Lack of Pain Associated with Microfabricated Microneedles

Kaushik, Shilpa; Hord, Allen H.; Denson, Donald D.; McAllister, Devin V.; Smitra, Sudhasinee; Allen, Mark G.; Prausnitz, Mark R.

doi:10.1213/00000539-200102000-00041

Cited by 420 publications

(210 citation statements)

References 3 publications

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“…We postulate that shallow penetration of microjets into skin is essential to mitigate pain because the density of blood vessels and nerves is less in the top 100 to 200 m of skin. Literature studies have confirmed painless insertion of microscale objects such as microneedles into skin (19). Specifically, Kaushisk et al reported that no pain was induced by insertion of microneedles (150 m in length and 80 m in diameter) into skin of human volunteers (19).…”

Section: Resultsmentioning

confidence: 91%

“…Literature studies have confirmed painless insertion of microscale objects such as microneedles into skin (19). Specifically, Kaushisk et al reported that no pain was induced by insertion of microneedles (150 m in length and 80 m in diameter) into skin of human volunteers (19). In contrast, insertion of a 26-G hypodermic needle caused significant pain.…”

Section: Resultsmentioning

confidence: 92%

See 1 more Smart Citation

Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets

Arora¹,

Hakim²,

Baxter

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

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Needle-free liquid jet injectors were invented >50 years ago for the delivery of proteins and vaccines. Despite their long history, needle-free liquid jet injectors are not commonly used as a result of frequent pain and bruising. We hypothesized that pain and bruising originate from the deep penetration of the jets and can potentially be addressed by minimizing the penetration depth of jets into the skin. However, current jet injectors are not designed to maintain shallow dermal penetration depths. Using a new strategy of jet injection, pulsed microjets, we report on delivery of protein drugs into the skin without deep penetration. The high velocity (v >100 m/s) of microjets allows their entry into the skin, whereas the small jet diameters (50 -100 m) and extremely small volumes (2-15 nanoliters) limit the penetration depth (Ϸ200 m).In vitro experiments confirmed quantitative delivery of molecules into human skin and in vivo experiments with rats confirmed the ability of pulsed microjets to deliver therapeutic doses of insulin across the skin. Pulsed microjet injectors could be used to deliver drugs for local as well as systemic applications without using needles.MEMS ͉ nanotechnology ͉ noninvasive ͉ piezoelectric ͉ transdermal

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 92%

Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets

Arora¹,

Hakim²,

Baxter

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

139

View full text Add to dashboard Cite

show abstract

“…We have hypothesized that microneedles may be small enough to capture the convenience of patches but large enough to create micrometer-scale pathways across the skin for drug delivery. Previous studies have shown that microneedles can be painlessly inserted into the skin of human subjects (23). Additional studies will be needed to further establish the ease and efficacy of microneedle-based delivery in a clinical environment.…”

Section: Discussionmentioning

confidence: 99%

Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies

McAllister

Wang

Davis

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

714

430

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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 ͞...

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“…A two-layered diffusion model was established herein to analyze the FD-4 permeation profiles. FD-4 concentration in the SC layer can be expressed by Fick's second law of diffusion as follows: (8) FD-4 concentration, C ved , in the viable epidermis and dermis layers at a position, x and time, t can be expressed by Eq. 4.…”

Section: Analysis Of Diffusivity From Skin Permeation Profilesmentioning

confidence: 99%

Macromolecular Delivery into Skin Using a Hollow Microneedle

Wonglertnirant

Todo

Opanasopit

et al. 2010

Biological & Pharmaceutical Bulletin

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Recently much attention has been paid to a new approach for enhancing transdermal drug delivery employing needles in micron scale, termed microneedles. Such a technique combines the concepts of the user-friendly delivery of transdermal patches and the broad effectiveness of hypodermic injections. Several studies have established the increasing efficacy of microneedle-assisted transdermal delivery for a variety of compounds, [1][2][3][4] especially for high molecular weight hydrophilic compounds. [5][6][7] Microneedles are also expected to be safe, because they are minimally invasive and do not typically cause bleeding or any severe pain at the injection site. 8)Although microneedles assist in penetrating the stratum corneum (SC) barrier and offer several microchannels facilitating drug transport across the skin, the release of macromolecular drugs at the desired therapeutic rate might not be achieved by only (enhanced) passive diffusion from the patch-based drug reservoir due to the small diffusional area produced by needles.9) It is necessary to further improve the transdermal delivery of drugs of large molecular weight by contributing push pressure to propel the drug toward the skin, similar to conventional topical injection. Wu et al. reported that the combination of solid microneedle pretreatment and subsequent iontophoresis significantly enhanced FD flux compared with microneedle pretreatment alone or iontophoresis alone.9)It is difficult, however, to determine the penetration-enhancing effect as well as the parameters affecting the delivery efficiency produced by each enhancing technique and also by each individual microneedle. Yoshida et al. carried out a study to investigate the dermatopharmacokinetics (DPK) and systemic drug disposition after topical (intracutaneous (i.c.)) injection of sodium salicylate and concluded that the injection volume was one of the factors which can be utilized to control the drug migration rate from the injection site.10) Al-Qallaf et al. found that different surface areas of the hollow microneedle array-patch system affected the blood concentration of human growth hormone (hGH). 11)Moreover, information on the effect of several factors related to the delivery efficiency of hollow microneedles, for instance, various needle parameters, including injection conditions (e.g. length of microneedle/injection depth, needle numbers, distance between each needle, hollow size, pressure of injection, etc.), physicochemical properties of drugs (e.g. molecular weight, lipophilicity, etc.), and formulations must be considered for designing the optimum device.In this study, we therefore concentrated only on the influence of variables related to the hollow microneedle system on in vitro drug release behavior from skin. A single 33-gauge hypodermic needle, where the diameter was almost the same to the arrayed microneedles recently reported, 2,7,9,12,13) was used as a single type hollow microneedle in order to reduce the effect of needle parameters. The effects of injection volume and number o...

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Lack of Pain Associated with Microfabricated Microneedles

Cited by 420 publications

References 3 publications

Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets

Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets

Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies

Macromolecular Delivery into Skin Using a Hollow Microneedle

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