Search Results (61)

Microneedle (MN) technologies have emerged as a groundbreaking platform for transdermal and intradermal drug delivery, offering a minimally invasive alternative to oral and parenteral routes. Unlike passive transdermal systems, MNs allow the permeation of hydrophilic macromolecules, such as peptides, proteins, and vaccines, by penetrating the stratum corneum barrier without causing pain or tissue damage, unlike hypodermic needles. Recent advances in materials science, microfabrication, and biomedical engineering have enabled the development of various MN types, including solid, coated, dissolving, hollow, hydrogel-forming, and hybrid designs. Each type has unique mechanisms, fabrication techniques, and pharmacokinetic profiles, providing customized solutions for a range of therapeutic applications. The integration of 3D printing technologies and stimulus-responsive polymers into MN systems has enabled patches that combine drug delivery with real-time physiological sensing. Over the years, MN applications have grown beyond vaccines to include the delivery of insulin, anticancer agents, contraceptives, and various cosmeceutical ingredients, highlighting the versatility of this platform. Despite this progress, broader clinical and commercial adoption is still limited by issues such as scalable and reliable manufacturing, patient acceptance, and meeting regulatory expectations. Overcoming these barriers will require coordinated efforts across engineering, clinical research, and regulatory science. This review thoroughly summarizes MN technologies, beginning with their classification and drug-delivery mechanisms, and then explores innovations, therapeutic uses, and translational challenges. It concludes with a critical analysis of clinical case studies and a future outlook for global healthcare. By comparing technological progress with regulatory and commercial hurdles, this article highlights the opportunities and limitations of MN systems as a next-generation drug-delivery platform. Full article

Background/Objectives: A key disadvantage of DNA vaccines is ineffective uptake of plasmid DNA, resulting in low immunogenicity. A way to overcome it is forced DNA delivery, which requires specialized equipment and/or reagents. Effective delivery of plasmids without specialized devices or using commonly available ones would significantly increase DNA vaccine applicability. Here, we delivered DNA by intradermal injections, facilitating them by optimized sonoporation (SP) or electroporation (EP), and we compared these methods by their capacity to support the production of foreign proteins in mice. Methods: DNA delivery was optimized using the plasmid encoding firefly luciferase (Luc) (pVaxLuc). Luc production was assessed by bioluminescence imaging (BLI) (IVIS, PerkinElmer, Shelton, CT, USA; LumoTrace Fluo, Abisense, Dolgoprudny, Russia). Female BALB/c mice were injected intradermally (id) with pVaxLuc in phosphate buffers of varying ionic strengths. Injection sites were subjected to SP (Intelect Mobile, Chattanooga, UK) or EP (CUY21EDITII, BEX Co., Tokyo, Japan) or left untreated. Optimal delivery protocols were selected based on the highest in vivo levels of photon flux according to BLI. Optimal protocols for id injections with/without EP were applied to DNA-immunized mice with HIV-1 clade A reverse transcriptase. Antibody response induced by DNA immunization was assessed by ELISA. Results: The optimal phosphate buffers for id delivery had ionic strengths from 81 to 163 mmol/L. The optimal SP regimen included an acoustic pressure of 2.4 W/cm² applied in a duty cycle of 2%. The optimal EP regimen included bipolar driving pulses of 100 V, a pulse duration of 10 ms, and an interval between the pulses of 20 ms. Optimized DNA delivery by id/SP injection was inferior to both id/EP and id alone. DNA immunization with HIV-1 RT by id injections induced anti-RT antibodies in a titer of 10⁴ and by id/EP in a titer of 10⁵. Conclusions: Electroporation of the sites of id DNA injection provided the highest levels of production of luciferase reporters and induced a strong antibody response against HIV-1 RT. Full article

The development of advanced macromolecular systems with tailored structural and functional properties is a key objective in modern materials science, particularly for biomedical applications such as targeted drug delivery. In this study, hydrogel (HG), a polymer-based formulation, was investigated as a functional carrier for the enhanced intradermal and transdermal delivery of propranolol hydrochloride (PRO-HCl), a highly water-soluble model compound, and its potential was compared to other vehicles easily obtained by pharmacists: ointment (OM), liposomal cream (LCR), and microemulsion (ME). The formulations were characterized by their physicochemical and rheological characteristics, and evaluated in vitro and ex vivo using vertical diffusion cells equipped with synthetic membranes, intact porcine skin, and skin pretreated with solid microneedles (MNs). The HG formulation exhibited superior release performance (2396.85 ± 48.18 μg/cm²) and the highest intradermal drug deposition (19.87 ± 4.12 μg/cm²), while its combination with MNs significantly enhanced transdermal permeation (p = 0.0017). In contrast, the synergistic effect of MNs and ME led to a pronounced increase in drug accumulation within the skin (up to 60.3-fold). These findings highlight the crucial role of matrix composition and properties in modulating molecular transport through biological barriers. The study demonstrates that polymeric HGs represent versatile, functional materials with tunable structural and mechanical features, suitable for controlled release and potential systemic delivery applications. Full article

Tinea is a superficial fungal infection of keratinized structures caused by specific filamentous fungi called dermatophytes. Terbinafine, a drug used to treat tinea, is poorly soluble in water, and its delivery into the skin via nanoparticle formulation usingpoly(lactic-co-glycolic acid) (PLGA) has been demonstrated. In this study, we investigated the preparation conditions for nanoparticles (NPs) to achieve efficient intradermal delivery of terbinafine. Terbinafine-loaded PLGA NPs were prepared using the nanoprecipitation method, and the particle size distribution and average particle size were measured using dynamic light scattering. Skin permeability tests were conducted using mouse dorsal skin, and the amount of terbinafine delivered into the skin was measured to evaluate the release behavior in the skin. In the preparation of terbinafine-loaded PLGA NPs, under conditions where the external solution was purified water, the mean volume diameter was 40.49 ± 15.63 nm, the terbinafine-loaded content was 3.31 ± 0.29%, and the entrapment efficiency was 55.08 ± 4.88%. Under conditions of an external solution containing 1.0 × 10⁻³ w/v% arginine(Arg) aq. solution, the mean volume diameter was 41.71 ± 16.08 nm, the terbinafine-loaded content was 5.17 ± 0.37%, and the entrapment efficiency was 86.48 ± 6.01%. The entrapment efficiency and content were higher under the condition using 1.0 × 10⁻³ w/v% Arg aq. solution compared to purified water. In addition, in the skin permeability test, no drug was detected in the receptor solution sampled from both the NPs suspension group and the simple solution group, and no drug was detected in the intradermal solution in the simple solution group. The intradermal drug concentration was 77.94 ± 10.66 µg/g under conditions where purified water was used as the dialysate, and 96.42 ± 61.62 µg/g under conditions using 1.0 × 10⁻³ w/v% arginine, exceeding the reported minimum inhibitory concentration (MIC) of 8.87 µg/g, suggesting the efficacy of terbinafine-loaded PLGA NPs for the treatment of tinea versicolor. Since tinea treatment is a long-term process, it is desirable to deliver a stable amount of drug to the treatment site at all times. Therefore, the nanoparticle preparation conditions using purified water as the external solution, where the intradermal drug concentration exceeded the MIC and remained stable in the skin permeability test, were suggested to be suitable for tinea treatment. Full article

Wound healing remains a significant clinical challenge worldwide, and effective management strategies are essential for improving outcomes. This study investigates the therapeutic potential of the AcuCool™ system, a novel multifunctional device that combines high-velocity CO₂ cryotherapy with intradermal delivery of epidermal growth factor (EGF), in promoting wound healing. Using a full-thickness skin wound model in Sprague Dawley rats, we compared the effects of Device+EGF treatment to those of conventional microneedling-based EGF delivery and untreated controls. Macroscopic assessments revealed significantly accelerated wound closure in the Device+EGF group. Histological analysis showed enhanced re-epithelialization, reduced inflammatory cell infiltration, and increased collagen deposition. Molecular evaluations further demonstrated downregulation of pro-inflammatory markers (TNF-α, IL-1β, MCP-1) and upregulation of remodeling-related genes including TGF-β1, Collagen I, and Vimentin. In addition, nitrite assays confirmed reduced local nitric oxide levels, indicating suppression of oxidative stress. The AcuCool™ platform offers precise, non-invasive drug delivery with dual physical and biochemical therapeutic mechanisms, enabling superior control of inflammation and tissue regeneration. These findings suggest that AcuCool™ represents a promising therapeutic strategy for accelerating wound healing in acute models. While further studies are warranted in chronic wound settings, this approach may hold translational potential for future clinical applications. Full article

Skin aging is commonly characterized by increased wrinkles, loss of elasticity, and hyperpigmentation, significantly affecting personal appearance and quality of life. Although botulinum toxin type A (BTX-A) has been widely applied in cosmetic anti-wrinkle treatments, its intrinsic cytotoxicity limits broader clinical applications. In this study, we developed a novel exosome-based BTX-A composite delivery system designed to synergize the anti-aging properties of exosomes with the wrinkle-reducing effects of BTX-A while reducing toxicity. Human adipose-derived mesenchymal stem cells were genetically modified via lentiviral transduction to overexpress Synaptic Vesicle Glycoprotein 2C (SV2C), the receptor of BTX-A, thereby producing SV2C-enriched functionalized exosomes (EXO^SV2C). These exosomes (2.0 × 10⁷ particles/mL) were incubated with BTX-A (3 U/mL) to generate the EXO^SV2C-BTX-A complex. In vitro, EXO^SV2C-BTX-A significantly promoted the proliferation and migration of human dermal fibroblasts and effectively alleviated D-galactose (D-gal)-induced cellular senescence and collagen type I loss. These effects were superior to those observed with either BTX-A or exosomes alone. In vivo, intradermal injection of EXO^SV2C-BTX-A for 28 days markedly suppressed D-gal-induced skin aging in 8-week-old male KM mice, as evidenced by reduced malondialdehyde levels in dermal tissue, enhanced collagen type I expression, and preserved skin structure. Notably, the composite exhibited significantly lower toxicity compared to free BTX-A. Collectively, these findings highlight EXO^SV2C-BTX-A as a promising exosome-mediated BTX-A delivery platform with enhanced anti-aging efficacy and improved biocompatibility, offering a potential therapeutic strategy for skin rejuvenation. Full article

Background: Acne vulgaris, a prevalent inflammatory skin disorder, stems from factors like Cutibacterium acnes overgrowth, inflammation dysregulation, and immune dysfunction. Clinically, acne severity inversely correlates with serum zinc (Zn) levels, and oral Zn supplementation shows efficacy. Lactic acid bacteria are capable of converting inorganic Zn into organic forms via biological transformation, potentially generating Zn-enriched bacteria as superior Zn delivery vehicles. Methods: In this study, a Zn-deficient acne mouse model was established through dietary Zn restriction combined with intradermal C. acnes injection. The therapeutic effects of orally administered Zn-containing supplements, including Zn-enriched Bifidobacterium longum subsp. longum CCFM1195 (Zn-CCFM1195), were systematically evaluated through multiple parameters: histopathological evaluation of skin lesions, cutaneous inflammatory and oxidative stress markers, serum Zn concentration, and gene expression levels of pathway-associated proteins. Results: Induction of C. acnes led to decreased serum Zn levels (14.98 μmol/L in Control vs. 9.71 μmol/L in Model) and skin metallothionein content, causing Zn imbalance. Zn deficiency caused increased levels of lesion elevation (9.23 in Model vs. 10.53 in Zn-deficient Model), IL-17A, TNF-α, and MMP9 in skin, thereby exacerbating the inflammatory response in C. acnes-induced mice. Zn supplementation alleviated inflammatory responses and oxidative stress in Zn-deficient acne-like mice. Notably, inactivated Zn-CCFM1195 exhibited superior efficacy to ZnSO₄, significantly reducing lesion diameter and decreasing cutaneous levels of IL-1β, IL-17A, and MDA while enhancing GSH-Px activity. Similarly, viable Zn-CCFM1195 treatment significantly decreased IL-17A and enhanced GSH-Px activity compared with ZnSO₄ treatment. Furthermore, Zn supplementation downregulated the expression of TLR2, IκBα, and IKKβ, which may exert its anti-acne effect by regulating related pathways. Conclusions: Zn deficiency exacerbates skin inflammation, whereas Zn supplementation, particularly with Zn-CCFM1195, alleviates acne vulgaris through anti-inflammatory and antioxidant effects. Full article

Background/Objectives: The Tropis^® ID device (PharmaJet^®), a needle-free injection system, is a World Health Organization prequalified, hand-held device, which delivers intradermal injections without the use of needles and has previously been used for the delivery of fractional doses of inactivated polio vaccine (fIPV) in campaign and house-to-house settings. This implementation research study aimed to comparatively evaluate the vaccine coverage, cost, feasibility, and acceptability of using Tropis for fIPV for routine immunizations in two states in Nigeria (Kano and Oyo). Methods: The study included: (i) a cluster randomized trial (22 intervention facilities using Tropis for fIPV and 30 control facilities using the standard of care [SoC—full-dose IPV]) to assess the effectiveness in terms of improving the coverage of two doses of IPV, using a coverage survey involving 3433 children (aged 3–12 months); (ii) a pre- and post-implementation micro-costing evaluation involving the intervention facilities to estimate the costs; and (iii) mixed methods assessments (post-training assessment, provider survey, key informant interviews, and focus group discussions) to assess the feasibility and acceptability of fIPV delivery using Tropis. Results: The intention-to-treat analysis among the 3433 children surveyed did not show any difference between the intervention and control groups, primarily due to low compliance (approximately 50% of target beneficiaries reported Tropis use). The more relevant per protocol analysis, adjusting for lower compliance, showed that among those vaccinated with Tropis, second dose IPV coverage was 11.2% higher than the SoC. The delivery of fIPV using Tropis compared to the SoC resulted in incremental program cost savings, ranging from USD 0.07 to USD 1.00 per dose, administered across the scenarios evaluated. High acceptability was seen amongst caregivers (94%), and 95% of healthcare workers preferred Tropis over the SoC. Conclusions: Tropis is effective, feasible, acceptable, and saves costs when used as part of routine immunization programs. Full article

Background: Rutin is a natural flavonoid extracted primarily from plants with anti-inflammatory and antioxidant properties, and it is highly valuable in the cosmetics industry. However, the poor transdermal permeability of rutin limits its application via transdermal administration. Previous studies have predominantly focused on chemical methods for enhancing penetration. This study investigated the potential of ultrasound as a physical method by which to augment the transdermal absorption and anti-inflammatory effects of rutin. Method: Through in vitro diffusion experiments, we analyzed the effects of the ultrasonic frequency and intensity on percutaneous absorption. The optimal ultrasound parameters were determined based on the intradermal retention rate, which is defined as the proportion of intradermal retention to the total penetration. Parameters with higher retention rates were considered optimal. To validate the anti-inflammatory efficacy of rutin delivered using the ultrasound-assisted method, we employed a tape-stripping technique to induce inflammation in BALB/c nude mice. Eight mice were assigned to each treatment group: (A) self-repair (control group), (B) regular rutin treatment, and (C) ultrasound-assisted treatment. Results: The research findings indicate that ultrasound frequency and intensity of 1 MHz and 0.2 W/cm², as well as 3 MHz and 0.2 W/cm², result in the maximum proportion of rutin intradermal retention, exhibiting values 1.8 times (using porcine skin) and 2.63 times (using nude mouse skin) higher than those achieved without ultrasound, respectively. Group C showed the shortest recovery time and displayed complete skin barrier function restoration by the fourth day $(p<0.05)$, whereas group A exhibited the slowest recovery. Conclusions: This study offers an innovative approach for the transdermal delivery of rutin to facilitate skin barrier function repair. Full article

Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal disease worldwide, particularly in children in low- and middle-income countries. Its ability to rapidly colonize the intestinal tract through diverse colonization factors and toxins underpins its significant public health impact. Despite extensive research and several vaccine candidates reaching clinical trials, no licensed vaccine exists for ETEC. This review explores the temporal and spatial coordination of ETEC virulence factors, focusing on the interplay between adherence mechanisms and toxin production as critical targets for therapeutic intervention. Advancements in molecular biology and host–pathogen interaction studies have uncovered species-specific variations and cross-reactivity between human and animal strains. In particular, the heat-labile (LT) and heat-stable (ST) toxins have provided crucial insights into molecular mechanisms and intestinal disruption. Additional exotoxins, such as EAST-1 and hemolysins, further highlight the multifactorial nature of ETEC pathogenicity. Innovative vaccine strategies, including multiepitope fusion antigens (MEFAs), mRNA-based approaches, and glycoconjugates, aim to enhance broad-spectrum immunity. Novel delivery methods, like intradermal immunization, show promise in eliciting robust immune responses. Successful vaccination against ETEC will offer an effective and affordable solution with the potential to greatly reduce mortality and prevent stunting, representing a highly impactful and cost-efficient solution to a critical global health challenge. Full article

The application of dissolving microneedle arrays (DMNAs) is an emerging trend in drug and vaccine delivery as an alternative for hypodermic needles or other less convenient drug administration methods. The major benefits include, amongst others, that no trained healthcare personnel is required and that the recipient experiences hardly any pain during administration. However, for a successful drug or vaccine delivery from the DMNA, the microneedles should be inserted intact into the skin. A successful penetration into the upper skin layers may be challenging because of the elastic nature of the skin; therefore, a minimum insertion force is required to overcome the total resistance force of the skin. In addition, the microneedles need to stay intact, which requires a certain mechanical strength, and be able to resist the required insertion force. In addition to the type of material with which the DMNAs are produced, the geometry of the DMNAs will also have a profound effect, not only on the mechanical strength but also on the number of insertions and penetration depth into the skin. In this review, the effects of shape, aspect ratio, length, width of the base, tip diameter and angle, and spacing of DMNAs on the aforementioned effect parameters were evaluated to answer the following question: ‘What is the optimal geometry of dissolving microneedle arrays?’. Full article

Tumor whole-cell vaccines are designed to introduce a wide range of tumor-associated antigens into the body to counteract the immunosuppression caused by tumors. In cases of lymphoma of which the specific antigen is not yet determined, the tumor whole-cell vaccine offers distinct advantages. However, there is still a lack of research on an effective preparation method for the lymphoma whole-cell vaccine. To solve this challenge, we prepared a whole-cell vaccine derived from non-Hodgkin B-cell lymphoma (A20) via the photothermal effect mediated by Prussian blue nanoparticles (PBNPs). The immune activation effect of this vaccine against lymphoma was verified at the cellular level. The PBNPs-treated A20 cells underwent immunogenic cell death (ICD), causing the loss of their ability to form tumors while retaining their ability to trigger an immune response. A20 cells that experienced ICD were further ultrasonically crushed to prepare the A20 whole-cell vaccine with exposed antigens and enhanced immunogenicity. The A20 whole-cell vaccine was able to activate the dendritic cells (DCs) to present antigens to T cells and trigger specific immune responses against lymphoma. Whole-cell vaccines are primarily administered through direct injection, a method that often results in low delivery efficiency and poor patient compliance. Comparatively, the microneedle patch system provides intradermal delivery, offering enhanced lymphatic absorption and improved patient adherence due to its minimally invasive approach. Thus, we developed a porous microneedle patch system for whole-cell vaccine delivery using Gelatin Methacryloyl (GelMA) hydrogel and n-arm-poly(lactic-co-glycolic acid) (n-arm-PLGA). This whole-cell vaccine combined with porous gel microneedle patch delivery system has the potential to become a simple immunotherapy method with controllable production and represents a promising new direction for the treatment of lymphoma. Full article

Objectives: Non-viral mediated plasmid DNA transfection by electroporation (EP) is an established method for gene transfection. In this study, the usefulness of direct EP at an intradermal (i.d.) site (D_EP) with implanted electrodes to achieve a high protein expression level was investigated. In addition, D_EP application with various intervals with a low application voltage was also evaluated to confirm its effect on protein expression. Methods: Green fluorescent protein (GFP)- and luciferase-encoding DNA were administrated, and GFP and luciferase were evaluated. Results: A higher protein expression level was observed after green fluorescent protein (GFP)- and luciferase-encoding DNA were delivered by i.d. injection followed by D_EP application. When luciferase expression was observed with an in vivo imaging system, continuous expression was confirmed over 21 days after i.d. injection followed by D_EP at 100 V. This approach provided increased gene expression levels compared with conventional EP methods via the stratum corneum layer. In addition, the effect of application voltage on luciferase expression was investigated; two-time applications (repeated D_EP) at 20 V with 5 min intervals showed similar luciferase expression level to single D_EP application with 100 V. Histological observations showed the skin became thicker after a single D_EP at 100 V, whereas no apparent thickness changes were confirmed after repeated D_EP at 20 V with 5 min intervals. Conclusions: This study revealed that direct i.d. voltage application achieved high protein expression levels even at low voltages. Skin is a promising administration site for DNA vaccines, so this approach may be effective for DNA vaccine delivery into skin tissue. Full article

Compared with oral or injection administration, percutaneous immunotherapy presents a promising treatment modality for food allergies, providing low invasiveness and safety. This study investigated the efficacy of percutaneous immunotherapy using hen egg lysozyme (HEL)-loaded PLGA-PEG-PLGA nanoparticles (NPs), as an antigen model protein derived from egg white, compared with that of HEL-loaded chitosan hydroxypropyltrimonium chloride (CS)-modified PLGA NPs used in previous research. The intradermal retention of HEL in excised mouse skin was measured using Franz cells, which revealed a 2.1-fold higher retention with PLGA-PEG-PLGA NPs than that with CS-modified PLGA NPs. Observation of skin penetration pathways using fluorescein-4-isothiocyanate (FITC)-labeled HEL demonstrated successful delivery of HEL deep into the hair follicles with PLGA-PEG-PLGA NPs. These findings suggest that after NPs delivery into the skin, PEG prevents protein adhesion and NPs aggregation, facilitating stable delivery deep into the skin. Subsequently, in vivo percutaneous administration experiments in mice, with concurrent iontophoresis, demonstrated a significant increase in serum IgG1 antibody production with PLGA-PEG-PLGA NPs compared with that with CS-PLGA NPs after eight weeks of administration. Furthermore, serum IgE production in each NP administration group significantly decreased compared with that by subcutaneous administration of HEL solution. These results suggest that the combination of PLGA-PEG-PLGA NPs and iontophoresis is an effective percutaneous immunotherapy for food allergies. Full article

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects. Full article