel-on-a-chip, in simulating pathological processes and conducting drug screening at the organ level. We believe that the development of fully functional blood vessels will soon make great contributions to tissue engineering and regenerative medicine. 

Bioprinted vascular tissue: Assessing functions from cellular, tissue to organ levels

Gelatin methacryloyl (GelMA), a photocurable hydrogel, is widely used in 3D culture, particularly in 3D bioprinting, due to its high biocompatibility, tunable physicochemical properties, and excellent formability. However, as the properties and performances of GelMA vary under different synthetic conditions, there is a lack of standardization, leading to conflicting results. In this study, we established a uniform standard to understand and enhance GelMA applications. Firstly, we defined the basic concept of GelMA and the density of the molecular network (DMN). Secondly, we used two properties, degrees of substitution and ratio of solid content, as the main measurable parameters determining the DMN. Thirdly, we theoretically explained the mechanisms and relationships between DMN and its performance in various applications in terms of porosity, viscosity, formability, mechanical strength, swelling, biodegradation, and cytocompatibility. The main questions that we answered were: what does performance mean, why is it important, how to optimize the basic parameters to improve the performance, and how to characterize it reasonably and accurately? Finally, we hope that this knowledge will eliminate the need for researchers to conduct tedious and repetitive pre-experiments, enable easy communication for achievements between groups under the same standard, and fully explore the potential of the GelMA hydrogel. This article is protected by copyright. All rights reserved.

Gelatin Methacryloyl Hydrogel, from Standardization, Performance, to Biomedical Application.

Vessel-on-a-chips, which can be used to study microscale fluid dynamics, tissue-level biological molecules delivery and intercellular communication under favorable three-dimensional (3D) extracellular matrix microenvironment, are increasingly gaining traction. However, not many of them can allow for long-term perfusion and easy observation of angiogenesis process. Since angiogenesis is necessary for the expansion of tumor, antiangiogenic drugs play a significant role in cancer treatment. In this study, we established an innovative and reliable antiangiogenic drug screening chip that was highly modularly integrated for long-term perfusion (up to 10 days depending on the hydrogel formula) and real-time monitoring. To maintain an unobstructed flow of cell-laden tubes for subsequent perfusion culture on the premise of excellent bioactivities, a polycaprolactone stent inspired by coronary artery stents was introduced to hold up the tubular lumen from the inside, while the perfusion chip was also elaborately designed to allow for convenient observation. After 3 days of perfusion screening, distinct differences in human umbilical vein endothelial cell sprouting were observed for a gradient of concentrations of bevacizumab, which pointed to the effectiveness and reliability of the drug screening perfusion system. Overall, a perfusion system for antiangiogenic drug screening was developed, which can not only conduct drug evaluation, but also be potentially useful in other vessel-mimicking scenarios in the area of tissue engineering, drug screening, pharmacokinetics, and regenerative medicine.

Perfusable Vessel-on-a-Chip for Antiangiogenic Drug Screening with Coaxial Bioprinting

Many mammalian tissues adopt a specific cellular arrangement under stress stimulus that enables their unique function. However, conventional 3D (three-dimensional) encapsulation often fails to recapitulate the complexities of these arrangements, thus motivating the need for advanced cellular arrangement approaches. Here, an original 3D pre-stress bioprinting approach of directed tissues under the synergistic effect of static sustained tensile stress and molecular chain orientation, with an aid of slow crosslinking in bioink, is developed. The semi-crosslinking state of the designed bioink exhibits excellent elasticity for applying stress on the cells during the sewing-like process. After bioprinting, the bioink gradually forms complete crosslinking and keeps the applied stress force to induce cell-orientated growth. More importantly, multiple cell types can be arranged directionally by our approach, while the internal stress of the hydrogel filament is also adjustable. In addition, compared with conventional bioprinted skin, the 3D pre-stress bioprinted skin results in a better wound healing effect due to promoting the angiogenesis of granulation tissue. This study provides a prospective strategy to engineer skeletal muscles, as well as tendons, ligaments, vascular networks, or combinations thereof in the future. This article is protected by copyright. All rights reserved.

3D Pre-stress Bioprinting of Directed Tissues.

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Gelatin Methacryloyl Hydrogel, from Standardization, Performance, to Biomedical Application.

Gelatin-Based Metamaterial Hydrogel Films with High Conformality for Ultra-Soft Tissue Monitoring

Perfusable Vessel-on-a-Chip for Antiangiogenic Drug Screening with Coaxial Bioprinting

3D Pre-stress Bioprinting of Directed Tissues.