Dissolving Microneedle Arrays Research Articles

Transdermal delivery of colchicine using dissolvable microneedle arrays for the treatment of acute gout in a rat model

Colchicine (Col) is used to prevent and treat acute gout flare; however, its therapeutic use is strictly limited owing to severe gastrointestinal side effects after oral administration. Therefore, we developed a dissolvable Col-loaded microneedle (MN) with hyaluronic acid to deliver Col via the transdermal route. We studied the preparation, mechanical properties, skin insertion, skin irritation, drug content, and transdermal release of the Col-loaded MN. The pharmacokinetics of Col after Col-loaded MN application were compared with those of Col solution gavage over 24 h. Knee joint edema evaluation and the hindfoot mechanical threshold test were conducted to determine the pharmacodynamic profile. The dissolvable Col-loaded MN possessed sufficient mechanical strength to penetrate the skin and release the loaded drug. No skin irritation was observed for 3 days after application. We found that 3.36-fold more Col contained in MNs was delivered through the skin compared with that in gel in vitro, and moderate relative bioavailability in vivo. The Col-loaded MN significantly relieved swollen knee joints and mechanical hypernociception in an acute gout model in rats. The dissolvable Col-loaded MN array reduced inflammation and pain via topical administration when acute gout occurred. Reducing the gastrointestinal side effects of Col-loaded MNs is expected to optimize the therapeutic effects of Col and improve patient compliance.

Skin-targeted delivery of extracellular vesicle-encapsulated curcumin using dissolvable microneedle arrays

Therapeutic benefits of curcumin for inflammatory diseases have been demonstrated. However, curcumin's potential as a clinical therapeutic has been hindered due to its low solubility and stability in vivo. We hypothesized that a hybrid curcumin carrier that incorporates albumin-binding and extracellular vesicle (EV) encapsulation could effectively address the current challenges of curcumin delivery. We further postulated that using dissolvable microneedle arrays (dMNAs) for local delivery of curcumin-albumin-EVs (CA-EVs) could effectively control skin inflammation in vivo. Mild sonication was used to encapsulate curcumin and albumin into EVs, and the resulting CA-EVs were integrated into tip-loaded dMNAs. In vitro and in vivo studies were performed to assess the stability, cellular uptake, and anti-inflammatory bioactivity of dMNA-delivered CA-EVs. Curcumin in CA-EVs exhibited at least five-fold higher stability in vitro than naïve curcumin or curcumin-EVs without albumin. Incorporating CA-EVs into dMNAs did not alter their cellular uptake or anti-inflammatory bioactivity. The dMNA embedded CA-EVs retained their bioactivity when stored at room temperature for at least 12 months. In rat and mice models, dMNA delivered CA-EVs suppressed and significantly reduced lipopolysaccharide and Imiquimod-triggered inflammation. We conclude that dMNA delivery of CA-EVs has the potential to become an effective local-delivery strategy for inflammatory skin diseases. Statement of significanceWe introduce and evaluate a skin-targeted delivery system for curcumin that synergistically combines albumin association, extracellular-vesicle encapsulation, and dissolvable microneedle arrays (dMNAs) . In vitro, curcumin-albumin encapsulated extracellular vesicles (CA-EVs) inhibit and reverse the LPS-triggered expression of inflammatory transcription factor NF-κB. The integration of CA-EVs into dMNAs does not affect them physically or functionally. Importantly, dMNAs extend EV storage stability for at least 12 months at room temperature with minimal loss in their bioactivity. We demonstrate that dMNA delivered CA-EVs effectively block and reverse skin inflammation in vivo in mouse and rat models.

Levothyroxine sodium loaded dissolving microneedle arrays for transdermal delivery.

Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm2) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm2) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm2) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.

Elucidating the Impact of Surfactants on the Performance of Dissolving Microneedle Array Patches.

The need for biocompatible polymers capable of dissolving in the skin while exhibiting reasonable mechanical features and delivery efficiency limits the range of materials that could be utilized in fabricating dissolving microneedle array patches (MAPs). The incorporation of additives, such as surfactants, during microneedle fabrication might be an alternative solution to overcome the limited range of materials used in fabricating dissolving MAPs. However, there is a lacuna in the knowledge on the effect of surfactants on the manufacture and performance of dissolving MAPs. The current study explores the role of surfactants in the manufacture and performance of dissolving MAPs fabricated from poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) loaded with the model drugs, ibuprofen sodium and itraconazole. Three nonionic surfactants, Lutrol F108, Pluronic F88, and Tween 80, in solutions at varying concentrations (0.5, 1.0, and 2.0% w/w) were loaded into these dissolving MAPs. It was discovered that all of the dissolving MAPs that incorporated surfactant displayed a lower reduction in the microneedle height (≈10%) relative to the control formulation (≈20%) when subjected to a compressive force of 32 N. In addition, the incorporation of surfactants in some instances enhanced the insertion profile of these polymeric MAPs when evaluated using ex vivo neonatal porcine skin. The incorporation of surfactant into ibuprofen sodium-loaded dissolving MAPs improved the insertion depth of MAPs from 400 μm down to 600 μm. However, such enhancement was not apparent when the MAPs were loaded with the model hydrophobic drug, itraconazole. Skin deposition studies highlighted that the incorporation of surfactant enhanced the delivery efficiency of both model drugs, ibuprofen sodium and itraconazole. The incorporation of surfactant enhanced the amount of ibuprofen sodium delivered from 60.61% up to ≈75% with a majority of the drug being delivered across the skin and into the receptor compartment. On the other hand, when surfactants were added into MAPs loaded with the model hydrophobic drug itraconazole, we observed enhancement in intradermal delivery efficiency from 20% up to 30%, although this did not improve the delivery of the drug across the skin. This work highlights that the addition of nonionic surfactant is an alternative formulation strategy worth exploring to improve the performance and delivery efficiency of dissolving MAPs.

Intradermal Administration of Influenza Vaccine with Trehalose and Pullulan-Based Dissolving Microneedle Arrays

Most influenza vaccines are administered via intramuscular injection which has several disadvantages that might jeopardize the compliance of vaccinees. Intradermal administration of dissolving-microneedle-arrays (dMNAs) could serve as minimal invasive alternative to needle injections. However, during the production process of dMNAs antigens are subjected to several stresses, which may reduce their potency. Moreover, the needles need to have sufficient mechanical strength to penetrate the skin and subsequently dissolve effectively to release the incorporated antigen. Here, we investigated whether blends of trehalose and pullulan are suitable for the production of stable dMNA fulfilling these criteria. Our results demonstrate that production of trehalose/pullulan-based dMNAs rendered microneedles that were sharp and stiff enough to pierce into ex vivo human skin and subsequently dissolve within 15 min. The mechanical properties of the dMNAs were maintained well even after four weeks of storage at temperatures up to 37°C. In addition, immunization of mice with influenza antigens via both freshly prepared dMNAs and dMNAs after storage (four weeks at 4°C or 37°C) resulted in antibody titers of similar magnitude as found in intramuscularly injected mice and partially protected mice from influenza virus infection. Altogether, our results demonstrate the potential of trehalose/pullulan-based dMNAs as alternative dosage form for influenza vaccination.

Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis

Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). Invivo mouse models of contact hypersensitivity and exvivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD. We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.

Development of Microneedle Patch Loaded with Bacopa monnieri Solid Lipid Nanoparticles for the Effective Management of Parkinson's Disease.

The demand for drug delivery systems (DDS) to treat Parkinson's disease (PD) is still high, and microneedle (MN) assisted transdermal DDS offers enormous potential. Herbal products for PD have been shown to have antioxidant effects in reducing dopaminergic neurons from degeneration. Here, we attempted to incorporate solid lipid nanoparticles (SLNs) of Bacopa monnieri into dissolvable microneedle arrays and evaluate its neuroprotective activity. The bloodless and painless microneedle arrays through the transdermal route deliver the drug across the blood-brain barrier at the desired concentration. The quality by design (QbD) approach was employed for optimizing the SLNs formulations. The mechanical strength, in vitro release studies, ex-vivo permeation investigation, skin irritation test, histopathological studies, biochemical studies, and behavioural tests SLNs loaded microneedle arrays were performed. The microneedle patches obtained were shown to be mechanically robust and were also found to be nonirritant with a decreased degree of bradykinesia, high motor coordination, and balance ability. Compared to systemic delivery systems, such an MN method can achieve a considerably lower effective dose and allow long-term home-based treatment.

Bioimaging of Dissolvable Microneedle Arrays: Challenges and Opportunities.

The emergence of microneedle arrays (MNAs) as a novel, simple, and minimally invasive administration approach largely addresses the challenges of traditional drug delivery. In particular, the dissolvable MNAs act as a promising, multifarious, and well-controlled platform for micro-nanotransport in medical research and cosmetic formulation applications. The effective delivery mostly depends on the behavior of the MNAs penetrated into the body, and accurate assessment is urgently needed. Advanced imaging technologies offer high sensitivity and resolution visualization of cross-scale, multidimensional, and multiparameter information, which can be used as an important aid for the evaluation and development of new MNAs. The combination of MNA technology and imaging can generate considerable new knowledge in a cost-effective manner with regards to the pharmacokinetics and bioavailability of active substances for the treatment of various diseases. In addition, noninvasive imaging techniques allow rapid, receptive assessment of transdermal penetration and drug deposition in various tissues, which could greatly facilitate the translation of experimental MNAs into clinical application. Relying on the recent promising development of bioimaging, this review is aimed at summarizing the current status, challenges, and future perspective on in vivo assessment of MNA drug delivery by various imaging technologies.

Nanoemulsion-based dissolving microneedle arrays for enhanced intradermal and transdermal delivery

The development of dissolving microneedles (DMN) is one of the advanced technologies in transdermal drug delivery systems, which precisely deliver the drugs through a rapid dissolution of polymers after insertion into the skin. In this study, we fabricated nanoemulsion-loaded dissolving microneedle (DMN) arrays for intradermal and transdermal drug delivery. For this task, model drug (amphotericin B, AmB)-loaded nanoemulsion (NE) were prepared by the probe-sonication method. AmB-loaded-NE was prepared using Capmul MCM C-8 EP/NF, Tween® 80, poly(vinyl alcohol) (PVA-10 kDa), and poly (vinyl pyrrolidone) (PVP-360 kDa or K29/32) by using SpeedMixer™, followed by probe-sonication and evaluated for particle size and polydispersity index (PDI). Transmission electron microscopy (TEM) was also used to assess the particle size before and after DMN casting. AmB-NE embedded DMN arrays were found to be strong enough, revealed efficient skin insertion, and penetrated down to the fourth layer (depth ≈ 508 μm) of Parafilm M® (validated skin model). Ex vivo skin deposition experiments in full-thickness neonatal porcine demonstrated that after 24 h, AmB-NE-DMN arrays were able to deposit 111.05 ± 48.4 µg/patch AmB into the skin. At the same time, transdermal porcine skin permeation studies showed significantly higher permeability of AmB (29.60 ± 8.23 μg/patch) from AmB-NE-DMN compared to MN-free AmB-NE patches (5.0 ± 6.15 μg/patch) over 24 h. Antifungal studies of optimized AmB-NE-DMN, AmB-loaded discs and drug-free DMN against Candida albicans, confirmed the synergistic activity of Campul-MCM C-8, used in the nanoemulsion formulation. This study establishes that nanoemulsion based dissolving microneedle may serve as an efficient system for intradermal as well as transdermal drug delivery.Graphical abstract

Detachable dissolvable microneedles: intra-epidermal and intradermal diffusion, effect on skin surface, and application in hyperpigmentation treatment

Delivering bioactive compounds into skin tissue has long been a challenge. Using ex vivo porcine and rat skins, here we demonstrate that a detachable dissolvable microneedle (DDMN) array, a special dissolvable microneedle that allows needle detachment from the base within 2 min post administration, can effectively embed a model compound into epidermis and dermis. Diffusion of the compound from the needle embedding sites to the nearby skin tissue is demonstrated at various post administration periods. The relationship between the time that a conventional dissolvable microneedle array is left on skin without needle detachment from the base and the degree of skin surface abrasion at each microneedle penetration spot is also demonstrated on skin of human volunteers. Co-loading glutathione with vitamin C (vitC) can stabilize vitC in the DDMN. DDMN loaded with vitC and glutathione can help erasing post-acne-hyperpigmentation spots.

Trilayer microneedle array assisted transdermal and intradermal delivery of dexamethasone

Dexamethasone is a synthesised glucocorticoid that is widely used in the treatment of various inflammatory skin conditions. Novel trilayer dissolving microneedle arrays were manufactured to assist dexamethasone delivery via the skin. Both transdermal delivery and intradermal delivery of dexamethasone can be achieved this way. Additionally, we proposed a novel strategy of co-formulating dexamethasone and its pro-drug dexamethasone sodium phosphate into the same dissolving microneedle array, with a view to achieving a fast onset of action and also sustained treatment. Here, a 3D-printing technique was employed, for the first time, to fabricate a baseplate for these microneedle arrays. The 3D-printed baseplates provided strong support to aid the insertion of the drug-encapsulated tips. A simple and rapid HPLC method was developed, and validated, to separate and quantify dexamethasone and dexamethasone sodium phosphate in the same sample. Ex-vivo studies found that these trilayer dissolving microneedle arrays could achieve a delivery efficiency of over 40% in intradermal delivery and over 50% in transdermal delivery. Trilayer microneedle-assisted delivery of this glucocorticoid provided a promising alternative to oral and parenteral routes of dexamethasone administration.

Strategy for osteoarthritis therapy: Improved the delivery of triptolide using liposome-loaded dissolving microneedle arrays

Osteoarthritis (OA) is a chronic disease that seriously impairs people’s physical function and quality of life. Triptolide (TP), as a promising anti-inflammatory drug for the treatment of OA, has limited clinical application due to its severe systemic toxicity, poor solubility and rapid elimination in the body. To extend its application prospect for OA treatment. We have developed a liposome-loaded dissolving microneedle (DMN) system, which can effectively deliver poorly water-soluble TP and improve OA symptoms. To incorporate TP into DMNs, triptolide liposome (TP-Lipo) with entrapment efficiency of 90.25% was prepared by ethanol injection. Subsequently, TP-Lipo was concentrated by ultrafiltration tube and mixed with hyaluronic acid solution to prepare DMNs, TP-Lipo-loaded DMNs (TP-Lipo@DMNs) showed sufficient mechanical and insertion properties to penetrate about 200 μm of rat skin. The drug distribution in vivo showed that TP-Lipo@DMNs had a slow-release effect compared with intra-articular injection. In vivo pharmacodynamic research showed that TP-Lipo@DMNs significantly reduced knee joint swelling and the level of inflammatory cytokines (TNF-α, IL-1β, IL-6). Micro-CT and histological evaluation showed that TP-Lipo@DMNs effectively reduced cartilage destruction and alleviated OA symptoms. These results support that TP@Lipo@DMNs may be a promising option for OA treatment.

Research Techniques Made Simple: Skin-Targeted Drug and Vaccine Delivery Using Dissolvable Microneedle Arrays

Skin-targeted drug delivery is broadly employed for both local and systemic therapeutics and is an important tool for discovery efforts in cutaneous biology. Recently, emerging technologies support efforts toward skin-targeted biocargo delivery for local and systemic therapeutic benefit. Effective targeting of bioactive molecules, including large (molecular weight > 500 Da) or complex (hydrophilic and charged) molecules, to defined cutaneous microenvironments is intrinsically challenging owing to the protective barrier function of the skin. Dissolvable microneedle arrays (MNAs) have proven to be a promising technology to address the unmet need for controlled, minimally invasive, and reliable delivery of a wide range of biocargos to the skin. In this paper, we describe the unique properties of the skin that make it an attractive target for vaccine delivery, for immune-modulating therapies, and for systemic drug delivery and the structural characteristics of the skin that present obstacles to efficient intracutaneous and transdermal delivery of bioactive molecules. We provide an overview of MNA fabrication and the characteristics and mechanisms of dissolvable MNA cargo delivery to the cutaneous microenvironment. We present a representative example of a clinical application of MNAs and discuss future directions for MNA development and applications.

Chemical imaging analysis of active pharmaceutical ingredient in dissolving microneedle arrays by Raman spectroscopy.

The purpose of this study was to develop a quality evaluation method for dissolving microneedle arrays (DMNAs) and determine the spatial distribution pattern of drugs in DMNAs. Raman spectroscopy mapping was used to visualize the drug distribution in DMNAs and drug-loaded polymer films as a model. Powder X-ray diffraction (PXRD) and high-pressure liquid chromatography were also performed to characterize DMNAs. Drug-loaded polymer films and DMNAs were prepared by drying the aqueous solutions spread on the plates or casting. PXRD analysis suggested the crystallization of diclofenac sodium (DCF) in several forms depending on its amount in the sodium hyaluronate (HA)-based films. The Raman spectra of HA and DCF showed characteristic and non-overlapping peaks at 1376 and 1579cm-1 Raman shifts, respectively. The intensity of the characteristic peak of DCF in the DCF-loaded films increased linearly with the increasing drug content in the range of 4.8 to 16.7% (DCF, w/w). Raman imaging analysis revealed a homogenous dispersion of small DCF crystals in these films. Raman imaging indicates the distribution of DCF on the surface of the DMNA needle. This work highlights the benefit of using Raman spectroscopy mapping to reveal the spatial distribution of drugs in DMNAs.

Novel tip-loaded dissolving and implantable microneedle array patches for sustained release of finasteride

Finasteride (FND) is a competitive inhibitor of 5α-reductase, an enzyme involved in benign prostatic hyperplasia (BPH) and androgenic alopecia. FND is administered in oral, often lifelong treatments, increasing the pill burden of polymedicated patients. Microneedle array patches (MAPs) are minimally invasive devices that painlessly pierce the outermost layers of the skin, forming slowly-dissolving drug depots in the dermis, which can release drugs over weeks or months, making this platform an attractive, patient-friendly option for long-term treatments. This work describes the development of long-acting dissolving and implantable PLGA MAPs aimed for systemic release of FND for at least two weeks. Mechanically strong tip-loaded MAPs with pyramidal geometry were obtained using micromoulding methodology. In vitro studies revealed that the dissolving and implantable MAPs were able to release the drug for over 7 and 14 days, respectively. Skin deposition experiments in Franz cells demonstrated that after 24 h, dissolving and implantable MAPs were able to deposit 629.00 ± 214.54 μg and 1861.64 ± 383.30 μg of FND in the skin, respectively. On the other hand, transdermal permeation studies showed that both formulations produced a slow release of the drug to the receptor compartment of the Franz cells, with dissolving and implantable MAPs releasing 90.43 ± 6.20 μg and 27.80 ± 3.94 μg of FND after 24 h. The formulations described here could be an alternative to current oral treatments, having the potential to deliver the drug for extended periods, simplifying the treatment of BPH and androgenic alopecia.

Dissolving microneedle arrays that compensated for skin water loss due to microporation

Dissolving microneedle arrays that compensated for skin water loss due to microporation

Etravirine-loaded dissolving microneedle arrays for long-acting delivery

A key challenge of HIV treatment with multiple antiretroviral drugs is patient adherence. Thus, there is an urgent need for long-acting depot systems for delivering drugs over an extended duration. Although the parenteral route is preferred for depot systems, it is associated with obvious drawbacks, such as painful injections, potentially-contaminated sharps waste, and the necessity of trained healthcare personnel for administration. Amongst a small number of alternatives in development microneedles are versatile delivery systems enabling systemic drug delivery and potentially improving patient adherence due to their capacity for self-administration. We have developed dissolving microneedle (DMNs) embedded with etravirine nanosuspension (ETR NS) as a long-acting HIV therapy to improve patient adherence. The ETR NS prepared by sonoprecipitation yielded particle sizes of 764 ± 96.2 nm, polydispersity indices of of 0.23 ± 0.02, and zeta potentials of −19.75 ± 0.55 mV. The DMNs loaded with ETR NS demonstrated 12.84 ± 1.33% ETR deposition in ex-vivo neonatal porcine skin after 6 h application. In in vivo rat pharmacokinetic studies, the Cmax exhibited by DMNs loaded with ETR powder and ETR NS were 158 ± 10 ng/mL and 177 ± 30 ng/mL, respectively. DMN groups revealed a higher t1/2, Tmax, and mean residence time compared to intravenous ETR solutions, suggesting the long-acting potential of etravirine delivered intradermally using DMNs.

Simultaneous Delivery of Multiple Antimicrobial Agents by Biphasic Scaffolds for Effective Treatment of Wound Biofilms.

Biofilms pose a major challenge to control wound-associated infections. Due to biofilm impenetrability, traditional antimicrobial agents are often ineffective in combating biofilms. Herein, a biphasic scaffold is reported as an antimicrobial delivery system by integrating nanofiber mats with dissolvable microneedle arrays for the effective treatment of bacterial biofilms. Different combinations of antimicrobial agents, including AgNO3 , Ga(NO3 )3 , and vancomycin, are incorporated into nanofiber mats by coaxial electrospinning, which enables sustained delivery of these drugs. The antimicrobial agents-incorporated dissolvable microneedle arrays allow direct penetration of drugs into biofilms. By optimizing the administration strategies, drug combinations, and microneedle densities, biphasic scaffolds are able to eradicate both methicillin-resistant Staphylococcus aureus (MRSA) and MRSA/Pseudomonas aeruginosa blend biofilms in an ex vivo human skin wound infection model without necessitating surgical debridement. Taken together, the combinatorial system comprises of nanofiber mats and microneedle arrays can provide an efficacious delivery of multiple antimicrobial agents for the treatment of bacterial biofilms in wounds.

Engineering of an automated nano-droplet dispensing system for fabrication of antigen-loaded dissolving microneedle arrays

Dissolving microneedle arrays (dMNAs) are promising devices for intradermal vaccine delivery. The aim of this study was to develop a reproducible fabrication method for dMNAs based on an automated nano-droplet dispensing system that minimizes antigen waste. First, a polymer formulation was selected to dispense sufficiently small droplets (<18 nL) that can enter the microneedle cavities (base diameter 330 µm). Besides, three linear stages were assembled to align the dispenser with the cavities, and a vacuum chamber was designed to fill the cavities with dispensed droplets without entrapped air. Lastly, the dispenser and stages were incorporated to build a fully automated system. To examine the function of dMNAs as a vaccine carrier, ovalbumin was loaded in dMNAs by dispensing a mixture of ovalbumin and polymer formulation, followed by determining the ovalbumin loading and release into the skin. The results demonstrate that functional dMNAs which can deliver antigen into the skin were successfully fabricated via the automatic fabrication system, and hardly any antigen waste was encountered. Compared to the method that centrifuges the mould, it resulted in a 98.5% volume reduction of antigen/polymer solution and a day shorter production time. This system has potential for scale-up of manufacturing to an industrial scale.

Design of Dissolvable Microneedles for Delivery of a Pfs47-Based Malaria Transmission-Blocking Vaccine.

The development of effective malaria vaccines remains a global health priority. In addition to an effective vaccine, there is urgent demand for effective delivery technologies that can be easily deployed. The need for effective vaccine delivery tools is particularly pertinent in resource-poor settings where access to healthcare is limited. Microneedles are micron-scale structures that offer distinct advantages for vaccine delivery by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. Here, we developed and characterized a candidate malaria vaccine loaded and deployed using dissolvable microneedle arrays. Of note, a newly indicated human-relevant antigen was employed, Plasmodium falciparum surface protein P47. P47 and a potent toll-like receptor (TLR9) agonist vaccine adjuvant, CpG, were fabricated into microneedles using a gelatin polymer. Protein binding, ELISA, and fluorescence analysis confirmed the molecular structure, and the function of the P47 antigen and CpG was maintained after fabrication, storage, and release from microneedles. In cell culture, the cargo released from the microneedle arrays triggered TLR9 signaling and activated primary dendritic cells at levels similar to native, unincorporated vaccine components. Together, these studies demonstrate the potential of microneedles as an easily deployable strategy for a P47-based malaria vaccine.