Microneedle arrays for the treatment of chronic wounds

Abstract

Introduction: Chronic wounds are seen frequently in diabetic and bedbound patients. Such skin injuries, which do not heal in a timely fashion, can lead to life-threatening conditions. In an effort to resolve the burdens of chronic wounds, numerous investigations have explored the efficacy of various therapeutics on wound healing. Therapeutics can be topically delivered to cutaneous wounds to reduce the complications associated with systemic drug delivery because the compromised skin barrier is not expected to negatively affect drug distribution. However, researchers have recently demonstrated that the complex environment of chronic wounds could lower the localized availability of the applied therapeutics. Microneedle arrays (MNAs) can be exploited to enhance delivery efficiency and consequently improved healing.

Areas covered: In this review, we briefly describe the pathophysiology of chronic wounds and current treatment strategies. We further introduce methods and materials commonly used for the fabrication of MNAs. Subsequently, the studies demonstrating the benefits of MNAs in wound care are highlighted.

Expert opinion: Microneedles have great potential to treat the complicated pathophysiology of chronic wounds. Challenges that will need to be addressed include development of a robust chronic wound model and MNAs that combine complex functionality with simplicity of use.

Keywords: Microneedle arrays; intradermal drug delivery; microfabrication; wound healing.

Figure 1.

Common materials and fabrication technologies used for development of MNAs in biomedical applications. (A) Solid[66] and (B) hollow[67] silicon MNAs fabricated using reactive ion etching. (C) Glass microneedles fabricated by micro-pulling fire-polished borosilicate glass pipettes[68]. Inset shows the assembled microneedles in an MNA. (D) Al₂O₃ ceramic MNAs fabricated by micromolding[69]. Inset demonstrates their porous structure. (E) Metal MNAs fabricated by assembly of 31 G stainless steel needless on a polystyrene support backing layer[70]. (F) Methacrylated hyaluronic acid MNAs fabricated by molding precursor followed by UV crosslinking[71]. Inset shows a patch consisting of a 10x10 array of these microneedles. (G) Complex-shaped polymeric MNAs fabricated out of PEGDA using an improved photolithography approach[72]. (H) Long SU-8 MNAs produced by drawing lithography[73]. (I) 3D printed resin-based flexible MNAs using an FDM approach[12]. (J) Polymeric microneedles fabricated using SLA printing (left) followed by inkjet printing of drug loaded polymer coating (right)[74]. (K) PEGDA MNAs with backward-facing barbs fabricated using DLP-based 3D printing for improved adhesion[71]. (L) High resolution MNAs with sharp tips fabricated using TPP[75]. Subfigures were reproduced with permission from National Academy of Sciences[66] (Copyright (2003) National Academy of Sciences, U.S.A.), Elsevier[68,69,74], Public Library of Science[70], Wiley[12,71,73], and Nature[67,72,75] publishing groups.

Figure 2.

Stem-cell laden hydrogel MNAs for enhanced wound healing. (A) The core-shell structure of MNAs offer high mechanical strength for facile insertion as well as cell-favorable scaffolding material for preserving the functionality of stem-cells. (B) The mechanism of MNA-based stem cell delivery action for enhanced regeneration. (C) Improved wound healing characterized by enhanced wound closure and re-epithelialization. (D) Enhanced wound bed angiogenesis as a result of MNA-based stem cell delivery. Reproduced with permission from Wiley[95].

Figure 3.

Active MNA-based drug delivery systems for treatment of diabetic wounds. (A-E) On demand delivery of oxygen into the wound bed using NIR exposure-responsive MNAs[111]. (A) The MNA patch mechanism of action. (B) Molded microneedles (top) and their drug loading capability demonstrated through encapsulation of fluorescent-labeled protein (bottom). The effect of oxygen delivery using the proposed strategy on healing of wounded diabetic rats, indicated by the thickness of regenerated (C) granulation tissue and (D) epithelium, as well as (E) level of angiogenesis. (F-H) Controlled pumping of therapeutics through hollow MNAs into the wound bed using a POC system[12]. (F) A microfluidic flexible patch integrated with MNAs for distribution of various drugs in the wound bed. Inset shows an SEM image of 3D printed hollow microneedles. (G) The pumping system wirelessly controlled by a smartphone to enable on-demand delivery of therapeutics. (H) Enhanced healing of wounds in diabetic mice through MNA-based intradermal delivery of VEGF. Reproduced with permission from American Chemical Society[111] and Wiley[12].

Figure 4.

MNA-based smart drug delivery for improved wound healing. (A-D) Antibacterial and thermo-responsive MNAs[107]. (A) The mechanism of VEGF release into the wound bed upon temperature increase during wound inflammation. (B) MNA fabricated by molding chitosan followed by impregnation of VEGF-loaded NIPAM. (C) Antibacterial properties of chitosan. (D) Infected wound healing in rats through the application of the developed smart MNA bandage. (E-G) Bacteria-responsive MNA system for treatment of infected wounds[109]. (E) The MNA patch mechanism of action. (F) Fabricated MNA (top) loaded with fluorescent-labeled drugs (bottom). (G) Application of smart system for elimination of bacterial biofilms. Reproduced with permission from Elsevier[107] and American Chemical Society[109].