Electro-mechanical coupling directs endothelial activities through intracellular calcium ion deployment.

Conversion between mechanical and electrical cues is usually considered unidirectional in cells with cardiomyocytes being an exception. Here, we discover a material-induced external electric field (Eex) triggers an electro-mechanical coupling feedback loop in cells other than cardiomyocytes, human umbilical vein endothelial cells (HUVECs), by opening their mechanosensitive Piezo1 channels. When HUVECs are cultured on patterned piezoelectric materials, the materials generate Eex (confined at the cellular scale) to polarize intracellular calcium ions ([Ca2+]i), forming a built-in electric field (Ein) opposing Eex. Furthermore, the [Ca2+]i polarization stimulates HUVECs to shrink their cytoskeletons, activating Piezo1 channels to induce influx of extracellular Ca2+ that gradually increases Ein to balance Eex. Such an electro-mechanical coupling feedback loop directs pre-angiogenic activities such as alignment, elongation, and migration of HUVECs. Activated calcium dynamics during the coupling further modulate the downstream angiogenesis-inducing eNOS/NO pathway. These findings lay a foundation for developing new ways of electrical stimulation-based disease treatment.

A Pd-catalyzed highly selective three-component protocol for trisubstituted allenes.

Herein we report the first example of a Pd-catalyzed highly selective three-component reaction of alkynyl-1,4-diol dicarbonates, organoboronic acids, and malonate anions for the efficient synthesis of trisubstituted 2,3-allenyl malonates not readily available by the known protocols. The reaction demonstrates an excellent regio- and chemo-selectivity for both the oxidative addition referring to the two C-O bonds and the subsequent coupling with the nucleophile with a remarkable functional group compatibility. A series of control experiments confirm a unique mechanism involving ß-O elimination forming alka-1,2,3-triene and the subsequent insertion of its terminal C[double bond, length as m-dash]C bond into the Ar-Pd bond.

Copper-catalyzed aerobic oxidation of primary alcohols to carboxylic acids.

Here, the first copper-catalyzed aerobic oxidation of primary alcohols to carboxylic acids with TEMPO and KHSO4 as the co-catalysts has been developed. The reaction exhibits excellent substrate scope and functional group compatibility under mild conditions. Even the very sensitive chiral alcohols, chiral amino alcohols, and alcohol-containing steroid skeletons may be oxidized to afford the corresponding carboxylic acids or lactones without racemization.

Reactivity of vinylidene-π-allyl palladium(II) species.

The reactivity of a new type of organometallic intermediate, vinylidene-π-allyl palladium species, has been demonstrated: the reaction between 4-alken-2-ynyl carbonates and stabilized carbon nucleophiles afforded functionalized 1,2,3,-butatriene compounds in moderate to high yields and excellent regioselectivities.

Molecular Mechanism of the Role of Apigenin in the Treatment of Hyperlipidemia: A Network Pharmacology Approach.

The therapeutic effect of apigenin (APG) on hyperlipidemia was investigated using network pharmacology combined with molecular docking strategy, and the potential targets of APG in the treatment of hyperlipidemia were explored. Genetic Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis of common targets were performed. Then, molecular docking was used to predict the binding mode of APG to the target. Finally, Sprague Dawley rats were used to establish a hyperlipidemia model. The expression levels of insulin (INS) and vascular endothelial growth factor A (VEGFA) mRNA in each group were detected by quantitative reverse transcription-polymerase chain reaction. Network pharmacological studies revealed that the role of APG in the treatment of hyperlipidemia was through the regulation of INS, VEGFA, tumor necrosis factor, epidermal growth factor receptor, matrix metalloprotein 9, and other targets, as well as through the regulation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway, fluid shear stress, and atherosclerosis signaling pathways, vascular permeability; APG also participated in the regulation of glucose metabolism and lipid metabolism, and acted on vascular endothelial cells, and regulated vascular tone. Molecular docking showed that APG binds to the target with good efficiency. Experiments showed that after APG treatment, the expression levels of INS and VEGFA mRNA in the model group were significantly decreased (p<0.01). In conclusion, APG has multiple targets and affects pathways involved in the treatment of hyperlipidemia by regulating the HIF-1 signaling pathway, fluid shear stress, and the atherosclerosis pathway.

Janus electro-microenvironment membrane with surface-selective osteogenesis/gingival healing ability for guided bone regeneration.

Guided bone regeneration is widely applied in clinical practice to treat alveolar bone defects. However, the rate of healing of severe alveolar bone defects is slow, and there is a high incidence of soft tissue wound dehiscence. In this study, we propose a barrier membrane with a Janus electro-microenvironment (JEM) to achieve side-selective bone regeneration and soft tissue healing. The JEM membrane was constructed using a polarized polyvinylidene fluoride ferroelectric membrane with different surface potentials on either side. It promoted osteogenic differentiation and bone regeneration on the negatively polarized side (JEM-) and soft tissue regeneration on the positively polarized side (JEM+). Further investigation revealed that the JEM-mediated promotion of bone formation was related to mitochondrial autophagy, as indicated by depolarization of the mitochondrial membrane potential and the expression of LC3, Pink I, and Parkin. Moreover, the gingival healing promoted by JEM+ was related to oxidative phosphorylation in mitochondria, as indicated by the upregulation of mitochondrial complexes I-V and an increase in ATP generation. The design concept of the JEM provides a new avenue for regulating tissue regeneration between different tissue interfaces.

Internal Wireless Electrical Stimulation from Piezoelectric Barium Titanate Nanoparticles as a New Strategy for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive BC subtype with a higher metastatic rate and a worse 5-year survival ratio than the other BC. It is an urgent need to develop a noninvasive treatment with high efficiency to resist TNBC cell proliferation and invasion. Internal wireless electric stimulation (ES) based on piezoelectric materials is an emerging noninvasive strategy, with adjustable ES intensity and excellent biosafety. In this study, three different barium titanate nanoparticles (BTNPs) with different crystal phases and piezoelectric properties were studied. Varying intensities of internal ES were generated from the three BTNPs (i.e., BTO, U-BTO, P-BTO). In vitro tests revealed that the internal ES from BTNPs was efficient at reducing the proliferative potential of cancer cells, particularly BC cells. In vitro experiments on MDA-MB-231, a typical TNBC cell line, further revealed that the internal wireless ES from BTNPs significantly inhibited cell growth and migration up to about 82% and 60%, respectively. In vivo evaluation of MDA-MB-231 tumor-bearing mice indicated that internal ES not only resisted almost 70% tumor growth but also significantly inhibited lung metastasis. More importantly, in vitro and in vivo studies demonstrated a favorable correlation between the anticancer impact and the intensities of ES. The underlying mechanism of MDA-MB-231 cell proliferation and metastasis inhibition caused by internal ES was also investigated. In summary, our results revealed the effect and mechanism of internal ES from piezoelectric nanoparticles on TNBC cell proliferation and migration regulation and proposed a promising noninvasive therapeutic strategy for TNBC with minimal side effects while exhibiting good therapeutic efficiency.

Plasmon-Enhanced Electrocatalysis of Conductive Polymer-Based Nano-Heterojunction for Small Molecule Metabolites Diagnostics.

Conductive polymers are promising electrode candidates in the nonenzymatic catalytic detection of small molecule metabolites, due to the tunable electronic conductivity and versatile modifiability. However, the complex catalytic reaction pathway of conductive polymers results in lower detection sensitivity and a narrower linear range compared with clinical metal-based and carbon-based electrodes. Localized surface plasmon resonance (LSPR), characterized by deep strong light-matter coupling, has great potential in driving surface catalytic reactions at an ultrafast rate. Here, we constructed a salix argyracea-like polypyrrole nanowires/silver nanoparticles (PPy/AgNPs) heterojunction electrode using polydopamine as a dopant and chelator. Through cyclic voltammetry, the Mott-Schottky curve, and COMSOL simulation, we demonstrated that the LSPR-excited photocarriers enhanced PPy/AgNPs electrode electrocatalysis. Thus, the detection current response and linear range were significantly improved under the LSPR excitation when taking glucose and hydrogen peroxide as models of small molecule metabolites. Furthermore, we discussed the LSPR-enhanced detection mechanism of PPy/AgNPs electrode from the aspects of the Tafel slope, the apparent electron diffusion coefficient, and the charge transfer resistance. This strategy opens a new avenue toward the design of LSPR-enhanced conductive polymer electrodes.

In Situ Construction of Black Titanium Oxide with a Multilevel Structure on a Titanium Alloy for Photothermal Antibacterial Therapy.

Postsurgical infection of orthopedic fixation materials is considered to be the main cause of fixation failure. To address the problem, clinical treatment often relies on long-term antibiotics, secondary surgery, and so forth, which cause pain and suffering to patients. Constructing a light-responsive surface structure on the implant has attracted widespread attention for the management of postsurgical infections because of its noninvasiveness and controllability. Nevertheless, the application of light-responsive structures on implants is still limited by their unsafety and instability. In this work, a black titanium oxide layer with a multilevel structure and lattice defects was in situ constructed on a titanium alloy through pulsed laser ablation treatment. Under the synergistic effect of the multilevel structure and crystal defects, the surface of the titanium alloy exhibited good near-infrared light-responsive photothermal ability. The black titanium oxide multilevel structure reached high antibacterial efficiencies of about 99.37 and 99.29% against Staphylococcus aureus and Escherichia coli under 10 min near-infrared light irradiation. Furthermore, the black titanium oxide layer possessed similar biocompatibility compared with the titanium alloy. This near-infrared light-responsive photothermal therapy based on the construction of a multilevel structure and introduction of lattice defects provides an effective strategy for clinical postsurgical infections of orthopedic fixation.

Piezoelectric Hydrogel for Prophylaxis and Early Treatment of Pressure Injuries/Pressure Ulcers.

Pressure injuries/pressure ulcers (PIs/PUs) are a critical global healthcare issue and represent a considerable burden on healthcare resources. Prevention of PIs/PUs is the least costly approach and minimizes the patient suffering compared with treatment. Besides, sustained tissue load alleviation and microenvironment management are the most crucial properties for dressings in PI/PU prevention. Hydrogel dressings have attracted a lot of attention to prevent PIs/PUs because of their unique mechanical properties and ability to manage the microenvironment of skin. However, auxiliary prophylaxis and early treatment of PIs/PUs remain a challenge and an acute clinical demand. Here, we report on an electroactive hydrogel with large stretchability (∼380%) and skinlike ductility, and Young's modulus (0.48 ± 0.03 MPa) matches that of human skin (0.5-1.95 MPa). The hydrogel displayed piezoelectric properties and mechanical-electric response stability and sensitivity. Our results indicated that the hydrogel was able to promote in vitro angiogenesis under piezoelectric stimulation and exhibited biocompatibility, which has the potential for forming fine vessels at the damaged sites of PIs/PUs. Furthermore, finite element analysis and pressure dispersion experiments demonstrated that the hydrogel was suitable for preventing PIs/PUs by redistributing force, reducing tissue distortion, and maintaining the microenvironment for skin. This work offers a new strategy for designing and evaluating the dressing for prophylaxis and the early treatment of PIs/PUs.

Programmable biological state-switching photoelectric nanosheets for the treatment of infected wounds.

Recurrent bacterial infection is a major problem that threatens the tissue repair process. However, most current therapeutic strategies fail to deal with management of the overlap dynamics of bacterial killing and tissue repair. Here, in accord with the different responses of eukaryotic and prokaryotic cells to electric potential, we developed high performance photoelectric BiOCl nanosheets that dynamically switch between conditions that favor either tissue regrowth or antibacterial microenvironments due to light stimulated and bi-modal switching of their surface electrical polarization. In vitro assays demonstrate that, under light illumination, the mannitol modified BiOCl nanosheets show high relative surface potential and achieve robust antibacterial performance. Conversely, under dark conditions, the nanosheets exhibit relatively low surface potential and promote Bone Marrow Stem Cell (BMSCs) proliferation. In vivo studies indicate that BiOCl nanosheets with light switch capabilities promote the significant regeneration of infected skin wounds. This work offers a new insight into treating recurrent bacterial infections with photoelectric biomaterials for light controlled selection of alternative electrical microenvironments, thereby benefiting the capability for either antisepsis or repair of damaged tissues.

Wireless electrical stimulation at the nanoscale interface induces tumor vascular normalization.

Pathological angiogenesis frequently occurs in tumor tissue, limiting the efficiency of chemotherapeutic drug delivery and accelerating tumor progression. However, traditional vascular normalization strategies are not fully effective and limited by the development of resistance. Herein, inspired by the intervention of endogenous bioelectricity in vessel formation, we propose a wireless electrical stimulation therapeutic strategy, capable of breaking bioelectric homeostasis within cells, to achieve tumor vascular normalization. Polarized barium titanate nanoparticles with high mechano-electrical conversion performance were developed, which could generate pulsed open-circuit voltage under low-intensity pulsed ultrasound. We demonstrated that wireless electrical stimulation significantly inhibited endothelial cell migration and differentiation in vitro. Interestingly, we found that the angiogenesis-related eNOS/NO pathway was inhibited, which could be attributed to the destruction of the intracellular calcium ion gradient by wireless electrical stimulation. In vivo tumor-bearing mouse model indicated that wireless electrical stimulation normalized tumor vasculature by optimizing vascular structure, enhancing blood perfusion, reducing vascular leakage, and restoring local oxygenation. Ultimately, the anti-tumor efficacy of combination treatment was 1.8 times that of the single chemotherapeutic drug doxorubicin group. This work provides a wireless electrical stimulation strategy based on the mechano-electrical conversion performance of piezoelectric nanoparticles, which is expected to achieve safe and effective clinical adjuvant treatment of malignant tumors.

Hybrid gelatin/oxidized chondroitin sulfate hydrogels incorporating bioactive glass nanoparticles with enhanced mechanical properties, mineralization, and osteogenic differentiation.

Biopolymer based hydrogels are characteristic of their biocompatibility and capability of mimicking extracellular matrix structure to support cellular behavior. However, these hydrogels suffer from low mechanical properties, uncontrolled degradation, and insufficient osteogenic activity, which limits their applications in bone regeneration. In this study, we developed hybrid gelatin (Gel)/oxidized chondroitin sulfate (OCS) hydrogels that incorporated mesoporous bioactive glass nanoparticles (MBGNs) as bioactive fillers for bone regeneration. Gel-OCS hydrogels could be self-crosslinked in situ under physiological conditions in the presence of borax. The incorporation of MBGNs enhanced the crosslinking and accelerated the gelation. The gelation time decreased with increasing the concentration of MBGNs added. Incorporation of MBGNs in the hydrogels significantly improved the mechanical properties in terms of enhanced storage modulus and compressive strength. The injectability of the hydrogels was not significantly affected by the MBGN incorporation. Also, the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells in vitro and rat cranial defect restoration in vivo were significantly promoted by the hydrogels in the presence of MBGNs. The hybrid Gel-OCS/MBGN hydrogels show promising potential as injectable biomaterials or scaffolds for bone regeneration/repair applications given their tunable degradation and gelation behavior as well as favorable mechanical behavior and osteogenic activities.

Ultrafast and On-Demand Oil/Water Separation Membrane System Based on Conducting Polymer Nanotip Arrays.

Ultrafast oil/water separation based on tunable superwettability switch remains a big challenge. Here, inspired by the ultrafast water transport mechanism in sarracenia, we develop a micro/nanostructured porous membrane with conducting polymer nanotip arrays through the surface-initiated polymerizations. By modulating the height (ranging from 49-529 nm) and redox states of nanotips, a smart reversible superwettability switch is facile to obtain with contact angles of water/oil arranging from 161° to about 0°. Besides, liquid transport speed was accelerated more than 1.5 times by increasing the nanotip length. The water flux could reach up to 50326 L m-2 h-1 (1000 times that of a typical industrial ultrafiltration membrane). This is attributed to the stable and continuous water film along the nanotips, which provide a lubrication layer, leading to an increase of permeability. This work provides significant insights into macro/nanostructured membrane design for smart separation, blood lipid filtration, and smart nanoreactors with high permeability.

Bioactive glass functionalized chondroitin sulfate hydrogel with proangiogenic properties.

Blood vessels play an important role in bone defect repair and growth, and a critical challenge of bone defect repair is the promotion of blood vessel formation. Most of the current methods promote vascularization by adding specific growth factors, which are costly and easy to inactivate. In this study, we developed a covalently cross-linked aminated bioactive glass nanoparticle-chondroitin sulfate methacrylate (ABGN-CSMA) organic-inorganic composite hydrogel with angiogenic properties. The amino groups of the ABGNs form covalent bonds with the carboxyl groups on CSMA. Surface amination modification of BGNs not only improved the dispersion of BGNs in CSMA but also significantly improved the mechanical properties of the composite hydrogel. The largest storage modulus (1200 Pa), the largest loss modulus (560 Pa) and the strongest resistance to deformation of the hydrogel are seen at 10% concentration of ABGNs. Simultaneously, the local pH stability and sustained ion release of the composite hydrogel are conducive to cell adhesion, proliferation, and angiogenesis. This work provides evidence for the development of covalently cross-linked organic-inorganic composite hydrogels with angiogenic properties.

Nanomaterials as photothermal therapeutic agents.

Curing cancer has been one of the greatest conundrums in the modern medical field. To reduce side-effects associated with the traditional cancer therapy such as radiotherapy and chemotherapy, photothermal therapy (PTT) has been recognized as one of the most promising treatments for cancer over recent years. PTT relies on ablation agents such as nanomaterials with a photothermal effect, for converting light into heat. In this way, elevated temperature could kill cancer cells while avoiding significant side effects on normal cells. This theory works because normal cells have a higher heat tolerance than cancer cells. Thus, nanomaterials with photothermal effects have attracted enormous attention due to their selectivity and non-invasive attributes. This review article summarizes the current status of employing nanomaterials with photothermal effects for anti-cancer treatment. Mechanisms of the photothermal effect and various factors affecting photothermal performance will be discussed. Efficient and selective PTT is believed to play an increasingly prominent role in cancer treatment. Moreover, merging PTT with other methods of cancer therapies is also discussed as a future trend.

Polypyrrole Nanocones and Dynamic Piezoelectric Stimulation-Induced Stem Cell Osteogenic Differentiation.

Imitating the physiological microenvironment of living cell and tissues opens new avenues of research into the application of electricity to medical therapies. In this study, dynamic piezoelectric stimulation is generated in a dynamic culture because of the piezoelectric effect of the poly(vinylidene fluoride)-polypyrrole (PVDF-PPy) electroactive composite. Combined with PPy nanocones, dynamic piezoelectric signals are effectively and continuously provided to cells. In the presence of dynamic piezoelectric stimulation and PPy nanocones, PPy-PVDF NS samples show promoted bone mesenchymal stem cell (BMSCs) adhesion, spreadin, and osteogenic differentiation. On the basis of the results of this study, PPy nanocones and dynamic piezoelectric stimulation can be administered to modulate cell behavior, paving the way for the exploration of cellular responses to dynamic electrical stimulation.

Soft Conducting Polymer Hydrogels Cross-Linked and Doped by Tannic Acid for Spinal Cord Injury Repair.

Mimicking soft tissue mechanical properties and the high conductivity required for electrical transmission in the native spinal cord is critical in nerve tissue regeneration scaffold designs. However, fabricating scaffolds of high conductivity, tissue-like mechanical properties, and excellent biocompatibility simultaneously remains a great challenge. Here, a soft, highly conductive, biocompatible conducting polymer hydrogel (CPH) based on a plant-derived polyphenol, tannic acid (TA), cross-linking and doping conducting polypyrrole (PPy) chains is developed to explore its therapeutic efficacy after a spinal cord injury (SCI). The developed hydrogels exhibit an excellent electronic conductivity (0.05-0.18 S/cm) and appropriate mechanical properties (0.3-2.2 kPa), which can be achieved by controlling TA concentration. In vitro, a CPH with a higher conductivity accelerated the differentiation of neural stem cells (NSCs) into neurons while suppressing the development of astrocytes. In vivo, with relatively high conductivity, the CPH can activate endogenous NSC neurogenesis in the lesion area, resulting in significant recovery of locomotor function. Overall, our findings evidence that the CPHs without being combined with any other therapeutic agents have stimulated tissue repair following an SCI and thus have important implications for future biomaterial designs for SCI therapy.

Electroactive polymers for tissue regeneration: Developments and perspectives.

Human body motion can generate a biological electric field and a current, creating a voltage gradient of -10 to -90 mV across cell membranes. In turn, this gradient triggers cells to transmit signals that alter cell proliferation and differentiation. Several cell types, counting osteoblasts, neurons and cardiomyocytes, are relatively sensitive to electrical signal stimulation. Employment of electrical signals in modulating cell proliferation and differentiation inspires us to use the electroactive polymers to achieve electrical stimulation for repairing impaired tissues. Electroactive polymers have found numerous applications in biomedicine due to their capability in effectively delivering electrical signals to the seeded cells, such as biosensing, tissue regeneration, drug delivery, and biomedical implants. Here we will summarize the electrical characteristics of electroactive polymers, which enables them to electrically influence cellular function and behavior, including conducting polymers, piezoelectric polymers, and polyelectrolyte gels. We will also discuss the biological response to these electroactive polymers under electrical stimulation. In particular, we focus this review on their applications in regenerating different tissues, including bone, nerve, heart muscle, cartilage and skin. Additionally, we discuss the challenges in tissue regeneration applications of electroactive polymers. We conclude that electroactive polymers have a great potential as regenerative biomaterials, due to their ability to stimulate desirable outcomes in various electrically responsive cells.

Directing Induced Pluripotent Stem Cell Derived Neural Stem Cell Fate with a Three-Dimensional Biomimetic Hydrogel for Spinal Cord Injury Repair.

Current treatment approaches for spinal cord injuries (SCIs) are mainly based on cellular transplantation. Induced pluripotent stem cells (iPSCs) without supply constraints and ethical concerns have emerged as a viable treatment option for repairing neurological disorders. However, the primarily limitations in the neuroregeneration field are uncontrolled cell differentiation, and low cell viability caused by the ischemic environment. The mechanical property of three-dimensional (3D) hydrogel can be easily controlled and shared similar characteristics with nerve tissue, thus promoting cell survival and controlled cell differentiation. We propose the combination of a 3D gelatin methacrylate (GelMA) hydrogel with iPSC-derived NSCs (iNSCs) to promote regeneration after SCI. In vitro, the iNSCs photoencapsulated in the 3D GelMA hydrogel survived and differentiated well, especially in lower-moduli hydrogels. More robust neurite outgrowth and more neuronal differentiation were detected in the soft hydrogel group. To further evaluate the in vivo neuronal regeneration effect of the GelMA hydrogels, a mouse spinal cord transection model was generated. We found that GelMA/iNSC implants significantly promoted functional recovery. Further histological analysis showed that the cavity areas were significantly reduced, and less collagen was deposited in the GelMA/iNSC group. Furthermore, the GelMA and iNSC combined transplantation decreased inflammation by reducing activated macrophages/microglia (CD68-positive cells). Additionally, GelMA/iNSC implantation showed striking therapeutic effects of inhibiting GFAP-positive cells and glial scar formation while simultaneously promoting axonal regeneration. Undoubtedly, use of this 3D hydrogel stem cell-loaded system is a promising therapeutic strategy for SCI repair.