http://drugdelivery.chbe.gatech.edu/Papers/2004/Prausnitz%20ADDR%202004.pdf

Microneedles for transdermal drug delivery.

The past twenty five years have seen an explosion in the creation and discovery of new medicinal agents. Related innovations in drug delivery systems have not only enabled the successful implementation of many of these novel pharmaceuticals, but have also permitted the development of new medical treatments with existing drugs. The creation of transdermal delivery systems has been one of the most important of these innovations, offering a number of advantages over the oral route. In this article, we discuss the already significant impact this field has made on the administration of various pharmaceuticals; explore limitations of the current technology; and discuss methods under exploration for overcoming these limitations and the challenges ahead.

Current status and future potential of transdermal drug delivery

Microneedles for drug and vaccine delivery.

Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery

Dissolving microneedles for transdermal drug delivery.

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 μm. 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.

/pdf/microfabricated-needles-for-transdermal-delivery-of-1j0yuh8xqv.pdf

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

http://drugdelivery.chbe.gatech.edu/Papers/2004/Davis%20J%20Biomech%202004.pdf

Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force.

Purpose. The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. 
Methods. Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. 
Results. Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. 
Conclusions. 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.

/pdf/transdermal-delivery-of-insulin-using-microneedles-in-vivo-32wbrdvk2r.pdf

Transdermal Delivery of Insulin Using Microneedles 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 electrodeposition 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 /spl mu/m in length with a 75 /spl mu/m 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.

Hollow metal microneedles for insulin delivery to diabetic rats

Three-dimensional arrays of hollow and solid microneedles have been fabricated using laser micromachining techniques. Excimer (UV) and infrared (IR) laser machining was used to create molds for electrodeposition of metals. Mold materials included polyimide (Kapton), polyethylene terephthalate (Mylar), and titanium. IR laser machining was also used to cut solid needle designs directly from stainless steel. The mechanical stability and insertion characteristics of hollow microneedles were tested. The force necessary for insertion was found to vary linearly with the interfacial area of the microneedle. The force necessary for the fracture of a microneedle was found to increase with the tip diameter, wall angle, and wall thickness. Over the range of microneedle geometries tested, the margin of safety between the force for insertion and the force for fracture was the greatest for microneedles with the smallest diameter and the greatest wall thickness.

Shawn P. Davis

Papers

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

Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force.

Transdermal Delivery of Insulin Using Microneedles in Vivo

Hollow metal microneedles for insulin delivery to diabetic rats

Fabrication and characterization of laser micromachined hollow microneedles