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

Abstract

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 ͞...

The effect of heat on skin permeability

“…Electroporation similarly makes nanometer disruptions to skin, although electroporation combined with chemical enhancers has been shown to produce micron scale holes (Ilic et al, 2001). Microneedles create micron scale holes in the skin (McAllister et al, 2003).…”

Coated microneedles for transdermal delivery

“…Unlike transdermal patches, microneedles have been successfully used to deliver a variety of large and hydrophilic compounds into the skin, including proteins and DNA. In vitro skin permeability enhancement of two to four orders of magnitude was observed for small molecules like calcein and large compounds like proteins and nanoparticles [11,12]. In vivo delivery has been shown for peptides, such as insulin and desmopressin [13,14]; genetic material, including plasmid DNA and oligonucleotides [15,16]; and vaccines directed against hepatitis B, anthrax and Japanese encephalitis [10,17,18].…”

Transdermal Drug Delivery by Microneedles: Does Skin Metabolism Matter?

“…For the sake of simplicity, the one-dimensional diffusion has been assumed as this allows one to consider the effects of drug metabolism alone and not any other effects (e.g., dimensionality). Such assumption has been used in many mathematical models to describe the transdermal drug delivery using microneedles (Lv et al, 2006;McAllister et al, 2003). In particular, several studies have been obtained by carrying out simulations using SKIN-CAD ® which assume one-dimensional method (Kimura and Tojo, 2007;Tojo and Hikima, 2007;Mori et al, 2003).…”

“…A number of mathematical frameworks have been developed for evaluating both the skin permeation and blood concentration of drug delivered using microneedle arrays (Al-Qallaf and Das, 2009a;Das, 2009b, Davidson et al, 2008;Al-Qallaf et al, 2007;Lv et al, 2006;McAllister et al, 2003). In most of these cases, the metabolism of the drug has not been considered.…”

“…Consequently the skin permeation and blood concentration of the drug have been modelled assuming no drug metabolism in the viable skin. For example, we have previously evaluated the effects of volume of distribution (V b ) and elimination rate constant (K e ) on the fentanyl concentration in blood without considering the skin metabolism (Al-Qallaf et al, 2007;McAllister et al, 2003). Other general mathematical models for molecule transport across skin have also been proposed which have not included the influence of skin metabolism, see e.g., the reviews by Godin and Touitou (2007) and, Yamashita and Hashida (2003).…”