Unconstrained Piezoelectric Vascular Electronics for Wireless Monitoring of Hemodynamics and Cardiovascular Health.

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.

Enhanced Sonodynamic Cancer Therapy through Iron-Doping and Oxygen-Vacancy Engineering of Piezoelectric Bismuth Tungstate Nanosheets.

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 (H2 O2 ) 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.

Piezoelectric Ba0.85 Sr0.15 TiO3 Nanosonosensitizer with Nitric Oxide Delivery for Boosting Cancer Therapy.

The efficacy of sonodynamic therapy (SDT) mainly relies on the sonosensitizers, which generate reactive oxygen species (ROS) upon ultrasound (US) stimulation. However, the limited availability of high-efficiency sonosensitizers hampers the therapeutic effectiveness of SDT as a standalone modality. In this work, a robust sonodynamic and gas cancer therapeutic platform is constructed based on strontium (Sr) doped barium titanate (BST) piezoelectric nanoparticles functionalized with L-arginine (BST@LA). The doping of Sr into A site of the ABO3 piezoelectric nanocrystals not only introduces oxygen vacancies into the nanoparticles and enhance the intrinsic piezoelectricity, but also narrows the semiconductor band gap and enhances charge carrier migration, all of which facilitate the sonodynamic production of superoxide anion (•O2 - ) and hydroxyl radical (•OH). In addition, the generated ROS promotes the decomposition of the surface-tethered LA, enabling the controlled release of nitric oxide (NO) gas at the tumor site, thereby achieving a combination therapeutic effect. In vivo experiments exhibit remarkable tumor suppression rate (89.5%) in 4T1 tumor mice model, demonstrating the effectiveness of this strategy. The ion doping and oxygen vacancy engineering to improve sonosensitizers, along with the synergistic combination of sonodynamic and gas therapy, provides promising avenues for improving cancer therapy.

Manganese Dioxide Coated Piezoelectric Nanosonosensitizer for Cancer Therapy with Tumor Microenvironment Remodeling and Multienzyme-Like Catalysis.

Sonodynamic therapy (SDT) as an emerging method for cancer therapy has encountered difficulty in insufficient production of reactive oxygen species (ROS), especially in tumor microenvironment (TME) with elevated antioxidants and hypoxic conditions. In this work, the authors have fabricated heterostructured manganese dioxide (MnO2)-coated BaTiO3 nanoparticles (BTO@M NPs) as a piezoelectric sonosensitizer, which exhibits the capacity of remodeling TME and multienzyme-like catalysis for boosting SDT. Benefitting from the piezotronic effect, the formation of a p-n junction between MnO2 and piezoelectric BTO with a built-in electric field and band bending efficiently promotes the separation of charge carriers, facilitating the generation of superoxide anion (•O2 -) and hydroxyl radical (•OH) under ultrasound (US) stimulation. Moreover, BTO@M NPs can catalyze the overexpressed hydrogen peroxide (H2O2) in TME to produce oxygen for replenishing the gas source in SDT, and also deplete antioxidant glutathione (GSH), realizing TME remodeling. During this process, the reduced Mn(II) can convert H2O2 into •OH, further amplifying cellular oxidative damage. With these combination effects, the versatile BTO@M NPs exhibit prominent cytotoxicity and tumor growth inhibition against 4T1 breast cancer. This work provides a feasible strategy for constructing high-efficiency sonosensitizers for cancer SDT.

Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation.

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.

Self-Driven Electrical Stimulation-Promoted Cancer Catalytic Therapy and Chemotherapy Based on an Implantable Nanofibrous Patch.

The efficacy of cancer catalytic therapy is still hindered by the inefficient generation of reactive oxygen species (ROS). Herein, we report a self-driven electrical stimulation-promoted cancer catalytic therapy and chemotherapy by integrating a human-driven triboelectric nanogenerator (TENG) with an implantable and biodegradable nanofibrous patch. The gelatin/polycaprolactone nanofibrous patch incorporates doxorubicin (DOX) and graphitic carbon nitride (g-C3N4), in which the peroxidase (POD)-like activity of g-C3N4 to produce hydroxyl radical (•OH) can be distinctly enhanced by the self-driven electrical stimulation for 4.12-fold, and simultaneously DOX can be released to synergize the therapy, especially under a weakly acidic tumor microenvironment (TME) condition. The in vitro and in vivo experimental results on a mouse breast cancer model demonstrate superior tumor suppression outcome. The self-powered electrical stimulation-enhanced catalytic therapy and chemotherapy via multifunctional nanofibrous patches proposes a new complementary strategy for the catalytic therapy of solid tumors.

Manganese oxide-modified bismuth oxychloride piezoelectric nanoplatform with multiple enzyme-like activities for cancer sonodynamic therapy.

Sonodynamic therapy (SDT) is considered as a new-rising strategy for cancer therapeutics, but the inefficient production of reactive oxygen species (ROS) by current sonosensitizers seriously hinders its further applications. Herein, a piezoelectric nanoplatform is fabricated for enhancing SDT against cancer, in which manganese oxide (MnOx) with multiple enzyme-like activities is loaded on the surface of piezoelectric bismuth oxychloride nanosheets (BiOCl NSs) to form a heterojunction. When exposed to ultrasound (US) irradiation, piezotronic effect can remarkably promote the separation and transport of US-induced free charges, and further enhance ROS generation in SDT. Meanwhile, the nanoplatform shows multiple enzyme-like activities from MnOx, which can not only downregulate the intracellular glutathione (GSH) level, but also disintegrate endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) and hydroxyl radicals (•OH). As a result, the anticancer nanoplatform substantially boosts ROS generation and reverses tumor hypoxia. Ultimately, it reveals remarkable biocompatibility and tumor suppression in a murine model of 4 T1 breast cancer under US irradiation. This work provides a feasible pathway for improving SDT using piezoelectric platforms.

Emerging polymeric electrospun fibers: From structural diversity to application in flexible bioelectronics and tissue engineering.

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.

Stretchable Unsymmetrical Piezoelectric BaTiO3 Composite Hydrogel for Triboelectric Nanogenerators and Multimodal Sensors.

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.

Piezotronic Effect-Augmented Cu2-xO-BaTiO3 Sonosensitizers for Multifunctional Cancer Dynamic Therapy.

Ultrasound (US)-triggered sonodynamic therapy (SDT) based on semiconductor nanomaterials has attracted considerable attention for cancer therapy. However, most inorganic sonosensitizers suffer from low efficiency due to the rapid recombination of electron-hole pairs. Herein, the Cu2-xO-BaTiO3 piezoelectric heterostructure was fabricated as a sonosensitizer and chemodynamic agent, simultaneously, for improving reactive oxygen species (ROS) generation and cancer therapeutic outcome. Under US irradiation, the Cu2-xO-BaTiO3 heterojunction with a piezotronic effect exhibits high-performance singlet oxygen (1O2) and hydroxyl radical (•OH) generation to enhance SDT. Moreover, it possesses Fenton-like reaction activity to convert endogenous H2O2 into •OH for chemodynamic therapy (CDT). The integration of SDT and CDT substantially boosts ROS generation and cellular mitochondria damage, and the in vitro and in vivo results demonstrate high cytotoxicity and tumor inhibition on murine refractory breast cancer. This work realizes improvement in cancer therapy using piezoelectric heterostructures with piezotronic effects.

Acidity-responsive nanocages as robust reactive oxygen species generators with butterfly effects for maximizing oxidative damage and enhancing cancer therapy.

Recently, with the rational design of transition metal-containing nanoagents, chemodynamic therapy (CDT) has been developed and considered a promising method for cancer therapy through Fenton and Fenton-like reaction-induced hydroxyl radical (·OH) generation and cellular oxidative damage. However, it is still a great challenge to realize high reactive oxygen species (ROS) generation and therapeutic efficiency under the strict conditions of the tumor microenvironment (TME). Herein, we design and fabricate a TME-responsive core-shell nanocage composed of a CaCO3 nanolayer and a heterogeneous CoP core (CaCO3@CoP, CCP) with the synergy of CDT and calcium overload to maximize oxidative damage and enhance cancer therapy. The CaCO3 nanoshell is sensitive to pH and can be rapidly degraded upon endocytosis, leading to intracellular Ca2+ accumulation, which further triggers the production of mitochondrial ROS. Subsequently, the CoP hollow nanocage with fully exposed Co active sites has high Fenton-like reactive activity to produce ·OH and induce mitochondrial damage. Mitochondrial damage and ROS elevation, in turn, can modulate Ca2+ dynamics and augment calcium overload. The reciprocal interaction and loop feedback between calcium overload and photoenhanced ROS generation via photothermal therapy (PTT) can further trigger the immunogenic cell death (ICD) process to activate the maturation of dendritic cells (DCs), activation of cytotoxic and helper T cells, and excretion of proinflammatory cytokines to enhance antitumor immunity in vivo. With the butterfly effect, CCP finally brings forth a greatly enhanced cancer therapeutic outcome in murine models.

Electroactive Biomaterials and Systems for Cell Fate Determination and Tissue Regeneration: Design and Applications.

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.

π-π conjugation promoted nanocatalysis for cancer therapy based on a covalent organic framework.

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 O2 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.

Cell-Traction-Triggered On-Demand Electrical Stimulation for Neuron-Like Differentiation.

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.