A Comprehensive Review of Microneedles: Types, Materials, Processes, Characterizations and Applications

Abstract

Drug delivery through the skin offers many advantages such as avoidance of hepatic first-pass metabolism, maintenance of steady plasma concentration, safety, and compliance over oral or parenteral pathways. However, the biggest challenge for transdermal delivery is that only a limited number of potent drugs with ideal physicochemical properties can passively diffuse and intercellularly permeate through skin barriers and achieve therapeutic concentration by this route. Significant efforts have been made toward the development of approaches to enhance transdermal permeation of the drugs. Among them, microneedles represent one of the microscale physical enhancement methods that greatly expand the spectrum of drugs for transdermal and intradermal delivery. Microneedles typically measure 0.1-1 mm in length. In this review, microneedle materials, fabrication routes, characterization techniques, and applications for transdermal delivery are discussed. A variety of materials such as silicon, stainless steel, and polymers have been used to fabricate solid, coated, hollow, or dissolvable microneedles. Their implications for transdermal drug delivery have been discussed extensively. However, there remain challenges with sustained delivery, efficacy, cost-effective fabrication, and large-scale manufacturing. This review discusses different modes of characterization and the gaps in manufacturing technologies associated with microneedles. This review also discusses their potential impact on drug delivery, vaccine delivery, disease diagnostic, and cosmetics applications.

Keywords: 3D printing; advanced manufacturing; characterization; drug delivery; microneedle; polymers; therapeutics; transdermal.

Figure 1

Different types of transdermal drug delivery systems [16]. Reprinted from Biomedicine & Pharmacotherapy, Vol. 109, Tejashree Waghule et al., Microneedles: A smart approach and increasing potential for transdermal drug delivery system, Pages 1249–1258, Copyright (2019), with permission from Elsevier.

Figure 2

(a) Schematic illustration of the human skin. (b) First-generation transdermal drug delivery technology via natural diffusion of drugs. (c) Second-generation transdermal drug delivery technology for actuated drug delivery via external stimulation. (d) Third-generation transdermal drug delivery technology for enhanced drug transport via microneedle-mediated destruction of skin layer and various functionalities accompanying microneedles. (e) Fourth-generation transdermal drug delivery technology for patient-customized therapy with the assistance of wearable devices [18]. Reprinted from Advanced drug delivery reviews, Vol. 127, Hyunjae Lee et al., Device-assisted transdermal drug delivery, Pages 35–45, Copyright (2018), with permission from Elsevier.

Figure 3

Current microneedle devices (single needle with applicator, microneedles array patch, microneedles pen, microneedle pump patch, and microneedle roller) [36]. Reprinted from Emerging nanotechnologies for diagnostics, drug delivery and medical devices, Rubi Mahato, Microneedles in Drug Delivery, 331–353, Copyright (2017), with permission from Elsevier.

Figure 4

Historic timeline for MN technologies.

Figure 5

Different types of microneedles: (a) Solid microneedles with a poke with patch approach are used for pre-treatment of the skin. (b) Coated microneedles use the coat and poke approach, where a coating of the drug solution is applied on the needle surface. (c) Dissolving microneedles are made of biodegradable polymers. (d) Hollow microneedles are filled with the drug solution and deposit the drug in the dermis [16]. Reprinted from Biomedicine & Pharmacotherapy, Vol. 109, Tejashree Waghule et al., Microneedles: A smart approach and increasing potential for transdermal drug delivery system, Pages 1249–1258, Copyright (2019), with permission from Elsevier.

Figure 6

Solid microneedles made of (a–d) silicon, (e–h) metals and (i–l) polymer [41]. Reprinted from Advanced Drug Delivery Reviews, Vol. 64, Yeu-Chun Kim et al., Microneedles for drug and vaccine delivery, Pages 1547–1568, Copyright (2012), with permission from Elsevier.

Figure 7

Hollow microneedles fabricated out of silicon, metal, and glass imaged by optical and scanning electron microscopy. (A) Straight-walled metal microneedle from a 100-needle array fabricated by electrodeposition onto a polymer mold (200 μm tall). (B) Tip of a tapered, beveled, glass microneedle made by conventional micropipette puller (900 μm length shown). (C) Tapered, metal microneedle (500 μm tall) from a 37-needle array made by electrodeposition onto a polymeric mold. (D) Array of tapered metal microneedles (500 μm height) shown next to the tip of a 26-gauge hypodermic needle [74]. Reproduced with permission from Devin V. McAllister et al., Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies; published by National Academy of Sciences, 2003.

Figure 8

Fabrication of the coated polymer MNs: (A) A schematic diagram of the process to fabricate the coated polymer MNs. The coated polymer MNs were fabricated by (I) covering up the surface of the polydimethylsiloxane (PDMS) cavities with heated and melted PLA, (II) filling the mold cavities with melted PLA, (III) exerting pressure on the melted PLA and cooling it down to room temperature, (IV) dipping the coating solution using PLA MNs, and (V) drying the coated polymer MNs. Image (A1) is an image of the 650 μm long PLA MNs. Image (A2) is an image of the 650 μm long MNs coated with formulation III. Image (B) is a schematic diagram of the adjustable apparatus that can be lifted and lowered. Image (B1) shows the portable holder with the PLA MNs descending into the reservoir. Image (B2) shows the PLA MNs dipped in the coating solution, and image (B3) shows the portable holder rising from the reservoir [79]. Reprinted from Journal of Controlled Release, Vol. 265, Yang Chen et al., Fabrication of coated polymer MNs for transdermal drug delivery, Pages 14–21, Copyright (2017), with permission from Elsevier.

Figure 9

Schematic illustration of the process to fabricate the tip-loaded fast-dissolving HA MN patch [84]. Reprinted from Journal of Controlled Release, Vol. 286, Xiao Zhao et al., Tip-loaded fast-dissolving MN patches for photodynamic therapy of subcutaneous tumor, Pages 201–209, Copyright (2018), with permission from Elsevier.

Figure 10

Yield strength vs. Young’s modulus of different materials used for the fabrication of MNs. Plastics: PC, Epoxy, PMMA, PGA, PLA. Metals and alloys: nickel, stainless steel, tantalum, and nickel–titanium. Ceramics: alumina and silicon. Chitison and Borosilicate glass [99]. Reprinted (adapted) with permission from (Cahill, Ellen M., and Eoin D. O’Cearbhaill. “Toward biofunctional MNs for stimulus responsive drug delivery.” Bioconjugate chemistry 26, no. 7 (2015): 1289–1296). Copyright © 2021, American Chemical Society.

Figure 11

Fabrication of MN mold: (a) CO₂ laser cutter was used to fabricate MN acrylic mold using the proposed cross-over lines (COL) technique. (b) The acrylic mold was used to fabricate polydimethylsiloxane (PDMS) MNs mold, which can be used to fabricate a variety of polymer-based MNs [125]. Reproduced with permission from Hojatollah Rezaei Nejad et al., Low-cost and cleanroom-free fabrication of MNs; published by Springer Nature, 2018.

Figure 12

Drawing lithography to produce a 3D UHAR MN. The inset shows a drawing system with patterned pillars for drawing lithography. Stainless drills with a diameter of 200mm and a length of 3 mm were used as pillars and fixed in a 3 × 3 array on a PDMS frame. (a) The SU-8 2050 photoresist was spin coated and cooled. (b) After the photoresist contacted the patterned pillar, drawing lithography was performed. (c) Drawing caused the appearance of an extended conical-shaped bridge between the substrate and pillar. (d) The desired UHAR micro-needle mold was cured to generate a rigid structure. (e) The separation of the 3D microstructure bridge produced a solid MN mold. (f) Chemical deposition on the solid MN molds. (g) The upper portion of the MN mold was coated with electroless material using a drawing system. (h) Nickel electroplating on conducted solid MN molds. (i) The hollow metallic MN array was created upon elimination of the electroless protection and the photoresist MN mold [145]. Reproduced with permission from Kwang Lee et al., Drawing Lithography: Three-Dimensional Fabrication of an Ultrahigh-Aspect-Ratio MN; published by John Wiley and Sons, 2010. Copyright © 2021 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 13

Schematic fabrication process of multilayer MNs: (A) Aluminum master fabrication using micro-milling. (B) Replication of PDMS mold from the master. (C) Fabrication of PLA master by micromolding and tip-sharpening using oxygen plasma. (D) Replication of PDMS mold from the PLA master. (E) Spray deposition of drug-containing polymer solution to fill the mold cavity. Multilayer MN is formed by sequential deposition of polymer solutions. (F) Application of backing material (yellow) on the mold and drying at room temperature for polymer solidification. (G) Demolding solidified multilayer MN array from the mold. Green and red represent PLGA and PVP layers, respectively [147]. Reproduced with permission from Min Jung Kim et al., Fabrication of Circular Obelisk-Type Multilayer MNs Using Micro-Milling and Spray Deposition; published by Frontiers in Bioengineering and Biotechnology, 2018.

Figure 14

Process steps of standard injection molding and step-and-repeat hot embossing [152]. Reproduced with permission from Herwig Juster et al., A review on microfabrication of thermoplastic polymer-based MN arrays; published by John Wiley and Sons, 2019. copyright © 2021 Society of Plastics Engineers.

Figure 15

Overview of “Print and Fill” fabrication method: (a) Needle array basin design followed by 3D printing of the design using a Form 2 SLA printer. (b) MNA master mold fabrication method (i) take 3D printed needle array basin; (ii) washing followed by UV curing and baking of printed needle array basin; (iii) filing of needle array basin with UV-curable resin; (iv) second UV curing and baking; (v) obtain MNA master; (vi) silicone casting of MNA master; (vii) silicone mold is degassed followed by heat cure in oven; (viii) demolding to obtain usable MN mold [63]. Reproduced with permission from Kevin J. Krieger et al., Simple and customizable method for fabrication of high-aspect ratio MN molds using low-cost 3D printing; published by Springer Nature, 2019.

Figure 16

(A) Digital photograph of SA MN pressed against the metal mill during axial fracture force measurement with the micromechanical tester (Instron^® Model 5969; Instron, Norwood, MA). (B) MN shafts were transversely pressed against the metal mill for measurement of the transverse fracture force by way of the micromechanical tester (Instron^® Model 5969, Instron, Norwood, MA) [80]. Reproduced with permission from Demir et al., Characterization of Polymeric MN Arrays for Transdermal Drug Delivery; published by PLoS One, 2013.

Figure 17

Microscopy images and histological examinations of hairy and hairless pig cadaver skin: (a) Hairless pig cadaver skin before DMN insertion. (b) 50 μm insertion of 600 μm tall DMN. The DMN was inserted 650 μm deep into the skin. (c) The base area of the DMN that was inserted 100 μm deep was less apparent on the skin surface compared with those inserted 50 μm deep. Histological examination showed that the DMNs were inserted 700 μm deep into the skin. (d) Hairy pig cadaver skin before DMN insertion. (e) The appearance of DMNs inserted 50 μm deep into hairy skin was similar to the appearance of DMNs inserted into hairless pig cadaver skin. (f) DMNs inserted 100 μm deep into the hairy pig cadaver skin penetrated 700 μm deep. Scale bars: microscopy images, 2 mm; histological images, 500 μm [175]. Reproduced with permission from Shayan F. Lahiji et al., A patchless dissolving MN delivery system enabling rapid and efficient transdermal drug delivery; published by Springer Nature, 2015.

Figure 18

In vivo skin penetration study: (A) Troy MNs were assembled with an applicator into an array (5 × 5). (B) The applicator was applied to rat dorsal skin vertically by hand. (C) Image of skin with applied Troy MNs. The array of red spots indicates the penetrated site of rhodamine B-encapsulated Troy MNs and the white dotted line represents the vertically sliced line used to obtain sectional tissue. (D) Skin sectional image. Red spots mark delivered rhodamine B in the skin and the white arrow indicates undissolved parts of DMNs. Scale bars, 10 mm (A,B) and 1.0 mm (C,D) [176]. Reproduced with permission from Kim et al., The Troy MN: A Rapidly Separating, Dissolving MN Formed by Cyclic Contact and Drying on the Pillar (CCDP); published by PLoS One, 2013.

Figure 19

Faster hair re-growth at 1 week noted in Microneedling treated group [215]. Reproduced with permission from Rachita Dhurat et al., A Randomized Evaluator Blinded Study of Effect of Microneedling in Androgenetic Alopecia: A Pilot Study; published by International Journal of Trichology, 2013.