Cell-cell adhesion is crucial for maintaining cell functions and the integrity of tissue structure in organisms. However, cell-cell adhesion cues have not been effectively replicated in biomaterials and the associated mechanisms that enhance neural regeneration remained largely unexplored. Here, we present a diffusive N-cadherin functionalized hydrogel system, which provided cell-cell adhesion cues to modulate intercellular communications to significantly promote the formation of active neural network via thrombospondin-1 mediated neural communication and activation of TGF-β/Smad pathway. The dynamic assembly of N-cadherin at cell-hydrogel interface driven by adhered neurons effectively facilitated the reshaping of membrane protrusions to initiate intercellular adherens junctions. Further, this hydrogel system promisingly promoted neurological function recovery in rats following traumatic brain injury. Our study provides the principle of replicating diffusive cell adhesion molecules to mediate cell-cell adhesion in hydrogels, which may have broad applications in developing engineered biomaterials aimed at modulating cell fates in regeneration of various tissues.

Due to urethral strictures post hypospadias and bacterial infection, desirable urethral repair remains a great challenge in clinic. In situ formed hydrogels have shown great capacity on promoting tissue regeneration and can be delivered to fill irregularities in injury sites. In this study, we developed an in situ antibacterial hydrogel system (SFPLMA) by combining methacrylated silk fibroin (SFMA) and methacrylated polylysine (PLMA). The rapid photo-crosslinking of the methacryloyl moieties in SFMA and PLMA enabled the SFPLMA hydrogel to effectively fill the congenital irregularities associated with hypospadias, while exhibiting excellent biocompatibility and appropriate mechanical properties. Notably, the introduction of PLMA into the hydrogel system not only conferred promising antimicrobial efficacy against pathogens such as Escherichia coli and Staphylococcus aureus, thereby reducing the risk of post-surgical infections, but also enhanced the capacity for promoting axonal regrowth. Furthermore, treatment with the SFPLMA hydrogel resulted in a significant reduction in strictures and fistulas, alongside improved regeneration of urethral epithelium and smooth muscle in a rabbit model. Overall, we present a multifunctional hydrogel system that holds promise as a valuable tool in urethral reconstructive therapy.

Massive hemorrhage and chronic wounds caused by bacterial infections after trauma are significant challenges in clinical practice. An ideal hemostatic wound dressing should simultaneously manage bleeding and prevent bacterial infections and also hold excellent biocompatibility and bioactivities to successfully modulate immune microenvironments to promote wound healing. In this study, a silk fibroin-based light-responsive film was demonstrated to possess effective capacity of light-induced non-compressible hemostasis on liver hemorrhage and tail bleeding in vivo by binding with blood platelets to promote the clotting cascade. The blood loss of the rats was significantly less after C-MASiF films were applied, which were 1223.33 ± 347.9 mg (liver trauma) and 363.33 ± 60.28 mg (tail trimming). Importantly, the films exhibited photo-controllable modulation activity on macrophages through repeated near-infrared irradiation to regulate the immune microenvironment to enhance photodynamic antibacterial therapy. Moreover, the light-responsive silk fibroin film effectively promoted Staphylococcus aureus infected burn wound healing in vivo. The quantity of residual bacteria in the wound sites of mice in the C-MASiF films group (0.05 ± 0.0047 × 108 CFU mL-1) was considerably less than that in the control group (3.18 ± 0.75 × 108 CFU mL-1), and the wound area in the C-MASiF group (78.03% ± 4.12%) was considerably smaller than that in the control group (60.33% ± 8.81%) after 14 days. Overall, this light-responsive silk fibroin film can provide a powerful strategy for wound healing of burns.

Scar formation on skin wounds remains a considerable challenge in regenerative medicine. Various wound dressings, composed of biomaterials alone or in combination with bioactive factors, have been developed to improve healing outcomes. In this study, we designed a recombinant neurotrophin-3 (NT3) containing a silk fibroin light chain (SFL) and developed a silk fibroin (SF) hydrogel with NT3 activity. The SFL-NT3 protein bound to the heavy-light chains of SF and was efficiently integrated into the SF hydrogel. We evaluated the effect of the recombinant NT3-SFL hydrogel on wound healing in a mouse skin injury model. This hydrogel enhanced wound healing. Remarkably, SFL-NT3 increased the levels of type III collagen (Col3) during the healing process and induced hair follicle formation, which is a characteristic of scar-less healing. Further investigation revealed that SFL-NT3 upregulated Col3 expression in skin fibroblasts expressing the NT3 receptor, TrkC. NT3 activation of TrkC leads to Akt phosphorylation, resulting in elevated Sox2 levels, which in turn enhances Col3 transcription. Notably, TrkC inhibition abrogated the beneficial effects of SF + SFL-NT3 on wound healing, confirming its involvement in this signaling pathway. In conclusion, the SF hydrogel loaded with SFL-NT3 facilitated rapid and reduced scarring during wound healing, providing a promising approach for the clinical treatment of SF-based biomaterials that incorporate bioactive factors.

The emergence of precision cancer treatment has triggered a paradigm shift in the field of oncology, facilitating the implementation of more effective and personalized therapeutic approaches that enhance patient outcomes. The pH of the tumor microenvironment (TME) plays a pivotal role in both the initiation and progression of cancer, thus emerging as a promising focal point for precision cancer treatment. By specifically targeting the acidic conditions inherent to the tumor microenvironment, innovative therapeutic interventions have been proposed, exhibiting significant potential in augmenting treatment efficacy and ameliorating patient prognosis. The concept of ultra-pH-sensitive (UPS) nanoplatform was proposed several years ago, demonstrating exceptional pH sensitivity and an adjustable pH transition point. Subsequently, diverse UPS nanoplatforms have been actively explored for biomedical applications, enabling the loading of fluorophores, therapeutic drugs, and photosensitizers. This review aims to elucidate the design strategy and response mechanism of the UPS nanoplatform, with a specific emphasis on its applications in surgical therapy, immunotherapy, drug delivery, photodynamic therapy, and photothermal therapy. The potential and challenges of translating in the clinic on UPS nanoplatforms are finally explored. Thanks to its responsive and easily modifiable nature, the integration of multiple functional units within a UPS nanoplatform holds great promise for future advancements in tumor precision theranositcs.

Liquid metal (LM) bioelectronics are widely used in wearable devices and healthcare monitoring. However, engineering bioelectronics simultaneously exhibiting high stretchability, thermal management, and sufficient biocompatibility remains challenging. Here, a bioelectronic device containing an electrospun fiber mat embedded with LM-polyvinyl alcohol (PVA) composite and a passive radiative cooling (PRC) layer is shown to harvest the abovementioned properties. With the help of abundant dynamic hydrogen bonds, the PRC layer shows high adhesion energy of 71.2 J m-2 to the fiber mat, which provides the device with an enhanced radiative cooling performance, with a reduced Joule heat temperature of 17.1 degrees C under the applied voltage of 2.0 V. When stretched to 100% strain, their performance shows negligible change compared to the original state. The as-prepared devices also exhibit outstanding conductivity (1661.7 S cm-1), antimicrobial properties, high air permeability (111.4 mm s-1), and moisture permeability (4102.5 g m-2 day-1). With all these features, a skin-interfaced wound management e-patch is constructed, demonstrating high efficiency for accelerating wound healing under sunlight.

Organoids have emerged as powerful tools for disease modeling, mechanistic exploration, drug screening, and regenerative medicine. Spinal cord and peripheral nerve organoids mimic real organs in terms of cell morphology, tissue structure, and function, offering new possibilities for tissue engineering therapies in spinal cord injury (SCI) and peripheral nerve injury (PNI). In this review, we introduce the genesis and structure of the spinal cord and peripheral nervous system and summarize the key factors for constructing spinal cord and peripheral nerve organoids. We then discuss the recent advances in the formation of three-dimensional (3D) organoid structures through engineering approaches and explore their potential applications in neural tissue engineering. Finally, we address current challenges such as the high heterogeneity among neural organoids and incomplete replication of organ functions. Future development of engineered matrix materials and manufacturing methods is crucial for further clinical translation of organoids in spinal cord and peripheral nerve repair.

Peripheral nerve injury (PNI) has emerged as a critical clinical challenge due to its high disability rate and socioeconomic burden. Traditional autologous nerve grafting, limited by donor shortages and risks of secondary surgeries, has driven tissue-engineered nerve conduits to become a research hotspot. This review systematically summarizes recent advances in immunomodulatory nerve conduits, focusing on the biological properties, degradation mechanisms, and pivotal roles of natural materials (e.g., collagen, chitosan, silk fibroin) and synthetic materials (e.g., poly (lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) in regulating macrophage polarization. The potential of composite materials to synergistically optimize mechanical performance and bioactivity of nerve conduits is also discussed. Furthermore, this review envisions future trends in nerve conduits, including the integration of 4D printing, smart-responsive systems, and personalized designs to overcome current therapeutic limitations. By integrating multidisciplinary perspectives from materials science, immunology, and regenerative medicine, this review aims to provide innovative theoretical frameworks and technical pathways for efficiently repairing PNI, advancing clinical translation.

Bacterial infection has been regarded as a life-threatening problem in clinic. In addition to screening of new antibiotics, it is important to develop highly effective antibacterial materials against antibiotic resistance with capacities on modulating chronic inflammation. Herein, aligned Chlorin e6 (Ce6) conjugated silk fibroin electrospun fibers were successfully fabricated on silk fibroin based film via electrospining to achieve effective photodynamic antibacterial activities under near infrared (NIR) irradiation. The aligned electrospun fiber based film composite (SFCF@Film) exhibited good mechanical properties and desirable hemocompatibility. SFCF@Film provided a promising guidance cue for directing cell orientation and promoting cell growth. Significantly, SFCF@Film effectively generated ROS under NIR irradiation to kill S. aureus for treating wound infections within 10 min and promoted M2 polarization of macrophages for wound healing at later stage. Therefore, we believed that this engineered bioscaffold can be a powerful strategy for handling wound infection.

Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases.

The liver is the most complex vascular anatomy of all human organs, with extremely rich blood flow and fragile texture. Massive liver bleeding usually occurs after traumatic liver injury, causing severe systematic issues. Thus, bleeding control is critical in hindering mortality rates and complications in patients. In this study, non-compression hemostasis materials based on chitosan lactate particles (CLP) were developed for handling liver bleeding after injuries. CLP showed good blood biocompatibility and antibacterial performance against S. aureus. Taking advantage of the vital capacity of CLP to promote red blood cell and platelet adhesion, CLP exhibited in vivo homeostasis properties as non-compression hemostasis materials for traumatic liver injury, both in SD rats, New Zealand rabbits, or in beagles. Whereas CLP has better hemostasis than the commercial hemostatic agent Celox™.

Due to the complex spatial-temporal pathophysiology of spinal cord injury (SCI), effective modulation of SCI-specific inflammatory pathogenesis to achieve desirable therapeutic effects on functional recovery still remains challenging. Herein, cell-enhanced photocrosslinked silk fibroin hydrogels with extracellular matrix-mimicking cues of mechanical properties and RGD (Arg-Gly-Asp) signals are gelled in situ to fill the lesion site to modulate injury-induced neuroinflammation and promote neurite regrowth after SCI. The bionic hydrogel system provides biomimetic mechanical cues to promote neuronal differentiation of neural stem/progenitor cells (NPCs) and neurite growth by activating YAP nuclear expression. Importantly, favored by the strong capacity of silk fibroin hydrogels on macrophage/microglia recruitment, NPCs encapsulated hydrogel (NPCs@SFRGD0.1) effectively promotes recruited macrophages/microglia to M2 polarization in the lesion site by releasing S100A4 and thereby remodels the inflammatory microenvironment after SCI. Moreover, NPCs@SFRGD0.1 successfully reduces glial scar formation and accelerates corticospinal tract axon regrowth to improve locomotor recovery. Overall, this work contributes to illustrating the therapeutic mechanism of NPCs development based biomaterial therapies on modulating inflammatory microenvironment and this NPCs enhanced silk fibroin hydrogel provides a promising therapeutic strategy for SCI.

Peripheral nerve injury (PNI) is a neurological disorder caused by trauma that is frequently induced by accidents, war, and surgical complications, which is of global significance. The severity of the injury determines the potential for lifelong disability in patients. Artificial nerve scaffolds have been investigated as a powerful tool for promoting optimal regeneration of nerve defects. Over the past few decades, bionic scaffolds have been successfully developed to provide guidance and biological cues to facilitate Schwann cell myelination and orientated axonal growth. Numerous assessment techniques have been employed to investigate the therapeutic efficacy of nerve scaffolds in promoting the growth of Schwann cells and axons upon the bioactivities of distinct scaffolds, which have encouraged a greater understanding of the biological mechanisms involved in peripheral nerve development and regeneration. However, it is still difficult to compare the results from different labs due to the diversity of protocols and the availability of innovative technologies when evaluating the effectiveness of novel artificial scaffolds. Meanwhile, due to the complicated process of peripheral nerve regeneration, several evaluation methods are usually combined in studies on peripheral nerve repair. Herein, we have provided an overview of the evaluation methods used to study the outcomes of scaffold-based therapies for PNI in experimental animal models and especially focus on Schwann cell functions and axonal growth within the regenerated nerve.

The immune system is essential in the process of nerve repair after injury. Successful modulation of the immune response is regarded as an effective approach to improving treatment outcomes. T cells play an important role in the immune response of the nervous system, and their beneficial roles in promoting regeneration have been increasingly recognized. However, the diversity of T-cell subsets also delivers both neuroprotective and neurodegenerative functions. Therefore, this review mainly discusses the beneficial impact of T-cell subsets in the repair of both peripheral nervous system and central nervous system injuries and introduces studies on various therapies based on T-cell regulation. Further discoveries in T-cell mechanisms and multifunctional biomaterials will provide novel strategies for nerve regeneration.

Peripheral nerve injury is a clinically common injury that causes sensory dysfunction and locomotor system degeneration, which seriously affects the quality of the patients’ daily life. Long gapped defects in large nerve are difficult to repair via surgery and limited donor source of autologous nerve greatly challenges the successful nerve repair by transplantation. Significantly, remarkable progress has been made in repairing the peripheral nerve injury using artificial nerve grafts and a variety of products for peripheral nerve repair have emerged been approved globally in recent years. The raw materials of these commercial products includes natural/synthetic polymers, extracellular matrix. Despite a lot of effort, the desirable functional recovery still remains great challenges in long gapped nerve defects. Thus this review discusses the recent development of tissue engineering products for peripheral nerve repair and the design of bionic grafts improving the local microenvironment for accelerating nerve regeneration against locomotor disorder, which may provide potential strategies for the repair of long gaps or thick nerve defects by multifunctional biomaterials.

Successful control of massive hemorrhage in deep wounds with irregular shape and low elasticity still remains great challenges in the clinic. As the wound sites are usually at risk of bacterial infection, it is necessary to design an ideal hemostatic agent with rapid hemostasis and excellent antibacterial activity. In this study, we developed a light responsive hemostatic film for effective handling of liver bleeding with promising photodynamic therapy against S. aureus onnear infrared (NIR) irradiation. Based on silk fibroin, the film exhibited desirable biocompatibility and mechanical property as a hemostat tape. Significantly, the film tape achieved excellent tissue adhesion and hemostasis in vivo within 2 min of UV exposure, which would have a great potential as a multifunctional biomedical material in the field of tissue repair such as wound healing, bone repair, and nerve regeneration.

Gliomas are among the most common malignant tumors in the central nervous system and lead to poor life expectancy. However, the effective treatment of gliomas remains a considerable challenge. The recent development of near infrared (NIR) II (1000–1700 nm) theranostic agents has led to powerful strategies in diagnosis, targeted delivery of drugs, and accurate therapy. Because of the high capacity of NIR-II light in deep tissue penetration, improved spatiotemporal resolution can be achieved to facilitate the in vivo detection of gliomas via fluorescence imaging, and high contrast fluorescence imaging guided surgery can be realized. In addition to the precise imaging of tumors, drug delivery nano-platforms with NIR-II agents also allow the delivery process to be monitored in real-time. In addition, the combination of targeted drug delivery, photodynamic therapy, and photothermal therapy in the NIR region significantly improves the therapeutic effect against gliomas. Thus, this mini-review summarizes the recent developments in NIR-II fluorescence-based theranostic agents for glioma treatment.

Precise diagnosis and effective treatment of cancer metastasis remain a great challenge in the clinic. Theranostic agents that consist of both diagnostic and therapeutic components have gained great interest in cancer therapy. Herein, we report an intraoperative theranostic strategy for the accurate live detection of micrometastases with selective chemotherapeutic activity using a small multifunctional agent (CBHAc). Combining histone deacetylase (HDACs) targeting and pH-responsive fluorescence characteristics, CBHAc provided highly sensitive and selective real-time fluorescence diagnosis for microtumors in zebrafish and hepatic micrometastases in mice. Furthermore, CBHAc demonstrated significant tumor inhibition against colon cancer and hepatic matastasis, prolonging the survival of tumor-bearing mice through attenuating epithelial-mesenchymal transition (EMT). Therefore, this cancer-targeting fluorescence agent delivers a new platform for both intraoperative diagnosis and suppression of cancer metastasis in surgery, broadening the impact of multifunctional agents for theranostic precision medicine.