Dextran-based microneedle patch Co-delivering safflower polysaccharide and ROS-responsive tetramethylpyrazine micelles for diabetic wound repair.

Diabetic wound healing is a global biomedical challenge. Bacterial infection and microenvironmental modulation are major factors in the refractory healing of diabetic wounds. Conventional therapeutic approaches are often hindered by limitations, such as inadequate drug penetration, the rise of antimicrobial resistance, and restricted depth of drug delivery. Nanomedicine is emerging as a prospective drug delivery and anti-infective therapeutic approach in the field of wound management. Herein, all-trans retinoic acid (ATRA) was loaded into a zeolite imidazolate framework-91 salt+ (ZIF-91 salt+). A gelatin methacryloyl (GelMA) hydrogel microneedles (MNs) patch based on this multifunctional ZIFs (denoted as GelMA-ZIF-91 salt+@ATRA MNs patch) was developed, which makes transdermal drug delivery and combinatory treatment for diabetic wound healing feasible. Significantly, ATRA-containing ZIF-91 salt+ provides nanocomposites with anti-inflammatory activity through their modulation of macrophage polarization. Crucially, the prepared ZIF-91 salt+ showed efficient antibacterial activity against Staphylococcus aureus and Escherichia coli in vitro. Therapeutic effects of the GelMA-ZIF-91 salt+@ATRA MNs patch were verified in a diabetic mouse model with full-thickness cutaneous wounds. A unique MNs patch with antimicrobial, angiogenesis-inducing, and anti-inflammatory properties was designed in accordance with the physiological characteristics of wounds. Collectively, the designed MNs patch based on this multifunctional ZIF-91 salt+ provides new insights into diabetic wound therapy.

Programmed modulation of inflammation in diabetic wounds via a dual-stage CuTA/RvD1 microneedle system.

Increasing needs of painless, self-administrable and readily available home healthcare applications have driven the advancement of transdermal drug delivery system (TDD), aiming to replace current therapeutic and health monitoring schemes that require physical attendance and sophisticated process. Microneedle (MN) technology as third generation TDD system has been exploited in many bio-functional applications such as transdermal drug delivery and biosensing due to its greater skin disruption in minimal invasive manner as compared to previous generations that have molecular size limit and with needs of external power supply. MN device is designed in patch form with a collection of microscale-needles attachment as this allows simultaneous breaching of skin barrier in wider area for drug delivery and biosensing purposes. An ideal MN system should allow consistent and uniform penetration over target skin region especially when human skin is curved at most body areas while viscoelastic in nature. MN patch that failed to conform effectively onto target site could lead to under-desired therapeutic outcome and poor signal recording. Moreover, current MN systems are designed for finger-pressing administration therefore often in miniatured size, limiting the adaptability for most protein and peptide delivery dosage. To date, these issues have not been addressed effectively, hindering global commercialization of MN technology. Inspired by brilliant evolution of ancient fish armour system which has shown co-existence of rigidity and flexibility, we have found that they possess great similarities with the ideal MN system from micro- to macroscale aspects. Therefore, in this thesis, I mainly focus on improvement on penetration efficiency of individual MN tips through 1) mechanical reinforcement at micro-scale (Chapter 3) and 2) adaptive tip configuration of flexible MN substrates depending on surface geometry at macro-scale (Chapter 4). Particularly, in this thesis, rapid dissolving biopolymer low molecular weight hyaluronic acid (HA) was used for dissolving MN (DMN) systems due to its high dissolution rates and abundant availability in human body naturally with reasonable drug loading capabilities. However, the degradable polymer-based MN systems often experience significantly reduced transdermal penetration, especially when polymers have intrinsically weak mechanical strength as compared to other non-biodegradable materials like metal. Therefore, first, an in situ precipitation of silica network in HA matrix was proposed to improve intrinsic mechanical strength and improved physiological stability during administration of MN patches. Silica is a widely used bioactive additive with rapid physiological decay rate. Optimization of silica content in HA matrix was first studied through structural characterization to ensure minimal morphological defects in fabricated MN. Moreover, chemical analyses were used to characterize micro-structure and distribution of silica network in HA matrix. The HA-Si MNs fabricated demonstrated improved penetration efficiency and slight effect on dissolution behavior to pure HA MNs. Moreover, no cytotoxicity was found in the optimized HA-Si sample, indicating that the proposed hybridization of bioactive additive was encouraging. Moreover, MN system comprises of tip region and base substrate where flexible and continuous base substrates have been proposed in previous studies to address skin conformity issue of traditional MN systems with rigid base substrate. However, existing flexible MN system only offers bidirectional flexibility, therefore not yet able to address conformity issues at movable joint regions like elbow. Furthermore, upscaling of MN patch dimension is expected in future market in order to resolve issue of limited drug loading and skin coverage for biosensing of wider body areas. Therefore, in this project, a kirigami-based auxetic fractal cut pattern was introduced into the flexible base substrate design, resembling that of wavy patterned fish tissue. Numerical and experimental evaluations have demonstrated significant improvement in terms of contact stability, complex skin geometry coverage, penetration depth and insulin delivery. These tests were designed and compared among traditional rigid, flexible continuous and proposed flexible fractal cut patch. Moreover, novel two-step fabrication of proposed fractal cut MN patch using DLP printing was accomplished with high precision, lower production time/cost and promising functionality by exploiting working principle of DLP printing. Finally, customizability of FF MN patch in terms of patch size, subunit shape design and heterogeneity of MN material-drug formulation were displayed and proven to be a promising platform for diverse biomedical applications. The two approaches presented in this thesis have shown to be the key aspects to consider when designing an ideal MN patch with excellent penetration efficiency, high drug loading and skin coverage, in micro- and macroscopic perspectives. With further development of such flexible MN system, MN technology will soon to be adopted in more therapeutic and biosensing applications, finally bringing revolution to the biomedical fields as a pain-free and multipurpose healthcare tool.

Diabetic wounds with complex pathological features and a difficult-to-heal nature remain a formidable challenge. To address this challenge, we design and fabricate a self-powered enzyme-linked microneedle (MN) patch composed of anode and cathode MN arrays, which respectively contain glucose oxidase (GOx) and horseradish peroxidase (HRP) encapsulated in ZIF-8 nanoparticles. The enzymatic cascade reaction in the MN patch can effectively reduce local hyperglycemia in diabetic wounds while generating stable microcurrents to promote rapid healing of diabetic wounds. Therefore, the diabetic wounds treated with this MN patch exhibit rapid, complete, and scar-preventative healing, which can be attributed to the synergistic actions of hypoglycemic, antibacterial, anti-inflammatory, and bioelectrical stimulation. In brief, the self-powered MN patch is an effective method to rapidly promote diabetic wound healing and prevent scar formation.

Efficient management of difficult-to-heal diabetic wounds remains a clinical challenge owing to bacterial infections, as well as oxidative and hyperglycemic complex pathology. Therefore, developing intelligent strategies for diabetic wound healing is urgently needed. Herein, an ultrasound (US)-responsive microneedle (MN) patch (MN@GOX@TiO2-X@CO) capable of controlled delivery of carbon monoxide (CO) gas within the skin for effective treatment of diabetic infected wounds is developed. Benefiting from the specific form of microneedle (MN) patch, sonosensitizer (TiO2-X), •OH-responsive CO prodrug (MPA-CO), and glucose oxidase (GOX) can be loaded together and effectively delivered to infectious wounds. With the semi-fluidic hyaluronic acid (HA) coating under the physiological condition, CO could be released efficiently in situ and directly acted on infected wound tissue upon US triggering. Both in vitro and in vivo results showed that US-triggered CO release from MN@GOX@TiO2-X@CO not only effectively inhibited the S. aureus and MRSA infection but also promoted fibroblasts proliferation and migration under hyperglycemic physiology, thereby accelerating diabetic wound healing. Collectively, the approach effectively addresses the impaired skin regeneration function in diabetic wounds and offers a promising therapeutic strategy for the efficient healing of infected diabetic wounds.

A Zn-MOF-GOx-based cascade nanoreactor promotes diabetic infected wound healing by NO release and microenvironment regulation

Thermosensitive hydrogel microneedles for controlled transdermal drug delivery

Chronic non-healing of diabetic wound (DW) remains a critical clinical challenge worldwide. Sustained oxidative stress and prolonged inflammatory responses disrupt the wound microenvironment, while bacterial colonization and biofilm formation on the wound bed compromise drug penetration, consequently leading to suboptimal outcomes with conventional approaches. Here, we developed a core-shell structured microneedle (MN) patch system, designated as MN@Ple/ExoQ10, to precisely regulate the DW microenvironment through sequential drug release. The photothermal-responsive microneedle patch MN@Ple/ExoQ10 features a dual-phase release: the outer shell's antimicrobial peptide (Pleurocidin) addresses initial infection, while the core's engineered exosomes (ExosQ10) mitigate oxidative stress and subsequently regulate immune responses. When combined with near-infrared (NIR)-triggered photothermal therapy, this system effectively promotes the healing of DW. This study details that the sustained release of ExosQ10 effectively inhibits high glucose (HG)-induced ferroptosis in vitro, demonstrating potent antioxidant activity and anti-inflammatory capacity. Furthermore, in a S. aureus-infected diabetic mouse wound model, MN@Ple/ExoQ10 demonstrates potent antibacterial activity while mitigating oxidative stress, suppressing inflammation and promoting angiogenesis, thereby accelerating wound healing. Collectively, the developed spatiotemporally controlled MN system overcomes bacterial barriers and stabilizes exosomal delivery, enabling comprehensive regulation of the microenvironment in DWs. This breakthrough approach presents a novel and translational strategy for DW therapy.

Spatiotemporally responsive cascade bilayer microneedles integrating local glucose depletion and sustained nitric oxide release for accelerated diabetic wound healing

Cell growth and metabolism require an adequate supply of oxygen. However, obtaining sufficient oxygen from the blood circulating around diabetic wounds is challenging. Nevertheless, achieving a continuous and stable oxygen supply is required for these wounds to heal. Hence, in this study, we report a novel antibacterial oxygen-producing silk fibroin methacryloyl hydrogel microneedle (MN) patch comprising tips encapsulated with calcium peroxide and catalase and a base coated with antibacterial Ag nanoparticles (AgNPs). The tip of the MN patch continuously releases oxygen and inhibits the production of reactive oxygen species. This accelerates diabetic wound healing by promoting cellular accretion and migration, macrophage M2 polarization, and angiogenesis. The AgNPs at the base of the MN patch effectively combat microbial infection, further facilitating wound repair. These findings suggest that using this multifunctional oxygen-producing MN patch may be a promising strategy for diabetic wound healing in clinical settings.

Diabetes chronic wound is a severe and frequently occurring medical issue in patients with diabetes that often leads to more serious complications. Microneedles (MNs) can be used for wound healing as they can effectively pierce the epidermis and inject drugs into the wound tissue. However, common MN patches cannot provide sufficient skin adhesion to prevent detachment from the wound area. Inspired by the barb hangnail microstructure of porcupine quills, a porcupine quill-like multilayer MN patch with an adhesive back patching for tissue adhesion and diabetic wound healing was designed. Sodium hyaluronate-modified CaO2 nanoparticles and metformin (hypoglycemic agent) were loaded into the polycaprolactone tips of MNs, endowing them with exceptional antibacterial ability and hypoglycemic effect. A flexible and adhesive back patching was formed by polyacrylamide-polydopamine/Cu2+ composite hydrogel, which ensures that the MN patches do not peel off from the application sites and reduce bacterial infection. The bioinspired multilayer structure of MN patches exhibits satisfactory mechanical and antibacterial properties, which is a potential multifunctional dressing platform for promoting wound healing. STATEMENT OF SIGNIFICANCE: The porcupine quill-like microneedles (MNs) with PAM-PDA/Cu2+ (PPC) composite hydrogel back patching have been fabricated, which can enhance the adhesion property of MNs to the skin through a physical interlock of multilayer MNs and chemical bonding of hydrogel patching. CaO2-HA NPs and metformin were loaded into the polycaprolactone tips of MNs, endowing them with the exceptional antibacterial ability and hypoglycemic effect, which could accelerate diabetic wound healing. As a safe and effective strategy in transdermal delivery of drugs, the as-fabricated flexible multilayer MN patch with good antibacterial, hypoglycemic, and biocompatibility has been used to promote the healing of diabetic wound by releasing oxygen and inhibiting inflammation at the wound site.

Excessive and continuous production of reactive oxygen species (ROS) is a significant factor contributing to severe inflammation, bacterial infections, and poor angiogenesis, and it can also delay the healing of diabetic wounds. However, traditional clinical treatment methods are unable to effectively eliminate ROS. Herein, a dual ROS-scavenging platform that integrates multifunctional niobium carbide (Nb2C) reinforced with curcumin (Cur) with UV-crosslinked hydrogel microneedles (MN) is presented. In this system, Cur, acting as the primary scavenger, can rapidly neutralize extracellular ROS. Under near-infrared (NIR) irradiation, the embedded Nb2C not only triggers the on-demand release of curcumin but also, through its enzyme-like peroxidase-mimicking activity, acts as a secondary scavenger to eliminate deep intracellular ROS, thus providing a two-stage antioxidant defense mechanism. This NIR-enhanced dual-action synergistic effect can balance the oxidative microenvironment, promote the repolarization of macrophages from the M1 type to the M2 type, facilitate angiogenesis, and produce a powerful photothermal combined antibacterial effect. The results of in vivo experiments indicate that the use of Nb2C-CurCD-GelMA MNs can significantly accelerate the healing of full-thickness diabetic wounds. The mechanism lies in coordinating the reduction of inflammation and tissue regeneration. This study offers a sophisticated and safe treatment strategy for refractory diabetic wounds.

Diabetic wounds constitute one of the most prevalent complications among diabetic patients, characterized by a low healing rate and a high recurrence rate. These wounds frequently result in ulceration, amputation, and, in severe cases, life-threatening conditions. The difficulty of wound healing in diabetic patients is primarily attributed to the invasion of pathogenic bacteria, dysregulation of the inflammatory response, and insufficient angiogenesis. In this study, we developed a core-shell microneedle (MN) patch that delivers antimicrobial agents, anti-inflammatory agents, and angiogenic agents in a biphasic release mode for the treatment of diabetic wound healing. Tetracycline hydrochloride (TCH) and drug-carrying nanoparticles (SIM-PLGA NPs) were coated in the inner layer of the tip to respond to early bacterial infection and subsequently induce angiogenesis. Metformin hydrochloride (Met) was loaded onto the outer shell of the needle tip to regulate the inflammatory response. The core-shell MN patch (TCH/SIM-PLGA NPs/Met MN) inhibited bacterial infection and promoted cell migration and angiogenesis. The application of the TCH/SIM-PLGA NPs/Met MN patch in the constructed diabetic wound model reduced inflammation, induced angiogenesis, encouraged collagen deposition and tissue regeneration during wound healing and repair, and accelerated diabetic wound closure. This biphasic release system, combined with MN, exhibits significant potential for broader applications in wound healing.

Mxene-based mild hyperthemia microneedle patch for diabetic wound healing

Diabetic chronic wounds heal slowly due to persistent inflammation, impaired macrophage polarization, and compromised angiogenesis, while conventional therapies fail to effectively modulate the wound microenvironment. This study aimed to develop pagoda-like microneedle (MN) patches incorporating isoliquiritigenin (ISL)-loaded hollow mesoporous copper sulfide nanoparticles (HMCuS@ISL MNs) with near-infrared (NIR) photothermal functionality to achieve local immunometabolic regulation and promote angiogenesis, antibacterial activity, and wound repair. HMCuS@ISL nanoparticles were integrated into a collagen/hyaluronic acid matrix to form pagoda-like MN patches. Nanoparticles were characterized by TEM, DLS, and UV-vis-NIR spectroscopy, and their photothermal performance under 808nm irradiation was evaluated. MN mechanical strength, dissolution, cytocompatibility, antibacterial activity, and in vitro angiogenesis were systematically assessed. ISL-mediated macrophage polarization was analyzed via RNA sequencing, qPCR, flow cytometry, and metabolic flux assays. In vivo efficacy and biosafety were evaluated in streptozotocin-induced diabetic mouse wound models. HMCuS@ISL nanoparticles displayed uniform hollow-mesoporous morphology with strong NIR absorption and efficient photothermal conversion. MN patches exhibited excellent mechanical strength, rapid dissolution, and good biocompatibility. ISL promoted M2 macrophage polarization by suppressing glycolysis and enhancing fatty acid oxidation. HMCuS@ISL MNs, especially under NIR irradiation, significantly enhanced fibroblast migration, angiogenesis, antibacterial activity, and accelerated wound closure. Histological and immunostaining analyses confirmed improved re-epithelialization, collagen deposition, vascularization, and immune microenvironment balance without systemic toxicity. HMCuS@ISL MN patches integrating metabolic immune modulation with photothermal therapy provide an effective, safe, and minimally invasive strategy for diabetic wound healing.