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      Flexible and Stretchable Microneedle Patches with Integrated Rigid Stainless Steel Microneedles for Transdermal Biointerfacing

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          Abstract

          This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring.

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          Most cited references25

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          Multifunctional wearable devices for diagnosis and therapy of movement disorders.

          Wearable systems that monitor muscle activity, store data and deliver feedback therapy are the next frontier in personalized medicine and healthcare. However, technical challenges, such as the fabrication of high-performance, energy-efficient sensors and memory modules that are in intimate mechanical contact with soft tissues, in conjunction with controlled delivery of therapeutic agents, limit the wide-scale adoption of such systems. Here, we describe materials, mechanics and designs for multifunctional, wearable-on-the-skin systems that address these challenges via monolithic integration of nanomembranes fabricated with a top-down approach, nanoparticles assembled by bottom-up methods, and stretchable electronics on a tissue-like polymeric substrate. Representative examples of such systems include physiological sensors, non-volatile memory and drug-release actuators. Quantitative analyses of the electronics, mechanics, heat-transfer and drug-diffusion characteristics validate the operation of individual components, thereby enabling system-level multifunctionalities.
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            Microneedles for drug and vaccine delivery.

            Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990's when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications. Copyright © 2012 Elsevier B.V. All rights reserved.
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              Microneedles for transdermal drug delivery.

              The success of transdermal drug delivery has been severely limited by the inability of most drugs to enter the skin at therapeutically useful rates. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery, especially for macromolecules. Using the tools of the microelectronics industry, microneedles have been fabricated with a range of sizes, shapes and materials. Most drug delivery studies have emphasized solid microneedles, which have been shown to increase skin permeability to a broad range of molecules and nanoparticles in vitro. In vivo studies have demonstrated delivery of oligonucleotides, reduction of blood glucose level by insulin, and induction of immune responses from protein and DNA vaccines. For these studies, needle arrays have been used to pierce holes into skin to increase transport by diffusion or iontophoresis or as drug carriers that release drug into the skin from a microneedle surface coating. Hollow microneedles have also been developed and shown to microinject insulin to diabetic rats. To address practical applications of microneedles, the ratio of microneedle fracture force to skin insertion force (i.e. margin of safety) was found to be optimal for needles with small tip radius and large wall thickness. Microneedles inserted into the skin of human subjects were reported as painless. Together, these results suggest that microneedles represent a promising technology to deliver therapeutic compounds into the skin for a range of possible applications.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 December 2016
                2016
                : 11
                : 12
                : e0166330
                Affiliations
                [1 ]KTH Royal Institute of Technology, School of Electrical Engineering, Department of Micro and Nanosystems, Stockholm, Sweden
                [2 ]Karlsruhe Institute of Technology (KIT), Institute of Nanotechnology, Karlsruhe, Germany
                Institute of Materials Research and Engineering, SINGAPORE
                Author notes

                Competing Interests: Novo Nordisk A/S of Denmark has supported this study by providing stainless steel needles. This does not alter our adherence to PLOS ONE policies on sharing data and materials. We have no other potential competing or financial interests to report.

                • Conceptualization: MR NR FN ACF.

                • Formal analysis: MR.

                • Funding acquisition: FN NR.

                • Investigation: MR NR FN ACF GS WW.

                • Methodology: MR NR FN.

                • Project administration: GS FN NR.

                • Resources: MR TH RZS.

                • Supervision: FN NR.

                • Validation: MR FN NR.

                • Writing – original draft: MR.

                • Writing – review & editing: FN NR GS ACF WW TH.

                Article
                PONE-D-16-29999
                10.1371/journal.pone.0166330
                5147815
                27935976
                8310c563-3625-472e-b17e-be8434f14932
                © 2016 Rajabi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 July 2016
                : 26 October 2016
                Page count
                Figures: 5, Tables: 1, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 277879
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 267528
                Award Recipient :
                The authors are grateful to European Research Council (ERC) for the grant agreements No. 277879 M&M’s and No. 267528 xMEMS. Novo Nordisk A/S is gratefully acknowledged for kindly providing stainless steel needles.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Polymer Chemistry
                Macromolecules
                Polymers
                Physical Sciences
                Materials Science
                Materials by Structure
                Polymers
                Physical Sciences
                Materials Science
                Metallurgy
                Alloys
                Steel
                Stainless Steel
                Biology and Life Sciences
                Anatomy
                Integumentary System
                Skin
                Skin Physiology
                Medicine and Health Sciences
                Anatomy
                Integumentary System
                Skin
                Skin Physiology
                Physical Sciences
                Materials Science
                Materials by Attribute
                Magnets
                Biology and Life Sciences
                Anatomy
                Integumentary System
                Skin
                Medicine and Health Sciences
                Anatomy
                Integumentary System
                Skin
                Physical Sciences
                Physics
                Condensed Matter Physics
                Magnetism
                Magnetic Fields
                Engineering and Technology
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                Optical Equipment
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                Physical Sciences
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                Classical Mechanics
                Deformation
                Physical Sciences
                Physics
                Classical Mechanics
                Damage Mechanics
                Deformation
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