Shawn P. Davis

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

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.

Transdermal Delivery of Insulin Using Microneedles in Vivo

AbstractPurpose. 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.

Hollow metal microneedles for insulin delivery to diabetic rats

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.

Fabrication and characterization of laser micromachined hollow microneedles

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.

Micromachined biodegradable microstructures

We present a fabrication approach for the production of micromachined biodegradable microstructures, and illustrate its application in two areas: biodegradable microneedles for transdermal drug delivery, and biodegradable ratcheting surgical ties for blood vessel surgery. We fabricated solid polymer microneedles out of polyglycolide, polylactide and their copolymer using a micromolding technique that created needles with beveled tips. Polymer microneedles were strong enough to be inserted into cadaver skin without breaking. Polymer microneedles impregnated with both low- and high- molecular weight model compounds to simulate drug release were fabricated and inserted into full thickness cadaver skin. Quantitative measurement of model compound release as a function of time was obtained. The fabrication technology was also utilized to produce more mechanically complex biodegradable microstructures: cable ties for surgical ratcheting. These devices were successfully integrated with blood vessel tissue. The change in the mechanical properties of these devices under physiological conditions was investigated and shown to depend on the chemical and physical properties of polymer, implant temperature, and chemical environment.

The mechanics of microneedles

We have developed arrays of microscopic needles capable of providing pathways for drug delivery across skin without the pain associated with conventional injections. We measured the force to insert microneedles into human subjects and compared it to the force to cause microneedles to break. Insertion force measured with a force, deflection and electrical resistance meter showed that microneedle insertion force was directly proportional to interfacial area of the needle tip over a broad range of needle geometries. Force of insertion for a representative needle with 42 micron tip radius and 10 micron wall thickness was 1.3 N, which permits easy insertion of needles by hand. Breaking of microneedles under load was measured as a function of needle geometry and found to agree with predictions by ANSYS finite element simulation and thin-shell analytic theory. For example, the applied force at failure for a needle with the same geometry as above was 3.4 N, providing a 2.6-fold margin of safety between insertion and failure. In comparison, the simulation and analytical predictions were 3.5 N and 2.2 N, respectively. Both predictions and experimental results reveal that microneedles over a range of geometries are capable of withstanding the force of insertion.