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      Engineering Microneedle Patches for Improved Penetration: Analysis, Skin Models and Factors Affecting Needle Insertion

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          Highlights

          • Factors affecting microneedle insertion into skin are reviewed.

          • The use of artificial and computational skin models for the simulation of needle insertion is summarized.

          • Skin structures and models, as well as mechanical analyses, used to determine transdermal microneedle ability to insert into skin are highlighted in the review.

          Abstract

          Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.

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          Most cited references201

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          Cellular and molecular mechanisms of pain.

          The nervous system detects and interprets a wide range of thermal and mechanical stimuli, as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
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            Collagen structure and stability.

            Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen-the prototypical collagen fibril-has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.
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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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                Author and article information

                Contributors
                pooyan.makvandi@iit.it , pooyanmakvandi@gmail.com
                virgilio.mattoli@iit.it
                r.donnelly@qub.ac.uk
                Journal
                Nanomicro Lett
                Nanomicro Lett
                Nano-Micro Letters
                Springer Singapore (Singapore )
                2311-6706
                2150-5551
                16 March 2021
                16 March 2021
                December 2021
                : 13
                : 93
                Affiliations
                [1 ]GRID grid.25786.3e, ISNI 0000 0004 1764 2907, Istituto Italiano Di Tecnologia, Centre for Materials Interface, ; Viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa Italy
                [2 ]GRID grid.4777.3, ISNI 0000 0004 0374 7521, School of Pharmacy, , Queen’s University Belfast, ; 97 Lisburn Road, Belfast, BT9 7BL UK
                [3 ]GRID grid.263145.7, ISNI 0000 0004 1762 600X, The BioRobotics Institute, Scuola Superiore Sant’Anna, ; Viale Rinaldo Piaggio 34, 56025 Pontedera, Pisa Italy
                [4 ]GRID grid.194645.b, ISNI 0000000121742757, Paediatric Dentistry and Orthodontics, Faculty of Dentistry, , The University of Hong Kong, Prince Philip Dental Hospital, ; Hong Kong SAR, China
                [5 ]GRID grid.4691.a, ISNI 0000 0001 0790 385X, Department of Chemical, Materials and Industrial Production Engineering, , University of Naples Federico II, ; 80125 Naples, Italy
                [6 ]GRID grid.25786.3e, ISNI 0000 0004 1764 2907, Center for Advanced Biomaterials for Health Care (iit@CRIB), , Italian Institute of Technology, ; 80125 Naples, Italy
                Article
                611
                10.1007/s40820-021-00611-9
                8006208
                34138349
                fabd09a3-c723-4a09-83cb-0c4fce131ff4
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 November 2020
                : 5 January 2021
                Categories
                Review
                Custom metadata
                © The Author(s) 2021

                insertion responsive,implantable microneedles,skin indentation,transdermal microneedles,pain management

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