Silk Microneedles Deliver Controlled-Release Drugs Painlessly

Silk Microneedles Deliver Controlled-Release Drugs Painlessly

MEDFORD/SOMERVILLE, Mass. – Bioengineers at Tufts University School of Engineering have developed a new silk-based microneedle system able to deliver precise amounts of drugs over time and without need for refrigeration. The tiny needles can be fabricated under normal temperature and pressure and from water, so they can be loaded with sensitive biochemical compounds and maintain their activity prior to use. They are also biodegradable and biocompatible.

The research paper “Fabrication of Silk Microneedles for Controlled-Release Drug Delivery” appeared in Advanced Functional Materials December 2 online in advance of print.

The Tufts researchers successfully demonstrated the ability of the silk microneedles to deliver a large-molecule, enzymatic model drug, horseradish peroxidase (HRP), at controlled rates while maintaining bioactivity. In addition, silk microneedles loaded with tetracycline were found to inhibit the growth of Staphylococcus aureus, demonstrating the potential of the microneedles to prevent local infections while also delivering therapeutics.

“By adjusting the post-processing conditions of the silk protein and varying the drying time of the silk protein, we were able to precisely control the drug release rates in laboratory experiments,” said Fiorenzo Omenetto, Ph.D., senior author on the paper. “The new system addresses long-standing drug delivery challenges, and we believe that the technology could also be applied to other biological storage applications.”

The Drug Delivery Dilemma

While some drugs can be swallowed, others can’t survive the gastrointestinal tract. Hypodermic injections can be painful and don’t allow a slow release of medication. Only a limited number of small-molecule drugs can be transmitted through transdermal patches. Microneedles—no more than a micron in size and able to penetrate the upper layer of the skin without reaching nerves—are emerging as a painless new drug delivery mechanism. But their development has been limited by constraints ranging from harsh manufacturing requirements that destroy sensitive biochemicals, to the inability to precisely control drug release or deliver sufficient drug volume, to problems with infections due to the small skin punctures.

The process developed by the Tufts bioengineers addresses all of these limitations. The process involves ambient pressure and temperature and aqueous processing. Aluminum microneedle molding masters were fabricated into needle arrays of about 500 µm needle height and tip radii of less than 10 µm. The elastomer polydimethylsiloxane (PDMS) was cast over the master to create a negative mold; a drug-loaded silk protein solution was then cast over the mold. When the silk was dry, the drug-impregnated silk microneedles were removed. Further processing through water vapor annealing and various temperature, mechanical and electronic exposures provided control over the diffusity of the silk microneedles and drug release kinetics.

“Changing the structure of the secondary silk protein enables us to ‘pre-program’ the properties of the microneedles with great precision,” said David L. Kaplan, Ph.D., coauthor of the study, chair of biomedical engineering at Tufts and a leading researcher on silk and other novel biomaterials. “This is a very flexible technology that can be scaled up or down, shipped and stored without refrigeration and administered as easily as a patch or bandage. We believe the potential is enormous.”

Other co-authors on the paper, all associated with the Department of Biomedical Engineering, are Konstantinos Tsioris, doctoral student; Waseem Raja, post-doctoral associate; Eleanor Pritchard, post-doctoral associate; and Bruce Panilaitis, research assistant professor.

The research was based on work supported in part by the U.S. Army Research Laboratory, the U.S. Army Research Office, the Defense Advanced Research Projects Agency-Defense Sciences Office and the Air Force Office of Scientific Research.

Tsioris, K., Raja, W. K., Pritchard, E. M., Panilaitis, B., Kaplan, D. L. and Omenetto, F. G. (2011), Fabrication of Silk Microneedles for Controlled-Release Drug Delivery. Advanced Functional Materials. doi: 10.1002/adfm.201102012

Located on Tufts’ Medford/Somerville campus, the School of Engineering offers a rigorous engineering education in a unique environment that blends the intellectual and technological resources of a world-class research university with the strengths of a top-ranked liberal arts college. Close partnerships with Tufts’ undergraduate, graduate and professional schools, coupled with a long tradition of collaboration, provide a strong platform for interdisciplinary education and scholarship. The School of Engineering’s mission is to educate engineers committed to the innovative and ethical application of science and technology in addressing the most pressing societal needs, to develop and nurture twenty-first century leadership qualities in its students, faculty, and alumni, and to create and disseminate transformational new knowledge and technologies that further the well-being and sustainability of society in such cross-cutting areas as human health, environmental sustainability, alternative energy, and the human-technology interface.

Abstract

Microneedles are emerging as a minimally invasive drug delivery alternative to hypodermic needles. Current material systems utilized in microneedles impose constraints hindering the further development of this technology. In particular, it is difficult to preserve sensitive biochemical compounds (such as pharmaceuticals) during processing in a single microneedle system and subsequently achieve their controlled release. A possible solution involves fabricating microneedles systems from the biomaterial silk fibroin. Silk fibroin combines excellent mechanical properties, biocompatibility, biodegradability, benign processing conditions, and the ability to preserve and maintain the activity of biological compounds entrained in its material matrix. The degradation rate of silk fibroin and the diffusion rate of the entrained molecules can be controlled simply by adjusting post-processing conditions. This combination of properties makes silk an ideal choice to improve on existing issues associated with other microneedle-based drug delivery system. In this study, a fabrication method to produce silk biopolymer microstructures with the high aspect ratios and mechanical properties required to manufacture microneedle systems is reported. Room temperature and aqueous-based micromolding allows for the bulk loading of these microneedles with labile drugs. The drug release rate is decreased 5.6-fold by adjusting the post-processing conditions of the microneedles, mainly by controlling the silk protein secondary structure. The release kinetics are quantified in an in vitro collagen hydrogel model, which allows tracking of the model drug. Antibiotic loaded silk microneedles are manufactured and used to demonstrate a 10-fold reduction of bacterial density after their application. The processing strategies developed in this study can be expanded to other silk-based structural formats for drug delivery and biologicals storage applications.

Transdermal administration represents a useful route for drug and vaccine delivery due to the ease of access and avoidance of macromolecular degradation in the gastrointestinal tract. Microneedles are evolving as a safe and pain-free alternative1 to the widely adopted skin delivery via hypodermic needles. Microneedles can be efficient, easily applied, and relatively painless, but currently face limitations due to a lack of appropriate biomaterials, an inability to precisely control the release kinetics of drugs, harsh processing conditions that limit the types of drugs that can be delivered, larger drug dose delivery, and the onset of local infections at the needle–skin interface. Options to overcome these limitations would open up new therapeutic utility for microneedle devices.

One current microneedle technology utilizes a dissolvable poly(lactide-co-glycolide) (PLGA) polymer microneedle body loaded with microparticles (either PLGA or carboxymethylcellulose) filled with the drug of interest to provide sustained drug release.2 However, the fabrication method for this microneedle system constitutes a limitation, as polymer melting temperatures above 135 °C and vacuum are necessary for processing and these conditions can be detrimental to various temperature-sensitive drugs, particularly peptides and proteins. Recently developed microneedle systems employ room-temperature processing by coating solid metallic microneedle structures with polymer (a blend of carboxymethylcellulose, Lutrol F-68NF and D-(+)-trehalose dehydrate) containing an influenza vaccine.3 The mild processing conditions resulted in some preservation of the activity of the incorporated vaccine during processing and storage over 2 to 4 weeks.4, 5 However, the coating approach to microneedle drug loading provides only a small volume to entrap therapeutic substances compared to bulk loaded structures. In addition, metal-based microneedle systems have limitations that compromise their function, such as the risk of breaking if improperly applied6 and the possibility of an inflammatory response or infection if small metal structures remain in the skin.

The limitations described above can be addressed by fabricating bulk loaded microneedles from biocompatible and dissolvable materials like polyvinylpyrrolidone (PVP) and carbohydrates.3, 7 Relatively large doses can be administered due to the bulk loading of this dissolvable system and drug degradation caused by elevated temperatures during processing is avoided, since the polymers are cured at room temperature. However, curing requires ultraviolet light, which can impact the incorporated drug. In addition, the rapid dissolution of the microneedles provides limited control over drug release kinetics other than relatively short-term burst delivery. Previously fabricated microneedle arrays from silk protein also exhibited rapid, uncontrolled burst release.8

To move microneedle systems to more complete utility as a new drug delivery mode, these systems require materials that are mechanically robust,9 biocompatible, exhibit controllable drug-release behavior, and degrade to non-toxic products in vivo within a prescribed lifetime after application.7 Microneedle systems should also employ mild processing conditions to avoid the degradation of incorporated drugs while also promoting the stabilization of the incorporated drugs or vaccines to preserve efficacy during storage until use. Towards this need, we propose an approach that can overcome all of the established barriers, while also adding new functions to such microneedle systems, such as stabilization of the drugs in the device and programmable degradability from days to weeks. Further, since drugs such as antibiotics can be stabilized in the materials, control of infections at the site of use provides an added benefit to this technology. The proposed microneedle system combines mild fabrication conditions and controllable slow release drug delivery in a single device.

Silk fibroin has recently been shown to be a material suitable for biomedical applications due to its excellent biocompatibility and biodegradability.10, 11 Enzymes or drugs can be incorporated into the silk matrix due to the all-aqueous and mild processing conditions.12, 13 Additionally, nano- and microfabrication with silk at room temperature and atmospheric pressure has been demonstrated.14–17 Furthermore, bioactive species have been stabilized in dry silk films for extended periods of time12 and can be released in a controlled fashion.18–21 Due to these properties, silk is a suitable biomaterial for bulk microneedle devices for transdermal drug delivery systems. In addition, silk outperforms other biopolymers utilized in microneedles in terms of mechanical properties.10, 11, 22, 23 Consequently, silk provides the necessary mechanical strength for functional microneedle devices.

We anticipate that silk microneedle systems could be exploited to meet a range of urgent clinical needs, including sustained delivery of peptide therapeutics and vaccines with short half-lives.24 In particular, human growth hormone therapy25, 26 and vaccines requiring long-term exposure27 would benefit from this delivery system. The stabilizing effect silk has been shown to exert on incorporated proteins could be combined with the convenience and self-administration of microneedles to produce drug delivery platforms that are safe and easy to self-administer and that can be stored at elevated temperatures.

We report on a fabrication method to produce silk biopolymer microstructures with the high aspect ratios required to manufacture microneedle systems. Room temperature and aqueous-based micromolding allow for the bulk loading of these microneedle structures with temperature-sensitive drugs such as peptides, antibiotics and vaccines, or any temperature-labile therapeutic. Additionally, we demonstrate loading of silk microneedles with various model drugs, as well as with antibiotic. Controlled release of a model drug is achieved by adjusting the post-processing conditions of the microneedle structures, mainly by controlling the silk protein secondary structure. A collagen hydrogel-based in vitro skin model allows quantification of the varied drug release profiles, as they are demonstrated in this study.

Source : http://now.tufts.edu/news-releases/silk-microneedles-deliver-drugs-painlessly-

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