Barrier-disrupting microneedle technology: Overcoming physical, physiological, and pathological skin defenses to enhance therapeutic efficacy

Abstract

Microneedles (MNs) have gained increasing attention as an advanced transdermal delivery platform owing to their enhanced delivery performance compared to traditional systems. The key to enhancing MNs efficacy lies in overcoming multiple skin barriers that hinder efficient skin insertion and drug permeation: (1) Physical barriers, such as the tough stratum corneum and skin elasticity, impede complete MN insertion; (2) Physiological barriers, including the extracellular matrix (ECM) and biofilms, limit drug diffusion into deeper skin layers for optimal absorption; (3) Pathological microenvironments lead to uncontrollable drug release and insufficient drug accumulation in target tissue. In this review, we outline strategies to address these barriers for improved therapeutic outcomes. First, we discuss optimization approaches for MN geometry, administration methods, and separation performance to enhance skin penetration efficiency. Next, we explore passive (e.g., hyaluronidase, α-amylase) and active (e.g., light, sound, electricity, magnet, and gas) permeation-enhancing strategies to overcome physiological barriers and boost drug bioavailability. Additionally, we examine the design of stimuli-responsive MNs for on-demand drug release in pathological microenvironments, ensuring precise therapeutic effects. Finally, we analyze the challenges and future prospects of MNs-based delivery systems, providing insights to guide their design and clinical application. This review aims to inspire the development of advanced "microneedle warriors" capable of circumventing multiple skin barriers for enhanced therapeutic efficacy.

Keywords: Drug delivery efficiency; Microneedle; Skin barriers; Skin puncture rate; Transdermal permeability.

Graphical abstract

Fig. 1

(a) Annual publication trends related to MNs over the past two decades, based on data retrieved from the Web of Science database. (b) Main barriers involved in the transdermal drug delivery process of MNs and various strategies used to breach multiple drug delivery barriers.

Fig. 2

(a) Schematic diagram of the geometrics affecting the mechanical performance of MNs. Representative images of MNs with different geometries: (b) cMN, (c) tMN, (d) sqMN, (e) sMN, (f) Candlelit MNs, (g) Obelisk-shaped MN, (h) Turret MN, and (i) MNs with microstructured barbs. Fig. 2(b–e) adapted from Ref. [40] with permission. Fig. 2(f) adapted from Ref. [41] with permission. Fig. 2(g) adapted from Ref. [42] with permission. Fig. 2(h) adapted from Ref. [43] with permission. Fig. 2(i) adapted from Ref. [44] with permission.

Fig. 3

(a) Penetration rate of MNs with different base diameters (a1: 200 μm, a2: 300 μm, a3: 400 μm) and tip-to-tip interspacing in isolated rat skin. Adapted from Ref. [45] with permission. (b) Fracture force of MNs with base diameters of 100 μm and 200 μm. Adapted from Ref. [47] with permission. (c) Effect of tip diameter on the penetration depth of MNs at a certain displacement. Adapted from Ref. [48] with permission (d) Variation in maximum plasma insulin concentration with penetration depth for diverse MN geometries (A: cylindrical, B: conical, C: bevelled, D: rocket, E: arrow, F: wedge). (e) The influence of needle length on normalized pain scores. Fig. 3(d and e) adapted from Ref. [49] with permission.

Fig. 4

Commonly used materials for dissolving MN fabrication and their classification based on mechanical properties. (a) The percentage of each material reported to fabricate dissolving MNs. Fig. 4a was reproduced from Ref. [52] with permission. (b) Typical stress-displacement curves of materials: (b1) weak and brittle materials, (b2) hard and strong materials, (b3) strong and tough materials, (b4) soft and tough materials, and (b5) soft and weak materials.

Fig. 5

(a) Schematic illustration of the GelMA-β-CD synthesis route. (b) Schematic illustration of the MNs fabrication process, including (I) centrifugation, (II) UV crosslinking, and (III) drying followed by removal from the PDMS mold. (c) Strain–displacement curves of MNs subjected to 0, 15, and 30 s of photo-crosslinking. (d) Formation of hydrogen bonding interactions between PVA and GelMA. (e) Stress–displacement curves of MNs fabricated using varying PVA-to-GelMA ratios. Fig. 5(a–e) were reproduced from Ref. [56] with permission. (f) Schematic illustration of IPN hydrogel. (g) Tensile strength of the IPN hydrogel. Fig. 5(f and g) adapted from Ref. [38] with permission.

Fig. 6

Schematic illustration of rapidly separable MNs with different separation mechanism.

Fig. 7

(a) The separation mechanism of MNs with a rapidly dissolving backing. (b) Schematic illustration and separation process of MNs with an effervescent baking. (c) Optical images illustrating the gas generation and separation performance of the R6G separable MNs within 30 s. (d) The separation ratio of R6G MN and R6G separable MNs at different timepoints. (e) Variations in mice blood glucose after treatment with metformin separable MNs and metformin MNs. Fig. 7b–e was reproduced from Ref. [74].

Fig. 8

(a) Schematic illustrating the separation mechanism and fabrication process of MNs with a porous backing layer. (b) Comparison of the skin insertion and detachment ability of MNs with a porous backing and MNs with solid backing. Fig. 8(a and b) were adapted from Ref. [75] with permission. (c) The design and separation mechanism of MNs with air bubble backing. (d) Optical microscope images of MNs with bubble structure. (e) The penetration, detachment, and delivery efficiency of MNs with and without bubble structures. Fig. 8(c–e) were adapted from Ref. [76] with permission. (f) Fluorescence intensity of MNs with and without bubble structures at different timepoints after piercing the skin. Fig. 8(f and g) were adapted from Ref. [77] with permission.

Fig. 9

(a–b) optical microscope image, and (c) fabrication process of separable arrowhead MNs. (d) Drug delivery efficiency into the skin without the application of vibration. (e) Drug delivery efficiency under 1-s vibration stimulation. Fig. 9(a–e) were reproduced from Ref. [72] with permission. (f) Mechanism of rocket MNs separation from the micropillars after applying a shearing force. (g) Optical microscope images of MNs with different micropillars. (h) MNs top views captured before and after administration. (i) Skin insertion success rate and (j) separation rate of MNs with different micropillars. Fig. 9(g–j) were reproduced from Ref. [82] with permission.

Fig. 10

Design and separation mechanism of responsive detachable MNs: (a) Schematic diagram of NIR-activated separable MNs and its separation mechanism. Reproduced from Ref. [85] with permission. (b) Schematic illustrating the separation process of temperature-responsive detachable MNs. Reproduced from Ref. [86] with permission.

Fig. 11

(a) Penetration efficiency of MNs administered with manual insertion and applicator in 15 participants. (b) RSD of penetration efficiencies for different administration per participant. Fig. 11(a and b) adapted from Ref. [89] with permission. (c) Schematic diagram of a latch applicator and its application process. Adapted from Ref. [92] with permission. (d) Comparison of MN insertion force under applied vibration. Adapted from Ref. [93] with permission. (e) Illustration of an applicator with ERM and LRA. (f) Penetration depth of model drugs at different vibration frequencies of LRA and ERM¹⁰⁶¹⁰⁴ [94]. Fig. 11(e and f) were reproduced from Ref. [94] with permission.

Fig. 12

(a) The permeation-enhancing mechanism of hyaluronidase. HMHA and LMHA represents the MNs loaded with high-dose and low-dose hyaluronidase, respectively. (b) Fluoresce distribution in the skin of different formulations. (c) The resultant mean fluorescent intensity of different groups. (d) Pharmacokinetic profiles of sCT from different formulations. Fig. 12(a–d) were reproduced from Ref. [109] with permission. (f) Development of HSPN and PIC co-loaded MNs for synergetic photothermal-immunotherapy of melanoma. Adapted from Ref. [119] with permission. (g) Schematic diagram of the synergistic therapeutic mechanism of α-amylase and PTT. Adapted from Ref. [118] with permission.

Fig. 13

Development of photo-responsive MNs for enhanced drug delivery and therapeutic efficiency: (a) Schematic illustration of photoresponsive MN patches loaded with IL-17 mAbs and Mxene for the treatment of psoriasis; (b) The diffusion distance of the fluorescence probe released from non-irradiated and NIR-irradiated MNs in skin tissue at different time points; (c) Representative images and (d) PASI score of the dorsal skin of the mice receiving different treatments: i) Control, ii) Model, iii) MNs, iv) IL-17 mAb, v) mAb-MNs, vi) mAb-MNs + NIR. Adapted from Ref. [130] with permission.

Fig. 14

Ultrasonic drive and magnetothermal response enhance the drug penetration efficiency: (a) Schematic diagram of dermal drug delivery by nano-bubble ultrasound-responsive MNs; (b) 3D projection of a vertical section of simulated skin (gelatin gel) post MN patch treatment with/without ultrasound; (c) Histology of MN-inserted skin tissues with/without ultrasound treatment; Fig. 14(a–c) were reproduced from Ref. [142] with permission. (d) Diagram of Fe-Se-HA MNs bilayer magnetothermal MNs for the treatment of infected diabetic wounds; (e) NIR images of Fe-Se-HA MNs under 0.5, 1, 5 min treatment of disk-shaped magnetic field; (f) Statistics of wound bacteria in different sample groups; (g) Comparison of wound area ratios among different groups. Fig. 14(d–g) were reproduced from Ref. [144] with permission.

Fig. 15

Electrical stimulation enhances drug delivery efficiency and therapeutic effect of MNs: (a) Diagram of an IBMN device to enable wireless electrostimulation and drug delivery; (b) The representative photographs of the muscle before treatment and after treatments for 5 days and 9 days; (c) The wound depth of the muscle following treatment with or without electrostimulation; Fig. 15(a–c) were reproduced from Ref. [153] with permission. (d) Schematic diagram of the drug delivery mechanism and compositions of c-TDDS; (e) Fluorescence images and (f) resultant fluorescent intensity of the skin treated with t-EMNP at different working voltage. Fig. 15(d–f) were reproduced from Ref. [154] with permission.

Fig. 16

Implementation of iontophoresis and TENGs to improve delivery efficacy and therapeutic effect of MNs: (a) Schematic diagram of wearable iontophoresis-driven MN patch for percutaneous delivery of vaccine; (b) In vitro cumulative OVA release quantity; Fig. 16(a and b) were reproduced from Ref. [158] with permission. (c) Structure diagram of the mD-eMN system for promoting drug uptake and tissue homeostasis reconstitution; (d) Cumulative permeated amount of BM and TAZ across rat skin from mD-MNs and mD-eMNs. Fig. 16(d–f) were reproduced from Ref. [161] with permission.

Fig. 17

(a) Schematic illustration of CO₂-propelled MNs. (b) Comparison of the transdermal permeability of passive MNs and gas-propelled MNs in the isolated rat skin. Fig. 17(a and b) were reproduced from Ref. [171] with permission. (c) Development of NO nanomotor-propelled MNs for AT healing and their therapeutic mechanism. Adapted from Ref. [172] with permission. (d) Development of O₂-propelled MNs for enhanced delivery of Ce6 in the melanoma and antitumor effects. Adapted from Ref. [173] with permission. (e) Schematic diagram of hydrogen-propelled MNs loaded with Mg particles. (f–g) Release profiles of IgG from active MNs compared to passive MNs. Fig. 17(e–g) were reproduced from Ref. [174] with permission.

Fig. 18

Development of responsive MNs for enhanced drug delivery and therapeutic efficiency. (a) Schematic diagram of glucose-responsive MNs for smart management of diabetes. Adapted from Ref. [191] with permission. (b) Schematic diagram of pH-responsive MNs for wound anesthesia. Adapted from Ref. [192] with permission. (c) Schematic diagram of ROS-responsive MNs for acne treatment. Adapted from Ref. [193] with permission. (d) Schematic diagram of dual responsive MNs for management of diabetic wounds. Adapted from Ref. [194] with permission.