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.

Influence of Surrounding Cations on the Surface Degradation of Magnesium Alloy Implants under a Compressive Pressure.

The effect of cations in the surrounding solutions on the surface degradation of magnesium alloys, a well-recognized biodegradable biomaterial, has been neglected compared with the effect of anions in the past. To better simulate the compressive environment where magnesium alloys are implanted into the body as a cardiovascular stent, a device is designed and employed in the test so that a pressure, equivalent to the vascular pressure, can be directly applied to the magnesium alloy implants when the alloys are immersed in a medium containing one of the cations (K(+), Na(+), Ca(2+), and Mg(2+)) found in blood plasma. The surface degradation behaviors of the magnesium alloys in the immersion test are then investigated using hydrogen evolution, mass loss determination, electron microscopy, pH value, and potentiodynamic measurements. The cations are found to promote the surface degradation of the magnesium alloys with the degree decreased in the order of K(+) > Na(+) > Ca(2+) > Mg(2+). The possible mechanism of the effects of the cations on the surface degradation is also discussed. This study will allow us to predict the surface degradation of magnesium alloys in the physiological environment and to promote the further development of magnesium alloys as biodegradable biomaterials.

Magnesium with micro-arc oxidation coating and polymeric membrane: an in vitro study on microenvironment.

Numerous modification methods have been reported to enhance the corrosion resistance of magnesium with positive results. However, little attention has been paid on their impact on micro-environment, particularly the ion concentration and local pH value. In this study, two different coatings were prepared on magnesium, one with porous micro-arc oxidation (MAO) coating alone, and the other with additional polymer polyhydroxybutyrate (PHB) membrane using spinning technique. Their in vitro corrosional and biological behaviors were investigated and compared. Both coatings were found to reduce the degradation rate of magnesium, but an additionally deposited PHB membrane was superior to MAO-coated magnesium since it could produce a micro-environment with preferable local pH value and ion concentration for osteoblast proliferation. Our study suggests that micro-environment should be another critical issue in evaluation of a modification method for orthopaedic implants.

Taurine-induced fabrication of nano-architectured conducting polypyrrole on biomedical titanium.

In this article, taurine, one of the small biomolecules associated with bone metabolism, is firstly utilized to induce the fabrication of nano-architectured conducting polypyrrole (NCPPy) on biomedical titanium in diverse pH values of phosphate buffer solution (PBS). Accordingly, the possible mechanism for the fabrication of NCPPy is proposed, which is dependent on the states of polytaurine from the polymerization of taurine, i.e., the inability of forming polytaurine and unordered restricted space results in taurine-incorporated and polytaurine-incorporated tightly packed nanoparticles (pH 6.2 and 8.0), respectively, and however, ordered restricted space constructed by polytaurine chains induces the fabrication of polytaurine-incorporated nanopillars (pH 6.8) and polytaurine-incorporated nanowire networks (pH 7.4).

Reversibly controlling preferential protein adsorption on bone implants by using an applied weak potential as a switch.

A facile method is needed to control the protein adsorption onto biomaterials, such as, bone implants. Herein we doped taurocholic acid (TCA), an amphiphilic biomolecule, into an array of 1D nano-architectured polypyrrole (NAPPy) on the implants. Doping TCA enabled the implant surface to show reversible wettability between 152° (superhydrophobic, switch-on state) and 55° (hydrophilic, switch-off state) in response to periodically switching two weak electrical potentials (+0.50 and -0.80 V as a switch-on and switch-off potential, respectively). The potential-switchable reversible wettability, arising from the potential-tunable orientation of the hydrophobic and hydrophilic face of TCA, led to potential-switchable preferential adsorption of proteins as well as cell adhesion and spreading. This potential-switchable strategy may open up a new avenue to control the biological activities on the implant surface.

Tough, Antifreezing, and Piezoelectric Organohydrogel as a Flexible Wearable Sensor for Human-Machine Interaction.

Piezoelectric hydrogel sensors are becoming increasingly popular for wearable sensing applications due to their high sensitivity, self-powered performance, and simple preparation process. However, conventional piezoelectric hydrogels lack antifreezing properties and are thus confronted with the liability of rupture in low temperatures owing to the use of water as the dispersion medium. Herein, a kind of piezoelectric organohydrogel that integrates piezoelectricity, low-temperature tolerance, mechanical robustness, and stable electrical performance is reported by using poly(vinylidene fluoride) (PVDF), acrylonitrile (AN), acrylamide (AAm), p-styrenesulfonate (NaSS), glycerol, and zinc chloride. In detail, the dipolar interaction of the PVDF chain with the PAN chain facilitates the crystal phase transition of PVDF from the α to ß phase, which endows the organohydrogels with a high piezoelectric constant d33 of 35 pC/N. In addition, the organohydrogels are highly ductile and can withstand significant tensile and compressive forces through the synergy of the dipolar interaction and amide hydrogen bonding. Besides, by incorporating glycerol and zinc chloride, the growth of ice crystals is inhibited, allowing the organohydrogels to maintain stable flexibility and sensitivity even at -20 °C. The real-time monitoring of the pulse signal for up to 2 min indicates that the gel sensor has stable sensitivity. It is believed that our organohydrogels will have good prospects in future wearable electronics.

Nanostructured conducting polymers as intelligent implant surface: fabricated on biomedical titanium with a potential-induced reversible switch in wettability.

Conducting polypyrrole (PPy) nanotube arrays, nanotube networks and irregular films are deposited on biomedical titanium. By in situ application of weak periodic potentials, the nanostructured conducting polymers undergo a reversible switch in wettability, which is a redox process of dopant molecules (as hydrophilic groups) immobilized and de-immobilized on the surface of the conducting polymers.

Soft, Super-Elastic, All-Polymer Piezoelectric Elastomer for Artificial Electronic Skin.

Piezoelectric sensors are widely used in wearable devices to mimic the functions of human skin. However, it is considerably challenging to develop soft piezoelectric materials that can exhibit high sensitivity, stretchability, super elasticity, and suitable modulus. In this study, a soft skin-like piezoelectric polymer elastomer composed of poly(vinylidene fluoride) (PVDF) and a novel elastic substrate polyacrylonitrile is prepared by combining the radical polymerization and freeze-drying processes. Dipole-dipole interaction results in the phase transition of PVDF (α phase to ß phase), which enhances the electrical and mechanical performances. Thus, we achieve a high piezoelectric coefficient (d33max = 63 pC/N), good stretchability (211.3-259.3%), super compressibility (subjected to 99% compression strain without cracking), and super elasticity (100% recovery after extreme compression) simultaneously for the elastomer. The soft composite elastomer produces excellent electrical signal output (Vocmax = 253 mV) and responds rapidly (15 ms) to stress-induced polarization effects. In addition, the elastomer-based sensor accurately detects various physiological signals such as gestures, throat vibrations, and pulse waves. The developed elastomers exhibit excellent mechanical properties and high sensitivity, which helps facilitate their application as artificial electronic skin to sense subtle external pressure in real time.

Strong Biopolymer-Based Nanocomposite Hydrogel Adhesives with Removability and Reusability for Damaged Tissue Closure and Healing.

Bioadhesives are widely used in a variety of medical settings due to their ease of use and efficient wound closure and repair. However, achieving both strong adhesion and removability/reusability is highly needed but challenging. Here, we reported an injectable mesoporous bioactive glass nanoparticle (MBGN)-incorporated biopolymer hydrogel bioadhesive that demonstrates a strong adhesion strength (up to 107.55 kPa) at physiological temperatures that is also removable and reusable. The incorporation of MBGNs in the biopolymer hydrogel significantly enhances the tissue adhesive strength due to an increased cohesive and adhesive property compared to the hydrogel adhesive alone. The detachment of bioadhesive results from temperature-induced weakening of interfacial adhesive strength. Moreover, the bioadhesive displays injectability, self-healing, and excellent biocompatibility. We demonstrate potential applications of the bioadhesive in vitro, ex vivo, and in vivo for hemostasis and intestinal leakage closure and accelerated skin wound healing compared to surgical wound closures. This work provides a novel design of strong and removable bioadhesives.

Extracellular Matrix-Based Conductive Interpenetrating Network Hydrogels with Enhanced Neurovascular Regeneration Properties for Diabetic Wounds Repair.

The critical effects that impair diabetic wound healing are characterized by poor vascularization and severe peripheral neuropathy. Current management strategies for diabetic wound healing are unsatisfactory, due to the paucity of neurovascular regeneration at the wound site. Importantly, conductivity in skin tissue is reported to be essential for modulating myriad biological processes especially vascular and nerve regeneration. Herein, an extracellular matrix (ECM)-based conductive dressing is synthesized from an interpenetrating polymer network hydrogel composed of gelatin methacryloyl, oxidized chondroitin sulfate (OCS), and OCS-polypyrrole conductive nanoparticles that can promote diabetic wound repairing by enhancing local neurovascular regeneration. The conductive hydrogels combine the advantageous features of water-swollen hydrogels with conductive polymers (CPs) to provide tissue-matching electrical conductivity and mechanical properties for neurovascular regeneration. In vitro and in vivo studies show that the conductive hydrogel can promote neurovascular regeneration by increasing intracellular Ca2+ concentration, which subsequently promotes phosphorylation of proteins in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways. Furthermore, the conductive hydrogel stimulates full-thickness diabetic wound repair on day 14 by promoting local neurovascular regeneration and collagen deposition. These findings corroborate that the ECM-based conductive interpenetrating network hydrogel dressing significantly promotes wound repairing due to its neurovascular regeneration properties, suggesting that they are suitable candidates for diabetic wound repair.

Dual Receptor-Targeted and Redox-Sensitive Polymeric Micelles Self-Assembled from a Folic Acid-Hyaluronic Acid-SS-Vitamin E Succinate Polymer for Precise Cancer Therapy.

PURPOSE: Poor site-specific delivery and insufficient intracellular drug release in tumors are inherent disadvantages to successful chemotherapy. In this study, an extraordinary polymeric micelle nanoplatform was designed for the efficient delivery of paclitaxel (PTX) by combining dual receptor-mediated active targeting and stimuli response to intracellular reduction potential. METHODS: The dual-targeted redox-sensitive polymer, folic acid-hyaluronic acid-SS-vitamin E succinate (FHSV), was synthesized via an amidation reaction and characterized by 1H-NMR. Then, PTX-loaded FHSV micelles (PTX/FHSV) were prepared by a dialysis method. The physiochemical properties of the micelles were explored. Moreover, in vitro cytological experiments and in vivo animal studies were carried out to evaluate the antitumor efficacy of polymeric micelles. RESULTS: The PTX/FHSV micelles exhibited a uniform, near-spherical morphology (148.8 ± 1.4 nm) and a high drug loading capacity (11.28% ± 0.25). Triggered by the high concentration of glutathione, PTX/FHSV micelles could quickly release their loaded drug into the release medium. The in vitro cytological evaluations showed that, compared with Taxol or single receptor-targeted micelles, FHSV micelles yielded higher cellular uptake by the dual receptor-mediated endocytosis pathway, thus leading to significantly superior cytotoxicity and apoptosis in tumor cells but less cytotoxicity in normal cells. More importantly, in the in vivo antitumor experiments, PTX/FHSV micelles exhibited enhanced tumor accumulation and produced remarkable tumor growth inhibition with minimal systemic toxicity. CONCLUSION: Our results suggest that this well-designed FHSV polymer has promising potential for use as a vehicle of chemotherapeutic drugs for precise cancer therapy.

Wireless Electrochemotherapy by Selenium-Doped Piezoelectric Biomaterials to Enhance Cancer Cell Apoptosis.

Cancer residues around the surgical site remain a significant cause of treatment failure with cancer recurrence. To prevent cancer recurrence and simultaneously repair surgery-caused defects, it is urgent to develop implantable biomaterials with anticancer ability and good biological activity. In this work, a functionalized implant is successfully fabricated by doping the effective anticancer element selenium (Se) into the potassium-sodium niobate piezoceramic, which realizes the wireless combination of electrotherapy and chemotherapy. Herein, we demonstrate that the Se-doped piezoelectric implant can cause mitochondrial damage by increasing intracellular reactive oxygen species levels and then trigger the caspase-3 pathway to significantly promote apoptosis of osteosarcoma cells in vitro. Meanwhile, its good biocompatibility has been verified. These results are of great importance for future deployment of wireless electro- and chemostimulation to modulate biological process around the defective tissue.

The antibacterial effect of potassium-sodium niobate ceramics based on controlling piezoelectric properties.

The implant infection is one of the most serious postsurgical complications of medical device implantation. Therefore, the development of biocompatible materials with improved antibacterial properties is of great importance. It might be a new insight to apply the intrinsic electrical properties of biomaterials to solve this problem. Here, potassium-sodium niobate piezoceramics (K0.5Na0.5NbO3, KNN) with different piezoelectric constants were prepared, and the microstructures and piezoelectric properties of these piezoceramics were evaluated. Moreover, the antibacterial effect and biocompatibility of these piezoceramics were assayed. Results showed that these piezoceramics were able to decrease the colonies of bacteria staphylococcus aureus (S. aureus), favor the rat bone marrow mesenchymal stem cells (rBMSCs) proliferation and promote the cell adhesion and spreading. The above effects were found closely related to the surface positive charges of the piezoceramics, and the sample bearing the most positive charges on its surface (sample 80KNN) had the best performance in both antibacterial effect and biocompatibility. Based on our work, it is feasible to develop biocompatible antibacterial materials by controlling piezoelectric properties.

A spatially varying charge model for regulating site-selective protein adsorption and cell behaviors.

Implanted materials that enter the body first interact with proteins in body fluids, and cells then perceive and respond to the foreign implant through this layer of adsorbed proteins. Thus, spatially specific regulation of protein adsorption on an implant surface is pivotal for mediating subsequent cellular behaviors. Unlike the surface modulation strategy for traditional biomaterials, in this research, materials with a nonuniform spatial distribution of surface charges were designed to achieve site-selective protein adsorption and further influence cell behavior by charge regulation. Spatially varying microdomains with different levels of piezoelectricity were generated via a focus laser beam-induced phase transition. In addition, after polarization, the zones with different levels of piezoelectricity showed significant differences in surface charge density. The results of scanning Kelvin probe force microscopy (SKPM) showed that the surface charge on the material exhibits a nonuniform spatial distribution after laser irradiation and polarization. Site-specific charge-mediated selective protein adsorption was demonstrated through a protein adsorption experiment. Cell behavior analysis showed that the increase in charge density was conducive to promoting cell adhesion and the formation of filopodia while the nonuniform spatial distribution of charge promoted an oriented arrangement of cells; both features accelerated cell migration. This study provides a new method for spatially regulating protein adsorption through surface charges to further influence cell behaviors.

Elastomeric conductive hybrid hydrogels with continuous conductive networks.

Elastomeric conductive hybrid hydrogels (ECHs) combining conducting polymers with elastomeric hydrogels have recently attracted interest due to their wide range of applications in bioelectronics such as wearable or implantable sensing devices. However, the conductivity of ECHs is typically compromised when conductive polymers are used as fillers in hydrogel networks because the inherent limitations of ECHs severely restrict their applicability. Here, we significantly improved the electrical conductivity of ECHs by using a bioinspired catechol derivative, dopamine (DA), as the dopant and mediator for the in situ polymerization of conducting polypyrrole (PPy) within the elastomeric hydrogel dual-networks. In general, ECHs prepared by conventional methods tend to form separate island structures of conductive polymers dispersed within porous hydrogel matrices. We found that a continuous conductive PPy network prepared using the DA mediator facilitated fast electron transfer within the ECHs, which showed good elastomeric mechanical properties, excellent biocompatibility and high force- or strain-responsiveness suitable for implantable strain-sensing applications.

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.

Development and characterization of nanostructured lipid carriers based chitosan thermosensitive hydrogel for delivery of dexamethasone.

This study aims to explore a novel composite thermosensitive in situ gelling formulation which the nanostructured lipid carriers (NLC) was incorporated into hydroxypropyltrimethyl ammonium chloride chitosan (HACC)-based hydrogels, and the resulting formulation investigated for its potential to act as a potential sustained ocular delivery system. NLC formulation loaded with dexamethasone (DXM) were prepared using the melt-emulsification method. The particle size, zeta potential, encapsulation efficiency, and morphological properties of the NLC were characterized. The HACC was synthesized and structure was analyzed by FT-IR and 1H NMR. A thermosensitive hydrogel was designed and prepared by simply mixing HACC and ß-glycerophosphate (ß-GP). The obtained formulation showed a rapid solution-to-gel transition at 35°C. The NLC were then incorporated in HACC/ß-GP hydrogel to form a NLC-loaded hydrogel carrier. In vitro release studies, 88.65% of total DXM was released from the NLC-HACC/GP gel within 3days, indicating DXM-based NLC-gel could release drug sustainably. Taken together, DXM-based NLC-HACC/GP gel is a promising drug delivery system.

Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate.

The aim of this study was to develop and characterize a novel colloidal system, namely, timolol maleate chitosan coated liposomes (TM-CHL) to enhance the ocular permeation, precorneal residence time and bioavailability. The resulting TM-CHL was the most promising formulation with a mean particle size of 150.7nm and an EE% of 75.83±1.61%. In vitro release of the TM-CHL showed an extended drug release profile. The TM-CHL exhibited significant mucin adhesion and compared with commercial eye drops, TM-CHL produced a 3.18-fold increase in the apparent permeability coefficient (Papp), resulting in a significant enhancement of corneal permeation. In addition, the gamma scintigraphic study and the pharmacokinetic study showed that TM-CHL could be retained at the corneal surface for longer time compared with eye drops. The ocular irritation study indicated that the developed liposomes produced no significant irritant effects. Furthermore, pharmacodynamics results showed that the maximum intraocular pressure(IOP) produced by TM-CHL was (19.67±1.14) mmHg compared with the (23.80±1.49) mmHg for TM eye drops, revealing that TM-CHL was more effective in reducing the IOP. These results demonstrate that CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM.

Periodic Nanoneedle and Buffer Zones Constructed on a Titanium Surface Promote Osteogenic Differentiation and Bone Calcification In Vivo.

Rapid and effective bone mineralization at the bone/implant interface is required for successful orthopedic and dental implants. In this study, two periodic microscale functionalized zones on titanium (MZT) are created, namely, nanoneedle zones and buffer zones. The aim of this design is to provide spatially regulated topographical cues on titanium to enhance the efficacy of bone regeneration. This goal is achieved using a versatile and effective technique in which nanoneedle structures are hydrothermally constructed on the surface of titanium sheets, after which selective laser irradiation is used to construct buffer zones. The zonal structures of the MZT overcome the suppressive effect of the nanoneedle film on osteoblasts. Additionally, the MZT exhibits zone-selective apatite deposition and protein adsorption. The accelerated in vitro osteoblast differentiation and nodule deposition on the MZT are confirmed. Elemental analysis of the bone nodules formed by the osteoblasts growing on the titanium and MZT demonstrates they have different compositions. Histological and scanning electron microscope analysis of the bone formation on in vivo implants shows that this process is also enhanced by the MZT implant. The concept of constructing functionalized zones on titanium implant could facilitate future research on improving the design of orthopedic and dental implant surfaces.

The synergistic antibacterial activity and mechanism of multicomponent metal ions-containing aqueous solutions against Staphylococcus aureus.

Silver (Ag+), zinc (Zn2+) and copper (Cu2+) ions, are well known for their broad-spectrum antibacterial activities while generating low resistance. However, whether or multiple metal ions in aqueous solutions acted synergistically or antagonistically antimicrobial properties, remained unknown. Therefore, it was of great significance to investigate the antibacterial properties of multicomponent metal ions-containing aqueous solutions. In this study, the antibacterial activities of multicomponent metal ions-containing aqueous solutions were investigated for the first time. We found that the antibacterial activities of multicomponent metal ions-containing aqueous solutions were higher than those of single metal ion-containing aqueous solution. Furthermore, the synergistic antibacterial mechanism of these multicomponent metal ions-containing aqueous solutions was first investigated. The generation of reactive oxygen species (ROS) through electron transfer in the enzymes and Fenton reactions formed the main synergistic antibacterial mechanism of the multicomponent metal ions-containing aqueous solutions. Therefore, the encouraging results demonstrate the great potential applications of multicomponent metal ions for the design of new biomaterials or prosthesis containing Ag-Cu-Zn alloy which can release Ag+, Zn2+ and Cu2+ and minimize the risk of hospital acquired infection.