Integration of metformin-loaded MIL-100(Fe) into hydrogel microneedles for prolonged regulation of blood glucose levels.

The transdermal drug delivery based on microneedles (MNs) provides a suitable and painless self-administration for diabetic patients. In this work, the hydrogel-forming MNs were firstly fabricated using poly(vinyl alcohol) (PVA) and chitosan (CS) as matrix. A hypoglycemic drug, metformin (Met), had been loaded into MIL-100(Fe). Then, both of free Met and Met-loaded MIL-100(Fe) were integrated into hydrogel-forming MNs for regulation of blood glucose levels (BGLs) on diabetic rats. After penetrated into the skin, the free Met could be firstly released from MNs. Due to the absorption of interstitial fluid and subsequent release of loaded Met from MIL-100(Fe), leading to a sustainable and long-term drug release behaviors. A notable hypoglycemic effect and low risk of hypoglycemia could be obtained on diabetic rat modelsin vivo. The as-fabricated hydrogel-forming MNs expected to become a new type of transdermal drug delivery platform for transdermal delivery of high-dose drugs to form a long-term hypoglycemic effect.

Rizatriptan benzoate-loaded dissolving microneedle patch for management of acute migraine therapy.

In this study, dissolving microneedles (MNs) using polyvinyl alcohol (PVA) and poly (1-vinylpyrrolidone-co-vinyl acetate) (P(VP-co-VA)) as matrix materials were developed for transdermal delivery of rizatriptan benzoate (RB) for acute migraine treatment. In-vitro permeation studies were conducted to assess the feasibility of the as-fabricated dissolving MNs to release RB. Drug skin penetration were tested by Franz diffusion cells, showing an increase of the transdermal flux compared to passive diffusion due to the as-fabricated dissolving MNs having a sufficient mechanical strength to penetrate the skin and form microchannels. The pharmacological study in vivo showed that RB-loaded dissolving MNs significantly alleviated migraine-related response by up-regulating the level of 5-hydroxytryptamine (5-HT) and down-regulating the levels of calcitonin gene-related peptide (CGRP) and substance P (SP). In conclusion, the RB-loaded dissolving MNs have advantages of safety, convenience, and high efficacy over conventional administrations, laying a foundation for the transdermal drug delivery system treatment for acute migraine.

Fabrication of lidocaine-loaded polymer dissolving microneedles for rapid and prolonged local anesthesia.

There is an urgent need for research into effective interventions for pain management to improve patients' life quality. Traditional needle and syringe injection were used to administer the local anesthesia. However, it causes various discomforts, ranging from brief stings to trypanophobia and denial of medical operations. In this study, a dissolving microneedles (MNs) system made of composite matrix materials of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and sodium hyaluronate (HA) was successfully developed for the loading of lidocaine hydrochloride (LidH). The morphology, size and mechanical properties of the MNs were also investigated. After the insertion of MNs into the skin, the matrix at the tip of the MNs was swelled and dissolved by absorption of interstitial fluid, leading to a rapid release of loaded LidH from MNs' tips. And the LidH in the back patching was diffused into deeper skin tissue through microchannels created by MNs insertion, forming a prolonged anesthesia effect. In addition, the back patching of MNs could be acted as a drug reservoir to form a prolonged local anesthesia effect. The results showed that LidH MNs provided a superior analgesia up to 8 h, exhibiting a rapid and long-lasting analgesic effects. Additionally, tissue sectioning and in vitro cytotoxicity tests indicated that the MNs patch we developed had a favorable biosafety profile.

Core-shell structured microneedles with programmed drug release functions for prolonged hyperuricemia management.

An appropriate non-oral platform via transdermal delivery of drugs is highly recommended for the treatment of hyperuricemia. Herein, a core-shell structured microneedle patch with programmed drug release functions was designed to regulate serum uric acid (SUA) levels for prolonged hyperuricemia management. The patch was fabricated using a three-step casting method. Allopurinol (AP), an anti-hyperuricemic drug, was encapsulated within the carboxymethyl cellulose (CMC) layer, forming the "shell" of the MNs. The MN's inner core was composed of polyvinylpyrrolidone (PVP) loaded with urate oxidase-calcium peroxide nanoparticles (UOx-CaO2 NPs). When the as-fabricated core-shell structured microneedles were inserted into the skin, the loaded AP was first released immediately to effectively inhibit the production of SUA due to the water solubility of CMC. Subsequently, the internal SUA was further metabolized by UOx, leading to exposure of CaO2 NPs. The sustained release of UOx accompanied by the decomposition of CaO2 NPs contributed to maintaining a state of normal uric acid levels over an extended period. More attractively, uric acid could be oxidized due to the strong oxidant of CaO2, which was beneficial to the continuous consumption of uric acid. In vivo results showed that the as-fabricated MNs exhibited an excellent anti-hyperuricemia effect to reduce SUA levels to the normal state within 3 h and maintain the normouricemia state for 12 h. In addition, the levels of creatinine (Cr) and blood urea nitrogen (BUN) in the serum remained within the normal range, and the activities of adenosine deaminase (ADA) and xanthine oxidase (XOD) in the liver were effectively inhabited, mitigating the risk of liver and kidney damage for clinical anti-hyperuricemia management.

Red blood cell membrane-coated functionalized Cu-doped metal organic framework nanoformulations as a biomimetic platform for improved chemo-/chemodynamic/photothermal synergistic therapy.

Nanoformulations for combining chemotherapy, chemodynamic therapy, and photothermal therapy have enormous potential in tumor treatment. Coating nanoformulations with cell membranes endows them with homologous cellular mimicry, enabling nanoformulations to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused multifunctional biomimetic nanoformulations based on Cu-doped zeolitic imidazolate framework-8 (ZIF-8). Hydroxycamptothecin (HCPT), a clinical anti-tumor drug, was encapsulated into ZIF-8, which was subsequently coated with polydopamine (PDA) and red blood cell membrane. The as-fabricated biomimetic nanoformulations showed an enhanced cell uptake in vitro and the potential to prolong blood circulation in vivo, producing effective synergistic chemotherapy, chemodynamic therapy, and photothermal therapy under the 808 nm laser irradiation. Together, the biomimetic nanoformulations showed a prolonged blood circulation and evasion of immune recognition in vivo to provide a bio-inspired strategy which may have the potential for the multi-synergistic therapy of breast cancer.

Red Blood Cell Membrane-Camouflaged Polydopamine and Bioactive Glass Composite Nanoformulation for Combined Chemo/Chemodynamic/Photothermal Therapy.

Combinations of different therapeutic strategies, including chemotherapy (CT), chemodynamic therapy (CDT), and photothermal therapy (PTT), are needed to effectively address evolving drug resistance and the adverse effects of traditional cancer treatment. Herein, a camouflage composite nanoformulation (TCBG@PR), an antitumor agent (tubercidin, Tub) loaded into Cu-doped bioactive glasses (CBGs) and subsequently camouflaged by polydopamine (PDA), and red blood cell membranes (RBCm), was successfully constructed for targeted and synergetic antitumor therapies by combining CT of Tub, CDT of doped copper ions, and PTT of PDA. In addition, the TCBG@PRs composite nanoformulation was camouflaged with a red blood cell membrane (RBCm) to improve biocompatibility, longer blood retention times, and excellent cellular uptake properties. It integrated with long circulation and multimodal synergistic treatment (CT, CDT, and PTT) with the benefit of RBCms to avoid immune clearance for efficient targeted delivery to tumor locations, producing an "all-in-one" nanoplatform. In vivo results showed that the TCBG@PRs composite nanoformulation prolonged blood circulation and improved tumor accumulation. The combination of CT, CDT, and PTT therapies enhanced the antitumor therapeutic activity, and light-triggered drug release reduced systematic toxicity and increased synergistic antitumor effects.

Fabrication of carboxymethyl cellulose/hyaluronic acid/polyvinylpyrrolidone composite pastes incorporation of minoxidil-loaded ferulic acid-derived lignin nanoparticles and valproic acid for treatment of androgenetic alopecia.

Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a higher prevalence among young individuals. Traditional oral or subcutaneous injections are often used to treat AGA, however, they may cause severe side-effects and therefore effective treatments for AGA are currently lacking. In this work, to treat AGA, we developed a composite paste system based on minoxidil (MXD)-loaded nanoparticles and valproic acid (VPA) with the assistance of roller-microneedles (roller-MNs). The matrix of composite paste systems is carboxymethyl cellulose (CMC), hyaluronic acid (HA) and polyvinylpyrrolidone (PVP). The roller-MNs can create microchannels in the skin to enhance drug transdermal efficiency. With the combined effects of the stimulation hair follicle (HF) regrowth by upregulating Wnt/beta-catenin of VPA and the mechanical microchannels induced by roller-MNs, the as-prepared composite paste systems successfully boost perifollicular vascularization, and activate hair follicle stem cells, thereby inducing notably faster hair regeneration at a lower administration frequency on AGA mouse model compared with minoxidil. This approach offers several benefits, including the avoidance of efficacy loss due to the liver's first-pass effect associated with oral drug, reduction in the risk of infection from subcutaneous injection, and significant decrease in the side effects of lower-dose MXD.

Porcupine-inspired microneedles coupled with an adhesive back patching as dressing for accelerating diabetic wound healing.

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.

Transdermal delivery of allopurinol to acute hyperuricemic mice via polymer microneedles for the regulation of serum uric acid levels.

Allopurinol (AP) is widely used to treat hyperuricemia which may cause severe side effects upon oral administration. Alternative means for the treatment of hyperuricemia are demanded to simultaneously facilitate drug absorption, patient compliance, and fewer side effects. In this study, a new polymer microneedle (MN) system was developed for the transdermal delivery of AP to acute hyperuricemic mice. This study aims to achieve the controllable regulation of serum uric acid (SUA) levels with fewer side effects compared with oral administration. The matrix of polymer MNs consisted of polyvinylpyrrolidone (PVP) and polycaprolactone (PCL), in which the rapid dissolution of PVP offers a rapid dissolution of AP into the blood and the biodegradability of PCL resulting in a sustainable drug release behavior. An in vivo study demonstrated that the AP-loaded MN system can effectively reduce the SUA levels as oral administration with lower side effects, which will be conducive to reducing the adverse reactions and improving the bioavailability of AP. This MN-mediated strategy can facilitate transcutaneous hyperuricemia treatment and provide a new alternative for the exploration of clinical treatment of hyperuricemia and improvement of patient compliance.

Design of 3D polycaprolactone/ε-polylysine-modified chitosan fibrous scaffolds with incorporation of bioactive factors for accelerating wound healing.

Electrospun nanofibrous scaffolds show great application potentials for wound healing owing to their effective simulation of extracellular matrix (ECM). Three-dimensional (3D) nanofibrous dressings exhibit relatively high specific surface areas, better mimicry of native ECM, adjustable hydrophilicity and breathability, good histocompatibility, enhanced wound healing, and reduced inflammation. In the present work, we designed the 3D polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) nanofibrous scaffolds by an electrospinning and gas foaming process. Then, gelatin and heparin (Gel/Hep) were assembled onto the surface of PCL/PCS nanofibers by electrostatic adsorption, and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into Gel/Hep layer to form a multifunctional 3D nanofibrous scaffold (PCL/PCS@Gel/Hep+VEGF) for accelerating wound healing. The as-fabricated 3D PCL/PCS@GEL/Hep+VEGF nanofibrous scaffold showed excellent antibacterial ability, hemocompatibility and biocompatibility in vitro and wound healing ability in vivo. Immunological analysis showed that the as-fabricated nanofibrous scaffold inhibited inflammation at the wound sites while promoting angiogenesis during the wound healing process. STATEMENT OF SIGNIFICANCE: The electrospun 3D fibrous scaffolds using polycaprolactone/ε-polylysine modified chitosan (PCL/PCS) have been fabricated as backbone for mimicking the extracellular matrix (ECM). Gelatin and heparin (Gel/Hep) were wrapped onto the surface of PCL/PCS fibers by electrostatic adsorption and vascular endothelial growth factors (VEGFs) were also synchronously incorporated into surface Gel/Hep layer to form multifunctional 3D fibrous scaffolds. The as-fabricated multifunctional 3D fibrous scaffolds with good antibacterial ability and biocompatibility have been used as dressings for accelerating wound healing by inhibiting inflammation at the wound sites while promoting angiogenesis during the wound healing process.

Fabrication of Curcumin-Loaded Silk Fibroin and Polyvinyl Alcohol Composite Hydrogel Films for Skin Wound Healing.

Skin regeneration of full-thickness wounds remains a challenge, requiring a well-regulated interplay of cell-cell and cell-matrix signaling. Herein, the composite hydrogel films composed of silk fibroin (SF) and polyvinyl alcohol (PVA) as scaffolds loaded with curcumin nanoparticles (Cur NPs) were developed for skin wound healing. The structure and physicochemical properties of hydrogel films were first evaluated by scanning electron microscopy (SEM), water contact angle, and chemical and mechanical measurements. In addition, the as-fabricated composite hydrogel films have a unique 3D structure and excellent biocompatibility that facilitates the adhesion and growth of cells. Antimicrobial tests in vitro showed that they could inhibit the growth of bacteria due to the incorporation of Cur NPs into composite hydrogel films. The efficacy of the curcumin-loaded SF/PVA composite hydrogel films for skin wound healing was investigated on the skin defect model in vivo. Immunological analysis showed that the as-fabricated Cur NP-loaded SF/PVA composite hydrogel films inhibited inflammation at the wound sites, while promoting angiogenesis during the wound healing process.

Rational design of flexible microneedles coupled with CaO2@PDA-loaded nanofiber films for skin wound healing on diabetic rats.

Skin ulcers are one of the complications of diabetes. At present, the treatment of diabetic skin wounds is still not satisfactory, and the efficiency of drug delivery is limited by the depth of penetration. Herein, a synergistically flexible microneedle dressing is presented for effectively promoting diabetic wound healing. Metformin, as an anti-diabetic drug, can be loaded into microneedles, which can effectively pierce into the skin of diabetic rats to trigger a response for regulating blood glucose levels. A novel multifunctional nanosystem CaO2@polydopamine (CaO2@PDA) was introduced into polycaprolactone and gelatin (PCL/Gel) electrospun nanofiber films as microneedle back patches to inhibit inflammation, provide oxygen, and absorb the excess exudate. Besides, the CaO2@PDA in back patches also provided effective antibacterial properties against both S. aureus and E. coli. Additionally, the as-fabricated flexible microneedle dressings loaded with metformin and CaO2@PDA nanoparticles demonstrated a high level of CD31 and low level of TNF-α, leading to accelerated diabetic skin-wound closure. These distinctive features demonstrate that our microneedle system can be a facile candidate for efficient wound healing in patients with diabetes and may be applied in various biomedical fields.