During natural tissue regeneration, tissue microenvironment and stem cell niche including cell–cell interaction, soluble factors, and extracellular matrix (ECM) provide a train of biochemical and ...biophysical cues for modulation of cell behaviors and tissue functions. Design of functional biomaterials to mimic the tissue/cell microenvironment have great potentials for tissue regeneration applications. Recently, electroactive biomaterials have drawn increasing attentions not only as scaffolds for cell adhesion and structural support, but also as modulators to regulate cell/tissue behaviors and function, especially for electrically excitable cells and tissues. More importantly, electrostimulation can further modulate a myriad of biological processes, from cell cycle, migration, proliferation and differentiation to neural conduction, muscle contraction, embryogenesis, and tissue regeneration. In this review, endogenous bioelectricity and piezoelectricity are introduced. Then, design rationale of electroactive biomaterials is discussed for imitating dynamic cell microenvironment, as well as their mediated electrostimulation and the applying pathways. Recent advances in electroactive biomaterials are systematically overviewed for modulation of stem cell fate and tissue regeneration, mainly including nerve regeneration, bone tissue engineering, and cardiac tissue engineering. Finally, the significance for simulating the native tissue microenvironment is emphasized and the open challenges and future perspectives of electroactive biomaterials are concluded.
A comprehensive understanding of endogenous bioelectricity and piezoelectricity is provided, along with recent progress in the study of electroactive biomaterials and systems, and their mediated electrostimulation in tissue regeneration.
Owing to their self‐renewal and differentiation ability, stem cells are conducive for repairing injured tissues, making them a promising source of seed cells for tissue engineering. The extracellular ...microenvironment (ECM) is under dynamic mechanical control, which is closely related to stem cell behaviors. During the design and fabrication of biomaterials for regenerative medicine, the physiochemical properties of the natural ECM should be closely mimicked, which can reinforce stem cell lineage choice and tissue engineering. By reproducing the biophysical stimulations that stem cells may experience in vivo, many studies have highlighted the key role of biophysical cues in regulation of cell fate. Optimization of biophysical factors leads to desirable stem cell functions, which can maximize the effectiveness of regenerative treatment. In this review, the main biophysical cues of biomaterials, including stiffness, topography, mechanical force, and external physical fields are summarized, and their individual and synergistic influence on stem cell behavior is discussed. Subsequently, the current progress in tissue regeneration using biomaterials is presented, which directs the design and fabrication of functional biomaterial. The mechanisms via which biophysical cues activate cellular responses are also analyzed. Finally, the challenges in basic research as well as for clinical translation in this field are discussed.
Biophysical cues of biomaterials can simulate the characteristics of natural extracellular matrix to manipulate the fate of stem cells. This review discusses the biophysical cues integrated by functional biomaterials and the cellular response at the cell–biomaterial interface via mechanotransduction. The related application in bone, nerve, and cardiac tissue engineering is also summarized.
Sonodynamic therapy (SDT) is regarded as a new‐rising strategy for cancer treatment with low invasiveness and high tissue penetration, but the scarcity of high‐efficiency sonosensitizers has ...seriously hindered its application. Herein, the iron‐doped and oxygen‐deficient bismuth tungstate nanosheets (BWO‐Fe NSs) with piezotronic effect are synthesized for enhanced SDT. Due to the existence of oxygen defects introduced through Fe doping, the bandgap of BWO‐Fe is significantly narrowed so that BWO‐Fe can be more easily activated by exogenous ultrasound (US). The oxygen defects acting as the electron traps inhibit the recombination of US‐induced electrons and holes. More importantly, the dynamically renewed piezoelectric potential facilitates the migration of electrons and holes to opposite side and causes energy band bending, which further promotes the production of reactive oxygen species. Furthermore, Fe doping endows BWO‐Fe with Fenton reactivity, which converts hydrogen peroxide (H2O2) in tumor microenvironment into hydroxyl radicals (•OH), thereby amplifying the cellular oxidative damage and enhancing SDT. Both in vitro and in vivo experiments illustrate their high cytotoxicity and tumor suppression rate against refractory breast cancer in mice. This work may provide an alternative strategy to develop oxygen‐deficient piezoelectric sonosensitizers for enhanced SDT via doping metal ions.
The work designs high‐performance sonosensitizers via ion doping and defect engineering of piezoelectric nanomaterials for enhanced sonodynamic cancer therapy. The in vitro and in vivo results demonstrate that the iron‐doped and oxygen‐deficient bismuth tungstate nanosheets exhibit enhanced sonodynamic effect and Fenton reactivity to generate reactive oxygen species for cancer therapy.
Electromechanical interaction of cells and extracellular matrix are ubiquitous in biological systems. Understanding the fundamentals of this interaction and feedback is critical to design ...next‐generation electroactive tissue engineering scaffold. Herein, based on elaborately modulating the dynamic mechanical forces in cell microenvironment, the design of a smart piezoelectric scaffold with suitable stiffness analogous to that of collagen for on‐demand electrical stimulation is reported. Specifically, it generated a piezoelectric potential, namely a piezopotential, to stimulate stem cell differentiation with cell traction as a loop feedback signal, thereby avoiding the unfavorable effect of early electrical stimulation on cell spreading and adhesion. This is the first time to adapt to the dynamic microenvironment of cells and meet the electrical stimulation of cells in different states by a constant scaffold, diminishing the cumbersomeness of inducing material transformation or trigging by an external stimulus. This in situ on‐demand electrical stimulation based on cell‐traction‐mediated piezopotential paves the way for smart scaffolds design and future bioelectronic therapies.
An innovative loop feedback strategy between cells and biominic biomaterials is proposed for cell fate modulation. A piezoelectric fibrous network with mechanical stiffness similar to that of collagen can be trigged by cell traction for on‐demand electrical stimulation to promote neuron‐like differentiation. This in situ on‐demand electrical stimulation paves the way for smart scaffold design and future bioelectronic therapies.
Electrospinning (e‐spin) technique has emerged as a versatile and feasible pathway for constructing diverse polymeric fabric structures, which show potential applications in many biological and ...biomedical fields. Owing to the advantages of adjustable mechanics, designable structures, versatile surface multi‐functionalization, and biomimetic capability to natural tissue, remarkable progress has been made in flexible bioelectronics and tissue engineering for the sensing and therapeutic purposes. In this perspective, we review recent works on design of the hierarchically structured e‐spin fibers, as well as, the fabrication strategies from one‐dimensional individual fiber (1D) to three‐dimensional (3D) fiber arrangements adaptive to specific applications. Then, we focus on the most cutting‐edge progress of their applications in flexible bioelectronics and tissue engineering. Finally, we propose future challenges and perspectives for promoting electrospun fiber‐based products toward industrialized, intelligent, multifunctional, and safe applications.
Electrospinning (e‐spin) technique has emerged as a versatile and feasible pathway for constructing polymeric fabric with structural diversity, which show potential applications in flexible bioelectronics and tissue engineering for the sensing and therapeutic purposes. This perspective focus on the fabrication strategies of hierarchically structured e‐spin fibers as well as the most cutting‐edge progress in these application fields. The future challenges and prospects are also highlighted.
The patient‐centered healthcare requires timely disease diagnosis and prognostic assessment, calling for individualized physiological monitoring. To assess the postoperative hemodynamic status of ...patients, implantable blood flow monitoring devices are highly expected to deliver real time, long‐term, sensitive, and reliable hemodynamic signals, which can accurately reflect multiple physiological conditions. Herein, an implantable and unconstrained vascular electronic system based on a piezoelectric sensor immobilized is presented by a “growable” sheath around continuously growing arterial vessels for real‐timely and wirelessly monitoring of hemodynamics. The piezoelectric sensor made of circumferentially aligned polyvinylidene fluoride nanofibers around pulsating artery can sensitively perceive mechanical signals, and the growable sheath bioinspired by the structure and function of leaf sheath has elasticity and conformal shape adaptive to the dynamically growing arterial vessels to avoid growth constriction. With this integrated and smart design, long‐term, wireless, and sensitive monitoring of hemodynamics are achieved and demonstrated in rats and rabbits. It provides a simple and versatile strategy for designing implantable sensors in a less invasive way.
A unconstrained and implantable piezoelectric vascular electronic system for real‐time, long‐term, and wireless hemodynamic monitoring is developed. Bioinspired by nature leaf sheath, a growable sheath with elasticity, and conformal shape adaptive to the dynamically growing arterial vessels is integrated with the piezoelectric biosensor.
The production of reactive oxygen species (ROS) to elicit lethal cellular oxidative damage is an attractive pathway to kill cancer cells, but it is still hindered by the low ROS production efficiency ...of the current methods. Herein, we design a one-dimensional (1D) π-π conjugated ferriporphyrin covalent organic framework on carbon nanotubes (COF-CNT) for activating nanocatalytic and photodynamic cancer therapy. The COF-CNT can catalyze the generation of ROS and O
in the tumor microenvironment (TME), and realize a self-oxygen-supplying PDT under near-infrared (NIR) light irradiation, simultaneously. With the full electron delocalization at the atomically dispersed active center, the catalytic activity of COF-CNT with extended π-conjugation is 6.8 times higher than that without the π-conjugated structure. The formation of the COF structure with π-π conjugation also changes the density of states (DOS) profile of its functional building block for improving PDT. Through one single treatment, it successfully achieves complete tumor regression of 4T1 breast carcinoma in mice with immunoregulation.
The healing process of infected skin lesions is often delayed by many factors including bacterial infection, excessive accumulation of wound exudate, poor local perfusion, and low cell recruitment. ...Development of wound dressing for efficient wound management and promotion of wound healing is a great challenge. Herein, we constructed a Janus nanofiber dressing with the comprehensive capacities of bacterial killing, piezoelectrical stimulation for promoting fibroblast migration, and wound exudate removal
via
unidirectional liquid delivery. The rationally designed Janus nanofibrous dressing with ultrathin, flexible, breathable, and piezoelectric characteristics is fabricated
via
the facile layer-by-layer electrostatic spinning technology. The hydrophilic layer of the dressing is composed of randomly arranged polycaprolactone/gelatin (PCL/Gel) nanofibers, while the hydrophobic layer consists of well-aligned Ag nanoparticles (Ag NPs)-doped piezoelectric polyvinylidene fluoride (PVDF/Ag) nanofibers. The
in vitro
and
in vivo
experimental results demonstrate that the Janus dressing can not only drain excess wound exudate out of the wound unidirectionally and kill local bacteria, but also generate dynamic piezopotential under normal body motions to promote fibroblast proliferation and migration, collagen deposition, angiogenesis, and re-epithelialization, which accelerates rapid wound healing on mice. The smart Janus dressing will provide a new approach for acceleration of wound healing and wound management.
The impaired differentiation ability of resident cells and disordered immune microenvironment in periodontitis pose a huge challenge for bone regeneration. Herein, we construct a piezoelectric ...hydrogel to rescue the impaired osteogenic capability and rebuild the regenerative immune microenvironment through bioenergetic activation. Under local mechanical stress, the piezoelectric hydrogel generated piezopotential that initiates osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) via modulating energy metabolism and promoting adenosine triphosphate (ATP) synthesis. Moreover, it also reshapes an anti-inflammatory and pro-regenerative niche through switching M1 macrophages to the M2 phenotype. The synergy of tilapia gelatin and piezoelectric stimulation enhances in situ regeneration in periodontal inflammatory defects of rats. These findings pave a new pathway for treating periodontitis and other immune-related bone defects through piezoelectric stimulation-enabled energy metabolism modulation and immunomodulation.
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•A wireless piezoelectric hydrogel was developed to generate electric signals effectively under various mechanical stresses.•The piezoelectric stimulation could energize impaired PDLSCs to osteogenic differentiation by boosting Δψm.•The piezoelectric hydrogel rebuilt an anti-inflammatory and pro-regenerative niche by phenotypic switching of macrophages.•The piezoelectric hydrogel enabled a high-quality regeneration of impaired tissue in periodontal inflammatory defects.
Improving output performance of triboelectric nanogenerators (TENGs) is crucial for expanding their applications in smart devices, especially for flexible and wearable bioelectronics. In this study, ...we design and fabricate a flexible, stretchable, and highly transparent TENG based on an unsymmetrical PAM/BTO composite film, made of polyacrylamide (PAM) hydrogel and BaTiO3 nanocubes (BTO NCs, BTO), and the TENG performance can be tailored by adjusting the amount and distribution location of BTO. The stretchable hydrogel electrode could bear over 8 times stretching. By changing the content and distribution location of BTO in the unsymmetrical hydrogel film, the output of the fabricated TENGs could be improved, acting as pressure sensors with high sensitivity to distinguish a spectrum of forces (0.25–6 N) at the low frequency. The mechanism of the enhanced output performance of the PAM/BTO composite hydrogel-based TENG is discussed in detail. By integrating piezoresistive, piezoelectric, and triboelectric effects, the optimized TENG and piezoresistive sensors are used as multimodal biomechanical sensors for detecting the motions of human bodies, pressure, and curvature with high sensitivity.
