Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

One-Pot Synthesis of Bi2 S3 /TiO2 /rGO Heterostructure with Red Light-Driven Photovoltaic Effect for Remote Electrotherapy-Assisted Wound Repair.

The past decades have witnessed the rational design of novel functional nanomaterials and the potential to revolutionize many applications. With the increasing focus on electronic biological processes, novel photovoltaic nanomaterials are highly expectable for empowering new therapeutic strategies such as establishing a link between endogenous electric field (EEF) and electrotherapy. Compared to traditional invasive stimulation, the light-initiating strategy has the advantages of non-invasion, non-power supply, and precise controllability. Whereas, common photoactivated materials require short-wavelength light excitation accompanied by poor tissue penetration and biohazard. Herein, by the construction of p-n heterostructured Bi2 S3 /TiO2 /rGO (BTG) nanoparticles, broadener light absorption and higher light conversion than regular UV excitation are realized. Simultaneously, the photoelectric performance of BTG heterostructure, as well as the synergistic effect of Bi2 S3 morphology, are revealed. Besides, the rationally designed biomimetic hydrogel matrix consisting of collagen and hyaluronic acid provides appropriate bioactivity, interface adhesion, mechanical matching, and electron transfer. Therefore, the photovoltaic BTG-loaded matrix provides a platform of light-driven electrical stimulation, coupling the EEF to modulate the electrophysiological and regeneration microenvironment. The implementation of photoelectric stimulation holds broad prospects for non-drug therapy and electrical-related biological process modulation including osseointegration, nerve regeneration, electronic skin, and wound healing.

Tunable Fast Relaxation in Imine-Based Nanofibrillar Hydrogels Stimulates Cell Response through TRPV4 Activation.

As a key mechanical signal of natural extracellular matrix (ECM), stress relaxation plays an essential role in cell fate decision. However, the biomimetic matrix with fast stress relaxation and its cellular response mechanism have received little attention. Meanwhile, the nanofibrillar architecture which is conductive to mechanical transduction has invariably been ignored in the previous viscoelastic matrix design. Herein, by introducing a dynamic covalent imine bond into a physically cross-linked collagen hydrogel, we prepared bionic fast-relaxing nanofibrillar hydrogels with relaxation time less than 10 s. Through a single control of imine bond content, we realized fine-tuning of the relaxation rate while maintaining a constant initial modulus and fiber density. Using MC3T3-E1 cells as a model, we then proved that the nanofibrillar matrix with fast relaxation mechanics can effectively promote cell spreading and differentiation. In particular, TRPV4 as a molecular sensor of matrix viscoelasticity was demonstrated to regulate cell fate on the nanofibrillar hydrogels by mediating calcium influx. It is expected that the material design principle combining both nanofibrillar structure and tunable fast-relaxation can provide a more broadly adaptable materials platform for simulating natural ECM mechanical cues, and the investigation of the TRPV4 ion channel mediated cellular response will facilitate discovery of more fundamental mechanisms in tissue growth and development.

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3'-untranslated regions (3'-UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.

Red-Light-Excited TiO2/Bi2S3 Heterojunction Nanotubes and Photoelectric Hydrogels Mediate Epidermal-Neural Network Reconstruction in Deep Burns.

Inspired by the strong light absorption of carbon nanotubes, we propose a fabrication approach involving one-dimensional TiO2/Bi2S3 QDs nanotubes (TBNTs) with visible red-light excitable photoelectric properties. By integrating the construction of heterojunctions, quantum confinement effects, and morphological modifications, the photocurrent reached 9.22 µA/cm2 which is 66 times greater than that of TiO2 nanotubes (TNTs). Then, a red light-responsive photoelectroactive hydrogel dressing (TBCHA) was developed by embedding TBNTs into a collagen/hyaluronic acid-based biomimetic extracellular matrix hydrogel with good biocompatibility, aiming to promote wound healing and skin function restoration. This approach is primarily grounded in the recognized significance of electrical stimulation in modulating nerve function and immune responses. Severe burns are often accompanied by extensive damage to epithelial-neural networks, leading to a loss of excitatory function and difficulty in spontaneous healing, while conventional dressings inadequately address the critical need for nerve reinnervation. Furthermore, we highlight the remarkable ability of the TBCHA photoelectric hydrogel to promote the reinnervation of nerve endings, facilitate the repair of skin substructures, and modulate immune responses in a deep burn model. This hydrogel not only underpins wound closure and collagen synthesis but also advances vascular reformation, immune modulation, and neural restoration. This photoelectric-based therapy offers a robust solution for the comprehensive repair of deep burns and functional tissue regeneration. STATEMENT OF SIGNIFICANCE: We explore the fabrication of 1D TiO2/Bi2S3 nanotubes with visible red-light excitability and high photoelectric conversion properties. By integrating heterojunctions, quantum absorption effects, and morphological modifications, the photocurrent of TiO2/Bi2S3 nanotubes could reach 9.22 µA/cm², which is 66 times greater than that of TiO2 nanotubes under 625 nm illumination. The efficient red-light excitability solves the problem of poor biosafety and low tissue penetration caused by shortwave excitation. Furthermore, we highlight the remarkable ability of the TiO2/Bi2S3 nanotubes integrated photoelectric hydrogel in promoting the reinnervation of nerve endings and modulating immune responses. This work proposes an emerging therapeutic strategy of remote, passive electrical stimulation, offering a robust boost for repairing deep burn wounds.

Flexible silk-fibroin-based microelectrode arrays for high-resolution neural recording.

High-precision neural recording plays a pivotal role in unraveling the intricate mechanisms that underlie information transmission of the nervous system, raising increasing interest in the development of implantable microelectrode arrays (MEAs). The challenge lies in providing a truly soft, highly conductive and low-impedance neural interface for precise recording of the electrophysiological signals of individual neurons or neural networks. Herein, by implementing a novel topological regulation strategy of silk fibroin (SF) crosslinking, we prepared a flexible, hydrophilic, and biocompatible MEA substrate, facilitating a biocompatible neural interface that minimizes mechanical mismatch with biological tissues. Additionally, we established a strategy involving screen-printing combined with post-coating to prepare MEAs with high conductivity, low impedance and high capacitance, by coating PEDOT:PSS on titanium carbide (Ti3C2) microarrays. The Ti3C2 nanosheets, as the conductive track of the MEAs, avoided the charge drifting associated with metals and facilitated the processing of the MEAs. Further coating PEDOT:PSS on the electrode points reduced the impedance 100-fold, from 105 to 103 Ω. Experimental validation confirmed the superior electrophysiological signal recording capabilities of the SF-based MEA (SMEA) in peripheral and cerebral nerves with a much higher signal-to-noise ratio (SNR) of 20. In particular, we achieved high-precision recording of the action potential (AP) induced by flash visual stimulation, demonstrating high performance in weak signal recording. In summary, the development of SMEA provides a robust foundation for future investigations into the mechanisms and principles of neural circuit information transmission in complex nervous systems.

Mild synthesis of ultra-bright carbon dots with solvatochromism for rapid lipid droplet monitoring in varied physiological processes.

Lipid droplets (LDs) participating in various cellular activities and are increasingly being emphasized. Fluorescence imaging provides powerful tool for dynamic tracking of LDs, however, most current LDs probes remain inconsistent performance such as low Photoluminescence Quantum Yield (PLQY), poor photostability and tedious washing procedures. Herein, a novel yellow-emissive carbon dot (OT-CD) has been synthesized conveniently with high PLQY up to 90%. Besides, OT-CD exhibits remarkable amphiphilicity and solvatochromic property with lipid-water partition coefficient higher than 2, which is much higher than most LDs probes. These characters enable OT-CD high brightness, stable and wash-free LDs probing, and feasible for in vivo imaging. Then, detailed observation of LDs morphological and polarity variation dynamically in different cellular states were recorded, including ferroptosis and other diseases processes. Furthermore, fast whole imaging of zebrafish and identified LD enrichment in injured liver indicate its further feasibility for in vivo application. In contrast to the reported studies to date, this approach provides a versatile conventional synthesis system for high-performance LDs targeting probes, combing the advantages of easy and high-yield production, as well as robust brightness and stability for long-term imaging, facilitating investigations into organelle interactions and LD-associated diseases.

A review of hydrogels used in endoscopic submucosal dissection for intraoperative submucosal cushions and postoperative management.

Endoscopic submucosal dissection (ESD) has been clinically proved to have prominent advantages in the treatment of early gastrointestinal cancers over traditional surgery, including less trauma, fewer complications, a quicker recovery and lower costs. During the procedure of ESD, appropriate and multifunctional submucosal injected materials (SIMs) as submucosal cushions play an important role, however, even with many advances in design strategies of SIMs over the past decades, the performance of the submucosal cushions with postoperative management function seems to be still unsatisfactory. In this review, we gave a brief historical recount about the clinical development of SIMs, then some common applications of hydrogels used as SIMs in ESD were summarized, while an account of the universal challenges during ESD procedure was also outlined. Going one step further, some cutting-edge functional strategies of hydrogels for novel applications in ESD were exhibited. Finally, we concluded the advantages of hydrogels as SIMs for ESD as well as the treatment dilemma clinicians faced when it comes to deeply infiltrated lesions, some technical perspectives about linking the clinical demand with commercial supply were also proposed. Encompassing the basic elements of SIMs used in ESD surgery and the corresponding postoperative management requirements, this review could be a good reference for relevant practitioners in expanding the research horizon and improving the well-being index of patients.

Functional material-mediated wireless physical stimulation for neuro-modulation and regeneration.

Nerve injuries and neurological diseases remain intractable clinical challenges. Despite the advantages of stem cell therapy in treating neurological disorders, uncontrollable cell fates and loss of cell function in vivo are still challenging. Recently, increasing attention has been given to the roles of external physical signals, such as electricity and ultrasound, in regulating stem cell fate as well as activating or inhibiting neuronal activity, which provides new insights for the treatment of neurological disorders. However, direct physical stimulations in vivo are short in accuracy and safety. Functional materials that can absorb energy from a specific physical field exerted in a wireless way and then release another localized physical signal hold great advantages in mediating noninvasive or minimally invasive accurate indirect physical stimulations to promote the therapeutic effect on neurological disorders. In this review, the mechanism by which various physical signals regulate stem cell fate and neuronal activity is summarized. Based on these concepts, the approaches of using functional materials to mediate indirect wireless physical stimulation for neuro-modulation and regeneration are systematically reviewed. We expect that this review will contribute to developing wireless platforms for neural stimulation as an assistance for the treatment of neurological diseases and injuries.

Bioactive cell niche mediating uniform thermal stimulus for BMSC neural differentiation through TRPV1 channel activation.

As one of the physical stimulus tools to target neuromodulation-related biological entities, mild thermal stimulus has attracted increasing attention in unraveling neural differentiation processing. However, thermal stimulus for neural behavior regulation has been relatively unexplored due to the challenge in finding a good method of exerting thermal stimulus. Considering the distance-dependent temperature preservation efficiency and the native importance of a bioactive matrix, we herein put forward the design of a photothermal hydrogel by immobilizing photothermal dopamine (DA) in hyaluronic acid (HA) chains. Benefitting from the minuscule disaccharide repeat unit size (≈1 nm) of HA used for the DA grafting, and the additional adhesion capacity of the DA for recruiting cells, a uniformly close distance from heating source to cells is realized. Therefore, we successfully established a near-infrared light initiated photothermal stimulus platform, with full bioactivity and high thermal manipulation efficiency. After extensive characterization, we proved that the thermal activation, from matrix to cells, triggered TRPV1 ion channel opening and Ca2+ influx, which finally promoted neural differentiation of bone marrow mesenchymal stem cells (BMSCs). This work broadens the possibilities of polymeric photothermal materials, and is of great significance for remotely manipulating neural and other cellular machinery for stem cell therapeutics in tissue engineering.

Orange-Emissive Carbon Dots with High Photostability for Mitochondrial Dynamics Tracking in Living Cells.

Mitochondria play significant roles in maintaining a stable internal environment for cell metabolism. Hence, real-time monitoring of the dynamics of mitochondria is essential for further understanding mitochondria-related diseases. Fluorescent probes provide powerful tools for visualizing dynamic processes. However, most mitochondria-targeted probes are derived from organic molecules with poor photostability, making long-term dynamic monitoring challenging. Herein, we design a novel mitochondria-targeted probe based on carbon dots with high performance for long-term tracking. Considering that the targeting ability of CDs is related to surface functional groups, which are generally determined by the reaction precursors, we successfully constructed mitochondria-targeted O-CDs with emission at 565 nm through solvothermal treatment of m-diethylaminophenol. The O-CDs are bright with a high quantum yield of 12.61%, high mitochondria-targeting ability, and good stability. The O-CDs possess a high quantum yield (12.61%), specific mitochondria-targeting ability, and outstanding optical stability. Owing to the abundant hydroxyl and ammonium cations on the surface, O-CDs showed obvious accumulation in mitochondria with a high colocalization coefficient of up to 0.90 and remained steady even after fixation. Besides, O-CDs showed outstanding compatibility and photostability under various interruptions or long-time irradiation. Therefore, O-CDs are preferable for the long-term tracking of dynamic mitochondrial behavior in live cells. We first observed the mitochondrial fission and fusion behaviors in HeLa cells, and then, the size, morphology, and distribution of mitochondria in physiological or pathological conditions were clearly recorded. More importantly, we observed different dynamics interactions between mitochondria and lipid droplets during the apoptosis and mitophagy processes. This study provides a potential tool for exploring interactions between mitochondria and other organelles, further promoting the research on mitochondria-related diseases.

Wireless-Powering Deep Brain Stimulation Platform Based on 1D-Structured Magnetoelectric Nanochains Applied in Antiepilepsy Treatment.

Electrical deep brain stimulation (DBS) is a top priority for pharmacoresistant epilepsy treatment, while less-invasive wireless DBS is an urgent priority but challenging. Herein, we developed a conceptual wireless DBS platform to realize local electric stimulation via 1D-structured magnetoelectric Fe3O4@BaTiO3 nanochains (FBC). The FBC was facilely synthesized via magnetic-assisted interface coassembly, possessing a higher electrical output by inducing larger local strain from the anisotropic structure and strain coherence. Subsequently, wireless magnetoelectric neuromodulation in vitro was synergistically achieved by voltage-gated ion channels and to a lesser extent, the mechanosensitive ion channels. Furthermore, FBC less-invasively injected into the anterior nucleus of the thalamus (ANT) obviously inhibited acute and continuous seizures under magnetic loading, exhibiting excellent therapeutic effects in suppressing both high voltage electroencephalogram signals propagation and behavioral seizure stage and neuroprotection of the hippocampus mediated via the Papez circuit similar to conventional wired-in DBS. This work establishes an advanced antiepilepsy strategy and provides a perspective for other neurological disorder treatment.

Magnetic manipulation of Fe3O4@BaTiO3 nanochains to regulate extracellular topographical and electrical cues.

Magnetic fields play an essential role in material science and biomedical engineering. Magnetic-responsive materials can be arranged orderly in matrix to realize the construction of an aligned scaffold under magnetic induction. However, a single topological cue is insufficient to activate neural tissue regeneration, demanding more cues to promote regeneration synergistically, such as electrical stimulation and a biomimetic matrix. Herein, we propose one-dimensional (1D) magnetoelectric Fe3O4@BaTiO3 nanochains with controllable lengths under the regulation of a magnetic field. These nanochains can be oriented in the biomimetic hydrogel under magnetic guidance and induce the hydrogel microfiber to align along the direction of the nanochains, which is beneficial for cell-oriented outgrowth. This aligned hydrogel enabled wireless electrical stimulation mediated by magnetoelectric nanochains under magnetic stimulation, thereby activating the voltage-gated ion channel. Consequently, topological and electrical cues in this multifunctional biomimetic hydrogel synergistically enhanced the expression of neural functional proteins, facilitating synapse remodeling and neural regeneration. Predictably, the construction of multifunctional hydrogels based on low-cost and facile synthesis of magnetoelectric nanochains is an emerging patient-friendly and effective therapeutic strategy for neural or other tissue regeneration. STATEMENT OF SIGNIFICANCE: A facile and controllable magnetic strategy is established to manipulate 1D nanomaterial growth, matrix topography, and wireless electrical stimulation of cells. First, the magnetic-assisted interface co-assembly was used to control the length of Fe3O4@BaTiO3 nanochains with enhanced magnetoelectric effect. Then, the motion of the magnetic-induced nanochains guided the orientation of nanofibers in a 3D biomimetic hydrogel matrix. Finally, wireless electrical signals and topological cues in the biomimetic matrix synergistically promoted orderly aligned cell outgrowth and membrane depolarization by Ca2+ influx, thus enhancing nerve cell synaptic plasticity and functional expression. Consequently, this work provides a conceptual strategy from material design to extracellular matrix signal manipulation and synergistic induction of tissue regeneration.

An upconversion nanoparticle-integrated fibrillar scaffold combined with a NIR-optogenetic strategy to regulate neural cell performance.

Optogenetics using light-sensitive proteins such as calcium transport channel rhodopsin (CatCh) opens up new possibilities for non-invasive remote manipulation of neural function. However, current optogenetic approaches for neurological disorder therapies rely on visible light excitation and are rarely applied to neurogenesis and nerve regeneration. Herein, we propose a new strategy for tissue engineering which combines optogenetic technology and biomimetic nerve scaffolds. Upconversion nanoparticles (UCNPs) were synthesized and integrated with oriented fibrillar PCL membranes with a collagen coating to establish neuro-matrix interfaces. Benefiting from the excellent bioactivity, oriented fibrillation and NIR-photoresponsivity, the CatCh-transfected PC12 cells on these interfaces exhibited enhanced cell elongation and neurite extension, as well as upregulated neurogenesis upon NIR excitation. Furthermore, a UCNP-integrated scaffold as an optogenetic actuator allowed NIR to penetrate dermal tissues to mediate neural activation, with an efficiency comparable to that of a 470 nm blue light. Compared with current visible light-excited optogenetics, our composite scaffold-mediated NIR stimulation addresses the problem of tissue penetration and will enable less-invasive neurofunctional manipulation, with the potential for remote therapy.

"Three-in-one" platform based on Fe-CDs nanozyme for dual-mode/dual-target detection and NIR-assisted bacterial killing.

As nanozymes, carbon dots (CDs) have attracted increasing attention due to their remarkable properties. Besides general enzyme activity, their photoluminescence and photothermal properties have been explored rarely, whereas their synergistic effects might produce CDs-based nanozymes of high performance. Here, iron-doped CDs (Fe-CDs) with tunable fluorescence and enhanced peroxidase-like activity were designed to develop a novel "three-in-one" multifunctional platform to provide dual-mode/dual-target detection and near infrared (NIR)-assisted antibacterial ability. This proposed strategy for a H2O2 test exhibited a wide linear relationship with a low limit of detection (LOD) of 0.16 µM (colorimetric) and 0.14 µM (ratiometric fluorescent). Furthermore, due to the nature of cholesterol being oxidized to H2O2 by cholesterol oxidase, sensitive and selective detection of cholesterol was realized, and the LOD was 0.42 µM (colorimetric) and 0.27 µM (ratiometric fluorescent), surpassing that reported previously. This result suggested that Fe-CDs could be used for dual-mode quantification of large family of H2O2-producing metabolites, thereby paving the way for developing multi-mode sensing strategies based on nanozymes. Moreover, this platform showed synergistic effects for antibacterial application, indicating great prospects for bacterial killing as well as wound disinfection and healing. Hence, this platform could contribute to the construction of multifunctional CDs with high performance.

Hydrogen-bonding topological remodeling modulated ultra-fine bacterial cellulose nanofibril-reinforced hydrogels for sustainable bioelectronics.

Bacterial cellulose (BC) with its inherent nanofibrils framework is an attractive building block for the fabrication of sustainable bioelectronics, but there still lacks an effective and green strategy to regulate the hydrogen-bonding topological structure of BC to improve its optical transparency and mechanical stretchability. Herein, we report an ultra-fine nanofibril-reinforced composite hydrogel by utilizing gelatin and glycerol as hydrogen-bonding donor/acceptor to mediate the rearrangement of the hydrogen-bonding topological structure of BC. Attributing to the hydrogen-bonding structural transition, the ultra-fine nanofibrils were extracted from the original BC nanofibrils, which reduced the light scattering and endowed the hydrogel with high transparency. Meanwhile, the extracted nanofibrils were connected with gelatin and glycerol to establish an effective energy dissipation network, leading to an increase in stretchability and toughness of hydrogels. The hydrogel also displayed tissue-adhesiveness and long-lasting water-retaining capacity, which acted as bio-electronic skin to stably acquire the electrophysiological signals and external stimuli even after the hydrogel was exposing to air condition for 30 days. Moreover, the transparent hydrogel could also serve as a smart skin dressing for optical identification of bacterial infection and on-demand antibacterial therapy after combined with phenol red and indocyanine green. This work offers a strategy to regulate the hierarchical structure of natural materials for designing skin-like bioelectronics toward green, low cost, and sustainability.

Hyaluronan-based hydrogel integrating exosomes for traumatic brain injury repair by promoting angiogenesis and neurogenesis.

With wide clinical demands, therapies for traumatic brain injury (TBI) are far from satisfactory. Combining the merits of stem cells but avoiding the risk of immunologic rejection, bone marrow mesenchymal stem cell-derived exosomes (BME) attract increasing interests and have been proved effective for TBI repair by intravenous or in situ injection. However, difficulties in sustained delivery or aggregation in lesion sites remain obstacle to using BME for TBI. Inspired by that hydrogels are promising to bridge the destroyed neural gap and provide neural niches, we raised a novel strategy of incorporating BME into hyaluronan-collagen hydrogel (DHC-BME) to achieve both mimicking of brain matrix and steady release of exosomes, and thus realizing TBI repair. External characterizations proved that the BME and DHC synergistically promoted neural stem cells (NSCs) differentiation into neurons and oligodendrocytes while inhibited astrocytes differentiation. DHC-BME induced angiogenesis and neurogenesis, from endogenous NSC recruitment to neuronal differentiation and vascularization to synergistically promote axonal regeneration, remyelination, synapse formation and even brain structural remodeling, and lastly, neurological functional recovery of TBI.

Dopamine induced multiple bonding in hyaluronic acid network to construct particle-free conductive hydrogel for reliable electro-biosensing.

Conductive hydrogel (CH) as flexible electrophysiology interface has become the new trend of bioelectronics, but still challenging in synergizing the biocompatibility, mechanics and comprehensive electrical performance. Hyaluronic acid (HA), featured with abundant active sites for personalized-modification and well-known biocompatibility, is one of the alterative candidates. The obstacle lies in the unstable conductivity from the ionic conduction, and the electronic conduction by embedding conductive nanoparticles (NPs) is likely to result in inhomogeneous CH with poor stretchability and discontinuous conductive network. Herein, inspired by catechol chemistry, dopamine (DA)-modified HA was homogeneously composited with DA-modified poly (3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS, named PP), to produce particle-free conductive hydrogel (HA-DA-PP). The DA-introduced multiple bondings in HA network and PP molecules brought aqueous conductive PP into HA hydrogel to form a homogeneous crosslinking network, imparted the flexible stretchability. By accurately regulation, HA-DA-PP achieved high stretchability with large tensile deformation (over 470 %) in the category of natural polymer-based hydrogels. Moreover, the interaction between DA and PP (conformational transition and charge transfer) could effectively enhance the hydrogel's conductivity. Consequently, HA-DA-PP hydrogel showed high sensibility to human movement, epidermal and in vivo electrophysiological signals monitoring. Overall, DA-mediated multiple bonding is a powerful strategy for constructing CH with high performance for bioelectronics.

A photoelectric effect integrated scaffold for the wireless regulation of nerve cellular behavior.

Electrical signals are a key factor to promote nerve cell neurogenesis. However, the traditionally used exogenous electrical stimulus mode requires additional equipment and complicated wiring, which is very inconvenient. To date, it has been challenging to provide electrical signals to nerve cells in a non-invasive and wireless controllable way, accompanied by the construction of a biomimetic cell microenvironment for supporting nerve cell survival and functional expression. Herein, a new concept of a light-powered oriented bioactive scaffold for remote and wireless electrical stimulation has been developed. By combining electrospinning and electrospraying, the highly oriented polycaprolactone (PCL) microfibrous scaffold with co-sprayed bioactive collagen and photoelectric poly-3-hexylthiophene nanoparticles (P3HT NPs) was obtained, named as PCL-P3HT-Col, which exhibits a considerable photoelectric effect and vital characteristics of the native nerve extracellular matrix. The results show that a photocurrent ranging from 20-80 pA was obtained by changing the light density of a 530 nm green light source. Further, the specific photoelectric conversion effect trigged by the P3HT NPs promotes the oriented elongation and up-regulation of neuronal characteristic factors in rat pheochromocytoma cells (PC12 cells), which is controlled by L-type voltage-gated calcium channel (L-VGCC) activity. This study provides new insights to engineer self-powered scaffolds towards the non-invasive and wireless-controlled stimulation mode of a variety of cells and tissues.

Neuroinduction and neuroprotection co-enhanced spinal cord injury repair based on IL-4@ZIF-8-loaded hyaluronan-collagen hydrogels with nano-aligned and viscoelastic cues.

Spontaneous recovery after spinal cord injury (SCI) is extremely limited since the severe inflammatory responses lead to secondary damage, and the diseased extracellular matrix (ECM) fails to provide inductive cues for nerve regeneration. To address these dilemmas, herein, we propose a biomaterial-based strategy combining neuroprotection and neuroinduction for SCI repair. Taking advantage of a microfluidic chip, we constructed imine-crosslinked aldehyde-methacrylate-hyaluronan/collagen hybrid hydrogel microfibers incorporating interleukin 4 (IL-4)-loaded ZIF-8 nanoparticles (IL4@ZIF-8 NPs). The hybrid hydrogel microfibers possess pivotal traits mimicking the natural ECM and hold neuroinductive nanoalignment and viscoelasticity, as well as the acidic microenvironment-responsive release of neuroprotective IL-4. Then, we elucidated the role of the tailored hydrogel microfibers in promoting the structural and functional recovery of SCI rats. The implanted hydrogel microfibers incorporating IL4@ZIF-8 NPs protected endogenous neural cells by promoting M2 polarization of recruited macrophages and suppressing inflammation. Additionally, the hydrogel microfibers enhanced neuronal differentiation, accelerated axonal regrowth, synapse formation and remyelination, resulting from their ECM-mimicking oriented nano-topography and viscoelasticity. Moreover, the locomotor function was also improved by the implanted microfibers combining neuroprotective cues and neuroinductive cues. This work not only paves the steps for the development of a novel class of multifunctional hydrogels that manipulate tissue behavior by modifying the cellular microenvironment but also provides intriguing insights for the repair of SCI and even other central nervous system (CNS) injuries via tissue engineering approaches.