Advances of Microneedles in Biomedical Applications

Abstract

A microneedle (MN) is a painless and minimally invasive drug delivery device initially developed in 1976. As microneedle technology evolves, microneedles with different shapes (cone and pyramid) and forms (solid, drug-coated, hollow, dissolvable and hydrogel-based microneedles) have been developed. The main objective of this review is the applications of microneedles in biomedical areas. Firstly, the classifications and manufacturing of microneedle are briefly introduced so that we can learn the advantages and fabrications of different MNs. Secondly, research of microneedles in biomedical therapy such as drug delivery systems, diagnoses of disease, as well as wound repair and cancer therapy are overviewed. Finally, the safety and the vision of the future of MNs are discussed.

Keywords: biomedical application; classification; manufacture; microneedle; pitfalls.

Figure 1

The comparison of skin penetration depths across different drug delivery systems. (Image was reproduced with permission from [2]).

Figure 2

Timeline of microneedle development. The time point listed represented the important events associated with microneedles from the idea of microneedles in 1976.

Figure 3

Keyword literature search of microneedles in Web of Science. The popularity of microneedles has been growing every year from 2000 until now.

Figure 4

Schematic representation of five types of microneedle administration methods. Solid MNs are inserted into the skin and removed, leaving a channel through which the drug enters. Drug-coated MNs are the same as solid MN, except the drug is on the surface of the microneedles. For hollow MNs, after adding pressure, drug is released from the hollow microneedle. For dissolvable MN, when the microneedle substrate is dissolving, the drugs on the tip of the needle are released. When hydrogel-based MNs swell up from absorbing (ISF), the drug is released into the body.

Figure 5

Characteristics of 3 types of microneedles. (A) Diagram (a) and dissolution curve (b) of dissolvable microneedles in mice. (B) Pharmacokinetics of TMN and BMN in mice with different inserting times (a,b) and the comparison of images before and after TMN and BMN are inserted into the skin (from 10 s to 120 s). TMN: traditional microneedle. BMN: bubble microneedle. (C) Schematic diagram of hollow microneedles for blood extraction. (D) Swelling images for hydrogel-based MNs loaded with α-arbutin in porcine skin (ex vivo) and in mice skin (in vivo) at different time points from 30 min to 5 h. (Images were reproduced with the permission from [40,41,43,44]).

Figure 6

Illustration of methods for making microneedles under different conditions. (A) The shape of the microneedle is fixed by heating–cooling thermal controller. (B) Fabrication process of the microneedle mold by UV. (C) Scheme of dual-nozzle spray deposition process. (D) Scheme of producing a personalized microneedle by 3D printing. (Images were reproduced with permission from [55,59,62,63]).

Figure 7

Schematic representation of MNs with small and large molecules in the application of wounds repair, diabetes and tumor therapy.

Figure 8

The number of publications on “microneedles” with different topics.

Figure 9

Schematic diagram of the principle and the wounds by microneedle therapy. (A) Inflammatory responses after microneedle was applied to the skin. (B) Release of SA from SA-IL-MNs. (C,D) Macroscopic images of skin or ileum wounds in DL-MN (double-layer-MN) treated rats. (E) Schematic diagram of the BP-loaded, oxygen-carrying responsive MNs in wound healing. (Images were reproduced with permission from [15,77,86,87]).

Figure 10

Illustration of microneedles for the diagnosis and therapy of diabetes. (A) Illustration of an insulin-releasing microneedle to detect glucose level. (B) Schematic diagram of a microneedle that can be used as a glucose signal amplifier (GSA). (C) Schematic diagram of painless patch for detecting blood sugar by colorimetry. (Images were reproduced with permission from [23,90,91]).

Figure 11

Schematic diagram of indocyanine green-nanoparticle microneedles (ICG-NP MN): preparation and treatment of melanoma cancer. (Images were reproduced with permission from [76]).

Figure 12

Analytical diagrams and schematics of microneedles used for vaccines and biosensors. (A) Enzyme-linked immunosorbent assay (ELISA) analyses of anti-trimer serum IgG responses over time in strong trimeric-specific humoral response maintained by MNs. (B) Procedures of microneedles to extract tissue fluid. (C) Fluvax IgG was captured from immunized mice to a certain extent by microneedles with different surface areas. In (A,C), 2-way ANOVA analysis is applied, and the significant difference is indicated by * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0010, while n.s. indicates no significant difference. (Images were reproduced with permission from [98,101,102]).

Figure 13

(A) Rupture forces of four types of MNs. (B) Rupture stress of four types of MNs. (C) Young’s modulus of four types of MNs. (D) The relationship between PLA MN insertion success rate and insertion times with different heights (600, 700 and 800 μm). (E) Skin irritation and barrier disruption were assessed by TEWL (200S as 200 µm, 300S as 300 µm, 400S as 400 µm). In (A–C), one-way ANOVA analysis is applied, and the significant difference is indicated by * p < 0.05, ** p < 0.01, *** p < 0.001. (Image was reproduced with permission from [111,112,113]).