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Background Polynucleotide (PN) filler often causes pain and can lead to delivery inaccuracies when applied via intradermal injection using a traditional needle. Aims To evaluate the efficacy of treatment and the pain during the procedure using conventional needle injection versus a needle‐free jet system for intradermal PN filler application. Methods In this split‐face clinical trial, 10 Korean subjects were enrolled. Each subject received an intradermal injection of PN filler on one side of the face and a needle‐free jet injection using CureJet on the other side. Assessments included global and 3D skin imaging at each visit. Pain intensity was evaluated using visual analogue scale (VAS) scores during the injection. Additionally, patient satisfaction and adverse events were documented. Results Findings revealed that Global Aesthetic Improvement Scale scores and patient satisfaction were significantly higher with the CureJet compared to the needle injection method. VAS scores were notably lower on the CureJet side. Improvements in both pore and wrinkle indices were observed from baseline, with a more pronounced improvement rate on the CureJet side compared to the needle injection side. Conclusions Needle‐free injection of PN for aging skin was found to be effective in enhancing pore and wrinkle improvement, while reducing associated discomfort.

Under the pandemic situation, there is an urgent need to produce and acquire sufficient quantities of prophylactic vaccines. It becomes important to devise a way to achieve reliable immunity with lower doses to distribute limited supplies of vaccines to maximum number of people very quickly. Intradermal (ID) vaccination is one such method to increase the effectiveness of vaccines. However, this method has not been widely used in general clinical practice because it is technically difficult to inject vaccines precisely into the ID tissue. Therefore, new ID delivery systems that allow reliable ID administration are under development. In this paper, we summarize its design and present the results of performance and usability testing for the Immucise™ Intradermal Injection System (Immucise™). This study showed that Immucise™ can reduce dead volume and inject drugs precisely into the ID tissues of subjects from infants to the elderly and can be used correctly and safely by healthcare professionals. This randomized controlled trial compared ID administration with Immucise™ and standard subcutaneous (SC) administration of seasonal influenza vaccine by analyzing the efficacy of the vaccine in the elderly group at 90 days and 180 days after administration. It was found that the vaccine for the ID group was as effective or more effective than that for the SC group up to 180 days later. It was also found that the geometric mean titer values, especially for B strains, were higher in the two-dose ID group than in the two-dose SC group. These findings suggest that Immucise™ is one of the best devices to distribute a small amount of vaccine quickly and widely to a larger number of people with little loss of vaccine during a pandemic.

Intradermal vaccine delivery has been shown to induce good immune responses with low vaccine doses. Technologies for drug-delivery which specifically target the skin may render intradermal vaccination more accessible. We conducted a prospective, randomized trial in 180 intended-to-treat healthy adults. Study objectives were to evaluate the safety and immunogenicity of low-dose intradermal (ID) influenza vaccines delivered using a novel microneedle device (MicronJet). This device replaces a conventional needle, and is designed specifically for intradermal delivery. Subjects were randomly assigned to receive either the full-dose standard flu shot (containing 15 μg hemagglutinin per strain) delivered intramuscularly using a conventional needle (IM group), a medium dose intradermal injection (6 μg hemagglutinin per strain) delivered with the MicronJet (ID2 group), or a low-dose intradermal injection (3 μg hemagglutinin per strain) delivered with the MicronJet (ID1 group). A marketed influenza vaccine for the 2006/2007 influenza season (α-RIX ® by GSK Biologicals) was used for all injections. Adverse events were recorded over a 42-day period. Immunogenicity was evaluated by changes in hemagglutination inhibition (HAI) antibody titer, and by comparing geometric mean titers (GMTs), seroconversion, and seroprotection rates between the study groups. Local reactions were significantly more frequent following intradermal vaccination, but were mild and transient in nature. At 21 days after injection, GMT fold increase was 22, 18 and 22 in the ID1, ID2 and IM groups respectively for the H1N1 strain; 9, 9 and 16 for the H3N2 strain and 9, 13 and 11 for strain B. The CPMP criteria for re-licensure of seasonal influenza vaccines were met in full for all study groups. Low-dose influenza vaccines delivered intradermally using microneedles elicited immunogenic responses similar to those elicited by the full-dose intramuscular vaccination. The microneedle injection device used in this study was found to be effective, safe, and reliable.

Injections using hypodermic needles cause pain, discomfort, localised trauma and apprehension. Additionally, careful use and disposal of needles is required to avoid transmission of blood-borne pathogens. As an alternative, microneedles can facilitate drug delivery without significantly impacting on pain receptors or blood vessels that reside beneath the skin outer layers. In this study we aim to determine the pain and sensory response to the application of wet-etch silicon microneedles, when used in such a way as to reliably penetrate skin, and provide a preliminary indication of how skin responds to microneedle injury with time. Twelve subjects received single-blinded insertions of a 25-G hypodermic needle and two microneedle arrays (36 needles of 180 and 280 μm height). The optimal method for microneedle application was determined in a pilot study. Pain intensity was scored using a visual analogue scale (VAS) and sensory perception determined using an adapted McGill Pain Questionnaire Short Form. Skin penetration was determined by external staining and measurement of trans-epidermal water loss (TEWL). Mean VAS scores, verbal descriptions and questionnaire responses showed that the 180 and 280 μm microneedles caused significantly less pain and discomforting sensation in participants than the hypodermic needle. Methylene blue staining and TEWL analysis confirmed that microchannels were formed in the skin following microneedle application. Evidence of microchannel repair and resealing was apparent at 8–24 h post-application. In summary, this study shows that pyramidal wet-etch microneedles can penetrate human skin with minimal pain and sensory discomfort, creating transient pathways for potential drug, vaccine and DNA delivery.

The World Health Organization recommends that as part of the polio end-game strategy a dose of inactivated poliovirus vaccine (IPV) be introduced by the end of 2015 in all countries currently using only oral poliovirus vaccine (OPV). Administration of fractional dose (1/5 of full dose) IPV (fIPV) by intradermal (ID) injection may reduce costs, but its conventional administration is with Bacillus Calmette-Guerin (BCG) needle and syringe (NS), which is time consuming and technically challenging. We compared injection quality achieved with BCG NS and three needle-free jet injectors and assessed ergonomic features of the injectors. Children between 12 and 20 months of age who had previously received OPV were enrolled in the Camaguey, Cuba study. Subjects received a single fIPV dose administered intradermally with BCG NS or one of three needle-free injector devices: Bioject Biojector 2000® (B2000), Bioject ID Pen® (ID Pen), or PharmaJet Tropis® (Tropis). We measured bleb diameter and vaccine loss as indicators of ID injection quality, with desirable injection quality defined as bleb diameter ≥5mm and vaccine loss <10%. We surveyed vaccinators to evaluate ergonomic features of the injectors. We further assessed the injection quality indicators as predictors of immune response, measured by increase in poliovirus neutralizing antibodies in blood between day 0 (pre-IPV) and 21 (post-vaccination). Delivery by BCG NS and Tropis resulted in the highest proportion of subjects with desirable injection quality; health workers ranked Biojector2000 and Tropis highest for ergonomic features. We observed that vaccine loss and desirable injection quality were associated with an immune response for poliovirus type 2 (P=0.02, P=0.01, respectively). Our study demonstrated the feasibility of fIPV delivery using needle-free injector devices with high acceptability among health workers. We did not observe the indicators of injection quality to be uniformly associated with immune response.

Administration of 1/5th dose of Inactivated poliovirus vaccine intradermally (fIPV) provides similar immune response as full-dose intramuscular IPV, however, fIPV administration with BCG needle and syringe (BCG NS) is technically difficult. We compared immune response after one fIPV dose administered with BCG NS to administration with intradermal devices, referred to as Device A and B; and assessed feasibility of conducting a door-to-door vaccination campaign with fIPV. In Phase I, 452 children 6–12months old from Karachi were randomized to receive one fIPV dose either with BCG NS, Device A or Device B in a health facility. Immune response was defined as seroconversion or fourfold rise in polio neutralizing antibody titer 28days after fIPV among children whose baseline titer ≤362. In Phase II, fIPV was administered during one-day door-to-door campaign to assess programmatic feasibility by evaluating vaccinators’ experience. For all three poliovirus (PV) serotypes, the immune response after BCG NS and Device A was similar, however it was lower with Device B (34/44 (77%), 31/45 (69%), 16/30 (53%) respectively for PV1; 53/78 (68%), 61/83 (74%), 42/80 (53%) for PV2; and; 58/76 (76%), 56/80 (70%), 43/77 (56%) for PV3; p<0.05 for all three serotypes). Vaccinators reported problems filling Device B in both Phases; no other operational challenges were reported during Phase II. Use of fIPV offers a dose-saving alternative to full-dose IPV.

Intradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa. Thirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1mL in adults; 0.05mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses. More infant BCG vaccinations by DSJI deposited >5μL fluid on the skin surface, compared to NS (49% versus 9%, p=0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p<0.001). Median wheal diameter, in participants for which an SOI wheal formed, did not differ significantly between groups in infants (combined 3.0mm IQR 2.0 to 4.0, p=0.59) or in adults (combined 9.0mm IQR 7.0 to 10.0, p=0.13). Adverse events were similar between study arms. Proportion of participants with BCG scars after three months did not differ in adults (combined 97%, p=0.67) or infants (combined 62%, p=0.13). Frequencies of BCG-specific clusters of differentiation 4 (CD4) and clusters of differentiation 8 (CD8) T-cells co-expressing IFN-γ, TNF-α, IL-2, and/or IL-17 were not different in the DSJI and NS groups. BCG vaccination of newborn infants via DSJI was more likely to deliver an appropriate intradermal wheal at the SOI as compared to NS, despite leaving more fluid on the surface of the skin. Safety, reactogenicity, and antigen-specific T-cell immune responses did not differ between DSJI and NS techniques.

Microneedle arrays (MA) have been extensively investigated in recent decades for transdermal drug delivery due to their pain-free delivery, minimal skin trauma, and reduced risk of infection. However, porous MA received relatively less attention due to their complex fabrication process and ease of fracturing. Here, we present a titanium porous microneedle array (TPMA) fabricated by modified metal injection molding (MIM) technology. The sintering process is simple and suitable for mass production. TPMA was sintered at a sintering temperature of 1250°C for 2 h. The porosity of TPMA was approximately 30.1% and its average pore diameter was about 1.3 μm. The elements distributed on the surface of TPMA were only Ti and O, which may guarantee the biocompatibility of TPMA. TPMA could easily penetrate the skin of a human forearm without fracture. TPMA could diffuse dry Rhodamine B stored in micropores into rabbit skin. The cumulative permeated flux of calcein across TPMA with punctured skin was 27 times greater than that across intact skin. Thus, TPMA can continually and efficiently deliver a liquid drug through open micropores in skin.

Intradermal immunization is gaining increased attention due to multiple factors: (1) intradermal (ID) vaccination has been shown to induce improved immunogenicity compared to intramuscular (IM) vaccination; (2) ID vaccination has been shown to have a dose-sparing potential over IM leading to a reduced vaccine cost and an increased availability of vaccines worldwide. However, the currently used Mantoux technique for ID injection is difficult to standardize and requires training. The aim of the study was (1) to assess the epidermal and dermal thickness at the proximal ventral and dorsal forearm (PVF & PDF) and deltoid in adults aged 18–65years (2) to determine the maximum penetration depth and needle characteristics for the development of a platform of medical devices suited for intradermal injection, VAX-ID™. Mean thickness of the PVF, PDF and deltoid were measured using high-frequency ultrasound of healthy adults aged 18–65years. Correlation with gender, age and BMI was assessed using Mann-Whitney U Test, Spearman correlation and Wilcoxon Signed Ranks Test, respectively. Results showed an overall mean skin thickness of 1.19mm (0.65–1.55mm) at the PVF, 1.44mm (0.78–1.84mm) at the PDF, and 2.12mm (1,16–3.19mm) at the deltoid. Thickness of PVF & PDF and deltoid were significantly different for men vs women (pmean<0.001, <0.001, <0.001, and pmin<0.001, 0.012, <0.001, respectively). A significant association was found for age at the deltoid region (p<0.001). Skin thickness for PVF, PDF & deltoid was significantly associated to BMI (p<0.001). Significant differences in skin thickness were seen for the PVF, PDF and deltoid region for gender, and BMI. Age only influenced the skin thickness at deltoid region. A needle length of 1.0mm is best option for intradermal injection at the dorsal forearm (NCT02363465).

•Various active and passive approaches available for cutaneous immunization.•Cutaneous immunization provides the potential to induce humoral, cellular and mucosal immune responses.•Adjuvants affect the type of immunity upon cutaneous immunization.•DNA vaccination successfully performed employing different cutaneous administration strategies. Technologies and strategies for cutaneous vaccination have been evolving significantly during the past decades. Today, there is evidence for increased efficacy of cutaneously delivered vaccines allowing for dose reduction and providing a minimally invasive alternative to traditional vaccination. Considerable progress has been made within the field of well-established cutaneous vaccination strategies: Jet and powder injection technologies, microneedles, microporation technologies, electroporation, sonoporation, and also transdermal and transfollicular vaccine delivery. Due to recent advances, the use of cutaneous vaccination can be expanded from prophylactic vaccination for infectious diseases into therapeutic vaccination for both infectious and non-infectious chronic conditions. This review will provide an insight into immunological processes occurring in the skin and introduce the key innovations of cutaneous vaccination technologies.