Micro- and nanofabrication methods in nanotechnological medical and pharmaceutical devices

Abstract

Micro- and nanofabrication techniques have revolutionized the pharmaceutical and medical fields as they offer the possibility for highly reproducible mass-fabrication of systems with complex geometries and functionalities, including novel drug delivery systems and bionsensors. The principal micro- and nanofabrication techniques are described, including photolithography, soft lithography, film deposition, etching, bonding, molecular self assembly, electrically induced nanopatterning, rapid prototyping, and electron, X-ray, colloidal monolayer, and focused ion beam lithography. Application of these techniques for the fabrication of drug delivery and biosensing systems including injectable, implantable, transdermal, and mucoadhesive devices is described.

Figure 1

Process of photolithography. A mask with opaque regions in the desired pattern is used to selectively illuminate a light-sensitive photoresist. Depending on the type of photoresist utilized, it will become more soluble (positive photoresist) or crosslinked (negative photoresist) after UV light exposure, thus generating the appropriate pattern upon developing.

Figure 2

Soft lithography includes the techniques of microfluidic patterning, microstamping and stencil patterning. All three techniques are based on the generation of the replica of a microstructure from a poly(dimethyl siloxane) (PDMS) mold prepared through other microfabrication methods such as photolithography.

Figure 3

Etching profiles generated with (A) isotropic etching, (B) dry anisotropic etching, and (C) wet anisotropic etching.

Figure 4

Schematic of electrically-induced nanopatterning process. (A) The system utilized for electrically induced micropatterning consists of two electrodes separated by an air gap of thickness δ. A thin film of a polymer to be molded is applied to the bottom electrode. Upon exposure of an external magnetic field, electrostatic forces surpass surface tension forces, and instabilities develop on the polymer at the sites where δ is smallest. (B) Columns formed at the sites of the major instabilities mimic the pattern of the top electrode. Based on a figure from Schäffer et al (2000).

Figure 5

Scanning electron microscopy image of relatively short solid silicon microneedles (25 μm in height) prepared by reactive ion etching. These nanoparticles were designed for cutaneous gene delivery. Reproduced with permission from McAllister D, Wang P, Davis S, et al. 2003. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci U S A, 100:13755-60. Copyright © 2003 National Academy of Sciences, U.S.A.

Figure 6

Schematic (left) and image captured with a Microscope II in Nomarski mode (right) of silicon cantilevers patterned with photolithography with environmentally sensitive hydrogels. Swelling of the hydrogel as a result of pH changes results in pH-dependent deflection that can be quantified based on the differences of focus planes A and B. The thickness of the patterned hydrogels was determined to be of approximately 2.5 μm. Unpublished images provided by Dr. Nicholas Peppas.