Inflammation-Responsive Drug-Loaded Hydrogels with Sequential Hemostasis, Antibacterial, and Anti-Inflammatory Behavior for Chronically Infected Diabetic Wound Treatment.

Developing a promising on-demand controllable microneedle drug delivery system could provide stronger self-control and precision delivery of a large payload capacity. Nevertheless, the efficacy of existing systems has been constrained by limitations in the therapeutic payload capacity and slow diffusion of molecules, as well as the necessity for external resource configurations. Drawing inspiration from the multidimensional biomimetic strategies observed in the material properties and functional mechanisms of the bombardier beetle’s defensive secretion system, a battery-free and self-propelled biomimetic microneedle system (BSBMs) is proposed for improving therapeutic outcomes and enabling controlled, on-demand drug delivery. The self-powered microneedle delivery platform fully emulates the structure and spray mechanism of bombardier, employing Pt nanoparticles and H2O2 loaded in the reaction chamber, as a built-in fuel source for active and controllable payload delivery. The robust bionic gas injector can serve as an active engine, facilitating the effective permeation of drugs through hollow microneedles without a complex pumping system. This BSBMs triggers the H2O2 decomposition reaction through thumb pressure, generating O2 pressure as an endogenous driving force to achieve transdermally precise and on-demand drug delivery. The pharmacokinetics of drug release from the BSBMs were evaluated in vivo by quantifying the levels of levonorgestrel (LNG). This active delivery system maintains in vivo LNG concentrations within the therapeutic window range, greatly enhancing on-demand, controlled, and stable drug delivery. This versatile and efficient self-propelled bionic microneedle delivery technology holds substantial promise for a broad spectrum of transdermal therapeutic applications, offering a simplified, convenient, and improved method of administration.

Microneedles (MNs) are a new type of drug delivery method that can be regarded as an alternative to traditional transdermal drug delivery systems. Recently, MNs have attracted widespread attention for their advantages of effectiveness, safety, and painlessness. However, the functionality of traditional MNs is too monotonous and limits their application. To improve the efficiency of disease treatment and diagnosis by combining the advantages of MNs, the concept of intelligent stimulus-responsive MNs is proposed. Intelligent stimuli-responsive MNs can exhibit unique biomedical functions according to the internal and external environment changes. This review discusses the classification and principles of intelligent stimuli-responsive MNs, such as magnet, temperature, light, electricity, reactive oxygen species, pH, glucose, and protein. This review also highlights examples of intelligent stimuli-responsive MNs for biomedical applications, such as on-demand drug delivery, tissue repair, bioimaging, detection and monitoring, and photothermal therapy. These intelligent stimuli-responsive MNs offer the advantages of high biocompatibility, targeted therapy, selective detection, and precision treatment. Finally, the prospects and challenges for the application of intelligent stimuli-responsive MNs are discussed.

Upconversion nanoparticles coated organic photovoltaics for near infrared light controlled drug delivery systems

A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy.

Reactive oxygen species-responsive polydopamine-PtCuTe nanoparticle-loaded microneedle system for promoting the healing of infected skin wounds

Backgrounds: The buildup of reactive oxygen species (ROS) in infected wounds triggers an excessive inflammatory response, while the overuse of antibiotics has contributed to increased bacterial resistance. Therefore, developing wound dressings that effectively eliminate ROS and inhibit bacterial growth is crucial. Methods: Inspired by mussel-derived proteins, we developed a polydopamine (PDA)-grafted MXene (PDA@MXene) and 3,4-dihydroxyphenylalanine-PonG1 (DOPA-PonG1)-modified photosensitive poly(vinyl alcohol) (PVA) hydrogel as a wound dressing. PDA@MXene was synthesized through dopamine self-polymerization on the MXene surface, while tyrosine hydroxylation was used to introduce DOPA into the antibacterial peptide ponericin G1 (PonG1). The hydrogel and its components were characterized, and their morphology was examined. The hydrogel's hemostatic ability, mechanical properties, and conductivity were evaluated. In vitro studies systematically evaluated antioxidative effects, antibacterial activity, biocompatibility, and expression of tissue regeneration-related factors. An infected full-thickness skin defect model was established in vivo, and different hydrogel treatments were applied. The wound-healing rate was then measured, followed by histological analysis using hematoxylin and eosin, Masson, Sirius Red, and immunofluorescence staining to investigate the healing mechanism. Results: The DOPA sequence enhanced PonG1 stability on the hydrogel surface, leading to sustained antibacterial ability. PDA@MXene significantly improved the hydrogel's conductivity and mechanical strength. Notably, the combined effects of DOPA-PonG1 and PDA@MXene contributed to enhanced antibacterial and ROS-scavenging properties. In vivo findings demonstrated that the DOPA-PonG1/PDA@MXene/PVA hydrogel accelerated infected wound healing by promoting angiogenesis and collagen deposition while reducing excessive inflammation. This study presents an innovative approach for treating infected wound defects and holds promise for clinical applications.

Currently available drug delivery systems for oral diseases suffer from short retention time and poor local concentrations at the target site. A biodegradable stimulus-responsive hydrogel was synthesized in the present study to evaluate its application as an environmentally sensitive carrier for on-demand intraoral drug delivery. The hydrogel was synthesized from diacrylate-containing polyethylene glycol–based scaffolds and a cysteine-terminated peptide crosslinker (CGPQG↓IWGQC) via a Michael-type addition reaction. Because CGPQG↓IWGQC can be cleaved by matrix metalloproteinase 8 (MMP-8), minocycline hydrochloride, bovine serum albumin, or an antibacterial peptide (KSL) was incorporated into the scaffolds to evaluate the MMP-8-responsive release behavior of the on-demand drug delivery system. Hydrogel characterization and gelation kinetics were examined with gel time, Fourier-transform infrared spectroscopy, scanning electron microscopy, and measurements of rheologic parameters. Degradation behavior and MMP-8-responsive drug release were performed by high-performance liquid chromatography and protein-specific assay. Biocompatibility evaluation indicated that the hydrogels were noncytotoxic. Antibacterial testing demonstrated that the released drugs were able to maintain bioactivity. Taken together, these results suggest that the MMP-8-sensitive hydrogel is a promising candidate for on-demand intraoral localized drug delivery. Because MMP-8 is one of the most important biomarkers for periodontitis, the MMP-8-responsive hydrogel has potential to be used for in situ adaptive degradation in response to chronic periodontitis and peri-implantitis. This notion has to be tested in animal models of periodontal disease.

Reactive oxygen species scavenging nanofibers with chitosan-stabilized Prussian blue nanoparticles for enhanced wound healing efficacy

Controlled and sequential drug delivery is a strategy to enhance the therapeutic effectiveness of drugs in a variety of biological processes and disease states. While many different drug delivery systems are developed recently, most cannot generate temporally complex delivery profiles of multiple therapeutics. These temporally complex profiles are critical for applications such as bone regeneration and cancer chemotherapy, where an orchestrated delivery of multiple drugs is required for an optimal outcome. Here, we developed three distinct biomaterial systems that each enable on-demand controlled or sequential drug release. These systems are based on varying external stimulus such as magnetic stimulation, radiofrequency heating, and near infrared (NIR) laser irradiation. The first system is a dual compartment hydrogel composed of an outer gelatin partition and an inner alginate ferrogel. While the outer compartment could be loaded with a recruitment factor to recruit and harbor cells, the inner compartment was capable of retaining and releasing a differentiation factor on-demand. The inner compartment was a biphasic ferrogel and stimulation was conducted using a custom magnetic stimulation set up. It was shown that delayed differentiation factor delivery can enhance mMSCs’ osteo-differentiation outcomes using 2D and 3D cell cultures. The second system is a magnetoliposome (ML) integrated hydrogel system. In this design, different sizes of magnetic iron oxide nanoparticles (IONPs) were used to develop two different MLs: ML-A and ML-B. Cationic and zwitterionic lipids were used to form positively charged liposomes that could electrostatically adsorb the IONPs on their surfaces and form MLs. The ratio of IONP/lipid was optimized to form stable ML-A and ML-B structures. These structures were integrated within 3D alginate hydrogels to enhance stability and provide localized drug delivery. As the different MLs could be stimulated at different frequencies, complex delivery profiles could be generated using these MLs in hydrogels. Controlled and delayed releases of a model drug (FITC-Dextran) from ML-A and ML-B in hydrogels were demonstrated. The third system is a single-walled carbon nanotube (SWCNT) liposome complex (CLC) integrated hydrogel. Here, unique NIR absorbance properties of SWCNTs were used to achieve drug release from liposomal structures. DNA sequences were used to wrap SWCNTs to uniformly disperse them in an aqueous solution and provide negative charge on their surface. These DNA-SWCNTs were then mixed with cationic liposomes to form CLCs. Optimal SWCNT to lipid ratio to form stable CLCs were determined. CLCs were then integrated within hydrogel structures and drug release was controlled using

Surgical site infections continue to be a common complication affecting surgical prognosis. Reactive oxygen species (ROS) are generated by ultrasound-irradiated titanium dioxide (TiO2 ) (UIT). Although excessive ROS production can cause cell damage, ROS at physiological levels mediate beneficial cellular responses, including angiogenesis. This study investigated whether UIT can promote healing of Escherichia coli-infected wounds. We used TiO2 and ultrasound irradiation using an ultrasonography machine at a frequency of 1.0 MHz and intensity of 0.4 W cm-2 . These levels are not bactericidal in vitro; therefore, we could study the effect of UIT on E. coli survival without interference of ultrasound effects. The number of cluster of differentiation 31-positive blood vessels, which are indicative of angiogenesis, was decreased by bacterial infection, and increased at the wound edges in the UIT-treated infected wounds, suggesting upregulation of neovascularization by UIT. Although UIT treatment did not decrease E. coli survival in vivo, it promoted healing of the infected wounds as evidenced by a significant decrease in the wound area in the UIT-treated mice. Our findings demonstrate that UIT promotes wound healing in surgical site infections and suggest beneficial use of the UIT-based approach as a novel therapeutic method to treat infected surgical wounds. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2344-2351, 2017.

The relevance of active research lies in the need to develop new technologies to improve drug delivery methods for the effective treatment of wound healing. Additionally, the potential application of organogels in other areas of biomedicine, such as creating medical patches with controlled drug delivery, indicates a wide range of possibilities for using this technology. This study focuses on developing controlled drug delivery systems using organogels as carriers for ceftriaxone and ofloxacin. By selecting optimal formulations, organogels were created to immobilize the drugs, facilitating their effective and sustained release. The swelling behavior of the hydrogels was studied, showing a swelling coefficient between 16 and 32%, indicating their ability to absorb liquid relative to their weight. Drug release studies demonstrated that ceftriaxone was released 1.8 times slower than ofloxacin, ensuring a more controlled delivery. Microbiological tests confirmed that the organogels containing ofloxacin exhibited antimicrobial activity against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. However, it was a challenge to estimate activity for the model antibiotic ceftriaxone due to bacterial resistance to it. Organogel poly(vinyl alcohol) (PVA)-DMSO-alginate modifications with surfactant cetylpyridinium bromide led to the formation of a polyelectrolyte complex on the interphase, allowing further enhanced the prolonged release of the drugs. The research identified that the optimal compositions for sustained drug release were organogels with compositions PVA (10%)-PVP (1%) DMSO (50%) and PVA (10%)-DMSO (50%) formulations, illustrating the transparent nature of these organogels making them suitable for ophthalmological application. Various organogels compositions (PVA-DMSO, PVA-poly(vinylpyrrolidone)-DMSO, PVA-DMSO-alginate, PVA-DMSO-PLGA, PVA-DMSO-drug-surfactant) loaded with ceftriaxone, ofloxacin, and surfactant were prepared and characterized, highlighting their potential use in antibiotic patches for wound healing. These organogels illustrate promising results for localized treatment of infections in wounds, cuts, burns, and other skin lesions.

Reducing the burden of death due to wound infection is an urgent global public health priority. Metal-phenolic networks (MPNs) have received widespread attention in antimicrobial infections due to their facile synthesis process, excellent biocompatibility, and antimicrobial properties brought about by polyphenols and metal ions. However, typical therapeutic MPNs show rapid release of metal ions due to their poor solution stability, impeding long-acting efficacy in multiple wound healing stages. To address these issues, copper-poly (tannic acid) nanoparticles (Cu-PTA NPs): robust (dually crosslinked), microenvironment-responsive, antibacterial, antioxidative, and anti-inflammatory are prepared, which hierarchically modulate the infected wound healing process. Covalently polymerized via phenol-formaldehyde condensation and crosslinked with bioactive Cu2+ , reactive polyphenols are preserved, and Cu2+ is efficiently entrapped in the PTA scaffold. The proposed strategy relieves the systemic toxicity, and only high reactive oxygen species (ROS)level as stimuli can "turn on" the catalytic activity of Cu2+ to implement antibacterial therapy specifically in an infected wound. Systematic tissue regeneration assessment on the infected full-thickness skin wounds of rats demonstrates enhanced wound healing rate. Cu-PTA NPs enables the direct application in infected wound and exertion of long-acting healing efficacy. This synergetic therapy strategy will pave the way for more complicated infections and inflammatory diseases.

Background: The healing of chronically infected wounds is severely hindered by persistent inflammation, bacterial infection, and oxidative stress, posing great challenges to clinical therapy. To address these challenges, we designed a multifunctional dual-layer microneedles patch (MN@DOX+RES) featuring reactive oxygen species (ROS) responsiveness and dual drug delivery capabilities. This patch is engineered to deliver synergistic antibacterial, anti-inflammatory, and antioxidant effects, thereby promoting the healing of infected wounds. Methods: The dual-layer microneedles patch comprises a rapidly dissolvable HA backing layer loaded with DOX and a ROS-responsive tips layer composed of a crosslinked AHA-PBA/PVA matrix that encapsulates water-soluble RES inclusion complexes. A series of in vitro experiments was conducted to evaluate the mechanical strength, biocompatibility, antibacterial activity against Staphylococcus aureus and Escherichia coli, antioxidant performance, and macrophage polarization. In vivo evaluations were performed on rat models with infected skin wounds. Results: The MN@DOX+RES microneedles exhibited strong skin penetration ability and excellent mechanical strength. It significantly inhibited bacterial growth, efficiently scavenged free radicals, reduced intracellular ROS levels, and enhanced M2 macrophage polarization. In vivo, the patch accelerated wound closure, suppressed the inflammatory cytokine IL-6, enhanced IL-10 expression, and activated the Keap1/Nrf2/HO-1 antioxidant signaling pathway. Conclusions: This study proposes an innovative therapeutic strategy that combines dual-drug delivery, oxidative microenvironment regulation, and immune modulation to promote the healing of chronic infected wounds. The MN@DOX+RES microneedles system demonstrates great potential in overcoming clinical challenges associated with infection, inflammation, and the limitations of conventional therapeutic approaches.

Microelectrode and microchannel integrated micro-robotic arm for bacteria sensing and on-demand drug delivery

On-demand drug delivery holds great promise to optimize pharmaceutical efficacy while minimizing the side effects. However, existing on-demand drug delivery systems often require complicated manufacturing processes that preclude their wide implementation of a broad range of drugs. In this work, we demonstrate the introduction of MXene-coated microneedles (MNs) into bioelectronics for digitally controllable gate-valve drug delivery. MXenes, featuring high electronic conductivity, excellent biocompatibility, and solution processibility, enable low-cost scalability for printable bioelectronics. In an electrolytic state (e.g., body fluid), the coated MXene is oxidized and desorbed due to redox reactions caused by electrical bias, allowing the underlying drug to be controllably released. The MXene-incorporated drug delivery system not only demonstrates excellent biocompatibility and operational stability, but also features low-cost construction and sustainable usage. Besides, these MXene-coated MNs allow both on-demand transformation and local-region customization, further increasing the structural versatility and capability of multidrug delivery systems.