Although modern biotechnology has produced extremely sophisticated and potent drugs, many of these compounds cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of skin. Because the primary barrier to transport is located in the upper 10-15 micron of skin and nerves are found only in deeper tissue, we used a reactive ion etching microfabrication technique to make arrays of microneedles long enough to cross the permeability barrier but not so long that they stimulate nerves, thereby potentially causing no pain. These microneedle arrays could be easily inserted into skin without breaking and were shown to increase permeability of human skin in vitro to a model drug, calcein, by up to 4 orders of magnitude. Limited tests on human subjects indicated that microneedles were reported as painless. This paper describes the first published study on the use of microfabricated microneedles to enhance drug delivery across skin.

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 m. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats.transdermal drug delivery ͉ skin ͉ microelectromechanical systems ͉ solid microneedle ͉ hollow needle injection H ypodermic needles have provided the gold standard for drug delivery for over a century, but advances in biotechnology make their limitations increasingly apparent. As devices that transport molecules of nanometer dimensions, the millimeter and larger length scales of conventional needles are often unnecessary, and they cause pain and limit targeted delivery. We therefore sought to test the hypothesis that needles of micrometer dimensions can create transport pathways large enough for small drugs, macromolecules, nanoparticles, and fluid flow, but small enough to avoid pain and facilitate highly localized and even intracellular targeting.The microelectronics revolution has provided tools for highly precise, reproducible, and scalable methods to fabricate structures of micrometer dimensions (1). This lithography-based approach can produce large arrays of microneedles that can be inserted into cells, skin, or other tissues. The increased importance of macromolecular therapeutics, combined with the newly acquired power of microfabrication, has recently prompted interest in fabricating (2-6) and testing (7, 8) microneedles for drug delivery.In this study, we describe fabrication techniques used to make needles out of silicon, metal, polymer, and glass that have a range of geometries, can produce needles ranging from in-plane to normally protruding from substrates, and can be formed in large two-dimensional arrays. These methods mostly require just one or two fabrication steps or a single molding step and use technologies that are readily scalable for inexpensive mass production. We also demonstrate the ability of these microneedles to deliver molecules into cells and skin by using cell culture, cadaver skin, and hairless rats. MethodsFabrication of Silicon Microneedles. Solid microneedles were etched from silicon substrates as described previously (9). Briefly, chromium was sputter deposited and then lithographically patterned (e.g., 20 ϫ 20 arrays of 80-m-diameter dots with 150-m center-to-center spacing) onto 2-inch (5-cm), ͗100͘ oriented silicon wafers. Reactive ion etching (RIE; Plasma Therm, St. Petersburg, FL) was then carried out with 20 standard cm 3 ͞...

Background Microneedle patches provide an alternative to conventional needle-and-syringe immunization, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability and safety. We describe safety, immunogenicity and acceptability of the first-in-human study on single, dissolvable microneedle patch vaccination against influenza. Methods The TIV-MNP 2015 study was a phase 1, partially blinded, placebo-controlled, randomized clinical trial conducted at Emory University that enrolled non-pregnant, immunocompetent adults (age 18–49 years) from Atlanta (USA) and naïve to 2014–2015 influenza vaccine. Participants were equally randomized among four groups and received a single dose of inactivated influenza vaccine 1) by microneedle patch or 2) by intramuscular injection, or received 3) placebo by microneedle patch, all administered by an unblinded healthcare worker; or received 4) inactivated influenza vaccine by microneedle patch self-administered by study participants. Primary safety outcomes were reactogenicity, grade 3 adverse events and serious adverse events within 8, 28 and 180 days and secondary safety outcomes were new-onset chronic illnesses within 180 days and unsolicited adverse events within 28 days all analyzed by intention to treat. Secondary immunogenicity outcomes were antibody titers at day 28 as well as seroconversion and seroprotection rates all determined by hemagglutination inhibition antibody. The trial is completed and registered with ClinicalTrials.gov, NCT02438423. Findings Twenty-five participants per group were enrolled between June 23 and September 25, 2015. There were no related serious adverse events, no related grade 3 or higher adverse events and no new-onset chronic illnesses. Overall incidence of solicited and unsolicited events was similar among vaccinated groups. Reactogenicity was mild, transient and most commonly reported as tenderness at 60% (95% CI, 39– 79%) and pain at 44% (95% CI, 24–65%) after intramuscular injection and tenderness at 66% (95% CI, 51–79%), erythema at 40% (95% CI, 26–55%) and pruritus at 82% (95% CI, 69–91%) after vaccination by microneedle patch application The geometric mean titers were comparable at day 28, between the microneedle patch administered by healthcare worker and the intramuscular route with values of 1197 (95% CI, 855– 1675) and 997 (95% CI, 703–1415) (p=0.5), respectively, for the H1N1 strain; 287 (95% CI, 192–430) and 223 (95% CI, 160–312) (p=0.4), respectively, for the H3N2 strain and 126 (95% CI, 86–184) and 94 (95% CI, 73–122) (p=0.06), respectively, for the B strain. Similar GMT titers were observed in participants who self-administered the microneedle patch. The seroconversion rates were significantly higher at day 28 after microneedle patch vaccination compared to placebo and were comparable to intramuscular injection. Interpretation Use of dissolvable microneedle patches for influenza vaccination was well-tolerated and generated robust antibody responses. Funding National Institutes of Health.

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By incorporating techniques adapted from the microelectronics industry, the field of microfabrication has allowed the creation of microneedles, which have the potential to improve existing biological-laboratory and medical devices and to enable novel devices for gene and drug delivery. Dense arrays of microneedles have been used to deliver DNA into cells. Many cells are treated at once, which is much more efficient than current microinjection techniques. Microneedles have also been used to deliver drugs into local regions of tissue. Microfabricated neural probes have delivered drugs into neural tissue while simultaneously stimulating and recording neuronal activity, and microneedles have been inserted into arterial vessel walls to deliver anti-restenosis drugs. Finally, microhypodermic needles and microneedles for transdermal drug delivery have been developed to reduce needle insertion pain and tissue trauma and to provide controlled delivery across the skin. These needles have been shown to be robust enough to penetrate skin and dramatically increase skin permeability to macromolecules.

To support translation of microneedle patches from pre-clinical development into clinical trials, this study examined the effect of microneedle patch application on local skin reactions, reliability of use and acceptability to patients. Placebo patches containing dissolving microneedles were administered to fifteen human participants. Microneedle patches were well tolerated in the skin with no pain or swelling and only mild erythema localized to the site of patch administration that resolved fully within seven days. Microneedle patches could be administered by hand without the need of an applicator and delivery efficiencies were similar for investigator-administration and self-administration. Microneedle patch administration was not considered painful and the large majority of subjects were somewhat or fully confident that they self-administered patches correctly. Microneedle patches were overwhelmingly preferred over conventional needle and syringe injection. Altogether, these results demonstrate that dissolving microneedle patches were well tolerated, easily usable and strongly accepted by human subjects, which will facilitate further clinical translation of this technology.

Microscopic needles previously shown capable of transdermal delivery of drugs and proteins are demonstrated to be painless when pressed into the skin of human subjects.

Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study we evaluated the immunogenicity of H1N1, H3N2 and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25°C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by SRID assay and immune responses to vaccination in BALB/c mice. After a single immunization all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least three months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability.