Abstract
Delivery of active pharmaceutical ingredients through transdermal route has been limited due to the excellent barrier properties of the stratum corneum (SC) of the skin. Only drugs with very specific physicochemical properties (molecular weight < 500 daltons, adequate lipophilicity and low melting point) can be successfully administered transdermally. Disrupting the barrier properties of the SC is one of the techniques utilised in enhancing transdermal drug delivery. With this intention, microneedle/s (MN/MNs) have been developed that can painlessly penetrate the SC and create micropores through which drug molecules can readily permeate to the dermal microcirculation for absorption. MNs consist of a plurality of micron-sized needles, generally ranging from 25 to 2000 μm in height, of a variety of different shapes and composition (e.g. silicon, metal, sugars and biodegradable polymers). Even though the concept of MNs was first conceived in 1976, it was not possible to make such micron-sized medical devices until the first exploitation of microelectromechanical systems (MEMS) for this purpose in 1998. MEMS utilise a variety of techniques and highly sophisticated tools to allow fabrication of MNs from different materials with varying designs. Now, due to the MEMS, MNs are considered as one of the few third-generation enhancement strategies that will have a significant impact on medicine. Therefore, this chapter will focus on recent progress on MN technology that includes discussion on the fabrication techniques of MNs using MEMS, the design and material consideration of MNs and the application of MNs in drug delivery and monitoring biological fluids.
References
Arora A, Prausnitz MR, Mitragotri S (2008) Micro-scale devices for transdermal drug delivery. Int J Pharm 364:227–236
Ashraf MW, Tayyaba S, Afzulpurkar N (2011) Micro Electromechanical Systems (MEMS) based microfluidic devices for biomedical application. Int J Mol Sci 126:3648–3704
Bai W, Li Y, Yang C, Liu J, He D, Sugiyama S (2012) Fabrication of metal micro needle array by LIGA process. Adv Mater Res 418:1911–1914
Ball J, Pike G (2008) Needlestick injury in 2008, Royal College of Nursing, 20 Cavendish Square, London, WIG ORN
Banga A (2009) Microporation applications for enhancing drug delivery. Expert Opin Drug Deliv 6(4):343–354
Banks D (2006) Microengineering, MEMS, and interfacing. A practical guide. CRC, Taylor and Francis, Boca Raton
Bodhale DW, Nisar A, Afzulpurkar N (2010) Structural and microfluidic analysis of hollow side-open polymeric microneedles for transdermal drug delivery applications. Microfluid Nanofluid 8(3):373–392
Bouissou C, Sylvestre J, Guy R, Delgado-Charro M (2009) Reverse iontophoresis of amino acids: identification and separation of stratum corneum and subdermal sources in vitro. Pharma Res 26(12):2630–2638
Brancazio D (2012) Systems and interfaces for blood sampling, 600/576 edn, A61B 5/15, US
Bystrova S, Luttge R (2011) Micromolding for ceramic microneedle arrays. Microelectron Eng 88(8):1681–1684
Chandrasekaran SK, Mohanty S, Frazier AB (2003) Autonomous microneedle system for biochemical analysis. Boston Transducers’03: Digest of Technical Papers 1 and 2, 1442–1445
Chaudhri B, Ceyssens F, De Moor P, Van Hoof C, Puers R (2010) A high aspect ratio SU-8 fabrication technique for hollow microneedles for transdermal drug delivery and blood extraction. J Micromech Microeng 20(6):064006
Ching C, Chou T, Sun T, Huang S, Shieh H (2011) Simultaneous, noninvasive, and transdermal extraction of urea and homocysteine by reverse iontophoresis. Int J Nanomedicine 6:417–423
Choi H, Yoo D, Bondy B, Quan F, Compans R, Kang S et al (2012) Stability of influenza vaccine coated onto microneedles. Biomaterials 33(14):3756–3769
Cormier M, Daddona PE (2003) Macroflux technology for transdermal delivery of therapeutic proteins and vaccines. Drugs Pharm Sci 126:589–598
Corrie S, Fernando G, Crichton M, Brunck M, Anderson C, Kendall M (2010) Surface-modified microprojection arrays for intradermal biomarker capture, with low non-specific protein binding. Lab Chip 10(20):2655–2658
Daddona P (2002) Macroflux® transdermal technology development for the delivery of therapeutic peptides and proteins. Drug Deliv Tech 2
Daugimont L, Baron N, Vandermeulen G, Pavselj N, Miklavcic D, Jullien MC et al (2010) Hollow microneedle arrays from intradermal drug delivery and DNA electroporation. J Membr Biol 236:117–125
DeMuth P, Su X, Samuel R, Hammond P, Irvine D (2010) Nano‐layered microneedles for transcutaneous delivery of polymer nanoparticles and plasmid DNA. Adv Mater 22(43):4851–4856
Donnelly RF, Singh TRR, Tunney MM et al (2009) Microneedle arrays allow lower microbial penetration than hypodermic needles in vitro. Pharm Res 26(11):2513–2522
Donnelly RF, Singh T, Woolfson AD (2010b) ‘Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety’, Drug Delivery 17(4):187–207
Donnelly RF, Singh TRR, Morrow D, Woolfson A (2012) Microneedle-mediated transdermal and intradermal drug delivery. Wiley, Chichester. doi:10.1002/9781119959687.index
Ebah LM, Read I, Sayce A, Morgan J, Chaloner C, Brenchley P, Mitra S (2012) ‘Reverse iontophoresis of urea in health and chronic kidney disease: a potential diagnostic and monitoring tool?’, European Journal of Clinical Investigation
Gardeniers HJGE, Luttge R, Berenschot EJW, de Boer MJ et al (2003) Silicon micromachined hollow microneedles for transdermal liquid transport. J Microelectromech Syst 12(6):855–862
Garland MJ, Migalska K, Mahmood TM, Singh TR, Woolfson AD, Donnelly RF (2011) Microneedle arrays as medical devices for enhanced transdermal drug delivery. Expert Rev Med Dev 8(4):459–482
Gerstel MS, Place VA (1976) Drug delivery device, in US Patent 1976; US39644821976
Gill HS, Prausnitz MR (2007) Coated microneedles for transdermal delivery. J Control Release 117(2):227–237
Goud J, Raj PM, Liu J, Narayan R, Iyer M (2007) Electrochemical biosensors and microfluidics in organic system-on-package technology. Institute of Electrical and Electronics Engineers, New York
Henry S, McAllister DV, Allen MG et al (1998) Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci 87(8):922–925
Jae-Ho O, Park HH, Ki-Young DO, Han M, Hyun DH, Kim CG et al (2008) Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein. Eur J Pharm Biopharm 69:1040–1045
Jin CY, Han MH, Lee SS, Choi YH (2009) Mass producible and biocompatible microneedle patch and functional verification of its usefulness for transdermal drug delivery. Biomed Microdevices 11(6):1195–1203
Khanna P, Strom J, Malone J, Bhansali S (2008) ‘Microneedle-based automated therapy for diabetes mellitus’, Journal of Diabetes Science and Technology 2(6):1122–1129
Khumpuang S et al (2004) Proceedings of the Nanotechnology Conference and Trade Show, Boston, USA. Nano Science Technology Inst, Cambridge 1: 205–208
Kim K, Park DS, Lu HM, Che W, Kim K, Lee JB et al (2004) A tapered hollow metallic microneedle array using backside exposure of SU-8. J Micromech Microeng 14:597
Kim A, Suecof L, Sutherland C, Gao L, Kuti J, Nicolau D (2008) In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers. Antimicrob Agents Chemother 52(11):3941–3946
Kim M, Jung B, Park JH (2012) Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin. Biomaterials 33(2):668–678
Kobayashi K, Suzuki H (2001) A sampling mechanism employing the phase transition of a gel and its application to a micro analysis system imitating a mosquito. Sens Actuators B Chem 80(1):1–8
Kong XQ, Wu CW (2010) Mosquito proboscis: an elegant biomicroelectromechanical system. Phys Rev E 82(1):011910
Koren G (1997) Therapeutic drug monitoring principles in the neonate. National Academy of Clinical Biochemistry. Clin Chem 43(1):222–227
Laermer F, Schilp A (1996) Method of Anisotropically Etching Silicon. US Patent Number 5:501–893
Leboulanger B, Aubry J, Bondolfi G, Guy R, Delgado-Charro M (2004) Lithium monitoring by reverse iontophoresis in vivo. Clin Chem 50(11):2091–2100
Lee C, Ching CT, Sun T, Tsai C, Huang W, Huang H et al (2010) Non-invasive and transdermal measurement of blood uric acid level in human by electroporation and reverse iontophoresis. Int J Nanomedicine 5:991–997
Liu J, Liu C, Liu H, Jiang L, Yang Q, Cai X (2007) ‘Study of noninvasive sampling of subcutaneous glucose by reverse iontophoresis’, IEEE Service Center, 445 Hoes Lane, PO Box 1331, Piscataway, NJ 08855–1331 USA
Liu R, Wang X, Tang F, Feng Y, Zhou Z (2005) ‘An in-plane microneedles used for sampling and glucose analysis’, Proceedings of 13th International on Solid-State Sensors, Actuators and Microsystems 2:1517–1520
Liu R, Wang X, Feng Y, Wang G, Liu J (2006) ‘Theoretical analytical ow model in hollow microneedles for non-forced uid extraction’, Proceedings of 1st IEEE International Conference on Nano/Micro Engineered and Molecular Systems, pp. 1039–1042
Luttge R, Berenschot EJW, de Boer MJ, Altpeter DM, Vrouwe EX, van den Berg A et al (2007) Integrated lithographic molding for microneedle-based devices. J Microelectromech Syst 16(4):872–884
Madou MJ (1997) Lithography. In: Madou MJ (ed) Fundamentals of microfabrication: the science of miniaturization, 2nd edn. CRC, Boca Raton, pp 1–71
Matriano JA, Cormier M, Johnson J, Young WA et al (2002) Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization. Pharm Res 19(1):63–70
McAllister DV, Allen MG, Prausnitz MR (2000) Microfabricated microneedles for gene and drug delivery. Annu Rev Biomed Eng 2(1):289–313
McAllister DV, Cros F, Davis SP, Matta LM, Prausnitz MR, Allen MG (1999) ‘Three dimensional hollow microneedle and microtube arrays’, Proceedings of 10th International Conference on Solid-State Sensor and Actuators Transducers, pp. 1098–1101.
McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, Prausnitz MR (2003) Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies. PNAS 100:13755–13760
Mikszta JA, Haider MI, Pettis RJ (2006) Microneedle for drug and vaccine delivery: when will the dream become a reality? In: Wille JJ (ed) Skin delivery systems: transdermals, dermatologicals, and cosmetic actives. Blackwell Publishing, Iowa, pp 309–325
Moon SJ, Lee SS, Lee HS, Kwon TH (2005) Fabrication of microneedle array using LIGA and hot embossing process. Microsyst Technol 11(4–5):311–318
Moreno M, Oracle C, Quero J (2008) High-integrated microvalve for Lab-on-chip biomedical applications. In: Proceedings of biomedical circuits and systems conference, pp 313–316
Moreno M, Aracil JC, Quero J (2009) Low cost fluid microextractor for Lab-on-chip. In: Proceedings of Spanish conference on electron devices, pp 274–277
Mukerjee E, Issseroff R, Collins S, Smith R (2003) Microneedle array with integrated microchannels for transdermal sample extraction and in situ analysis. In proceedings of: Transducers, Solid-State Actuators and Microsystems. 12th International Conference on Vol 2. 1440–1441
Mukerjee E, Collins S, Isseroff R, Smith R (2004) Microneedle array for transdermal biological fluid extraction and in situ analysis. Sensors Actuators A Phys 114(2–3):267–275
Nielsen JK, Freckmann G, Kapitza C, Ocvirk G, Caulker KH, Kamecke U et al (2009) Glucose monitoring by microdialysis: performance in a multicentre study. Diabet Med 26(7):714–721
Oka K, Aoyagi S, Arai Y, Isono Y, Hashiguchi G, Fujita H (2002) Fabrication of a micro needle for a trace blood test. Sensors Actuators A Phys 97–98:478–485
Omatsu T, Chujo K, Miyamoto K, Okie M, Nakamura K, Aoki N et al (2010) Metal microneedle fabrication using twisted light with spin. Opt Express 18(17):17967–17973
Paik S et al (2003) Proceedings of the 12th International Conference on Solid-State Sensors, Actuators and Microsystems, Boston, US. IEEE 2:1446–1449
Paik S et al (2004) ‘In-plane single-crystal-silicon microneedles for minimally invasive micro uid systems’, Sens Actuators A Phys A 114:276–284
Park JH, Allen MG, Prausnitz MR (2005) Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release 104:51–66
Peters EE, Ameri M, Wang X, Maa YF, Daddona PE (2012) Erythropoietin-coated ZP-microneedle transdermal system: preclinical formulation, stability, and delivery. Pharm Res 29(6):1–9
Potts R, Tamada J, Tierney M (2002) Glucose monitoring by reverse iontophoresis. Diabetes Metab Res Rev 18(S1):S49–S53
Prausnitz MR (2004) Microneedles for transdermal drug delivery. Adv Drug Deliv Rev 565:581–587
Ramasubramanian MK, Barham OM, Swaminathan V (2008) Mechanics of a mosquito bite with applications to microneedle design. Bioinspir Biomim 3(4):046001
Rapiti E, Prüss-Üstün A, Hutin Y (2005) Sharps injuries: assessing the burden of disease from sharps injuries to health-care at national and local levels, WHO environmental burden of disease series 11. WHO, Geneva
Roxhed N, Griss P, Stemme G (2007) ‘A method for tapered deep reactive ion etching using a modi ed Bosch process’, Journal of Micromechanics and Microengineering 17(5):1087–1092
Roxhed N, Patrick G, Stemme G (2008a) Membrane-sealed hollow microneedles and related administration schemes for transdermal drug delivery. Biomed Microdevices 10:271–279
Roxhed N, Samel B, Nordquist L, Griss P, Stemme G (2008b) Painless drug delivery through microneedle-based transdermal patches featuring active infusion. IEEE Trans Biomed Eng 55:1063–1071
Sato T, Okada S, Hagino K, Asakura Y, Kikkawa Y, Kojima J et al (2011) Measurement of glucose area under the curve using minimally invasive interstitial fluid extraction technology: evaluation of glucose monitoring concepts without blood sampling. Diabetes Technol Ther 13(12):1194–1200
Sieg A, Guy R, Delgado-Charro M (2004) Electroosmosis in transdermal iontophoresis: implications for noninvasive and calibration-free glucose monitoring. Biophys J 87(5):3344–3350
Stoeber B, Liepmann D (2002) Design, fabrication and testing of a MEMS syringe. Presented at the solid-state sensor. Actuator and microsystems workshop, Hilton Head, SC
Sun T, Shieh H, Ching C, Yao Y, Huang S, Liu C (2010) Carbon nanotube composites for glucose biosensor incorporated with reverse iontophoresis function for noninvasive glucose monitoring. Int J Nonacid 5:343–349
Suzuki H, Tokuda T, Kobayashi K (2002) A disposable intelligent mosquito with a reversible sampling mechanism using the volume-phase transition of a gel. Sensors Actuators B Chem 83(1–3):53–59
Suzuki H, Tokuda T, Miyagishi T, Yoshida H, Honda N (2004) A disposable on-line microsystem for continuous sampling and monitoring of glucose. Sensors Actuators B Chem 97(1):90–97
Tayyaba S, Ashraf M, Afzulpurkar N (2011) Blood filtration system for patients with kidney diseases. IET Communications, Manuscript ID COM-2011-0176
Teo AL, Shearwood C, Nga KC, Lu J, Moochhala S (2006) Transdermal microneedles for drug delivery applications. Mater Sci Eng B 132(1–2):151–154
Trzebinski J, Sharma S, Moniz A, Michelakis K, Zhang Y (2012) Microfluidic device to investigate factors affecting performance in biosensors designed for transdermal applications. Lab Chip 12(2):348–352
Tsuchiya K, Jinnin S, Yamamoto H, Uetsuji Y, Nakamachi E (2010) Design and development of a biocompatible painless microneedle by the ion sputtering deposition method. Precis Eng 34(3):461–466
Van der Maaden K, Jiskoot W, Bouwstra J (2012) Microneedle technologies for (trans)dermal drug and vaccine delivery. J Control Release. doi:10.1016/j.jconrel.2012.01.042
Venugopal M, Feuvrel K, Mongin D, Bambot S, Faupel M, Panangadan A (2008) Clinical evaluation of a novel interstitial fluid sensor system for remote continuous alcohol monitoring. IEEE Sensors J 8(1):71–80
Vesper HW, Wang PM, Archibold E, Prausnitz MR, Myers GL (2006) Assessment of trueness of a glucose monitor using interstitial fluid and whole blood as specimen matrix. Diabetes Technol Ther 8:76–80
Vrouwe E, Luttge R (2005) Sampling for point-of-care analysis of lithium in whole blood with chip based CE. Springer, New York
Wang P, Cornwell M, Prausnitz M (2005) Minimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles. Diabetes Technol Ther 7(1):131–141
Wilke N, Mulcahy A, Ye SR, Morrissey A (2005) Process optimization and characterization of silicon microneedles fabricated by wet etch technology. Microelectron J 36:650–656
Windmiller J, Zhou N, Chuang M, Valdes Ramirez G, Santhosh P, Miller P (2011a) Microneedle array-based carbon paste amperometric sensors and biosensors. Analyst 136(9):1846–1851
Windmiller J, Valdes Ramirez G, Zhou N, Zhou M, Miller P (2011b) Bicomponent microneedle array biosensor for minimally-invasive glutamate monitoring. Electroanalysis 23(10):2302–2309
Yung K, Xu Y, Kang C, Liu H, Tam K, Ko S et al (2012) Sharp tipped plastic hollow microneedle array by microinjection moulding. J Micromech Microeng 22:015016
Zahn J, Trebotich D, Liepmann D (2000) Microfabricated microdialysis microneedles for continuous medical monitoring. In: Proceedings of 1st annual international conference on microtechnologies in medicine and biology, pp 375–380
Zahn J, Trebotich D, Liepmann D, Trebotich D, Liepmann D (2005) Microdialysis microneedles for continuous medical monitoring. Biomed Microdevices 7(1):59–69
Zhang P, Jullien G (2003) Micromachined needles for microbiological sample and drug delivery system. In: Proceedings of International Conference on MEMS, NANO and Smart Systems, pp 247–250
Zhang P, Jullien G (2005) Microneedle arrays for drug delivery and fluid extraction. In: Proceedings of International Conference on MEMS, NANO and Smart Systems, pp 392–395
Zimmermann S, Fienbork D, Stoeber B, Flounders AW, Liepmann D (2003) A microneedle-based glucose monitor: fabricated on a wafer-level using in-device enzyme immobilization. The 12th international conference on solid state sensors, Actuators and Microsystems, Boston
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Singh, T.R.R., McMillan, H., Mooney, K., Alkilani, A.Z., Donnelly, R.F. (2017). Fabrication of Microneedles. In: Dragicevic, N., I. Maibach, H. (eds) Percutaneous Penetration Enhancers Physical Methods in Penetration Enhancement. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-53273-7_19
Download citation
DOI: https://doi.org/10.1007/978-3-662-53273-7_19
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-53271-3
Online ISBN: 978-3-662-53273-7
eBook Packages: MedicineMedicine (R0)