A responsive cascade drug delivery scaffold adapted to the therapeutic time window for peripheral nerve injury repair.

Peripheral nerve injury (PNI) is a common clinical challenge, requiring timely and orderly initiation of synergistic anti-inflammatory and reparative therapy. Although the existing cascade drug delivery system can realize sequential drug release through regulation of the chemical structure of drug carriers, it is difficult to adjust the release kinetics of each drug based on the patient's condition. Therefore, there is an urgent need to develop a cascade drug delivery system that can dynamically adjust drug release and realize personalized treatment. Herein, we developed a responsive cascade drug delivery scaffold (RCDDS) which can adapt to the therapeutic time window, in which Vitamin B12 is used in early controllable release to suppress inflammation and nerve growth factor promotes regeneration by cascade loading. The RCDDS exhibited the ability to modulate the drug release kinetics by hierarchically opening polymer chains triggered by ultrasound, enabling real-time adjustment of the anti-inflammatory and neuroregenerative therapeutic time window depending on the patient's status. In the rat sciatic nerve injury model, the RCDDS group was able to achieve neural repair effects comparable to the autograft group in terms of tissue structure and motor function recovery. The development of the RCDDS provides a useful route toward an intelligent cascade drug delivery system for personalized therapy.

Reshaping the Endogenous Electric Field to Boost Wound Repair via Electrogenerative Dressing.

The endogenous electric field (EF) generated by transepithelial potential difference plays a decisive role in wound reepithelialization. For patients with large or chronic wounds, negative-pressure wound therapy (NPWT) is the most effective clinical method in inflammation control by continuously removing the necrotic tissues or infected substances, thus creating a proproliferative microenvironment beneficial for wound reepithelialization. However, continuous negative-pressure drainage causes electrolyte loss and weakens the endogenous EF, which in turn hinders wound reepithelialization. Here, an electrogenerative dressing (EGD) is developed by integrating triboelectric nanogenerators with NPWT. By converting the negative-pressure-induced mechanical deformation into electricity, EGD produces a stable and high-safety EF that can trigger a robust epithelial electrotactic response and drive the macrophages toward a reparative M2 phenotype in vitro. Translational medicine studies confirm that EGD completely reshapes the wound EF weakened by NPWT, and promotes wound closure by facilitating an earlier transition of inflammation/proliferation and guiding epithelial migration and proliferation to accelerate reepithelialization. Long-term EGD therapy remarkably advances tissue remodeling with mature epithelium, orderly extracellular matrix, and less scar formation. Compared with the golden standard of NPWT, EGD orchestrates all the essential wound stages in a noninvasive manner, presenting an excellent prospect in clinical wound therapy.

Hybrid nanogenerator based closed-loop self-powered low-level vagus nerve stimulation system for atrial fibrillation treatment.

Atrial fibrillation is an "invisible killer" of human health. It often induces high-risk diseases, such as myocardial infarction, stroke, and heart failure. Fortunately, atrial fibrillation can be diagnosed and treated early. Low-level vagus nerve stimulation (LL-VNS) is a promising therapeutic method for atrial fibrillation. However, some fundamental challenges still need to be overcome in terms of flexibility, miniaturization, and long-term service of bioelectric stimulation devices. Here, we designed a closed-loop self-powered LL-VNS system that can monitor the patient's pulse wave status in real time and conduct stimulation impulses automatically during the development of atrial fibrillation. The implant is a hybrid nanogenerator (H-NG), which is flexible, light weight, and simple, even without electronic circuits, components, and batteries. The maximum output of the H-NG was 14.8 V and 17.8 µA (peak to peak). In the in vivo effect verification study, the atrial fibrillation duration significantly decreased by 90% after LL-VNS therapy, and myocardial fibrosis and atrial connexin levels were effectively improved. Notably, the anti-inflammatory effect triggered by mediating the NF-κB and AP-1 pathways in our therapeutic system is observed. Overall, this implantable bioelectronic device is expected to be used for self-powerability, intelligentization, portability for management, and therapy of chronic diseases.

Functionalization of TiO2 for Better Performance as Orthopedic Implants.

This review mainly focuses on the surface functionalization approaches of titanium dioxide (TiO2) to prevent bacterial infections and facilitate osteointegration simultaneously for titanium (Ti)-based orthopedic implants. Infection is one of the major causes of implant failure. Meanwhile, it is also critical for the bone-forming cells to integrate with the implant surface. TiO2 is the native oxide layer of Ti which has good biocompatibility as well as enriched physical, chemical, electronic, and photocatalytic properties. The formed nanostructures during fabrication and the enriched properties of TiO2 have enabled various functionalization methods to combat the micro-organisms and enhance the osteogenesis of Ti implants. This review encompasses the various modifications of TiO2 in aspects of topology, drug loading, and element incorporation, as well as the most recently developed electron transfer and electrical tuning approaches. Taken together, these approaches can endow Ti implants with better bactericidal and osteogenic abilities via the functionalization of TiO2.

Artificial tactile perception smart finger for material identification based on triboelectric sensing.

Tactile perception includes the direct response of tactile corpuscles to environmental stimuli and psychological parameters associated with brain recognition. To date, several artificial haptic-based sensing techniques can accurately measure physical stimuli. However, quantifying the psychological parameters of tactile perception to achieve texture and roughness identification remains challenging. Here, we developed a smart finger with surpassed human tactile perception, which enabled accurate identification of material type and roughness through the integration of triboelectric sensing and machine learning. In principle, as each material has different capabilities to gain or lose electrons, a unique triboelectric fingerprint output will be generated when the triboelectric sensor is in contact with the measured object. The construction of a triboelectric sensor array could further eliminate interference from the environment, and the accuracy rate of material identification was as high as 96.8%. The proposed smart finger provides the possibility to impart artificial tactile perception to manipulators or prosthetics.

An Ultra-Simple Charge Supplementary Strategy for High Performance Rotary Triboelectric Nanogenerators.

Free-standing rotary triboelectric nanogenerators (rTENG) can accomplish special tasks which require both high voltage and high frequency. However, the reported high performance rTENG all have complex structures for output enhancement. In this work, an ultra-simple strategy to build high performance rTENG is developed. With only one small paper strip added to the conventional structure, the output of the TENG is promoted hugely. The voltage is triplicated to 2.3 kV, and the current and charge are quintupled to 133 µA and 197 nC, respectively. The small paper strip, with the merits of ultra-simplicity, wide availability, easy accessibility and low cost, functions as a super-effective charge supplement. This simple and delicate structure enables ultra-high durability with the 2.3 kV voltage output 100% maintained after 1 000 000 cycles. This charge supplementary strategy is universally effective for many other materials, and decouples the output enhancement from any friction or contact on the metal electrodes, emphasizing a critical working principle for the rTENG. Atmospheric cold plasma is generated using the paper strip rTENG (ps-rTENG), which demonstrates strong ability to do bacteria sterilization. This simple and persistent charge supplementary strategy can be easily adopted by other designs to promote the output even further.

High-Throughput Identification and Screening of Single Microbial Cells by Nanobowl Array.

High-throughput screening and fast identification of single bacterial cells are crucial for clinical diagnosis, bioengineering, and fermentation engineering. Although single-cell technologies have been developed extensively in recent years, the single-cell technologies for bacteria still need further exploration. In this study, we demonstrate an identification and screening technology for single bacterial cells based on a large-scale nanobowl array, which is well-ordered and size-adjustable for use with different kinds of bacteria. When the culture medium with monodispersed bacteria was placed on the nanobowl array, it successfully enabled loading of single bacterium into a single nanobowl. Because of the limitative size and depth of the nanobowls, mixture of different bacteria species could be screened according to their sizes. In addition, with the help of a low electrical current, the bacteria can be further screened according to their intrinsic surface charges. If combined with micromanipulation technology, high-throughput single bacterial selection can be achieved in future.

An antibacterial platform based on capacitive carbon-doped TiO2 nanotubes after direct or alternating current charging.

Electrical interactions between bacteria and the environment are delicate and essential. In this study, an external electrical current is applied to capacitive titania nanotubes doped with carbon (TNT-C) to evaluate the effects on bacteria killing and the underlying mechanism is investigated. When TNT-C is charged, post-charging antibacterial effects proportional to the capacitance are observed. This capacitance-based antibacterial system works well with both direct and alternating current (DC, AC) and the higher discharging capacity in the positive DC (DC+) group leads to better antibacterial performance. Extracellular electron transfer observed during early contact contributes to the surface-dependent post-charging antibacterial process. Physiologically, the electrical interaction deforms the bacteria morphology and elevates the intracellular reactive oxygen species level without impairing the growth of osteoblasts. Our finding spurs the design of light-independent antibacterial materials and provides insights into the use of electricity to modify biomaterials to complement other bacteria killing measures such as light irradiation.

Nanogenerator for Biomedical Applications.

In the past 10 years, the development of nanogenerators (NG) has enabled different systems to operate without external power supply. NG have the ability to harvest the mechanical energies in different forms. Human body motions and activities can also serve as the energy source to drive NG and enable self-powered healthcare system. In this review, a summary of several major actual applications of NG in the biomedical fields is made including the circulatory system, the neural system, cell modulation, microbe disinfection, and biodegradable electronics. Nevertheless, there are still many challenges for NG to be actually adopted in clinical applications, including the miniaturization, duration, encapsulation, and output performance. It is also very important to further combine the NG development more precisely with the medical principles. In future, NG can serve as highly promising complementary or even alternative power suppliers to traditional batteries for the healthcare electronics.

Antibacterial effects of titanium embedded with silver nanoparticles based on electron-transfer-induced reactive oxygen species.

Although titanium embedded with silver nanoparticles (Ag-NPs@Ti) are suitable for biomedical implants because of the good cytocompatibility and antibacterial characteristics, the exact antibacterial mechanism is not well understood. In the present work, the antibacterial mechanisms of Ag-NPs@Ti prepared by plasma immersion ion implantation (PIII) are explored in details. The antibacterial effects of the Ag-NPs depend on the conductivity of the substrate revealing the importance of electron transfer in the antibacterial process. In addition, electron transfer between the Ag-NPs and titanium substrate produces bursts of reactive oxygen species (ROS) in both the bacteria cells and culture medium. ROS leads to bacteria death by inducing intracellular oxidation, membrane potential variation, and cellular contents release and the antibacterial ability of Ag-NPs@Ti is inhibited appreciably after adding ROS scavengers. Even though ROS signals are detected from osteoblasts cultured on Ag-NPs@Ti, the cell compatibility is not impaired. This electron-transfer-based antibacterial process which produces ROS provides insights into the design of biomaterials with both antibacterial properties and cytocompatibility.

Extracellular Electron Transfer from Aerobic Bacteria to Au-Loaded TiO2 Semiconductor without Light: A New Bacteria-Killing Mechanism Other than Localized Surface Plasmon Resonance or Microbial Fuel Cells.

Titania loaded with noble metal nanoparticles exhibits enhanced photocatalytic killing of bacteria under light illumination due to the localized surface plasmon resonance (LSPR) property. It has been shown recently that loading with Au or Ag can also endow TiO2 with the antibacterial ability in the absence of light. In this work, the antibacterial mechanism of Au-loaded TiO2 nanotubes (Au@TiO2-NT) in the dark environment is studied, and a novel type of extracellular electron transfer (EET) between the bacteria and the surface of the materials is observed to cause bacteria death. Although the EET-induced bacteria current is similar to the LSPR-related photocurrent, the former takes place without light, and no reactive oxygen species (ROS) are produced during the process. The EET is also different from that commonly attributed to microbial fuel cells (MFC) because it is dominated mainly by the materials' surface, but not the bacteria, and the environment is aerobic. EET on the Au@TiO2-NT surface kills Staphylococcus aureus, but if it is combined with special MFC bacteria, the efficiency of MFC may be improved significantly.

Systematic Study of Inherent Antibacterial Properties of Magnesium-based Biomaterials.

Magnesium-based materials are preferred in temporary orthopedic implants because of their biodegradability, mechanical properties, and intrinsic antibacterial properties. However, the fundamental mechanism of bacteria killing and roles of various factors are not clearly understood. In this study, we performed a systematic study of the antibacterial properties of two common Mg-based materials using a biofilm forming bacterium. Complete annihilation of the initial 3 × 10(4) bacteria is achieved with both materials in 0.1 mL LB medium in 24 h, whereas in the control, they proliferate to 10(10). The bacteria are killed more effectively in the solution than on the surface, and the bacteria killing efficiency depends more on the concentrations of the magnesium ions and hydroxyl ions than the corrosion rate. The killing process is reproduced using formula solutions, and killing is revealed to stem from the synergetic effects of alkalinity and magnesium ions instead of either one of them or Mg(OH)2 precipitate. Reactive oxygen species (ROS) are detected from the bacteria during the killing process but are not likely produced by the redox reaction directly, because they are detected at least 3 h after the reaction has commenced. The average cell size increases during the killing process, suggesting that the bacteria have difficulty with normal division which also contributes to the reduced bacteria population.

Mitigation of Corrosion on Magnesium Alloy by Predesigned Surface Corrosion.

Rapid corrosion of magnesium alloys is undesirable in structural and biomedical applications and a general way to control corrosion is to form a surface barrier layer isolating the bulk materials from the external environment. Herein, based on the insights gained from the anticorrosion behavior of corrosion products, a special way to mitigate aqueous corrosion is described. The concept is based on pre-corrosion by a hydrothermal treatment of Al-enriched Mg alloys in water. A uniform surface composed of an inner compact layer and top Mg-Al layered double hydroxide (LDH) microsheet is produced on a large area using a one-step process and excellent corrosion resistance is achieved in saline solutions. Moreover, inspired by the super-hydrophobic phenomenon in nature such as the lotus leaves effect, the orientation of the top microsheet layer is tailored by adjusting the hydrothermal temperature, time, and pH to produce a water-repellent surface after modification with fluorinated silane. As a result of the trapped air pockets in the microstructure, the super-hydrophobic surface with the Cassie state shows better corrosion resistance in the immersion tests. The results reveal an economical and environmentally friendly means to control and use the pre-corrosion products on magnesium alloys.

Engineering and functionalization of biomaterials via surface modification.

It is imperative to control the interactions between biomaterials and living tissues to optimize their therapeutic effects and disease diagnostics. Because most biomaterials do not have the perfect surface properties and desirable functions, surface modification plays an important role in tailoring the surface of biomaterials to allow better adaptation to the physiological surroundings and deliver the required clinical performance. This paper reviews recent progress pertaining to the surface treatment of implantable macro-scale biomaterials for orthopedic and dental applications as well as micro- and nano-biomaterials for disease diagnosis and drug/gene delivery. Recent advances in surface modification techniques encompassing adsorption, deposition, ion implantation, covalent binding, and conversion have spurred more expeditious development of new-generation biomaterials.

Preparation of La1-xKxFeO3 microtubes and their adsorption kinetics of methyl blue.

The nanocrystalline La1-xKxFeO3 (x < or = 0.2) microtubes with a high specific surface area were prepared by the citrate-gel and thermal transformation process. These microtubes were characterized by X-ray diffraction (XRD), Brunauere-Emmette-Teller method (BET), and field emission scanning electron microscopy (FE-SEM). With the increase in K content (x) from 0 to 0.2, the average grain size decreases from 32.4 to 24.4 nm, and the specific surface area increases from 8.9 to 36.4 m2/g. The adsorption of methyl blue was analyzed by UV visible spectrophotometer. The adsorption capacity increases with the increase of the substituted-K content and the surface area of the La1-xKxFeO3 microtubes. The adsorption results shows that all the La1-xKxFeO3 microtubes exhibit a high adsorption activity for methyl blue, with the value of x ranging from 0 to 0.2, the adsorbance increases from 139.7 to 173.7 mg/g at the initial methyl blue concentration of 0.5 mg/mL in aqueous solution, and the kinetics data related to the adsorption of methyl blue onto the La1-xKxFeO3 microtubes are in good agreement with the pseudo-second-order kinetic model in the initial methyl blue concentration of 0.1-0.5 mg/mL.

Synergistic effects of nanosecond pulsed electric fields combined with low concentration of gemcitabine on human oral squamous cell carcinoma in vitro.

Treatment of cancer often involves uses of multiple therapeutic strategies with different mechanisms of action. In this study we investigated combinations of nanosecond pulsed electric fields (nsPEF) with low concentrations of gemcitabine on human oral cancer cells. Cells (Cal-27) were treated with pulse parameters (20 pulses, 100 ns in duration, intensities of 10, 30 and 60 kV/cm) and then cultured in medium with 0.01 µg/ml gemcitabine. Proliferation, apoptosis/necrosis, invasion and morphology of those cells were examined using MTT, flow cytometry, clonogenics, transwell migration and TEM assay. Results show that combination treatments of gemcitabine and nsPEFs exhibited significant synergistic activities versus individual treatments for inhibiting oral cancer cell proliferation and inducing apoptosis and necrosis. However, there was no apparent synergism for cell invasion. By this we demonstrated synergistic inhibition of Cal-27 cells in vitro by nsPEFs and gemcitabine. Synergistic behavior indicates that these two treatments have different sites of action and combination treatment allows reduced doses of gemcitabine and lower nsPEF conditions, which may provide better treatment for patients than either treatment alone while reducing systemic toxicities.

MRI of auto-transplantation of bone marrow-derived stem-progenitor cells for potential repair of injured arteries.

BACKGROUND: This study was to validate the feasibility of using clinical 3.0T MRI to monitor the migration of autotransplanted bone marrow (BM)-derived stem-progenitor cells (SPC) to the injured arteries of near-human sized swine for potential cell-based arterial repair. METHODOLOGY: The study was divided into two phases. For in vitro evaluation, BM cells were extracted from the iliac crests of 13 domestic pigs and then labeled with a T2 contrast agent, Feridex, and/or a fluorescent tissue marker, PKH26. The viability, the proliferation efficiency and the efficacies of Feridex and/or PKH26 labeling were determined. For in vivo validation, the 13 pigs underwent endovascular balloon-mediated intimal damages of the iliofemoral arteries. The labeled or un-labeled BM cells were autotransplanted back to the same pig from which the BM cells were extracted. Approximately three weeks post-cell transplantation, 3.0T T2-weighted MRI was performed to detect Feridex-created signal voids of the transplanted BM cells in the injured iliofemoral arteries, which was confirmed by subsequent histologic correlation. PRINCIPAL FINDINGS: Of the in vitro study, the viability of dual-labeled BM cells was 95-98%. The proliferation efficiencies of dual-labeled BM cells were not significantly different compared to those of non-labeled cells. The efficacies of Feridex- and PKH26 labeling were 90% and 100%, respectively. Of the in vivo study, 3.0T MRI detected the auto-transplanted BM cells migrated to the injured arteries, which was confirmed by histologic examinations. CONCLUSION: This study demonstrates the capability of using clinical 3.0T MRI to monitor the auto-transplantation of BM cells that migrate to the injured arteries of large animals, which may provide a useful MRI technique to monitor cell-based arterial repair.

Magnetic resonance imaging of bone marrow cell-mediated interleukin-10 gene therapy of atherosclerosis.

BACKGROUND: A characteristic feature of atherosclerosis is its diffuse involvement of arteries across the entire human body. Bone marrow cells (BMC) can be simultaneously transferred with therapeutic genes and magnetic resonance (MR) contrast agents prior to their transplantation. Via systemic transplantation, these dual-transferred BMCs can circulate through the entire body and thus function as vehicles to carry genes/contrast agents to multiple atherosclerosis. This study was to evaluate the feasibility of using in vivo MR imaging (MRI) to monitor BMC-mediated interleukin-10 (IL-10) gene therapy of atherosclerosis. METHODOLOGY: For in vitro confirmation, donor mouse BMCs were transduced by IL-10/lentivirus, and then labeled with a T2-MR contrast agent (Feridex). For in vivo validation, atherosclerotic apoE(-/-) mice were intravenously transplanted with IL-10/Feridex-BMCs (Group I, n = 5) and Feridex-BMCs (Group II, n = 5), compared to controls without BMC transplantation (Group III, n = 5). The cell migration to aortic atherosclerotic lesions was monitored in vivo using 3.0T MRI with subsequent histology correlation. To evaluate the therapeutic effect of BMC-mediated IL-10 gene therapy, we statistically compared the normalized wall indexes (NWI) of ascending aortas amongst different mouse groups with various treatments. PRINCIPAL FINDINGS: Of in vitro experiments, simultaneous IL-10 transduction and Feridex labeling of BMCs were successfully achieved, with high cell viability and cell labeling efficiency, as well as IL-10 expression efficiency (≥90%). Of in vivo experiments, MRI of animal groups I and II showed signal voids within the aortic walls due to Feridex-created artifacts from the migrated BMCs in the atherosclerotic plaques, which were confirmed by histology. Histological quantification showed that the mean NWI of group I was significantly lower than those of group II and group III (P<0.05). CONCLUSION: This study has confirmed the possibility of using MRI to track, in vivo, IL-10/Feridex-BMCs recruited to atherosclerotic lesions, where IL-10 genes function to prevent the progression of atherosclerosis.