Microneedle Arrays (M. Allen)

Schematic of drug delivery using nano-tipped needles.

Schematic of drug delivery using nano-tipped needles.

Purpose: The delivery of drugs and/or genetic information across cell membranes while preserving the viability of the cells enables both scientific study of cellular mechanisms as well as the potential for genetic therapy. Such delivery can be accomplished by use of arrays of microneedles with tip sharpness on the nanoscale.  These delivery devices offer a unique route to interacting with tissue and cells in a diverse range of environments. By combining these delivery devices with microfluidics, the sequential and selective application of therapy and treatments to individual cells or groups of cells can be realized (a). Making such 3D micro/nanoscale structures via semiconductor processing is challenging because of the 2D nature of lithography and etching processes.  The Allen group has demonstrated the fabrication of nanoneedle-based drug delivery devices with areal densities as large as 106 needles per square centimeter, and demonstrated their efficacy using model compounds (Paik, 2012).

Efficacy of transmembrane delivery against positive and negative controls.

Efficacy of transmembrane delivery against positive and negative controls.

Method of Fabrication/Use: Nano-tipped needles are formed by lithography, anisotropic and isotropic etching of silicon, and oxidative sharpening (c). Fabrication is accomplished by patterning silicon dioxide on the surface of a silicon wafer using photolithography and oxide etching. Isotropic dry etching of Si is performed to achieve around arrays of 7 μm diameter circular SiO2 patterns leading to sharp tips at their centers through under-etching of silicon under the oxide mask. Anisotropic dry etching is then used to form the needle shanks. The etch masks are subsequently removed and the tips are oxidatively sharpened to achieve nm-scale radii of curvature. An SEM micrograph of the needle array is shown – note the density array and uniformity of the fabricated structures.

Fabrication process flow

Fabrication process flow

Results: In order to demonstrate the effectiveness of the microneedle arrays, the delivery of molecular probes into a cell system was examined.  A model cell line, confluent monolayers of human prostate cancer cells (DU145) were cultured in dishes containing a standard culture medium solution. A calcein fluorescent dye and a fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) were used as model molecules. In-vitro tests demonstrated that the nanoneedle array can effectively deliver these molecular probes across cell membranes without causing significant cell death. Uptake of molecular probes by up to 34% of cells after nanoneedle treatment was observed in experiments to date (c).  The needles are robust and potentially reusable as Si is hard, durable material.

EM micrograph of a microfabricated, nano-tipped needle array.

EM micrograph of a microfabricated, nano-tipped needle array.

References

Paik S, Park S, Zamitsyn V, Choi S, Guo X, Prausnitz M, Allen M. A highly dense nenoneedle array for intracellular gene delivery. 14th Solid State Sensors, Actuators and Microsystems Workshop; 2012:149-152.

 

 

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