Dissolving Microneedles Research Articles

Transforming Biologics Delivery through Microneedles

This review explores the potential of microneedles (MNs) in enhancing the delivery of biologics vital for treating conditions, including infectious diseases, cancer, and autoimmune disorders. The COVID-19 pandemic has amplified the demand for biologics, prompting research and development. The global biologics market is expected to grow substantially due to the rise of personalized medicine. Large, complex molecules, including proteins, peptides, and vaccines, are known as biologics, and a potential technique for their delivery is microneedles. MNs come in various forms: solid, hollow, coated, dissolvable, and hydrogel MNs. Traditional drug delivery methods have limitations, while transdermal drug delivery via Microneedles offers a promising alternative. Microneedles painlessly penetrate the skin's barrier, forming temporary microchannels for effective medication administration. This minimally invasive, self-administered technique increases patient comfort and compliance and eliminates the complications of oral medications and injections, indicating a bright future for biologic drug administration. Microneedles hold the promise to reshape healthcare delivery by facilitating broader access to vaccines, insulin, and other crucial biologics.

Facile minocycline deployment in gingiva using a dissolvable microneedle patch for the adjunctive treatment of periodontal disease

AbstractMinocycline is a commonly used drug for adjunctive therapy in periodontal disease. However, the current mainstream local medications primarily rely on intra‐pocket administration, which, while avoiding the side effects of traditional systemic drugs, presents challenges such as inconvenience, discomfort, and the need for professional assistance, thus affecting patient compliance. Herein, we introduce a minocycline‐loaded dissolvable microneedle (Mino‐DMN) patch that allows for local and efficient delivery of minocycline to gingiva for the treatment of periodontitis. A two‐step casting micro‐molding process involving vacuum drying and freeze drying is employed to concentrate minocycline in the microneedle part and limit its diffusion into the patch backing. The resulting Mino‐DMN patch features an array of minocycline‐enriched gelatin MNs with a porous HA patch backing. The microneedles can penetrate into gingiva with enough mechanical strength and quickly release minocycline into the gingival tissue, ensuring prolonged local residence of the drug and minimizing its loss to saliva. In vivo experiments show Mino‐DMN inhibits pro‐inflammatory factors, promotes anti‐inflammatory factors, and stimulates bone formation, surpassing topical application and comparable to the inconvenient and discomfort administration of Periocline®. This proposed Mino‐DMN offers a simple, efficient, user‐friendly strategy for the adjunctive treatment of periodontal disease.

Carrier Polymer-Free Dissolvable Microneedles Enable Superhigh Drug Payload for Percutaneous Protein Delivery

Carrier Polymer-Free Dissolvable Microneedles Enable Superhigh Drug Payload for Percutaneous Protein Delivery

Hispidulin-rich fraction of Clerodendrum fragrans Wild. (Sesewanua) dissolving microneedle as antithrombosis candidate: A proof of concept study

Existing conventional antithrombosis drugs have caused many side effects, opening up opportunities for the development of new thrombotic drugs. There is potential to use the hispidulin-rich fraction of sesewanua (HRFS) as a new antithrombotic. The oral route limitation of hispidulin, as a low water solubility and non-polar compound, can be addressed. This study explores the potential of HRFS in the form of dissolving microneedles (DMN). The formula was created using polymers such as polyvinyl alcohol (PVA), polyvinyl pyrrolidone K-30 (PVP), and non-ionic surfactant. Ex vivo permeation studies found that 184.95 µg/cm2 of hispidulin was released 60 h after the best formulation. After 14 days of applying HRFS-DMN, the anticoagulant and antioxidant activity in male albino rats showed higher Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) values and lower Inter Cellular Adhesion Molecule-1 (ICAM-1) values. No statistically significant differences were found between the effects of two and four HRFS-DMN and the injection of heparin at a dosage of 200 IU per kilogram. However, notable distinctions were observed when comparing HRFS-DMN to negative controls, oral and quercetin as positive controls at anti-ICAM activity. The findings confirmed the feasibility of HRFS-DMN for thrombosis and its effectiveness in delivering Hispidulin (HIS) into the bloodstream. This DMN is non-irritating, safe, and painless, showing promising outcomes in enhancing the efficacy of thrombosis treatment via the transdermal route.

Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (Cmax = 287.39 ± 106.82 ng/mL) and EMNs (Cmax = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.

Modeling of Dissolving Microneedle-Based Transdermal Drug Delivery: Effects of Dynamics of Polymers in Solution.

Dissolving microneedle (DMN)-assisted transdermal drug delivery (TDD) has received attention from the scientific community in recent years due to its ability to control the rate of drug delivery through its design, the choice of polymers, and its composition. The dissolution of the polymer depends strongly on the polymer-solvent interaction and polymer physics. Here, we developed a mathematical model based on the physicochemical parameters of DMNs and polymer physics to determine the drug release profiles. An annular gap width is defined when the MN is inserted in the skin, accumulating interstitial fluid (ISF) from the surrounding skin and acting as a boundary layer between the skin and the MN. Poly(vinylpyrrolidone) (PVP) is used as a model dissolving polymer, and ceftriaxone is used as a representative drug. The model agrees well with the literature data for ex vivo permeation studies, along with the percent height reduction of the MN. Based on the suggested mathematical model, when loading 0.39 mg of ceftriaxone, the prediction indicates that approximately 93% of the drug will be cleared from the bloodstream within 24 h. The proposed modeling strategy can be utilized to optimize drug transport behavior using DMNs.

50653 A Novel Topical Facial Serum Containing a Suspension of Dissolvable Hyaluronic Acid Microneedle and Retinol for Improved Skin Penetration and Antiaging Efficacy in Aged Skin

50653 A Novel Topical Facial Serum Containing a Suspension of Dissolvable Hyaluronic Acid Microneedle and Retinol for Improved Skin Penetration and Antiaging Efficacy in Aged Skin

M2 macrophage-polarized anti-inflammatory microneedle patch for accelerating biofilm-infected diabetic wound healing via modulating the insulin pathway

Macrophages play a pivotal role in the healing of diabetic ulcers. The sustained elevation of glucose levels damages the insulin signaling pathway in macrophages, leading to dysfunctional macrophages that struggle to transition from pro-inflammatory (M1) to reparative (M2) states. Therefore, modulating macrophage inflammatory responses via the insulin pathway holds promise for diabetic ulcer treatment. Additionally, the presence of biofilm impedes drug penetration, and the resulting immunosuppressive microenvironment exacerbates the persistent infiltration of pro-inflammatory M1 macrophages. Therefore, we designed an array of dissolvable microneedle (denoted as NPF@MN) loaded with self-assembled nanoparticles that could deliver NPF nanoparticles, acid-sensitive NPF-releasing Protocatechualdehyde (PA) with hypoglycemic and insulin-like effects, regulating macrophage polarization to an anti-inflammatory M2 phenotype. Additionally, this study extensively examined the mechanism by which NPF@MN accelerates the healing of diabetic ulcers through the activation of the insulin signaling pathway. Through RNA-seq and GSEA analysis, we identified a reduction in the expression of pathway-related factors such as IR, IRS-1, IRS-2, and SHC. Our work presents an innovative therapeutic approach targeting the insulin pathway in diabetic ulcers and underscores its translational potential for clinical management.

Inhibit diffusion of the small molecule drug lidocaine hydrochloride in dissolving microneedles based on a phase separation approach

Dissolving microneedles (DMNs) have emerged as a promising transdermal drug delivery modality. However, in the case of small-molecule drug delivery, there is a tendency for the drug to disperse from the needle layer into the backing layer, resulting in reduced drug concentration at the needle site and consequently compromising drug delivery efficiency. In this study, lidocaine hydrochloride (Lido) was employed as a model drug to prepare a series of Lido dissolving microneedles (Li-DMNs) through a two-step casting method. We detail their fabrication process and the composition of needle and backing solutions, conduct in vitro characterization, and investigate the impact of viscosity and phase separation effects on drug distribution. Li-DMNs exhibit excellent visual appearance, adequate mechanical strength, favorable puncture permeability, and effective transdermal release property which can effectively facilitate the transdermal delivery of Lido. The phase separation effect significantly impedes Lido diffusion into the backing layer during DMNs preparation. This approach holds immense potential for broad applications and bears great significance in enhancing both drug loading capacity and transdermal delivery efficiency of DMNs.

Dissolving microneedle integrated with benidipine loaded ethosomes for transdermal delivery

Benidipine HCl (BEN) is a drug used for the treatment of hypertension. However, this drug suffers from low oral bioavailability. This study introduces a novel approach to address this issue by developing BEN-loaded ethosomes (BEN-E) that integrate into dissolving microneedles for transdermal delivery. The BEN-E was prepared using a rotary evaporation method and optimised using the Box-Behnken design. Following that, the optimised BEN-E formulation was integrated into dissolving microneedles (DMNs). The optimised lipid vesicles selected comprised lipoid S75 (339.66 mg), ethanol (34.51 %), and sonication time (70 s) and showed a vesicle size of 149.4 ± 3.81 nm, an EE% of 88.57 ± 0.38 %, and a transdermal flux of 19.12 ± 0.19 μg/cm²/hr. On the other hand, the resulting BEN-E-DMNs exhibited sharp pyramidal microneedles, sufficient mechanical strength, good insertion capability, and fast dissolution in rat skin. In the ex vivo study, the permeation coefficient of BEN was significantly improved by BEN-E-DMNs compared with optimised BEN-E and BEN-DMNs. The pharmacokinetic studies showed that the BEN-E-DMNs had a Cmax of about 0.698 ± 0.037 μg/mL and an AUC₀₋ₜ of about 15.821 ± 0.868 μg/hr/mL. Moreover, it improved the relative bioavailability of BEN by about 1.58 times compared to the orally marketed BEN tablet and about 2.95 times compared to the BEN-DMNs. In conclusion, the ethosomes combined with dissolving microneedles have shown high potential as carriers for the transdermal delivery of BEN.

Dissolvable microneedle patch enables local delivery of immunomodulatory microparticles containing bifunctional molecules for periodontal tissue regeneration

Periodontitis is initiated by dysbiosis of the oral microbiome. Pathogenic bacteria elicit ineffective immune responses, which damage surrounding tissues and lead to chronic inflammation. Although current treatments typically aim for microbial eradication, they fail to address the significance of immune cell reactions in disease progression. Here, we searched for small molecules as drug candidates and identified a bifunctional antibiotic, azithromycin (AZM), that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation. We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues. Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro. In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration. In addition, microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles, had similar or slightly enhanced therapeutic outcomes respectively. The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents, providing a practical and streamlined approach for clinical treatment. Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation.Graphical

Micro/nano system-mediated local treatment in conjunction with immune checkpoint inhibitor against advanced-Stage malignant melanoma

Tumor relapse and metastasis become a big challenge in treating malignant melanoma because conventional therapeutic options often fail to eradicate the tumor residue after surgical resection, posing huge threat to human health. Herein, a feasible strategy is developed for fighting crafty melanoma pre- and postsurgery. Specifically, nitric oxide (NO)-carried micelles (NOM) are designed by conjugating S-nitrosoglutathione (GSNO) with poly(2-ethyl-2-oxazoline)-b-poly(D, L-lactide) (PEOz-b-PLA) to form amphipathic polymer, which can self-assemble into pH-sensitive micelle to encapsulate chemotherapeutic drug paclitaxel (PTX). By further loading PTX@NOM into the needle tips of dissolvable microneedle (MN) patch, a local synergistic strategy is achieved for combating melanoma via easy insertion. Meanwhile, due to the immunomodulatory ability of NO by inducing the immunogenic cell death (ICD) of tumor cells and polarizing M2-like tumor-associated macrophages (TAMs) into antitumoral M1-like type, the “cold” immune microenvironment of melanoma is effectively remodeled. When combining with aPD-L1-based immune checkpoint blockade therapy, the treatment outcome of aPD-L1 is dramatically boosted, which not only suppresses primary tumor growth, but also inhibits the notorious post-operative melanoma recurrence and metastasis. Overall, this local strategy mediated by nanoparticle-loaded MN patch expands the therapeutic regimen for melanoma treatment in clinic.

Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe.

Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of in vivo fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a "distinguishable" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.

Development of itraconazole ocular delivery system using β-cyclodextrin complexation incorporated into dissolving microneedles for potential improvement treatment of fungal keratitis

Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using β-cyclodextrin (β-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the β-CD was −5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using β-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

Determination of vat-photopolymerization parameters for microneedles fabrication and characterization of HPMC/PVP K90 dissolving microneedles utilizing 3D-printed mold

Three-dimensional (3D) printing serves as an alternative method for fabricating microneedle (MN) patches with a high object resolution. In this investigation, four distinct needle shapes: pyramid mounted over a long cube (shape A), cone mounted over a cylinder (shape B), pyramidal shape (shape C), and conical shape (shape D) were designed using computer-aided design (CAD) software with compensated bases of 350, 450 and 550 µm. Polylactic acid (PLA) biophotopolymer resin from eSun and stereolithography (SLA) 3D printer from Anycubic technology were used to print MN patches. The 3D-printed MN patches were employed to construct MN molds, and those molds were used to produce hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone (PVP) K90 dissolving microneedles (DMNs). Various printing parameters, such as curing time, printing angle, and anti-aliasing (AA), were varied to evaluate suitable printing conditions for each shape. Furthermore, physical appearance, mechanical property, and skin insertion ability of HPMC/PVP K90 DMNs were examined. The results showed that for shape A and C, the suitable curing time and printing angle were 1.5 s and 30° while for shapes B and D, they were 2.0 s and 45°, respectively. All four shapes required AA to eliminate their stair-stepped edges. Additionally, it was demonstrated that all twelve designs of 3D-printed MN patches could be employed for fabricating MN molds. HPMC/PVP K90 DMNs with the needles of shape A and B exhibited better physicochemical properties compared to those of shape C and D. Particularly, both sample 9 and 10 displayed sharp needle without bent tips, coupled with minimal height reduction (< 10%) and a high percentage of blue dots (approximately 100%). As a result, 3D printing can be utilized to custom construct 3D-printed MN patches for producing MN molds, and HPMC/PVP K90 DMNs manufactured by those molds showed excellent physicochemical properties.

Mechanics of dissolving microneedles insertion into the skin: Finite element and experimental analyses

AbstractTransdermal drug delivery using dissolving microneedles (DMNs) is promising due to increased patient compliance and safety. This article presents a comprehensive simulation and experimental analysis of DMNs with varying tip and base diameters and polymers. The objective of the simulation study is to identify the optimal tip and base diameter of DMNs, as well as the most suitable polymer, for achieving maximum penetration depth. The simulation results showed that the compound consisting of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) in a ratio of 2:1, with a tip radius of 17.5 μm and a base radius of 150 μm, achieved the deepest penetration among the different types of polymers investigated (including PVA, hyaluronic acid (HA), and PVA/PVP in ratios of 1:1 and 1:2). In addition, mechanical and skin penetration experiments were performed on PVA/PVP 2:1 DMNs with varying concentrations of 4, 7, 10, and 15% w/w to determine the optimal polymer concentration. The results of this study indicated that the optimal composition, considering the viscosity of the polymer solution and the simplicity of filling the silicone negative molds, is a PVA/PVP 2:1 with a concentration of 7% w/w.

Stress factors affecting protein stability during the fabrication and storage of dissolvable microneedles

Abstract Objectives The current review summarizes product and process attributes that were reported to influence protein integrity during manufacturing and storage of dissolvable microneedle arrays. It also discusses challenges in employing established protein characterization methods in dissolvable microneedle formulations. Methods Studies on dissolvable microneedles loaded with protein therapeutics that assess protein stability during or after fabrication and storage were collected. Publications addressing other types of microneedles, such as coated and vaccine-loaded microneedles, are also discussed as they face similar stability challenges. Key findings To date, various researchers have successfully incorporated proteins in dissolvable microneedles, but few publications explicitly investigated the impact of formulation and process parameters on protein stability. However, protein therapeutics are exposed to multiple thermal, physical, and chemical stressors during the fabrication and storage of microneedles. These stressors include increased temperature, shear and interfacial stress, transition to the solid state during drying, interaction with excipients, and suboptimal pH environments. While analytical methods are essential for monitoring protein integrity during manufacturing and storage, the performance of some well-established protein characterization techniques can be undermined by polymer excipients commonly employed in dissolvable microneedle formulations. Conclusions It is essential to understand the impact of key process and formulation parameters on the stability of protein therapeutics to facilitate their safe and effective administration by dissolvable microneedles.

Anti-Nociceptive Effect of Sufentanil Polymeric Dissolving Microneedle on Male Mice by Hot Plate Technique

Despite the widespread use of opioids to manage severe pain, its systemic administration results in side effects. Among the subcutaneous and transdermal drug delivery systems developed to deal with adverse effects, microneedles have drawn attention due to their rapid action, high drug bioavailability, and improved permeability. Sufentanil (SUF) is an effective injectable opioid for treating severe pain. In this study, we investigated the analgesic effects of SUF using dissolvable microneedles. SUF polymeric dissolvable microneedles were constructed through the mold casting method and characterized by SEM and FTIR analysis. Its mechanical strength was also investigated using a texture analyzer. Fluorescence microscopy was applied in vitro to measure the penetration depth of microneedle arrays. Irritation and microchannel closure time, drug release profile, and hemocompatibility test were conducted for the validation of microneedle efficiency. Hot plate test was also used to investigate the analgesic effect of microneedle in an animal model. Local administration of SUF via dissolving microneedles had an effective analgesic impact. One hour after administration, there was no significant difference between the subcutaneous and the microneedle groups, and the mechanical properties were within acceptable limits. Microneedling is an effective strategy in immediate pain relief compared to the traditional methods.

Evaluation test and analysis of a microneedle and iontophoresis based medical device "CELLADEEP Patch" in skin improvement on ex vivo human-derived skin tissue models.

Microneedles are tiny needles, typically ranging from tens to hundreds of micrometers in length, used in various medical procedures and treatments. The tested medical device named "CELLADEEP Patch" a dissolvable microneedle therapy system (MTS), made of hyaluronic acid and collagen. And the iontophoresis technique is also applied in the system. The study aimed to evaluate the effectiveness of the "CELLADEEP Patch" in skin improvement. Ex vivo human-derived skin tissue models were used in this study and they were divided into three different groups, namely, the Untreated Group, the Negative Control Group, and the Test Group respectively. The Untreated Group received no treatment measures, the Negative Control Group was exposed to ultraviolet B radiation (UVB) irradiation, and the Test Group was exposed to UVB irradiation and treated with "CELLADEEP Patch". Skin moisture content, transdermal water loss, and skin elasticity were evaluated by three clinical devices. Additionally, histological staining and related mRNA expression levels were also analyzed. The results of skin moisture content, transdermal water loss, and skin elasticity evaluation consistently illustrated that the application of "CELLADEEP Patch" led to remarkable skin improvement. And the analysis of histological staining images also confirmed the effectiveness of the "CELLADEEP Patch", especially for increasing collagen density. Moreover, the upregulation of Collagen type 1 a (COL1A1) and hyaluronan synthase 3 mRNA expression and the decrease of Matrix metalloproteinase 1 (MMP-1) and Interleukin-1 beta (IL-1β) mRNA expression reflected its wrinkle improvement, moisturizing and anti-inflammation function. "CELLADEPP Patch", the MTS combined with the iontophoresis technique, exhibits its effectiveness in moisturizing, skin elasticity improvement, and anti-inflammatory function when applied to ex vivo human-derived skin tissue models in experiments. The study has contributed to the understanding of the "CELLADEPP Patch" and laid the foundation for subsequent animal experiments and clinical trials.

Curcumin analogue AC17-loaded dissolvable microneedles activate FOXO3 and enhance localized drug delivery for oral squamous cell carcinoma treatment

Curcumin, a polyphenol extracted from turmeric, is a potential alternative for the treatment of oral squamous cell carcinoma (OSCC) due to its remarkable anticancer activity and low systemic toxicity. To further enhance the anticancer activity and bioavailability of curcumin, we synthesized a curcumin analogue, AC17, by modifying the benzene ring and methylene group of curcumin. A soluble hyaluronic acid microneedle patch (AC17@HAMN) was developed to ensure accurate and safe delivery of AC17 to tumor tissues. The inhibitory effect of AC17 on OSCC cells was stronger than that of curcumin and some common analogues. Transcriptome sequencing showed that the target genes of AC17 were mainly concentrated in apoptosis, cell cycle and cell senescence pathways. Among them, AC17 induces cell cycle arrest and inhibits cell proliferation mainly by activating FOXO3 signaling. With good penetration and dissolution properties, microneedles can deliver AC17 directly to the tumor site and show good anti-tumor effect. Moreover, AC17@HAMN showed good biosafety. In summary, AC17@HAMN offers high efficiency, minimal invasiveness, and few adverse reactions. This microneedle patch holds great promise for potential clinical applications, especially for the treatment of OSCC.