Template:MECH370 Polymer microneedles are micron-scale needles, usually in an array, in development for transdermal drug delivery and controlled-release.

Overview

The development of more advanced drugs has created the need for a more advanced way to administer them. DNA- and protein-based compounds cannot be administered orally (since they break down in the stomach before they can be absorbed), and hypodermic needles are fairly painful and invasive. This has led to transdermal drug delivery as an attractive solution. The problem faced by most W is the low W of skin. Skin permeability can be increased through the use of drugs and ultrasound although the results are limited. Microneedles have been shown to greatly increase the skin's permeability, allowing for an effective transfer of drugs.[1]

Typically, microneedles tips have a radius of curvature of less than 1 um for piercing of the skin. The are approximately 150 um long. The entire length does not pierce the skin since the surface of the skin is not flat - due to hair and W. The microneedles penetrate deep enough to pass the first ~15 um of skin, the barrier known as the W. However, they do not penetrate deep enough to touch nerves. The length can be modified as needed [1].

In the past, microneedles have been made from metal, silicon, and glass[2]. Today, some very promising technology is focused on polymers since they are biocompatible, biodegradable, and easy to manufacture. They also degrade rapidly in the body, providing a drug distribution method and eliminating the risk of the needles fracturing and becoming embedded in the skin.

Types of Microneedles

Polymer microneedles are fabricated in a variety of shapes and sizes depending on the specific application. Solid microneedles are used in order to pierce the skin, increasing permeability. A patch containing the required compound can then be administered or the compound can be placed directly on the needles. Hollow microneedles can be made to encapsulate a drug for either rapid-release or controlled-release.

Manufacturing

Most microneedles are manufactured through micromolding, which is similar to traditional W. This process lends itself well to mass production. However, a master structure must first be created to provide a mold.

Fig. 1: Tapered cone microneedle fabrication process

Microneedle master structures are usually produced through W. First a substrate, usually glass or silicon, is coated with an etch-resistant such as chromium or silicon nitride. This can be done through a variety of methods such as sputtering or chemical vapour deposition. This protective layer is then lithographically patterned to expose the substrate in a desired array of the required microneedle size and shape. The substrate can then be etched to create a microneedle tip shape (for bevelled-tip microneedles) or integrated microlenses (for tapered conical microneedles). The protective layer is removed through etching and SU-8 photoresist is spun onto the patterned substrate. In the case of bevelled-tip microneedles, a W of the desired shape and array is placed onto the W and it is exposed to UV light. This causes the molecular chains to crosslink and the exposed material solidifies. The non-crosslinked polymer is then developed away, leaving behind an array of the desired microneedles. The process is similar for tapered conical needles. The glass substrate is etched with an array of semi-circular microlenses. The back of the glass is patterned with an opaque photomask of this same array. W is coated onto the substrate and UV light is shone onto the back. The microlenses focus the UV light into a conical shape, crosslinking the polymer in that area. The non-crosslinked polymer is once again developed away leaving behind a master structure of the desired needles. These master structures are then baked to harden [1].

Next, polydimethylsiloxane (PDMS) is poured over the master structure to create a negative mold. The cured PDMS mold is filled with biocompatible polymer melt. When the melt cools the polymer microneedles are removed from the mold. [3]

Although the PDMS molding is rather quick and efficient, the master structure takes time to produce and can become complex for hollow needles. The molds can be reused, but often break during removal of the polymer array.

Efficiency

Although injection molding is typically a very quick and efficient process, there are difficulties at the micro-scale. Due to high aspect ratios and relatively high viscosity of the polymer melt, incomplete filling of the micro mold is common. So, the injection molding must be carried out at increased tool and melt temperatures. Both the tool and the part must be cooled down before ejection from the mold which also increases the cycle time. Most micromolding machines also include a vaccuum in order to prevent air bubbles and incomplete filling. These factors significantly increase the complexity of molding [4] One method of resolving these difficulties is through polymer-particle based micromolding.

Polymer Particle-based Micromolding

Polymer particle-based micromolding is the process of filling molds with polymer microparticles and using an appropriate method (W or melting) to bind, creating the desired structure.

First, microparticles ranging from 1 to 30μm are produced. This is done through W or double W. Both of these techniques require solutions containing the drugs to be encapsulated (if any), the polymer, and a solvent such as W(spray drying) or W(emulsion). In order to create layered microneedles, PLGA microparticles encapsulating any drug required are poured into a PDMS mold. They are baked for 5 minutes at 140◦C in a vacuum oven and then cooled. A reduction in volume upon melting allows the mold to be filled with more particles. This time W (PEG) particles and PLGA particles are poured into the mold. The mold is heated at 70◦C in a vacuum oven for 5 minutes. The PEG particles melt, but the PLGA particles and previous PLGA layer do not. In this way, drugs could be encapsulated in PLGA for release, and multi-layered structures could be created [5]

This technique proves to have many advantages over traditional melt micromolding. Firstly, the molds can be filled at room temperature and pressure since particles flow much easier than the viscous polymer melt. The drugs to be delivered are also not damaged and can be protected by a polymer with a high melting temperature. They are also heated for a much shorted time since in injection molding the melt must constantly be heated to remain fluid. This process can easily be scaled for mass production with cycle times just slightly higher than traditional micromolding. The cycle time would include: filling, baking for 5 minutes and cooling per layer. So, cycle times increase proportionally with layers. With only one layer the cycle time could be very similar to that for traditional melt molding.

One way to improve the efficiency of microneedle manufacturing is to remove the master structure fabrication step entirely. It is the step that takes the longest and requires very specific laboratory conditions. This can be done through photon polymerization.

Photon Induced Polymerization

Currently, photon polymerization has limited biocompatibility and biodegradability, however many studies are being done to further this technology. The materials fall under the name Ormocer and are hybrid organic-inorganic. However, they have been found to be non-toxic and biologically inert [6]. The photon polymerization method is described below:

Appropriate Applications

If further developed, polymer microneedles could prove useful for W and W in developing countries. The patches are small, portable and could be administered by someone with little or even no medical training. [7]

References

  1. 1.0 1.1 1.2 Sebastien Henry, Devin V. McAllister, Mark G. Allen, Mark R. Prausnitz, Microfabricated microneedles: A novel approach to transdermal drug delivery, Journal of Pharmaceutical Sciences, vol.87, no.8, 1998.
  2. Devin V. McAllister, Ping M. Wang, Shawn P. Davis, Jung-Hwan Park, Paul J. Canatella, Mark G. Allen, Mark R. Prausnitz, Microfabricated Needles for Transdermal Delivery of Macromolecules and Nanoparticles: Fabrication Methods and Transport Studies,Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 24, 2003.
  3. Jung-Hwan Park, Yong-Kyu Yoon, Seong-O Choi, Mark R. Prausnitz, and Mark G. Allen, Tapered Conical Polymer Microneedles Fabricated Using an Integrated Lens Technique for Transdermal Drug Delivery, IEEE Transactions on Biomedical Engineering, vol. 54, no. 5, 2007.
  4. V. Piotter, T. Hanemann, R. Ruprecht, J. Haußelt, Injection molding and related techniques for fabrication of microstructures, Microsystem Technologies, vol. 129, no. 133, 1996.
  5. Biomed Microdevices, 2006.
  6. A. Doraiswamy, C. Jin, R.J. Narayan, P. Mageswaran, P. Mente, R. Modi, R. Auyeung, D.B. Chrisey, A. Ovsianikov, B. Chichkov, Two photon induced polymerization of organic–inorganic hybrid biomaterials for microstructured medical devices, Acta Biomaterialia,vol. 2, no. 3, 2006.
  7. John Toon, Microneedles: Report describes progress in developing new technology for painless drug and vaccine delivery, gtresearchnews.gatech.edu/newsrelease/needlespnas.htm
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