Skin Penetration Efficiency Research Articles

Development and evaluation of biocompatible coated microneedle array for controlled insulin delivery: Fabrication, characterization, in vitro, and in vivo investigations

Traditional insulin administration for people with diabetes often involves painful injections, leading to discomfort and challenges with patient compliance. A promising alternative to these conventional methods is transdermal insulin delivery using microneedle arrays, which offer a more comfortable way to deliver insulin through the skin. This study introduces an innovative approach using 3D-printed microneedle arrays coated with insulin via a dip-coating process. These microneedles present a compelling alternative to traditional injections, particularly due to their ability to gently pierce the stratum corneum, the outermost layer of skin, while minimizing discomfort. The microneedle arrays were fabricated using biocompatible resin polymers through 3D printing, creating solid conical needles with a length of 1200 µm, a base diameter of 200 µm, a tip diameter of 80 µm, and a needle spacing of 1.2 mm. The insulin coating was achieved by dip-coating the microneedles in a solution of insulin and polyvinyl alcohol (PVA), with careful optimization of the solution concentration, immersion time, and withdrawal speed to ensure a uniform and controlled coating thickness. Mechanical stability and skin penetration capabilities of the microneedles were assessed using skin models such as parafilm and porcine skin. The tests confirmed that the coated microneedles are robust enough to consistently penetrate the skin. In vivo studies with diabetic rats were conducted to evaluate skin irritation, penetration, and drug delivery efficiency. The insulin-coated microneedle arrays successfully penetrated the skin and delivered the drug with approximately 90 % efficiency. The study also showed that the microneedles provided consistent drug delivery, and the skin recovered without any signs of injury. Additionally, the hypoglycemic effect of the insulin-coated microneedles was comparable to that of traditional subcutaneous insulin injections. These findings underscore the potential of microneedle arrays as a painless and effective method for insulin delivery, maintaining stable glucose levels over an extended period. The demonstrated safety and efficacy of the coated microneedles open the door for clinical trials and potential use in diabetic patients, offering a promising advancement in diabetes management.

Evaluation of the safety and efficacy of skin penetration enhancer Putocrin®.

Substances that can efficiently enhance skin penetration while exerting no adverse effect are useful for drug and cosmetics formulation. To investigate the safety and enhance skin penetration efficacy of Putocrin®, a combination containing 2% isosorbide dimethyl ether, 1% pentanediol, and 0.5% inositol. An invitro keratinocyte cell assay using 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide (MTT), and an invitro EpiKutis® skin study adopted hematoxylin and eosin staining, immunostaining, and liquid chromatography-mass spectrometry (LC-MS) analysis were carried out to investigate the safety of Putocrin®. A pigskin-Franz cell system experiment applied high-performance liquid chromatography (HPLC) to compare the skin penetration efficiency of fluorescein isothiocyanate (Fitc)-labeled tranexamic acid with or without the assistance of Putocrin®. The safety and efficacy of Putocrin® was further evaluated on zebrafish embryos. The MTT assay showed that Putocrin® at concentration ≤2.5% did not significantly affect cell viability. The invitro EpiKutis® skin study revealed that 2.5% Putocrin® did not affect skin morphology, filaggrin content, ceramide/protein, or fatty acid/protein ratios, but significantly increased loricrin content by 86.00% (p < 0.001). The pigskin-Franz cell penetration experiment demonstrated that Fitc-labeled tranexamic acid could barely penetrate the skin (with penetration rate of 1.121%), while Putocrin® significantly enhanced the penetration rate up to 83.983%, which was close to unlabeled tranexamic acid (90.013%). The zebrafish embryo study showed that 2.5% Putocrin® did not exert observable toxicity and obviously assisted the skin penetration of Fitc-labeled tranexamic acid into fish embryos. These results indicate the strong enhancing skin penetration potency of Putocrin®. This study demonstrated the safety as well as the strong enhancing skin penetration potency of Putocrin® for cosmetics formulation use.

Hydrogel forming microneedles loaded with VEGF and Ritlecitinib/polyhydroxyalkanoates nanoparticles for mini-invasive androgenetic alopecia treatment

Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.

Rapid miRNA detection in skin interstitial fluid using a hydrogel microneedle patch integrated with DNA probes and graphene oxide.

MicroRNA (miRNA) is a type of short, non-coding nucleic acid molecule that plays essential roles in diagnosing and prognosing various types of cancer. MiRNA is abundantly present in skin interstitial fluid (ISF), providing real-time and localized physiological information. Hydrogel microneedle (HMN) patches enable miRNA collection in a fast, pain-free, minimally invasive, and user-friendly manner. In this study, we introduced a fluorescence-based HMN assay, namely the HMN-miR sensor, composed of methacrylated hyaluronic acid (MeHA) and a graphene oxide-probe DNA (GO.pDNA) conjugate for miR21 and miR210 detection. The HMN-miR sensor demonstrates excellent skin penetration efficiency, rapid ISF collection capability, and sufficient miRNA detection and sequence identification specificity. The HMN-miR sensor facilitates a new assay that, with further optimization, could be applied in future clinical settings. Its simple fabrication process and excellent biocompatibility give it significant potential for various clinical uses, such as personalized cancer treatment and monitoring the healing progress of burn wounds.

Cedrol-loaded dissolvable microneedles based on flexible backing for promoting hair growth

ABSTRACT Objectives The dissolvable microneedles loaded with cedrol based on flexible backing were developed to deliver cedrol directly and continuously to the dermis, where the drug concentration in the hair follicle can be increased locally. Methods The tip-layer matrix solution was prepared by mixing cedrol and polyvinylpyrrolidone K25 (PVP K25), and the pedestal matrix solution was prepared with aqueous hyaluronic acid. The cedrol-loaded dissolvable microneedles (cedrol-DMNs) were prepared under vacuum conditions. The mechanical properties, pig skin penetration efficiency, in vitro cutaneous permeation test, and the amount of drug in the skin and receptor chamber were evaluated. Pharmacodynamical studies were performed with C57BL/6 mice. Results The mechanical properties of cedrol-DMNs were good. In vitro cutaneous permeation tests and pharmacodynamical studies demonstrated that cedrol-DMN could efficiently deliver the drug to the deep dermis and effectively promote hair growth. Conclusions The cedrol-DMNs offer a promising strategy for treating patients suffering from hair loss.

Investigation and Optimization of Hydrogel Microneedles for Transdermal Delivery of Caffeine.

Caffeine is therapeutically effective for treating apnea, cellulite formation, and pain management. It also exhibits neuroprotective and antioxidant activities in different models of Parkinson's disease and Alzheimer's disease. However, caffeine administration in a minimally invasive and sustainable manner through the transdermal route is challenging owing to its hydrophilic nature. Therefore, this study demonstrated a transdermal delivery approach for caffeine by utilizing hydrogel microneedle (MN) as a permeation enhancer. The influence of formulation parameters such as molecular weight (MW) of PMVE/MA (polymethyl vinyl ether/maleic anhydride) copolymer and sodium bicarbonate (NaHCO3) concentration on the swelling kinetics and mechanical integrity of the hydrogel MNs was investigated. In addition, the effect of different MN application methods and needle densities of hydrogel MN on the skin insertion efficiency and penetration depth was also evaluated. The swelling degree at equilibrium percentage (% Seq) recorded for hydrogels fabricated with Gantrez S-97 (MW = 1,500,000 Da) was significantly higher than formulation with Gantrez AN-139 (MW = 1,080,000 Da). Increasing the concentration of NaHCO3 also significantly increased the % Seq. Moreover, a 100% penetration was recorded for both the applicator and combination of applicator and thumb pressure compared with only 11% for thumb pressure alone. The average diameter of micropores created by the applicator method was 62.94 μm, which was significantly lower than the combination of both applicator and thumb pressure MN application (100.53 μm). Based on histological imaging, the penetration depth of hydrogel MN increased as the MN density per array decreased. The hydrogel MN with the optimized formulation and skin insertion parameters was tested for caffeine delivery in an in vitro Franz diffusion cell setup. Approximately 2.9 mg of caffeine was delivered within 24 h, and the drug release profile was best fitted to the Korsmeyer-Peppas model, displaying Super Case II kinetics. In conclusion, a combination of thumb and impact application methods and reduced needle density improved the skin penetration efficiency of hydrogel MNs. The results also show that hydrogel MNs fabricated from 3% w/w NaHCO3 and high MW of copolymer exhibit optimum physical and swelling properties for enhanced transdermal delivery.

Hyaluronic acid functionalization improves dermal targeting of polymeric nanoparticles for management of burn wounds: In vitro, ex vivo and in vivo evaluations.

Owing to its intricate pathophysiology, impaired wound healing is one of the substantial challenges in the treatment of burn wounds (BWs). Despite the variety of conventional therapies available, morbidities associated with BWs have not subsided. Therefore, aim of the present study was to design an advanced nanotechnology-composited therapy for effectual management of BWs. Hyaluronic acid (HA)-functionalized curcumin (CUR) and quercetin (QUE) co-loaded nanoparticle (HA-CUR-QUE-CSNPs) were fabricated, optimized, characterized and evaluated for successful co-encapsulation of drugs, morphology, stability, drug release, cell proliferation, penetration across the skin, localization in the epidermis and dermis, and in vivo wound healing efficacy. Fabricated HA-functionalized CSNPs exhibited ultra-small size (177±11nm), good zeta potential (+37.0±3.2mV), high encapsulation efficiency (EE) (QUE ∼84% and CUR ∼64%) and loading capacity (LC) (QUE ∼38% and CUR ∼43%), and spherical shape with uniformly rough surface. HA-functionalized CSNPs showed a triphasic release pattern with Fickian diffusion kinetics, a time-mannered progression in MC3T3-E1 cells proliferation, improved penetration of CUR (2414µg/cm2) and QUE (1984µg/cm2) through stratum corneum, and good localization of drugs in the epidermis and dermis. A superior wound healing efficacy (98% wound closure rate at day 28) with marked histological signs of minimal infiltration of inflammatory cells, re-epithelization, ECM formation, fibroblast infiltration at wound site, granulation tissue formation, angiogenesis, and collagen deposition were also evidenced. This study concludes that HA-functionalization of polymeric NPs could be a promising approach to maximize skin penetration efficiency, localization of drugs in skin tissues, tissue regeneration and BWs healing.

Augmented local skin accumulation efficiency of sertaconazole nitrate via glycerosomal hydrogel: Formulation, statistical optimization, ex vivo performance and in vivo penetration

This study aimed at formulating Sertaconazole nitrate (SZ), in a suitable glycerosomes based topical formulation that offers deep skin penetration and high local skin accumulation efficiency. SZ Glycerosomes were prepared using thin-film hydration technique according to a 24 full factorial design. Studied factors were Phosphatidylcholine (PhC) amount, Brij® L4: PhC ratio, glycerol concentration, and method of further treatment either sonication or freezing and thawing. The power of the design for each response was calculated before design implementation. Suitable models were elucidated for studied responses and their validity was checked. An optimized formula (O-GL) was numerically optimized using Design expert software®. The O-GL had suitable characterization with entrapment efficiency of 80.6 ± 2.9%, particle size of 418 ± 11 nm, polydispersity index of 0.452 ± 0.27, and zeta potential of −52.6 ± 0.6 mV. This O-GL was incorporated in a hydrogel (O-GL hydrogel). This O-GL hydrogel showed superior ex-vivo deposition in rat skin (Local accumulation efficiency: 55.1 ± 7.9) compared to O-GL (14.9 ± 1.1) and Dermofix® cream (marketed product) (13.1 ± 0.8). It also showed deep in-vivo penetration that reached deep dermal skin layers. Thus, the proposed formula (O-GL hydrogel) is promising for SZ topical delivery. It achieved deep skin penetration and high local skin accumulation efficiency for the effective treatment of fungal infections.

A Porous Reservoir-Backed Boronate Gel Microneedle for Efficient Skin Penetration and Sustained Glucose-Responsive Insulin Delivery.

Recently, phenylboronic acid (PBA) gel containing microneedle (MN) technology with acute and sustained glucose-sensitive functionality has attracted significant research attention. Herein, we report a polyvinyl alcohol(PVA)-coated MNs patch with an interconnected porous gel drug reservoir for enhanced skin penetration efficiency and mechanical strength. The hybrid MNs patch fabricated with a novel, efficient method displayed a “cake-like” two-layer structure, with the tip part being composed of boronate-containing smart gel attached to a porous gel layer as a drug reservoir. The porous structure provides the necessary structural support for skin insertion and space for insulin loading. The mechanical strength of the hybrid MNs patch was further enhanced by surface coating with crystallized PVA. Compared with MNs patches attached to hollow drug reservoirs, this hybrid MNs patch with a porous gel reservoir was shown to be able to penetrate the skin more effectively, and is promising for on-demand, long-acting transdermal insulin delivery with increased patient compliance.

Advanced nanocarrier- and microneedle-based transdermal drug delivery strategies for skin diseases treatment.

Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, acting as a global burden and affecting the world economy. Skin diseases severely impact the patients' quality of life and have influenced their physical and mental state. Treatment of these skin disorders with conventional methods shows a lack of therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic side effects due to improper drug delivery. However, these pitfalls can be overcome with the applications of advanced nanocarrier- and microneedle (MN)-based transdermal drug delivery strategies that provide efficient site-specific drug delivery at the target site. These advanced transdermal drug delivery strategies can be more effective than other drug administration routes by avoiding first-pass metabolism, enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. Compared with traditional transdermal delivery methods, nanocarrier- or MN-based drug delivery systems are painless, noninvasive, or minimum-invasive and require no expensive equipment. More importantly, they can introduce more advanced functions, including increased skin penetration efficiency, controlled drug release rates, enhanced targeting abilities, and theranostic functions. Here, the emergence of versatile advanced transdermal drug delivery systems for the transdermal delivery of various drugs is reviewed, focusing on the design principles, advantages, and considerations of nanocarrier- and MN-based transdermal drug delivery strategies and their applications in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery strategies for treating dermatological disorders are summarized.

Functional composite hydrogels entrapping polydopamine hollow nanoparticles for highly efficient resistance of skin penetration and photoprotection

Living organisms tend to evolve various naturally photoprotective mechanisms to avoid photodamage. Among them, polydopamine (PDA) is an effective sunscreen, a mimic of melanin, which is the main functional component of the photoprotective system of human skin. However, the concerns of its dark color, skin penetration and photoprotective efficiency remain yet to be solved. Herein, we have constructed melanin-inspired nanocomposite hydrogels (CS-PDAh-GP-HA) for photoprotection, in which PDA was prepared as hollow nanoparticles (PDAh NPs) and entrapped in a physically cross-linked hydrogel (CS-GP-HA) formed by chitosan (CS) and hyaluronic acid (HA) using β-glycerophosphate (β-GP) as a modulator. The CS-PDAh-GP-HA hydrogels exhibit a shear-thinning flow behavior with an elastic modulus of 300 Pa with the gel-sol transition temperature maintained at about 37 °C simply by adjusting the β-GP content in the hydrogels. The CS-PDAh-GP-HA hydrogels also possess excellent resistance toward skin penetration. The photoprotective performances of CS-PDAh-GP-HA hydrogels were evaluated by the determination of sun protection factor (SPF) and in vitro UVA protection efficacy (UVAPE) along with UV–Vis spectroscopy. Compared with the TiO2 nanoparticles in CS-GP-HA hydrogel, the CS-PDAh-GP-HA hydrogels show stronger shielding ability in both UVA and UVB regions. When protected by the CS-PDAh-GP-HA hydrogels, the cell viability of NIH-3T3 fibroblasts increases to 96% while it was only 14% in the case of non-protecting group. These results suggest that the CS-PDAh-GP-HA hydrogels could efficiently shield the UV irradiation and protect the skin from photodamage. This work introduces PDA-based nanocomposite hydrogels with safe, biocompatible and photoprotective properties, and provides a melanin-mimicking photoprotection system for the application in sunscreens.

Topical anesthetic and pain relief using penetration enhancer and transcriptional transactivator peptide multi-decorated nanostructured lipid carriers

Many strategies have been developed to overcome the stratum corneum (SC) barrier, including functionalized nanostructures. Chemical penetration enhancers (CPEs) and cell-penetrating peptides (CPP) were applied to decorate nanostructured lipid carriers (NLC) for topical anesthetic and pain relief. A novel pyrenebutyrate (PB-PEG-DSPE) compound was synthesized by the amide action of the carboxylic acid group of PB with the amido groups of DSPE-PEG. PB-PEG-DSPE has a hydrophobic group, hydrophilic group, and lipid group. The lipid group can be inserted into NLC to form PB functional NLC. In order to improve the penetrability, TAT and PB multi-decorated NLC were designed for the delivery of lidocaine hydrochloride (LID) (TAT/PB LID NLC). The therapeutic effects of NLC in terms of in vitro skin penetration and in vivo in animal models were further studied. The size of TAT/PB LID NLC tested by DLS was 153.6 ± 4.3 nm. However, the size of undecorated LID NLC was 115.3 ± 3.6 nm. The PDI values of NLC vary from 0.13 ± 0.01 to 0.16 ± 0.03. Zeta potentials of NLC were negative, between −20.7 and −29.3 mV. TAT/PB LID NLC (851.2 ± 25.3 µg/cm2) showed remarkably better percutaneous penetration ability than PB LID NLC (610.7 ± 22.1 µg/cm2), TAT LID NLC (551.9 ± 21.8 µg/cm2) (p < .05) and non-modified LID NLC (428.2 ± 21.4 µg/cm2). TAT/PB LID NLC exhibited the most prominent anesthetic effect than single ligand decorated or undecorated LID NLC in vivo. The resulting TAT/PB LID NLC exhibited good skin penetration and anesthetic efficiency, which could be applied as a promising anesthesia system.

Expression, purification and functional identification of the modified hEGF protein

Human epidermal growth factor (hEGF) plays an important role in the growth and division of epithelial cells and has good application prospects in skin-related injuries and diseases. Weak skin penetration and rapid clearance of hEGF in skin via the mononuclear phagocyte system have restricted the application of hEGF. To overcome these shortcomings, the recombinant gene TAT-hEGF-CD47 was constructed in our experiments, and the fusion protein TAT-hEGF-CD47 was expressed, purified and renatured. The cell proliferation-promoting function, skin penetration and concentration of TAT-hEGF-CD47 in skin after its application were determined. The results showed that TAT-hEGF-CD47 effectively promoted human skin fibroblast and skin epithelial cell proliferation, and the proliferation-promoting effect was positively correlated with the TAT-hEGF-CD47 concentration. After administration to the skin, TAT-hEGF-CD47 effectively penetrated the epidermal layer of the skin because of the TAT domain and stayed in the skin for a long time because the CD47 fragment slowed its clearance via the mononuclear phagocytic system. In conclusion, TAT-hEGF-CD47 exhibits high cell proliferation-promoting activity, high skin penetration efficiency and long retention time in skin and has laid the foundation for its wide application in skin repair, ulcer, diabetes and even cancer treatments.

Microneedles with Tunable Dissolution Rate.

Dissolvable microneedle (MN) patches have been widely investigated for transdermal drug delivery. The dissolution rate of MN controls the status of drug release from the MN, which in turn determines drug absorption through skin. However, no systematic approaches have been reported to tune the dissolution profile of dissolvable MN matrices. This is the first study to show polyvinylpyrrolidone (PVP)-based dissolvable MN patches with varying dissolution profiles when PVP is copolymerized with cellulose materials. The MN patches were fabricated through thermal curing and photolithography in tandem. The various grades of pharmaceutical cellulose, such as hydroxypropyl methylcellulose and methyl cellulose, have been investigated as dissolution modifier incorporated in the MN patches. The resultant MN patches had dissolution profiles ranging from 45 min to 48 h. The dissolution rates varied with the grades of cellulose materials. Besides dissolution examination, the MN patches were characterized for their mechanical strength, moisture absorption, and skin penetration efficiency. All of the MN patches were able to penetrate the human skin in vitro. Overall, the PVP MN patches have great potential for skin applications as drug carriers with tunable dissolution profiles.

Transdermal Delivery of Kidney-Targeting Nanoparticles Using Dissolvable Microneedles.

Chronic kidney disease (CKD) affects approximately 13% of the world's population and will lead to dialysis or kidney transplantation. Unfortunately, clinically available drugs for CKD show limited efficacy and toxic extrarenal side effects. Hence, there is a need to develop targeted delivery systems with enhanced kidney specificity that can also be combined with a patient-compliant administration route for such patients that need extended treatment. Towards this goal, kidney-targeted nanoparticles administered through transdermal microneedles (KNP/MN) is explored in this study. A KNP/MN patch was developed by incorporating folate-conjugated micelle nanoparticles into polyvinyl alcohol MN patches. Rhodamine B (RhB) was encapsulated into KNP as a model drug and evaluated for biocompatibility and binding with human renal epithelial cells. For MN, skin penetration efficiency was assessed using a Parafilm model, and penetration was imaged via scanning electron microscopy. In vivo, KNP/MN patches were applied on the backs of C57BL/6 wild type mice and biodistribution, organ morphology, and kidney function assessed. KNP showed high biocompatibility and folate-dependent binding in vitro, validating KNP's targeting to folate receptors in vitro. Upon transdermal administration in vivo, KNP/MN patches dissolved within 30 min. At varying time points up to 48 h post-KNP/MN administration, higher accumulation of KNP was found in kidneys compared with MN that consisted of the non-targeting, control-NP. Histological evaluation demonstrated no signs of tissue damage, and kidney function markers, serum blood urea nitrogen and urine creatinine, were found to be within normal ranges, indicating preservation of kidney health. Our studies show potential of KNP/MN patches as a non-invasive, self-administrable platform to direct therapies to the kidneys.

Geometrical optimisation of a personalised microneedle eye patch for transdermal delivery of anti-wrinkle small peptide

Acetyl-hexapeptide-3 (AHP-3) is a small peptide with good anti-wrinkle efficacy and safety profile. However, due to its hydrophilicity and high molecular weight, its skin permeation is generally poor. An innovative microneedle (MN) patch such as the curved, flexible or personalised MN patch is a viable avenue to deliver AHP-3. However, the well-researched geometrical relationship of MN on a flat MN patch cannot be assumed for these novel MN patches due to a complex mix of axial and shear forces. In this study, 3D printing was used for the fabrication of various MN patches with different MN geometries and curvatures. Both mechanical strength and skin penetration efficiency were used to determine the optimal MN geometry. The optimal MN geometry was then applied to the fabrication of a personalized MN patch (PMNP) for anti-wrinkle therapy, via 3D printing. In all, the general principles of MN geometrical effects on mechanical strength and skin penetration efficiency for a curved and a flat MN patch were similar. A MN height of 800 μm, tip diameter of 100 μm, interspacing of 800 μm and base diameter of 400 μm was observed to be the optimal MN geometry across all curvatures. In vitro skin permeation study demonstrated enhanced transdermal delivery of AHP-3 using the fabricated PMNP. Therefore, PMNP with optimized MN geometry can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.

Novel strategy for immunomodulation: Dissolving microneedle array encapsulating thymopentin fabricated by modified two-step molding technology

Thymopentin (TP5) is commonly used in the treatment for autoimmune diseases, with a short plasma half-life (30s) and a long treatment period (7 days to 6 months). It is usually administrated by syringe injection, resulting in compromised patient compliance. Dissolving microneedle array (DMNA) offers a superior approach for transdermal delivery of biological macromolecules, as it allows painless penetration through the stratum corneum and generates minimal biohazardous waste after dissolving in the skin. Despite recent advances in DMNA as a novel approach for transdermal drug delivery, problem of insufficient mechanical strength remains to be solved. In this study, TP5-loaded DMNA (TP5-DMNA) was uniquely developed using a modified two-step molding technology. The higher mechanical strength was furnished by employing bovine serum albumin (BSA) as a co-material to fabricate the needles. The obtained TP5-DMNA containing BSA displayed better skin penetration and higher drug loading efficiency than that without BSA. The in vivo pharmacodynamics study demonstrated that TP5-DMNA had comparative effect on immunomodulation to intravenous injection of TP5, in terms of ameliorating the CD4+/CD8+ ratio, SOD activity and MDA value to the basal level. Only mild irritation was observed at the site of administration. These results suggest that the novel TP5-DMNA utilizing BSA provides an alternative approach for convenient and safe transdermal delivery of TP5, which is a promising administration strategy for future clinical application.

Three-dimensional printing of a microneedle array on personalized curved surfaces for dual-pronged treatment of trigger finger

The hand function of patients who suffer from trigger finger can be impaired by the use of traditional splints. There is also a risk of systemic side effects with oral non-steroidal anti-inflammatory drugs (NSAIDs) used for pain relief. Microneedle-assisted transdermal drug delivery offers an attractive alternative for local delivery of NSAIDs. However, traditional microneedle arrays fabricated on flat surfaces are unable to deliver drugs effectively across the undulating skin surface of affected finger(s). In this study, using 3D printing, a dual-function microneedle array has been fabricated on personalized curved surfaces (microneedle splint) for drug delivery and splinting of the affected finger. The novel microneedle splint was assessed for its physical characteristics and the microneedles were shown to withstand up to twice the average thumb force without fracturing. An average skin penetration efficiency of 64% on dermatomed human cadaver skin was achieved and the final microneedle splint showed biocompatibility with human dermal cell lines. A significantly higher amount of diclofenac permeated through the skin by 0.5 h with the use of the microneedle splint as compared to intact skin. The fabricated microneedle splint can thus be a potential new approach to treat trigger finger via personalized splinting without affecting normal hand function.

Lipase-Sensitive Transfersomes Based on Photosensitizer/Polymerizable Lipid Conjugate for Selective Antimicrobial Photodynamic Therapy of Acne.

Acne vulgaris is a common skin problem affecting nearly 90% of adolescents and its development is associated with a colonization of Propionibacterium acnes (P. acnes). Although antibiotics have commonly been used to treat acne, antibiotic resistance of P. acnes is an emerging issue to be solved. In this study, a new way of photodynamic acne therapy is developed using P. acnes lipase-sensitive transfersome (DSPE-PEG-Pheo A (DPP) transfersome). For enhanced selectivity and skin penetration efficiency, DPP transfersomes are prepared from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000], pheophorbide A (Pheo A), cholesterol, and Tween-80. Incorporation of Tween-80 as an edge activator increases the deformability of DPP transfersomes, enhancing skin penetration efficiency to four times that of free Pheo A. The photoactivity of Pheo A quenched by DPP transfersomes is gradually recovered by selective cleavage of the ester linkage in DPP transfersomes by P. acnes lipases. In vitro P. acnes-specific photoactivity and subsequent selective antimicrobial effect exhibit a greater than 99% loss of P. acnes viability. In vivo antiacne therapeutic effect is confirmed by reduction of swelling volume and thickness of P. acnes-induced nude mice skin. These results demonstrate that DPP transfersome-mediated photodynamic therapy can be used as an alternative method to treat bacterial skin infections.

Porous Polymer Microneedles with Interconnecting Microchannels Toward Efficient Sensing of Interstitial Fluid

The microneedle array, the two-dimensional array of small needles of submillimeter length, is a minimally invasive alternative to conventional hypodermic needles. It penetrates skin and bypasses the diffusion barrier of stratum corneum and facilitates drug delivery as well as sampling and electrochemical sensing of biologically relevant molecules in interstitial fluid.1,2 Microneedles for sampling interstitial fluid fall into three types: hollow microneedles, hydrogel microneedles, and porous microneedles. Hollow microneedles have a bore inside the microneedle made by a photolithographic process. Hydrogel microneedles swell by absorption of interstitial fluid, and ex vivo analysis has been achieved. Porous microneedles have random pores in the body of the microneedle, and they have advantages such as a large pore volume ratio, efficient capillary action by many microchannels, large surface area for immobilization of sensor molecules, etc. Making porous microneedles with a polymer material has the advantages such as biocompatibility, easy fabrication by molding, a variety of molecular structures for tuning properties, etc. Despite their apparent advantages, the fabrication of porous polymer microneedles has been a challenge. In this study, we have fabricated microneedle arrays made of a porous polymer with interconnecting micropores.3 A porous polymer monolith is synthesized by polymerizing glycidyl methacrylate (GMA) with bi- and trifunctional crosslinkers by the irradiation of 365 nm UV in the presence of poly(ethylene glycol) in 2-methoxyethanol as a porogen, followed by washing with methanol/water.4 We fabricated a porous polymer monolith of this poly(glycidyl methacrylate) (PGMA) in a soft polydimethylsiloxane mold. The resulting microneedle array was a hard, opaque solid (Figure (a)), whereas a control with no porogen was transparent. Scanning electron microscopy (SEM) observation revealed that microneedles made with a porogen have interconnecting pores with ~1 µm in diameter on the surface and interior (Figure (b)). The porous microneedles with varied porogen ratios were fabricated to investigate its effects on porosity, water absorption speed, and skin penetration efficiency. Porosity was measured by weight increase of the porous microneedles after immersion into water. As an porogen ratio was increased, the porosity increased as well. The pore connectivity parameter, defined as (porosity)/(porogen ratio), versus a porogen ratio showed a sigmoidal profile that converges to unity, which indicated all the pores are interconnecting and accessible from the surface above a certain threshold of the porogen ratio. Water absorption speed of the porous microneedles was evaluated by a piece of water sensor paper that turns blue upon water absorption. The water sensor was attached on the top surface of the microneedle array, and the response time of the water sensor was measured. The response time decreased sharply to less than 20 minutes at the 36% porogen ratio, and this was consistent with the threshold of the porogen ratio for pore connectivity. The microneedle arrays were applied to a pig skin with the force of 1 N/needle, and punctured spots of the pig skin were stained with trypan blue. The microneedle arrays with lower porogen ratios had higher penetration efficiencies, and the porous microneedles with >80% penetration efficiency was achieved for the porogen ratio no more than 49%. With the lower porogen ratios, the porous microneedles become mechanically more robust, and the tips of the microneedles become sharper. In summary, by optimizing the porogen ratio (Figure (c)), we successfully developed porous polymer microneedles that combine fast water absorption speed and high skin penetration efficiency. The fabricated porous microneedles are a potentially versatile tool for sampling and sensing of interstitial fluid.