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 but the results are limited. Microneedles have been shown to greatly increase the skin's permeability, allowing for an effective transfer of drugs. When tested with W, a particularly difficult compound to deliver transdermally, the permeability of skin increased 1000-fold with the insertion of microneedles. When the microneedles were inserted for 10 seconds and removed, there was a 10000-fold increase in skin permeability, and when removed after an hour, a 25000-fold increase. The permeability is lower when the needles remain inserted because they themselves block the holes created in the skin [1].

Typically, microneedle tips have a radius of curvature of less than 1 um for effective piercing of the skin. They are approximately 150 um long, however, the entire length does not pierce the skin. Skin is covered in hair and tiny wrinkles, so it is not completely flat. The microneedles only penetrate deep enough to pass the first ~15 um of skin, the barrier known as the W. 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 [3] 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 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 W 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 W and W 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 SU-8 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, which is used for rapid reproduction with micromolding [4].

Although the injection micro-molding is rather quick and efficient, the master structure takes a long time to make. Hard-baking can take upwards of 12 hours and the PDMS mold takes 12 hours to cure [1].

Efficiency

W is a very well known and efficient process, however, 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 (essentially the melting temperature of the polymer). Both the tool and the part must be cooled down before ejection from the mold which also increases the cycle time. High-aspect ratio molding cycle times can run as high as 7-9 minutes. Most micromolding machines also include a vaccuum in order to prevent air bubbles and incomplete filling [5]. These factors significantly increase the complexity of molding. Polymer-particle based micromolding resolves many of these issues.

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 them together, creating the desired structure.

First, microparticles ranging in size 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 can be created [3]

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[3]. 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-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 (approximately 7-9 minutes).

Although this method significantly improves the efficiency of microneedle production, a master structure is still required and this is the most time consuming step. Master structure production can completely be eliminated through W induced W.

Two-Photon Induced Polymerization

Two-photon polymerization uses a laser in order to solidify photo-reactive polymer. Currently it is only available for hybrid organic-inorganic materials which fall under the trade name Ormocer. A resin of starter molecules and monomers is prepared. Femtosecond pulses from a titanium:sapphire laser are focused onto a volume of this resin. The resin in focus of the laser absorbs the photons from the pulse and is crosslinked into a polymer. The reaction is shown below:

2Ph + starter --> starter ion
starter ion + monomer --> polymer
polymer + polymer --> end of reaction

The laser passes through the out-of-focus resin without affecting it. The uncrosslinked polymer can be dissolved away with a solvent leaving behind the desired microstructure. This process would greatly simplify master structure manufacturing. Research is being conducted on achieving the same results with biocompatible and biodegradable ploymers, which could one day eliminate the need for molding altogether[6].

This is just one application of two-photon polymerization. It can be applied to a multitude of microprocessing needs, especially in the biomedical field.

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 1.3 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. 3.0 3.1 3.2 Jung-Hwan Park , Seong-O Choi, Rachna Kamath, Yong-Kyu Yoon, Mark G. Allen, Mark R. Prausnitz, “Polymer particle-based micromolding to fabricate novel microstructures”, Biomed Microdevices, 2007.
  4. 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.
  5. V. Piotter, T. Hanemann, R. Ruprecht, J. Haußelt, Injection molding and related techniques for fabrication of microstructures, Microsystem Technologies, vol. 129, no. 133, 1996.
  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, 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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