Abstract

Pathological scars-encompassing hypertrophic scars (HS)​ and keloids-represent abnormal wound healing responses characterized by excessive fibroblast proliferation and collagen deposition. Conventional therapies (physical, pharmacological, surgical) each carry significant limitations. Intralesional injection via hypodermic needles, while common, suffers from pain, poor patient compliance, uneven drug distribution, and tissue trauma. Microneedles (MNs) have emerged as a transformative transdermal drug delivery system (TDDS)​ that overcomes the stratum corneum barrier, enabling painless, uniform, high-bioavailability​ drug deposition with minimal invasiveness. This article provides a comprehensive review of MN classification, their expanding role in pathological scar management-spanning drug delivery, gene therapy, photodynamic therapy (PDT), and combination strategies-and their emerging potential in early scar prevention.

1. Introduction: The Pathological Scar Challenge

Pathological scars arise when the wound healing cascade veers toward excessive fibrosis. While moderate scarring is a normal reparative response, aberrant signaling transforms it into HS or keloids-conditions that cause functional impairment, disfigurement, pain, and pruritus. Current treatment modalities include physical therapy, pharmacotherapy, biologics, and surgery, but each is constrained by efficacy ceilings or adverse effects.

Pharmacotherapy is favored for its cost-effectiveness and convenience, yet the impermeable stratum corneum severely limits topical drug bioavailability. Intralesional injection bypasses this barrier but introduces needle phobia, injection pain, variable drug spread, and tissue damage. MNs address all these shortcomings: they create uniform microchannels with minimal nociceptor engagement, enable self-administration, and achieve superior drug utilization​ without first-pass metabolism or gastrointestinal degradation.

2. Classification of Microneedles

Based on drug delivery mechanisms, MNs are categorized into five major types:

3. Microneedles in Pathological Scar Treatment

3.1 Drug-Free (Mechanical) MN Therapy

Remarkably, MNs can exert therapeutic effects without any payload-purely through controlled mechanical modulation of skin tissue.

Yeo et al.​ developed a drug-free solid MN array fabricated from liquid crystal polymer (LCP). Tested on a rabbit ear HS model, it achieved 83.3% inhibition of dermal thickening.

Tan et al.​ demonstrated in a controlled trial that sustained use of drug-free solid MNs significantly reduced keloid volume​ and alleviated associated pain and pruritus.

Zhang et al.​ engineered a silk fibroin solid MN​ and identified the underlying mechanism: downregulation of the mechanosensitive gene ANKRD1, indicating reduced fibroblast contractility and mechanical stress. The MN further suppressed the integrin-FAK signaling axis, downregulating TGF-β1, α-SMA, collagen I, and fibronectin-resulting in measurable improvements in scar color, thickness, and hardness.

A comparative study across 7 materials​ (PMMA, PU, PC, PLGA, etc.) in rabbit ears showed all MN groups significantly reduced scar thickness. PMMA MNs inhibited collagen deposition, α-SMA, Ki-67, and TGF-β1 mRNA; PU suppressed collagen, α-SMA, and Ki-67; PC targeted collagen, Ki-67, and TGF-β1; PLGA reduced collagen, α-SMA, and TGF-β1-demonstrating that material selection directly tunes antifibrotic efficacy.

3.2 MN-Assisted Pharmacotherapy

Corticosteroids

Triamcinolone acetonide (TAC)-loaded DMNs effectively reduced scar volume and downregulated TGF-β1 and collagen I.

Decker et al.​ treated 5 burn patients with HS using betamethasone-loaded DMNs; all showed significant reductions in POSAS (Patient and Observer Scar Assessment Scale)​ scores with zero reported pain.

Chen et al.​ delivered compound betamethasone​ via hydrogel MNs in a rabbit model, achieving scar volume reduction, suppression of collagen I/III and TGF-β1, excellent biocompatibility, and controlled release.

Combination: Corticosteroids + Verapamil

Zhang et al.​ co-loaded TAC + verapamil​ (a calcium channel blocker that inhibits inflammation and collagen synthesis) into DMNs. The combination outperformed either drug alone in reducing scar thickness and TGF-β1 expression.

Corticosteroids + Botulinum Toxin A + HA

A clinical study showed that post-intralesional steroid injection, MN-mediated delivery of BoNT-A + hyaluronic acid​ provided synergistic antifibrotic effects while mitigating steroid-induced adverse reactions and reducing keloid recurrence.

5-Fluorouracil (5-FU)

Park et al.​ used CMNs to deliver 5-FU-loaded nanoparticles​ into keloids-demonstrating painless self-administration and effective inhibition of keloid fibroblasts.

A ROS/MMP-responsive MN​ achieved sustained 5-FU release, suppressed fibroblast proliferation, reduced collagen deposition, and remodeled the pathological scar microenvironment​ by scavenging ROS and depleting MMPs.

Yang et al.​ designed a bilayer MN​ with biphasic release: rapid TAC release (phase 1) + sustained 5-FU release (phase 2). This dual-drug system maximized synergy, significantly reducing fibroblast activity, collagen deposition, scar volume, TGF-β1, and collagen I.

Bleomycin

Xie et al.​ developed bleomycin-loaded DMNs that induced fibroblast apoptosis and suppressed TGF-β1. Skin barrier recovery occurred within 3 hours, confirming minimal invasiveness.

Tranilast

Chien et al.​ loaded tranilast​ (an antiallergic with antifibrotic TGF-β1 inhibition) into MNs for rabbit ear HS. Results: reduced scar volume and downregulated TGF-β1, collagen I, and α-SMA-overcoming tranilast's poor solubility and oral toxicity.

Losartan

Huang et al.​ encapsulated losartan​ (oral use limited by hypotension risk) in DMNs, achieving effective inhibition of fibroblast proliferation/migration and downregulation of TGF-β1, IL-6, and collagen I in rabbit models.

Traditional Chinese Medicine (TCM)

Shikonin-DMNs (Ning et al.): suppressed HS fibroblast viability and scar-related protein expression.

Protocatechualdehyde-DMNs (Hao et al.): induced fibroblast apoptosis, reduced collagen, and inhibited angiogenesis.

Gallic acid + Quercetin​ biphasic DMNs (Chen et al.): early GA release delayed proliferation; late QU release scavenged ROS. Together they downregulated scar-related genes and inhibited keloid formation.

3.3 MN-Mediated Gene Therapy

Gene therapy corrects aberrant gene expression, but delivery barriers persist. MNs provide an ideal transdermal conduit.

Meng et al.​ loaded miRNA-modified functionalized exosomes​ into DMNs. The system reduced HS thickness, improved fibroblast distribution and collagen alignment, and downregulated TGF-β2, α-SMA, and p-Smad2/3.

Wang et al.​ embedded TGF-βRⅠ siRNA​ within upconversion nanoparticles (UCNPs)​ inside MNs. Upon near-infrared excitation, siRNA was released into the dermis, silencing target mRNA and inhibiting fibroblast hyperproliferation and collagen overproduction.

3.4 MN-Assisted Photodynamic Therapy (PDT)

PDT efficacy is limited by poor photosensitizer penetration and protective autophagy.

Huang et al.​ combined a hyaluronidase-loaded MN​ (enhancing 5-ALA penetration) with a metformin-loaded MN​ (inhibiting autophagy). The synergy amplified PDT cytotoxicity, reduced scar volume, and downregulated collagen I and TGF-β1.

Chen et al.​ encapsulated a photocatalytic photosensitizer + chloroquine​ (autophagy inhibitor) in high-strength MNs. Direct deep-tissue delivery enhanced ROS generation and antifibrotic effects, validated in rabbit HS models.

3.5 MN Combined with Other Modalities

Ferroptosis-Inducing MN​ (Zhao et al.): Silver nanoclusters and trigonelline encapsulated in ZIF-8 MNs triggered ferroptosis-mediated synergistic HS therapy in rabbit models.

MN + Sonophoresis​ (Yang et al.): Ultrasound-enhanced MN delivery significantly improved drug penetration depth in keloid tissue.

MN + Electroporation​ (Krina et al.): Successfully treated one keloid patient-dramatically enhancing TAC penetration while minimizing pain.

4. Microneedles in Pathological Scar Prevention

Early detection and preemptive intervention are the ultimate goals in scar management. MNs are enabling both.

4.1 Early Detection via MN-Delivered Probes

Miao et al.​ developed a near-infrared fluorescent molecular probe​ activated by FAP-α​ (overexpressed in keloid fibroblasts). MN-assisted delivery enabled precise identification of keloid fibroblasts before full lesion development.

Zheng et al.​ designed a nucleic acid-based molecular probe​ delivered via biodegradable MNs to monitor and regulate CTGF mRNA​ in dermal fibroblasts. Released siRNA suppressed TGF-βRⅠ → reduced CTGF → prevented excessive collagen deposition.

4.2 Prophylactic Gene Silencing

Chun et al.​ created a tyramine-modified gelatin/SPARC siRNA nanocomposite MN. SPARC drives fibrosis via collagen overproduction. This MN silenced SPARC in mouse wound models, reducing collagen deposition during healing without triggering immune responses-effectively preventing pathological scar formation.

5. Summary and Future Perspectives

Microneedle-based delivery systems offer painless, minimally invasive, efficient, safe, and patient-friendly​ solutions for pathological scar management. Existing studies-spanning mechanical modulation, mono/combination pharmacotherapy, gene therapy, PDT, and ferroptosis induction-have established MNs as a versatile, multi-mechanism platform.

However, key challenges remain:

Enhancing mechanical strength​ without compromising biocompatibility

Improving drug loading capacity​ and formulation stability

Achieving spatiotemporally precise release control

Scaling up manufacturing under GMP-compliant​ conditions

Conducting rigorous clinical trials​ to bridge the bench-to-bedside gap

As novel biomaterials, 3D printing, and AI-driven design​ converge, MNs are poised to bring revolutionary change​ to both the treatment and prevention of pathological scars-ushering in an era of truly precision fibrotic disorder management.