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      Fabrication of a Ti porous microneedle array by metal injection molding for transdermal drug delivery

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          Abstract

          Microneedle arrays (MA) have been extensively investigated in recent decades for transdermal drug delivery due to their pain-free delivery, minimal skin trauma, and reduced risk of infection. However, porous MA received relatively less attention due to their complex fabrication process and ease of fracturing. Here, we present a titanium porous microneedle array (TPMA) fabricated by modified metal injection molding (MIM) technology. The sintering process is simple and suitable for mass production. TPMA was sintered at a sintering temperature of 1250°C for 2 h. The porosity of TPMA was approximately 30.1% and its average pore diameter was about 1.3 μm. The elements distributed on the surface of TPMA were only Ti and O, which may guarantee the biocompatibility of TPMA. TPMA could easily penetrate the skin of a human forearm without fracture. TPMA could diffuse dry Rhodamine B stored in micropores into rabbit skin. The cumulative permeated flux of calcein across TPMA with punctured skin was 27 times greater than that across intact skin. Thus, TPMA can continually and efficiently deliver a liquid drug through open micropores in skin.

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          Current status and future potential of transdermal drug delivery.

          Mark Prausnitz, Samir Mitragotri, Robert (Bob) Langer (2004)
          The past twenty five years have seen an explosion in the creation and discovery of new medicinal agents. Related innovations in drug delivery systems have not only enabled the successful implementation of many of these novel pharmaceuticals, but have also permitted the development of new medical treatments with existing drugs. The creation of transdermal delivery systems has been one of the most important of these innovations, offering a number of advantages over the oral route. In this article, we discuss the already significant impact this field has made on the administration of various pharmaceuticals; explore limitations of the current technology; and discuss methods under exploration for overcoming these limitations and the challenges ahead.
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            Microneedle technologies for (trans)dermal drug and vaccine delivery.

            Koen van der Maaden, Wim Jiskoot, Joke Bouwstra (2012)
            Microneedles have been used for the dermal and transdermal delivery of a broad range of drugs, such as small molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses. However, until now there are no microneedle-based (trans)dermal drug delivery systems on the market. In the past decade various types of microneedles have been developed by a number of production processes. Numerous geometries of microneedles have been designed from various materials. These microneedles have been used for different approaches of microneedle-based (trans)dermal drug delivery. Following a brief introduction about dermal and transdermal drug delivery, this review describes different production methods for solid and hollow microneedles as well as conditions that influence skin penetration. Besides, the four microneedle-based (trans)dermal drug delivery approaches are discussed: "poke and flow", "poke and patch", "poke and release", and "coat and poke". A separate section of this review is devoted to the use of microneedles for the delivery of therapeutic proteins and vaccines. Finally, we give our view on research and development that is needed to render microneedle-based (trans)dermal drug delivery technologies clinically useful in the near future. Copyright © 2012 Elsevier B.V. All rights reserved.
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              Current advances in the fabrication of microneedles for transdermal delivery.

              Sunaina Indermun, Regina Luttge, Yahya E. Choonara … (2014)
              The transdermal route is an excellent site for drug delivery due to the avoidance of gastric degradation and hepatic metabolism, in addition to easy accessibility. Although offering numerous attractive advantages, many available transdermal systems are not able to deliver drugs and other compounds as desired. The use of hypodermic needles, associated with phobia, pain and accidental needle-sticks has been used to overcome the delivery limitation of macromolecular compounds. The means to overcome the disadvantages of hypodermic needles has led to the development of microneedles for transdermal delivery. However, since the initial stages of microneedle fabrication, recent research has been conducted integrating various fabrication techniques for generating sophisticated microneedle devices for transdermal delivery including progress on their commercialization. A concerted effort has been made within this review to highlight the current advances of microneedles, and to provide an update of pharmaceutical research in the field of microneedle-assisted transdermal drug delivery systems.
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                Author and article information

                Contributors
                Hélder A. Santos: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 10 February 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 2
                Electronic Location Identifier: e0172043
                Affiliations
                [1 ]Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Engineering, Sun Yat-Sen University, Guangzhou, PR China
                [2 ]School of Mechanical and Automotive Engineering, South China University of Technology, Guangzhou, PR China
                Helsingin Yliopisto, FINLAND
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LJ JL.

                • Data curation: JL BL YZ ZC.

                • Formal analysis: JL BL YZ ZC.

                • Funding acquisition: LJ.

                • Investigation: JL YZ.

                • Methodology: JL LJ YZ BL.

                • Project administration: JL LJ.

                • Resources: JL LJ WY LL BL.

                • Software: JL LJ ZC.

                • Supervision: JL LJ WY LL BL.

                • Validation: JL LJ LL.

                • Visualization: JL.

                • Writing – original draft: JL.

                • Writing – review & editing: JL LJ LL BL WY.

                Article
                Publisher ID: PONE-D-16-42989
                DOI: 10.1371/journal.pone.0172043
                PMC ID: 5302820
                PubMed ID: 28187179
                SO-VID: eb44d11e-61d7-4216-9b8a-db40dc3d42eb
                Copyright © © 2017 Li et al
                License:

                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
                Date received : 28 October 2016
                Date accepted : 30 January 2017
                Page count
                Figures: 9, Tables: 1, Pages: 15
                Funding
                Funded by: National Nature Science Foundation of China
                Award ID: 51575543
                Award Recipient :
                Funded by: Natural Science Foundation of Guangdong Province, China
                Award ID: 2014A030313211
                Award Recipient :
                Funded by: Science and Technology Planning Project of Guangdong Province, China
                Award ID: 2015B010125004
                Award Recipient :
                This research is financially supported by the National Nature Science Foundation of China (Project No. 51575543); Natural Science Foundation of Guangdong Province, China (Project No. 2014A030313211); Guangdong-Hongkong Technology Cooperation Funding Scheme (2016A050503027); and Science and Technology Planning Project of Guangdong Province, China (No. 2015B010125004).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Delivery
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Delivery
                Subject: Transdermal Drug Delivery
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Rabbits
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Animals
                Subject: Vertebrates
                Subject: Amniotes
                Subject: Mammals
                Subject: Rabbits
                Subject: Engineering and Technology
                Subject: Manufacturing Processes
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Delivery
                Subject: Transdermal Drug Delivery
                Subject: Iontophoresis
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Titanium
                Subject: Physical Sciences
                Subject: Physics
                Subject: Classical Mechanics
                Subject: Continuum Mechanics
                Subject: Fluid Mechanics
                Subject: Fluid Dynamics
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Pharmacokinetics
                Subject: Drug Distribution
                Custom metadata
                Data Availability All relevant data are within the paper.

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