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Prickly Situation Makers of microneedles face challenges bringing product to market 38 | MAY/JUNE 2012 | MICROmanufacturing Sanofi Pasteur’s intradermal flu vaccine system incorporates a 1.55mm-long microneedle. FluGen Inc. was founded in 2007 with a simple-sounding mission: To generate flu vaccines “that actually work” for older people, said Paul Radspinner, CEO of the Madison, Wis.based company. “Flu vaccines are notoriously ineffective the older you get,” he said. That’s because of a phenomenon called immunosenescence, a decline of the immune system that affects everyone as they age. However, the skin ages less rapidly. If you stimulate the skin with a vaccine, you get a much stronger immune response than you would through traditional vaccine delivery. That’s why FluGen turned to developing microneedles, a technology best suited to deliver vaccines to the skin without penetrating it. Hundreds of needles can be placed on a single patch. They’re pain-free because they don’t hit nerve endings, and they can deliver precise drug dosages. However, while research on microneedles has been promising, there are few devices on the market today. Even large companies, such as Becton, Dickinson and Company (BD) and 3M, have been stymied in their efforts to bring microneedles to market. “The large companies are having some of the same challenges as the small companies— getting these microneedles to work efficiently,” Radspinner said. “There’s been a lot of talk about By Howard Lovy Sanofi Pasteur these needles for years, but not a lot of success.” In fact, the only microneedle product on the market that can be called a success is Sanofi Pasteur’s Fluzone influenza vaccine system, which features a 1.5mm-long microneedle developed and licensed by BD. The outer diameter of the needle is 0.305mm. Fluzone incorporates a single metal needle, not a patch with hundreds of microneedles. Initially, Radspinner said, it was thought that microneedles could only be made from metal. Metal needles, though, are difficult to shape. Plastic was considered unsuitable as a material because it couldn’t be formed to a sharp enough point, and there was the potential problem of flash, or excess plastic, being left in the skin. Radspinner said that FluGen, working with an undisclosed partner, has found a way to make its 1.5mm-long needle arrays out of medicalgrade plastic through injection micromolding. “They are amazingly clean, pointed and very effective,” he said. Five years in the making, the needle array should be in Phase I clinical trials in the next 8 or 9 months, according to Radspinner. Manufacturing research Etching, micromolding and deposition are three of the most common ways microneedles are fabricated.
Seong-O Choi, a postdoctoral fellow at the Georgia Institute of Technology, is working with many materials and methods in his research into fabricating microneedle arrays. The simplest method involves an infrared laser cutting a 2-D, drug-coated, 70 µm-thick metal sheet. Another method involves molding microneedles. First, a “master” structure is fabricated using various techniques, such as silicon etching or multi-directional photolithography. A micromold is then made by casting a material, typically polydimethylsiloxane (PDMS), onto the master, creating a “negative” of it. Once a PDMS mold is prepared, materials such as carboxymethyl cellulose (CMC) or polyvinyl alcohol (PVA) are cast in the mold. These water-soluble materials are dissolved and the water/ material solution is inserted into the mold by centrifugal force or vacuum. The water evaporates, leaving the polymer (CMC or PVA) in the form of water-soluble microneedles. After being inserted into the skin, these needles dissolve. “Compared to drug-coated microneedles, dissolving microneedles can encapsulate more drugs because they are composed of matrix materials (CMC or PVA) and drugs,” Choi said. “A highervolume fraction of the microneedle can be used for drug encapsulation.” In some cases, he said, the microneedle structure can be made out of the drug itself. However, the drug must be mixed with an excipient (inert substance), such as CMC, to enhance mechanical microneedle rigidity because it must pierce the skin without breaking. “The efficacy of drugs decreases during the fabrication process since there is a phase change—liquid to solid,” said Choi. “Therefore, we are working on enhancing the stability of drugs during the fabrication process and storage by changing filling methods and drug formation.” Choi is also experimenting with applying electrical fields to microneedles, allowing them to deliver DNA-based drugs directly into skin cells. This process is called “electroporation.” “We envisioned that it would be possible to deliver DNA-based drugs into skin cells using microneedles if the microneedle itself can act as an electrode,” Choi said. “We fabricated electrically Reproduced by permission of the Royal Society of Chemistry Scanning-electron-microscopy images of hollow polymer microneedles made via two-photon polymerization. (a) Image of individual microneedle obtained at 45º tilt. (b) Image of individual microneedle obtained at 0º tilt. The length and base diameters of these microneedles are 508µm (±33µm) and 212µm (±3µm), respectively. FluGen FluGen makes its 1.5mm-long needle arrays out of medical-grade plastic via injection micromolding. active microneedle arrays and tested their mechanical and electrical functionality in-vitro, and we are now preparing in-vivo tests.” 2PP approach Another method of manufacturing microneedles involves two-photon polymerization, or 2PP. Shaun Gittard, a former researcher at North Carolina State University and Laser Zentrum Hannover and now an R&D engineer Contributors Cook Medical Inc. (812) 339-2235 www.cookmedical.com FluGen Inc. (608) 441-2729 http://flugen.com Georgia Institute of Technology (678) 525-6260 www.gatech.edu North Carolina State University (919) 696-8488 www.ncsu.edu at Cook Medical Inc., helped pioneer 2PP, which basically lets the user draw features in liquid resins with a “3-D pencil,” he said. Using a high-speed femtosecond laser as the pencil, Gittard and his colleagues are able to control feature size based on the resolution of the microscope. With a 5× microscope, they can draw 30µm features. At 100×, they can create features smaller than a micron. A microneedle can be a complicated structure, and existing techniques are limited by whatever can be drawn in the operator’s line of sight. “You are limited to making straight lines and not very complicated features, or stuck with a 2-D structure on a wafer,” said Gittard. “But with 2PP, you can have direct, 3-D control over microscale structures, like imitating the structure of a mosquito needle, or needles that have grooves, or different shapes for interior channels in hollow microneedles. It allows you to have a lot more control over the structure than any other process.” Roger Narayan is another North Carolina State researcher and 2PP pioneer. Narayan and his colleagues have successfully delivered quantum dots—nanoscale semiconductor crystals that hold promise for drug delivery, micromanufacturing.com | 39
Page 2 and 3: Someone challenged us to a little g
Page 4 and 5: Features May/June 2012 • Volume 5
Page 6 and 7: FRONTpage Don Nelson Publisher Hybr
Page 8 and 9: TECHnews Applications abound for na
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Page 12 and 13: TECHnews these technologies creates
Page 14 and 15: TECHnews UM is suitable for workpie
Page 16 and 17: Micro End Mills l .002" to .125" Cu
Page 18 and 19: MEASUREMENT matters Video measureme
Page 20 and 21: DOWNsizing Silicon that goes pitter
Page 22 and 23: SWISSmachining By Kip Hanson, Contr
Page 24 and 25: SWISSmachining high-polish finishes
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Page 32 and 33: No Mass Appeal—Yet Additive manuf
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Page 36 and 37: Power Scavengers The market for ene
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Page 44 and 45: PRODUCTS/services CARBIDE DEBURRING
Page 46 and 47: PRODUCTS/services INDUCTION COILS.
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Page 50 and 51: LASTword One of the challenges of m
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