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.

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.

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.

"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.

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.

Flexible and temperature-responsive hydrogel dressing for real-time and remote wound healing monitoring.

Wound management is highly clinically desirable due to the complexity and diversity of the wound repair process. However, it is still a major clinical challenge to develop a wound dressing with the capabilities of real-time and remote monitoring during wound healing. Herein, we have designed a polymer-based wound dressing in the form of a conductive, soft, temperature-responsive, antibacterial and biocompatible hydrogel, which is composed of polyacrylic acid (PAA)-grafted poly(N-isopropylacrylamide) (PNIPAM), vinyl-based polyacrylamide (PAM) and silver nanowires (AgNWs). In this hydrogel dressing, PAA-grafted PNIPAM acts as conformal interface and intrinsic temperature-responsive matrix, PAM helps to construct semi-penetrating polymer networks (SIPNs) to improve the mechanical properties, while the AgNWs introduce a three-dimensional conductive hydrogel network with antibacterial properties and sensing properties. The constructed hydrogel matrix was connected to a Bluetooth module to transmit the temperature changes wirelessly to a smart device. The design integrating a conductive hydrogel dressing with a wireless transmission module realized the real-time and wireless monitoring of the wound temperature, which is helpful to provide an early diagnosis of infection. This proof-of-concept study is highly promising in the development of new strategies to significantly improve wound management and other pathological diagnostics or treatments.

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 Bioactive and Photoresponsive Platform for Wireless Electrical Stimulation to Promote Neurogenesis.

Delivering electrical signals to neural cells and tissue has attracted increasing attention in the treatment of nerve injuries. Unlike traditional wired electrical stimulation, wireless and remote light stimulation provides less invasive and longer-lasting interfaces, holding great promise in the treatment of nerve injuries and neurodegenerative diseases, as well as human-computer interaction. Additionally, a bioactive matrix that bridges the injured gap and induces nerve regeneration is essential for injured nerve repair. However, it is still challenging to construct a 3D biomimetic cell niche with optoelectrical responsiveness. Herein, a bioactive platform for remote and wireless optoelectrical stimulation is established by incorporating hydrophilic poly(3-hexylthiophene) nanoparticles (P3HT NPs) into a biomimetic hydrogel matrix. Moreover, the hydrogel matrix is modified by varying the composition and/or the crosslinking degree to meet the needs of different application scenarios. When exposed to pulsed green light, P3HT NPs in hydrogels convert light signals into electrical signals, resulting in the generation of tens of picoampere photocurrent, which is proved to promote the growth of cortical neurons that covered by hydrogels and the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) encapsulated in hydrogels. This work is of great significance for the design of next-generation neural electrodes and scaffolds.