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Objectives To evaluate the clinical PK/PD of PTH(1-34) delivered by a novel transdermal drug-coated microneedle patch system (ZP-PTH) for the treatment of osteoporosis. Methods Phase 1 PK studies evaluated the effect of site of administration, patch wear time and dose in normal volunteers, ages 40-85 yrs. Phase 2 was conducted in post-menopausal women with osteoporosis to determine the patch dose response compared to placebo patch and FORTEO® injection. Results Phase 1 ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with Tmax 3 times shorter and apparent T₁/₂ 2 times shorter than FORTEO®. In Phase 2, ZP-PTH 20, 30 and 40 µg doses showed a proportional increase in plasma PTH AUC. Inter-subject and intra-subject AUC variability was similar for all patch doses and comparable to injection. All patch doses produced a significant increase in spine bone mineral density. Unexpectedly, ZP-PTH also produced an early increase in hip bone mineral density, an effect not observed with the injection. Conclusions These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile. Based on encouraging Phase 2 safety and efficacy data, the program is advancing into a pivotal Phase 3 clinical study.

Introduction Melasma is a long‐term acquired disorder characterized by symmetrical darkening in facial regions exposed to sunlight. Although some risk factors have been identified, the etiology remains unclear, and interventions frequently do not totally improve outcomes. Aim It compares the efficacy and side effects of platelet‐rich plasma therapy administered by microneedling versus microinjection to detect any difference in the delivery methods, treatment outcomes, and safety profiles. Methods In this prospective, single‐center, randomized split‐face research, 62 patients' melasma was treated with PRP therapy using microneedling versus microinjection. Microneedling and microinjection were used to apply PRP to the face's two sides. Photographs were obtained before therapy, and the modified Melasma Area and Severity Index (MASI), Physician Global Assessment, and Patient Global Assessment were used for monthly follow‐up evaluation. In order to compare safety and efficacy, adverse events were recorded and statistical analysis was performed. Results A significantly significant difference (p < 0.001) was observed in the mean change in MASI score between microinjection and microneedling. The microneedling group showed a 73.33% improvement while the microinjection group had an 18.33% improvement, both of which were greater than 50%. The microneedling group showed a 46.67% improvement and the microinjection group had a 5% improvement of over 75%. There were no noteworthy negative effects observed. Conclusion PRP therapy with microneedling is superior to microinjection in treating melasma; patients who receive microneedling show noticeably better improvement.

Purpose To gather sub-surface in situ images of microneedle-treated human skin, in vivo, using optical coherence tomography (OCT). This is the first study to utilise OCT to investigate the architectural changes that are induced in skin following microneedle application. Methods Steel, silicon and polymer microneedle devices, with different microneedle arrangements and morphologies, were applied to two anatomical sites in human volunteers following appropriate ethical approval. A state-of-the-art ultrahigh resolution OCT imaging system operating at 800 nm wavelength and <3 µm effective axial resolution was used to visualise the microneedle-treated area during insertion and/or following removal of the device, without any tissue processing. Results Transverse images of a microneedle device, in situ, were captured by the OCT system and suggest that the stratified skin tissue is compressed during microneedle application. Following removal of the device, the created microchannels collapse within the in vivo environment and, therefore, for all studied devices, microconduit dimensions are markedly smaller than the microneedle dimensions. Conclusions Microchannels created in the upper skin layers by microneedles are less invasive than previous histology predicts. OCT has the potential to play a highly influential role in the future development of microneedle devices and other transdermal delivery systems.

Microneedles can be used for delivery of a wide range of drug substances for practically any medical condition and present a real opportunity for vaccines and medicines that are unsuitable for oral administration or conventional patch delivery.

Background: Melasma poses a great challenge as its treatment modalities are unsatisfactory. Treatment using tranexamic acid is a novel concept. Aim: This study aimed to compare the therapeutic efficacy and safety of oral tranexamic acid and tranexamic acid microinjections in patients with melasma. Methods: This is a prospective, randomized, open-label study with a sample size of 64, 32 in each treatment arm. Thirty-two patients were administered localized microinjections (4 mg/ml) of tranexamic acid monthly in 1 arm, while in the other arm, 32 were given oral tranexamic acid 250 mg twice a day. Patients were followed up for 3 consecutive months. Clinical photographs were taken at each visit, and a modified melasma area and severity index scoring was performed at the beginning and end of treatment. Results: Improvement in melasma area and severity index score in the oral group was 57.5% as compared to 43.5% in the intralesional group. All 32 patients in the oral group (100%) showed >50% improvement, out of which 8 showed >75% improvement. In the intralesional group, 17 (53%) patients had >50% improvement, of which 3 had >75% improvement. The remaining 15 patients in this group had <50% improvement. Thus, the oral group showed a more significant response as compared to the intralesional group. No major adverse effects were observed in both the groups. At 6-month follow-up, two patients (6.2%) in the oral group had recurrence as compared to three patients (9.4%) in the intralesional group. Limitations: A small sample size was one of the limitations in this study. The dose of tranexamic acid in microinjections and the frequency of injections could have been increased. Conclusion: Tranexamic acid provides rapid and sustained improvement in the treatment of melasma. It is easily available and affordable. Oral route is undoubtedly efficacious, but the results of microinjections, while encouraging, can probably be enhanced by either increasing the frequency of injections or increasing the concentration of the preparation.

Purpose Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. The purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans. Methods Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application. Results Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n  = 6), vs. 72 h in Group 2 (placebo + naltrexone, n  = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores). Conclusion This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases.

Background Intradermal vaccination provides direct and potentially more efficient access to the immune system via specialised dendritic cells and draining lymphatic vessels. We investigated the immunogenicity and safety during 3 successive years of different dosages of a trivalent, inactivated, split-virion vaccine against seasonal influenza given intradermally using a microinjection system compared with an intramuscular control vaccine. Methods In a randomised, partially blinded, controlled study, healthy volunteers (1150 aged 18 to 57 years at enrolment) received three annual vaccinations of intradermal or intramuscular vaccine. In Year 1, subjects were randomised to one of three groups: 3 μg or 6 μg haemagglutinin/strain/dose of inactivated influenza vaccine intradermally, or a licensed inactivated influenza vaccine intramuscularly containing 15 μg/strain/dose. In Year 2 subjects were randomised again to one of two groups: 9 μg/strain/dose intradermally or 15 μg intramuscularly. In Year 3 subjects were randomised a third time to one of two groups: 9 μg intradermally or 15 μg intramuscularly. Randomisation lists in Year 1 were stratified for site. Randomisation lists in Years 2 and 3 were stratified for site and by vaccine received in previous years to ensure the inclusion of a comparable number of subjects in a vaccine group at each centre each year. Immunogenicity was assessed 21 days after each vaccination. Safety was assessed throughout the study. Results In Years 2 and 3, 9 μg intradermal was comparably immunogenic to 15 μg intramuscular for all strains, and both vaccines met European requirements for annual licensing of influenza vaccines. The 3 μg and 6 μg intradermal formulations were less immunogenic than intramuscular 15 μg. Safety of the intradermal and intramuscular vaccinations was comparable in each year of the study. Injection site erythema and swelling was more common with the intradermal route. Conclusion An influenza vaccine with 9 μg of haemagglutinin/strain given using an intradermal microinjection system showed comparable immunogenic and safety profiles to a licensed intramuscular vaccine, and presents a promising alternative to intramuscular vaccination for influenza for adults younger than 60 years. Trial registration Clinicaltrials.gov NCT00703651.

Purpose To assess the effect of assisted hatching (AH) site on the clinical outcomes in vitrified-warmed blastocyst transfer cycles. Methods A total of 160 women who underwent vitrified-warmed blastocyst transfer cycles were randomized to either the ICM group (AH performing at the site near the inner cell mess, ICM), or the TE group (AH performing at the site opposite to the ICM). AH with laser zona drilling was performed 20 or 30 min after thawing once the ICM can be detected. Clinical pregnancy rate, implantation rate, live birth rate and the occurrence rate of monozygotic twins (MZT) pregnancy after transfer of these two groups were compared. Results No significant difference was found in the clinical pregnancy rate (63.8 % vs. 67.5 %), implantation rate (51.7 % vs. 53.6 %) and live birth rate (57.5 % vs. 62.5 %) between the ICM group and the TE group. The occurrence rate of MZT was comparable between the two groups (3.9 % vs. 5.6 %). Conclusions The site of assisted hatching has no influence on the implantation, pregnancy and live birth rate in human vitrified-warmed blastocyst transfer cycles.

Amphioxus is a promising model animal for evolutionary and developmental studies. However, as an emerging model organism, amphioxus lacks most molecular techniques applied in other well-developed model animals. Microinjection is a powerful technique for gene manipulation, and thus it undoubtedly is one of useful approaches in the studies of gene function and embryonic development. Although the method has been exploited in Florida and European amphioxus, it still remains to be optimized and introduced into other amphioxus species. In order to introduce the technique into our lab, we followed and optimized the previous description and successfully performed microinjection on unfertilized eggs of Asian amphioxus Branchiostoma belcheri. We made six solutions for practice: 200 mM KCl, 100 ng/μl actin-LacZ or 100 ng/μl actin-RFP vectors, LacZ or RFP vectors without promoter and RFP capped mRNA. More than 99.2 % of eggs injected with KCl were able to be fertilized, 94.3 % of them could hatch normally and 55.9 % survived until 2-day larvae, all of which were nearly equivalent to those obtained from normally fertilized eggs. Embryos injected with two plasmid constructs also showed very high fertilizing and hatching ratios, but normally developing ratios were slightly lower than that of KCl injection. Of those injected embryos, 91.8 % expressed exogenous gene LacZ and 80.5 % exhibited foreign RFP expression, which were driven by a promoter from amphioxus β-actin gene. The data indicated a successful modified microinjection method for the unfertilized eggs of Asian amphioxus, and those modifications improved the feasibility and efficiency of microinjection on amphioxus.

Genetic engineering of plants has enhanced crop productivity in the face of climate change and a growing global population by conferring desirable genetic traits to agricultural crops. Efficient genetic transformation in plants remains a challenge due to the cell wall, a barrier to exogenous biomolecule delivery. Conventional delivery methods are inefficient, damaging to tissue, or are only effective in a limited number of plant species. Nanoparticles are promising materials for biomolecule delivery, owing to their ability to traverse plant cell walls without external force and highly tunable physicochemical properties for diverse cargo conjugation and broad host range applicability. With the advent of engineered nuclease biotechnologies, we discuss the potential of nanoparticles as an optimal platform to deliver biomolecules to plants for genetic engineering. Plant biotechnology is key to ensuring food and energy security; however, biomolecule delivery and progeny regeneration continue to be key challenges in plant genetic engineering. Conventional biomolecule delivery methods in plants have critical drawbacks, such as low efficiency, narrow species range, limited cargo types, and tissue damage. Advances in nanotechnology have created opportunities to overcome limitations in conventional methods: nanoparticles are promising for species-independent passive delivery of DNA, RNA, and proteins. The advent of nuclease-based genome editing (e.g., CRISPR-Cas9) has ushered in a new era of precise genetic engineering that, among other impacts, has enabled the development of genetically engineered crops without harsh regulatory restrictions. The potential of nanoparticles to overcome limitations in conventional delivery makes them excellent candidates for delivery of nuclease-based genome editing cargo, thus making nanoparticle delivery a critical technology for the advancement of plant genetic engineering.