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 ͞...

No abstract

Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.

The goal of this study was to design, fabricate, and test arrays of hollow microneedles for minimally invasive and continuous delivery of insulin in vivo. As a simple, robust fabrication method suitable for inexpensive mass production, we developed a modified-LIGA process to micromachine molds out of polyethylene terephthalate using an ultraviolet laser, coated those molds with nickel by electrodepostion onto a sputter-deposited seed layer, and released the resulting metal microneedle arrays by selectively etching the polymer mold. Mechanical testing showed that these microneedles were sufficiently strong to pierce living skin without breaking. Arrays containing 16 microneedles measuring 500 microm in length with a 75 microm tip diameter were then inserted into the skin of anesthetized, diabetic, hairless rats. Insulin delivery through microneedles caused blood glucose levels to drop steadily to 47% of pretreatment values over a 4-h insulin delivery period and were then approximately constant over a 4-h postdelivery monitoring period. Direct measurement of plasma insulin levels showed a peak value of 0.43 ng/ml. Together, these data suggest that microneedles can be fabricated and used for in vivo insulin delivery.