Interfacial Polarization Locked Flexible ß-Phase Glycine/Nb2 CTx Piezoelectric Nanofibers.

Biomolecular piezoelectric materials show great potential in the field of wearable and implantable biomedical devices. Here, a self-assemble approach is developed to fabricating flexible ß-glycine piezoelectric nanofibers with interfacial polarization locked aligned crystal domains induced by Nb2 CTx nanosheets. Acted as an effective nucleating agent, Nb2 CTx nanosheets can induce glycine to crystallize from edges toward flat surfaces on its 2D crystal plane and form a distinctive eutectic structure within the nanoconfined space. The interfacial polarization locking formed between O atom on glycine and Nb atom on Nb2 CTx is essential to align the ß-glycine crystal domains with (001) crystal plane intensity extremely improved. This ß-phase glycine/Nb2 CTx nanofibers (Gly-Nb2 C-NFs) exhibit fabulous mechanical flexibility with Young's modulus of 10 MPa, and an enhanced piezoelectric coefficient of 5.0 pC N-1 or piezoelectric voltage coefficient of 129 × 10-3 Vm N-1 . The interface polarization locking greatly improves the thermostability of ß-glycine before melting (≈210°C). A piezoelectric sensor based on this Gly-Nb2 C-NFs is used for micro-vibration sensing in vivo in mice and exhibits excellent sensing ability. This strategy provides an effective approach for the regular crystallization modulation for glycine crystals, opening a new avenue toward the design of piezoelectric biomolecular materials induced by 2D materials.

Soft ferroelectret ultrasound receiver for targeted peripheral neuromodulation.

Bioelectronic medicine is a rapidly growing field where targeted electrical signals can act as an adjunct or alternative to drugs to treat neurological disorders and diseases via stimulating the peripheral nervous system on demand. However, current existing strategies are limited by external battery requirements, and the injury and inflammation caused by the mechanical mismatch between rigid electrodes and soft nerves. Here we report a wireless, leadless, and battery-free ferroelectret implant, termed NeuroRing, that wraps around the target peripheral nerve and demonstrates high mechanical conformability to dynamic motion nerve tissue. As-fabricated NeuroRing can act as an ultrasound receiver that converts ultrasound vibrations into electrostimulation pulses, thus stimulating the targeted peripheral nerve on demand. This capability is demonstrated by the precise modulation of the sacral splanchnic nerve to treat colitis, providing a framework for future bioelectronic medicines that offer an alternative to non-specific pharmacological approaches.

Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.

Advances in applications of piezoelectronic electrons in cell regulation and tissue regeneration.

Bioelectricity plays a significant role in major biological processes and electrical stimulation is an effective and non-invasive way to promote cellular growth, differentiation and tissue regeneration. In tissue engineering, piezoelectric materials not only act as modulators to regulate behaviors and functions of cells and tissues, but are also used as scaffolds to regulate and guide cell growth and matrix synthesis, thus promoting the formation of new tissue. Piezoelectronic electrons are produced from piezoelectric materials upon mechanical stimuli and have similar effects on cells as an external electrical field. Devices based on piezoelectronics have been widely applied in bioelectronics and biomedical fields. In this review, the effects of piezoelectronic electrons on cells and their possible mechanisms are briefly introduced. Then, we overview the applications of piezoelectronic electrons in cell regulation and tissue regeneration according to the type of cells and tissues. Finally, future perspectives and challenges are also provided.

Biofeedback electrostimulation for bionic and long-lasting neural modulation.

Invasive electrical stimulation (iES) is prone to cause neural stimulus-inertia owing to its excessive accumulation of exogenous charges, thereby resulting in many side effects and even failure of nerve regeneration and functional recovery. Here, a wearable neural iES system is well designed and built for bionic and long-lasting neural modulation. It can automatically yield biomimetic pulsed electrical signals under the driven of respiratory motion. These electrical signals are full of unique physiological synchronization can give biofeedback to respiratory behaviors, self-adjusting with different physiological states of the living body, and thus realizing a dynamic and biological self-matched modulation of voltage-gated calcium channels on the cell membrane. Abundant cellular and animal experimental evidence confirm an effective elimination of neural stimulus-inertia by these bioelectrical signals. An unprecedented nerve regeneration and motor functional reconstruction are achieved in long-segmental peripheral nerve defects, which is equal to the gold standard of nerve repair -- autograft. The wearable neural iES system provides an advanced platform to overcome the common neural stimulus-inertia and gives a broad avenue for personalized iES therapy of nerve injury and neurodegenerative diseases.

Physiologically Self-Regulated, Fully Implantable, Battery-Free System for Peripheral Nerve Restoration.

The long-segment peripheral nerve injury (PNI) represents a global medical challenge, leading to incomplete nerve tissue recovery and unsatisfactory functional reconstruction. However, the current electrical stimulation (ES) apparatuses fail perfect nerve repair due to their inability of the variable synchronous self-regulated function with physiological states. It is urgent to develop an implantable ES platform with physiologically adaptive function to provide instantaneous and nerve-preferred ES. Here, a physiologically self-regulated electrical signal is generated by integrating a novel tribo/piezoelectric hybrid nanogenerator with a nanoporous nerve guide conduit to construct a fully implantable neural electrical stimulation (FI-NES) system. The optimal neural ES parameters completely originate from the body itself and are highly self-responsive to different physiological states. The morphological evaluation, representative protein expression level, and functional reconstruction of the regenerated nerves are conducted to assess the PNI recovery process. Evidence shows that the recovery effect of 15 mm length nerve defects under the guidance of the FI-NES system is significantly close to the autograft. The designed FI-NES system provides an effective method for long-term accelerating the recovery of PNI in vivo and is also appropriate for other tissue injury or neurodegenerative diseases.

Cell activity modulation and its specific function maintenance by bioinspired electromechanical nanogenerator.

The biophysical characteristics of the extracellular matrix (ECM), such as a three-dimensional (3D) network and bioelectricity, have a profound influence on cell development, migration, function expression, etc. Here, inspired by these biophysical cues of ECM, we develop an electromechanical coupling bio-nanogenerator (bio-NG) composed of highly discrete piezoelectric fibers. It can generate surface piezopotential up to millivolts by cell inherent force and thus provide in situ electrical stimulation for the living cells. Besides, the unique 3D space in the bio-NGs provides an ECM-like growth microenvironment for cells. As a result, our bio-NGs effectively promote cell viability and development and, more importantly, maintain its specific functional expression. These advanced in vitro bio-NGs are expected to fill the gap between the inaccurate 2D systems and the expensive and time-consuming animal models, mimicking the complexity of the ECM and the physiological relevance of an in vivo biological system.

Power Generation from Moisture Fluctuations Using Polyvinyl Alcohol-Wrapped Dopamine/Polyvinylidene Difluoride Nanofibers.

Despite the boom in the water-triggered electric power generation technologies, few attempts have been made with a broader horizonyielding the electricity from sweat, which is of great value for low-power-consumption wearable electronics. Here, an electromechanical coupling and humidity-actuated two-in-one humidity actuator-driven piezoelectric generator (HAPG) are reported, that can yield continuous electric power from fluctuations in the ambient humidity. It is composed of polyvinyl alcohol (PVA)-wrapped highly aligned dopamine (DA)/polyvinylidene fluoride (PVDF) shell/core nanofibers (PVA@DA/PVDF NFs). As-received PVA@DA/PVDF NFs can exchange water with the ambient humidity to perform expansion and contraction and convert them into electric power. An all-fiber-based portable HAPG is fabricated and tested on human palm skin. The devices show high sensitivity and accuracy for converting the mental sweating-derived continuous moisture fluctuations into electric power. This electric power can be stored in capacitors, which is expected to power micro- and nano-electronic devices or be used in electrotherapy such as electrical stimulation to promote wound healing. Beyond this, the obtained voltage profiles exhibit unique features that can reflect the typical sweat damping oscillation curve features.

Dopamine/zinc oxide doped poly(N-hydroxyethyl acrylamide)/agar dual network hydrogel with super self-healing, antibacterial and tissue adhesion functions designed for transdermal patch.

Dual network (DN) hydrogels with excellent mechanical strength and controllable component adjustment characteristics have a broad application range in the field of biomedicine. However, the tissue adhesion, skin affinity, self-healing, and antibacterial properties of DN hydrogels are inadequate for their application as skin patches. In this work, we prepared dopamine/zinc oxide (DOPA/ZnO) doped poly(N-hydroxyethyl acrylamide) (p(HEAA))/agar DN hydrogels and combined them to obtain a bilayer hydrogel (two-layer gel) with moisturizing properties. Upon incorporating 0.86 wt% of dopamine (DOPA), the resultant DOPA/p(HEAA))/agar DN hydrogel (DOPA@DNG) exhibited high tensile strain (up to 1600%), excellent self-repair ability, and tissue adhesion. ZnO/p(HEAA))/agar DN hydrogel (ZnO NG) obtained by incorporating 2 w/v ZnO nanoparticles (ZnO NPs) achieved high tensile strength (1.2 MPa), good antibacterial ability, and low charge transfer resistance. Moreover, ZnO NG, which has a tight structure, was employed as a protective layer for the two-layer gel, which can effectively slow down the excessive evaporation of water to protect the DOPA@DNG stability as a skin patch. Evidence showed that the two-layer hydrogel has water retention. Water retention still remains at over 50% after keeping the hydrogel in air for 3 days. These properties mean the two-layer gel based on the DOPA/ZnO doped DN hydrogels could be used as a transdermal patch for numerous applications in drug delivery, wearable devices, and electronic skin.

High-Performance Poly(vinylidene difluoride)/Dopamine Core/Shell Piezoelectric Nanofiber and Its Application for Biomedical Sensors.

Fabrication of soft piezoelectric nanomaterials is essential for the development of wearable and implantable biomedical devices. However, a big challenge in this soft functional material development is to achieve a high piezoelectric property with long-term stability in a biological environment. Here, a one-step strategy for fabricating core/shell poly(vinylidene difluoride) (PVDF)/dopamine (DA) nanofibers (NFs) with a very high ß-phase content and self-aligned polarization is reported. The self-assembled core/shell structure is believed essential for the formation and alignment of ß-phase PVDF, where strong intermolecular interaction between the NH2 groups on DA and the CF2 groups on PVDF is responsible for aligning the PVDF chains and promoting ß-phase nucleation. The as-received PVDF/DA NFs exhibit significantly enhanced piezoelectric performance and excellent stability and biocompatibility. An all-fiber-based soft sensor is fabricated and tested on human skin and in vivo in mice. The devices show a high sensitivity and accuracy for detecting weak physiological mechanical stimulation from diaphragm motions and blood pulsation. This sensing capability offers great diagnostic potential for the early assessment and prevention of cardiovascular diseases and respiratory disorders.

Molecular simulations and understanding of antifouling zwitterionic polymer brushes.

Zwitterionic materials are an important class of antifouling biomaterials for various applications. Despite such desirable antifouling properties, molecular-level understanding of the structure-property relationship associated with surface chemistry/topology/hydration and antifouling performance still remains to be elucidated. In this work, we computationally studied the packing structure, surface hydration, and antifouling property of three zwitterionic polymer brushes of poly(carboxybetaine methacrylate) (pCBMA), poly(sulfobetaine methacrylate) (pSBMA), and poly((2-(methacryloyloxy)ethyl)phosporylcoline) (pMPC) brushes and a hydrophilic PEG brush using a combination of molecular mechanics (MM), Monte Carlo (MC), molecular dynamics (MD), and steered MD (SMD) simulations. We for the first time determined the optimal packing structures of all polymer brushes from a wide variety of unit cells and chain orientations in a complex energy landscape. Under the optimal packing structures, MD simulations were further conducted to study the structure, dynamics, and orientation of water molecules and protein adsorption on the four polymer brushes, while SMD simulations to study the surface resistance of the polymer brushes to a protein. The collective results consistently revealed that the three zwitterionic brushes exhibited stronger interactions with water molecules and higher surface resistance to a protein than the PEG brush. It was concluded that both the carbon space length between zwitterionic groups and the nature of the anionic groups have a distinct effect on the antifouling performance, leading to the following antifouling ranking of pCBMA > pMPC > pSBMA. This work hopefully provides some structural insights into the design of new antifouling materials beyond traditional PEG-based antifouling materials.

Design of high conductive and piezoelectric poly (3,4-ethylenedioxythiophene)/chitosan nanofibers for enhancing cellular electrical stimulation.

Electroactive nanofibrous scaffold is a vital tool for the study of the various biological research fields from bioelectronics to regenerative medicine, which can provide cell preferable 3D nanofiber architecture and programmed electrical signal. However, intrinsic non-biodegradability is a major problem that hinders its widespread application in the clinic. Herein, we designed, synthesized, and characterized shell/core poly (3,4-ethylenedioxythiophene) (PEDOT)/chitosan (CS) nanofibers by combining the electrospinning and recrystallization processes. Upon incorporating a trace amount of PEDOT (1.0 wt%), the resultant PEDOT/CS nanofibers exhibited low interfacial charge transfer impedance, high electrochemical stability, high electrical conductivity (up to 0.1945 S/cm), and ultrasensitive piezoelectric property (output voltage of 22.5 mV by a human hair prodding). With such unique electrical and conductive properties, PEDOT/CS nanofibers were further applied to brain neuroglioma cells (BNCs) to stimulate their adhesion, proliferation, growth, and development under an optimal external electrical stimulation (ES) and a pulse voltage of 400 mV/cm. ES-responsive PEDOT/CS nanofibers indeed promoted BNCs growth and development as indicated by a large number and density of axons. The synergetic interplay between external ES and piezoelectric voltage demonstrates new PEDOT-based nanofibers as implantable electroactive scaffolds for numerous applications in nerve tissue engineering, human health monitoring, brain mantle information extraction, and degradable microelectronic devices.

Magnetic Janus particles as a multifunctional drug delivery system for paclitaxel in efficient cancer treatment.

Paclitaxel is broad-spectrum anticancer drug which has been widely used in clinic. However, traditional drug delivery often suffers from the scarcity of resources and systemic toxic side effects caused by the localization to non-tumor areas, rendering cancer treatment extremely challenging. To address this problem, we developed a novel multifunctional drug delivery system of a poly(lactic-co-glycolic acid) (PLGA) drug-loaded magnetic Janus particles (DMJPs) using electrohydrodynamic (EDH) co-jetting. The DMJPs were loaded with three compartments each with distinct function, i.e. paclitaxel for killing cancer cell, Fe3O4 nanoparticles for target location, and rhodamine B for fluorescence tracing, respectively. The Janus structure of the DMJPs, as demonstrated by the loaded nano-quantum dots CdS/ZnS and CdSe/ZnS in different compartments, enhanced not only the drug loading and encapsulation efficiency but also the cumulative release rate of the loaded drugs from DMJPs in different media. More importantly, DMJPs exhibited specific and high toxicity only to human breast cancer cells (MDA-MB-231), but not to mouse embryonic fibroblasts (NIH-3 T3). Consistently, DMJPs induced the higher lethal effect on cancer cells than paclitaxel suspension of high concentrations. Under guidance of external magnetic field, DMJPs can readily target and accumulate on and inside cancer cells for cell elimination. The specific targetability, selectivity, and toxicity of DMJPs on cancer cells would greatly avoid any potential side effects and reduce the overdose of drugs for conventional drug delivery. This work hopefully provides a new drug delivery system for the development of anticancer drug systems for clinical and precision medicine treatment.

Core/Shell Piezoelectric Nanofibers with Spatial Self-Orientated ß-Phase Nanocrystals for Real-Time Micropressure Monitoring of Cardiovascular Walls.

Implantable pressure biosensors show great potential for assessment and diagnostics of pressure-related diseases. Here, we present a structural design strategy to fabricate core/shell polyvinylidene difluoride (PVDF)/hydroxylamine hydrochloride (HHE) organic piezoelectric nanofibers (OPNs) with well-controlled and self-orientated nanocrystals in the spatial uniaxial orientation (SUO) of ß-phase-rich fibers, which significantly enhance piezoelectric performance, fatigue resistance, stability, and biocompatibility. Then PVDF/HHE OPNs soft sensors are developed and used to monitor subtle pressure changes in vivo. Upon implanting into pig, PVDF/HHE OPNs sensors demonstrate their ultrahigh detecting sensitivity and accuracy to capture micropressure changes at the outside of cardiovascular walls, and output piezoelectric signals can real-time and synchronously reflect and distinguish changes of cardiovascular elasticity and occurrence of atrioventricular heart-block and formation of thrombus. Such biological information can provide a diagnostic basis for early assessment and diagnosis of thrombosis and atherosclerosis, especially for postoperative recrudescence of thrombus deep within the human body.

Neurogenic differentiation of adipose derived stem cells on graphene-based mat.

Adipose derived stem cells (ADSCs) have been proved as an abundant and accessible cell source with the ability to differentiate into neuron-like cells. However, the low differentiation efficiency puts forward an important challenge to practical applications in clinic. Considering of the good biocompatibility of graphene-based materials and the potential interaction between graphene and cells mentioned in previous studies, herein, we investigated the effect of graphene oxide (GO) and reduced graphene oxide (rGO) mats on neurogenic differentiation of the ADSCs. We demonstrated the excellent capabilities of graphene-based mats, especially GO to support the neural differentiation of ADSCs. By comparing the observation under an optical microscope and fluorescence microscope, the conversion rate of neuron-like cells reached about 90%. We consider that GO mat is better for promoting the differentiation of ADSCs into neuron-like cells, which compared to rGO based platforms. Meanwhile, we made an analysis of the mechanism by which graphene induced the differentiation of ADSCs to neuron-like cells. The data obtained here highlight the effect of GO mat on neurogenic differentiation of ADSCs and implicate the potential of graphene-based materials in application of neural tissue engineering for the limited self-repair capability of nerve cells.

Pure OPM nanofibers with high piezoelectricity designed for energy harvesting in vitro and in vivo.

Due to inhomogeneous molecular structure and inherent flexibility of organic piezoelectric materials, the improvement in piezoelectric performances is extremely challenging. Herein, a novel sheath-gas-assisted electrospinning method was designed to induce rapid recrystallization and a stretching effect on the PVDF molecular chains, which led to significant promotion in the formation of ß and γ crystal phases in PVDF nanofibers and the highest piezoelectric properties reported to date for pure organic piezoelectric materials. By using the PVDF nanofibers for energy harvesting in vivo and in vitro, the motion sensor and implantable nanogenerators displayed excellent sensitivity under an extremely low working frequency of ∼0.1 Hz and considerable output voltage of 0.4-0.6 V cm-2 driven by the femoral artery and carotid artery for the first time. Furthermore, we demonstrated that the nanofibers have outstanding biocompatibility and can provide a spontaneous microelectronic stimulation effect to improve the growth of nerve cells. Thus, we envision that the high-performance piezoelectric nanofibers may serve as a powerful tool for developing future flexible force-sensitive microelectric devices and generators for applications in bioelectronics and biomedicine.

Magnetic electrospun short nanofibers wrapped graphene oxide as a promising biomaterials for guiding cellular behavior.

Magnetic particles show extremely wide application prospects in the biomedical field, particularly in the success of cellular manipulation, drug delivery systems, magnetic hyperthermia and NRI contrast enhancement. Graphene oxide with functional groups has a promising biological effect. In this work, we develop magnetic short-fibers wrapped graphene oxide for guiding cellular behavior with the aid of high-speed shear of nanofibers fabricated through electrospinning technique. The diameter and the length of short-fibers are about 300nm and 80µm, respectively. The short-fibers exhibit superior magnetic properties (saturation magnetization value: 50.33emu/g), which has a strong response appearance to the NdFeB magnet. SEM images and laser confocal images display that there has an extremely tight adhesion between the short-fibers wrapped graphene oxide and cells. The control of cell-fibers structure behavior can be realized by applying external magnet. The results may provide an attractive perspective on the treatment of disease with magnetic field.

Mechanical tension applied to substrate films specifies location of neuritogenesis and promotes major neurite growth at the expense of minor neurite development.

One obstacle in neural repair is facilitating axon growth long enough to reach denervated targets. Recent studies show that axonal growth is accelerated by applying tension to bundles of neurites, and additional studies show that mechanical tension is critical to all neurite growth. However, no studies yet describe how individual neurons respond to tensile forces applied to cell bodies and neurites simultaneously; neither do any test motor neurons, a phenotype critical to neural repair. Here we examine the growth of dissociated motor neurons on stretchable substrates. E15 spinal motor neurons were cultured on poly-lactide-co-glycolide films stretched at 4.8, 9.6, or 14.3 mm day(-1). Morphological analysis revealed that substrate stretching has profound effects on developing motor neurons. Stretching increases major neurite length; it also forces neuritogenesis to occur nearest poles of the cell closest to the sources of tension. Stretching also reduces the number of neurites per neuron. These data show that substrate stretching affects neuronal morphology by specifying locations on the cell where neuritogenesis occurs and favoring major neurite growth at the expense of minor neurites. These results serve as a building block for development of new techniques to control and improve the growth of neurons for nerve repair purposes.

Soft Graphene Nanofibers Designed for the Acceleration of Nerve Growth and Development.

Soft graphene nanofibers with recoverable electrical conductivity and excellent physicochemical stability are prepared by a controlled assembly technique. By using the soft graphene nanofibers for cellular electrical stimulation, the common inhibitory effect of long-term electrical stimulation on nerve growth and development is avoided, which usually happens with traditional 2D conductive materials.

Preparation of N-doped graphene by reduction of graphene oxide with mixed microbial system and its haemocompatibility.

A steady, effective and environment friendly method of introducing nitrogen into graphene is by microbial reduction of graphene oxide with mixed microorganisms from the anode chamber of microbial fuel cells (MFC). Using this method, N-doped graphene is easily obtained under mild conditions and by simple treatment processes, with the N/C ratio reaching 8.14%. Various characterizations demonstrate that the as-prepared N-doped graphene has excellent properties and is comparable with, and in some aspects, even better than, pristine graphene (containing only elemental C) prepared by chemical methods. The N-doped graphene (mainly substitution of C in the plane of the graphene sheet) with uniform distribution of N was haemocompatible, nontoxic, and water-dispersible, all of which are desirable properties for biomaterials and attributable to a synergetic metabolic effect of mixed microorganisms.