Minimally invasive protein delivery with rapidly dissolving polymer microneedles.

Biomolecules, including proteins, peptides, and vaccines, make up a large and potent portion of all new drugs and hold great promise for the future of therapeutics. Although oral delivery of these biotherapeutics would be desirable, there is low bioavailability of biomolecules administered by this route due to enzymatic degradation and poor absorption in the GI tract, as well as first-pass metabolism of the liver. As a result, most biotherapeutics are administered by hypodermic injection, which causes pain, can lead to infection, requires trained personnel, and often needs frequent, repeated injections for the patient. Consequently, there exists the need for a minimally invasive, self-administered delivery system for biomolecules. An attractive non-invasive option is the transdermal patch, which has been well-received for the delivery of nicotine, estrogens, and other drugs. However, delivery across intact skin permits transport of small, lipophilic molecules only and excludes transport of biotherapeutics, due to their large size. This study presents a novel, hybrid delivery approach to achieve the delivery efficacy of injections and the safety and patient compliance of the patch. We designed and synthesized rapidly dissolving polymer needles of micrometer dimensions for the painless, self-administered delivery of biomolecules. In this design, the drug is encapsulated within polymer microneedles and, after insertion into the skin, the biocompatible polymer dissolves within minutes to release the encapsulated cargo, not requiring removal and leaving behind no biohazardous sharps. Previous work has shown that microscopically piercing the skin with micrometer-scale needles offers an effective and convenient alternative for the delivery of biomolecules because of the efficient delivery, lack of pain, ease of use, and the expected low cost of fabrication. Microneedles have been shown to be able to deliver proteins, DNA, and vaccines in vivo, using devices small enough to be integrated into a low-profile, self-administered patch.To date, most microneedles have been made of silicon or metal with little work involving polymers. There are, however, safety concerns if microneedles made of these materials break off in the skin, or if they are accidentally or intentionally reused. In contrast, the use of biocompatible polymers could eliminate these concerns, because the needles completely and safely dissolve within the skin, and the needle free patch backing could be safely discarded, leaving no biohazardous sharps. Achieving this goal presents significant material challenges. The ideal polymer material would be strong enough to penetrate the skin, dissolve rapidly once in the skin, and be safely excreted by the body. Also, the fabrication process for these microneedles should take place at ambient temperatures, without organic solvents, and avoid damaging fragile biomolecules during encapsulation. No current design allows for polymer microneedles to be fabricated in this manner. Previous studies have relied on either high-temperature molding processes that risk damaging biomolecules or methods unsuitable for large-scale fabrication of micrometer structures. In this study, we have developed the first rapidly dissolving polymer microneedles. This advance required the development of a new fabrication process to produce mechanically robust microneedles that encapsulate biomolecules under gentle processing conditions using methods suitable for inexpensive mass production. Here, we detail the new fabrication process, based on room-temperature in situ polymerization, and study the mechanical, encapsulation, dissolution, and delivery properties of the resulting polymer microneedles for the delivery of biomolecules to the skin. To develop rapidly dissolving polymer microneedles, we first prepared master structures made of a polymeric photoresist epoxy (SU-8) by a photolithography method. Then, we used these master structures to create reverse molds from polydimethylsiloxane (PDMS) (see Experimental Section). It C O M M U N IC A IO N