Advances in Microneedle-Based Therapeutic Platforms For Hypertrophic Scar Repair And Regeneration

Microneedle Review: Innovative Solutions for Hypertrophic Scar Treatment (From Precision Delivery to Skin Regeneration)

Hypertrophic scars are pathological fibrotic outcomes caused by trauma, burns and surgical wounds, affecting more than 20 million new patients worldwide every year. The incidence rate can reach up to 91% after severe burns. Patients usually suffer from persistent itching, pain, skin tightness and limited joint movement, which severely impair physical appearance, mental health and quality of life.

Traditional clinical treatments including compression therapy, local hormone injection, laser therapy and topical anti-scar ointments have obvious limitations. Dense fibrotic scar tissue forms a strong physical barrier that blocks transdermal drug penetration. Local injection leads to uneven drug distribution, skin atrophy and pigmentation disorders. Long treatment cycles and poor patient compliance further restrict therapeutic efficacy. Therefore, minimally invasive, precise and efficient innovative technologies are urgently needed for clinical scar management.

As an emerging minimally invasive transdermal delivery and tissue regulation platform, microneedle (MN) arrays can penetrate dense fibrotic scar tissue accurately, creating reversible microchannels for the targeted delivery and controlled release of small-molecule drugs, proteins, nucleic acids, living cells and exosomes. Microneedle technology fundamentally breaks the penetration bottleneck of traditional scar treatment and provides a novel strategy for precise intervention and functional skin regeneration of hypertrophic scars.

Recently, the research team led by Yiwei Wang and Chenxi Qian from Nanjing University of Chinese Medicine, together with Xin Yan's team from the Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, published an authoritative review in Burns & Trauma, titled Advances in Microneedle Design for the Delivery of Drugs, Proteins and Cells in the Treatment of Hypertrophic Scars. The article systematically summarizes the latest research progress of microneedle applications in hypertrophic scar therapy, demonstrating the evolution of microneedles from a simple physical puncture tool to an intelligent therapeutic platform integrating mechanical regulation, precise delivery, microenvironment remodeling and tissue regeneration.

1. Unique Advantages of Microneedles for Hypertrophic Scar Therapy

Hypertrophic scarring is a progressive and complex fibrotic pathological process rather than simple skin thickening. Its core pathological characteristics include excessive deposition of collagen and fibronectin forming dense physical barriers, continuously elevated mechanical tension activating fibroblast-to-myofibroblast transformation, and high metabolic activity leading to rapid local drug clearance. An ideal therapeutic strategy requires not only efficient drug penetration, but also precise, sustained and multi-dimensional intervention on scar microenvironment and fibrosis signaling.

Microneedle arrays can penetrate the stratum corneum and superficial dermis in a nearly painless and minimally invasive manner, constructing massive microchannels inside dense scar tissue. Compared with topical medications, microneedles significantly improve drug penetration and lesion enrichment. Compared with local injection, microneedle delivery achieves uniform drug distribution, minimal trauma and faster recovery, and can be fabricated into portable patch products for long-term home treatment.

More importantly, microneedles serve as both delivery carriers and mechanical regulators. Micro-invasive puncture precisely modulates mechanical signal transduction in scar tissue, inhibits abnormal fibroblast activation and reverses fibrotic progression. Combined with nanotechnology, photodynamic therapy and responsive materials, microneedles realize multi-target synergistic treatment, achieving refined scar repair that traditional methods cannot accomplish.

2. Microneedle-Mediated Mechanical Stress Regulation for Anti-Fibrosis

Abnormal mechanical tension is a core driving factor of hypertrophic scar formation. Sustained mechanical stress activates fibrosis-related signaling pathways and induces excessive collagen deposition. By optimizing microneedle length, density, hardness and material properties, microneedles can effectively intervene in mechanical crosstalk between cells and extracellular matrix (ECM).

Microneedle treatment significantly downregulates the expression of profibrotic factors including TGF-β1 and α-SMA, and inhibits the abnormal activation of TGF-β/Smad, YAP, MAPK and ILK-PI3K/AKT signaling pathways. It suppresses excessive fibroblast proliferation and myofibroblast transformation, loosens disordered collagen fibers, remodels normal skin mechanical structure, and fundamentally blocks scar hyperplasia progression.

3. Small-Molecule Drug Delivery via Microneedles: Improved Solubility, Sustained Retention and Reduced Side Effects

Small-molecule anti-scar drugs such as triamcinolone acetonide, 5-fluorouracil, losartan and verteporfin are widely used clinically, which inhibit fibrosis by suppressing fibroblast proliferation, inducing apoptosis, reducing collagen synthesis and regulating inflammation. However, poor water solubility, short half-life and repeated administration-induced side effects greatly limit their clinical efficacy.

This review summarizes optimized microneedle delivery strategies to solve the above bottlenecks:

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2. Hierarchical sustained-release structure: Double-layer and core-shell microneedles realize combined rapid anti-inflammation and long-term anti-fibrosis effects. For example, fast-released triamcinolone acetonide and slow-released 5-fluorouracil are loaded hierarchically for full-cycle scar intervention;

3. Multi-technology synergy: Combination with photodynamic therapy, electrical stimulation and stimulus-responsive materials achieves deep, precise and controllable local treatment with reduced systemic side effects.

4. Macromolecule Delivery via Microneedles: Preserved Bioactivity and Enhanced Transdermal Efficiency

Macromolecular therapeutics such as protein drugs feature high targeting, high bioactivity and low toxicity, but their large molecular weight and hydrophilicity lead to extremely low traditional transdermal delivery efficiency and easy denaturation. Microneedle technology provides an optimal delivery solution for bioactive macromolecules.

Representative drugs including interferon, hyaluronidase and recombinant proteoglycan-4 achieve superior therapeutic effects via microneedle delivery. Interferon inhibits fibroblast proliferation and collagen deposition and enhances collagenase activity. Hyaluronidase degrades dense hyaluronic acid matrix in scars, unblocks penetration channels for subsequent drugs and realizes synergistic treatment.

Biocompatible hydrogel materials such as gelatin methacryloyl (GelMA) and carboxymethyl cellulose are adopted to fabricate dissolvable microneedles, which preserve macromolecule bioactivity under mild conditions. The backing layer dissolves rapidly after application, while drug-loaded needle tips remain in scar tissue for sustained release, effectively improving scar thickness, stiffness and pigmentation.

5. Microneedle-Mediated siRNA Delivery: Enhanced Stability and Gene-Level Scar Intervention

siRNA can specifically silence profibrotic genes such as CTGF and TGF-β through RNA interference, intervening in scar formation at the genetic level. Nevertheless, natural siRNA is easily degraded by enzymes, with poor stability and low cellular uptake, restricting clinical transformation.

Microneedle delivery effectively solves these problems. siRNA is compounded with gelatin or tyramine to form nanocomplexes, or encapsulated in mesoporous silica nanoparticles, and then loaded into hyaluronic acid microneedles. This strategy significantly improves siRNA stability, resists enzymatic degradation, prolongs local retention and enhances cellular internalization.

This technology is especially suitable for early postoperative intervention, blocking fibrotic signals at the early stage of scar formation and realizing precise prevention of hypertrophic scars.

6. Cell and Exosome Delivery via Microneedles: From Scar Suppression to Functional Skin Regeneration

Stem cells, immune cells and exosomes have shown great potential in scar repair by regulating inflammation, inhibiting myofibroblast activation and remodeling collagen arrangement. However, poor local retention, insufficient targeting and unstable cell activity limit their practical application.

Microneedle platforms provide cutting-edge solutions for regenerative therapy. PLGA-GelMA core-shell microneedles maintain stem cell viability and achieve targeted local delivery. Keratin-hyaluronic acid composite microneedles co-loaded with adipose stem cell conditioned medium and triamcinolone acetonide realize synergistic anti-inflammation and anti-fibrosis effects. Porous hydrogel microneedles deliver engineered exosomes and gene-edited macrophages to regulate scar immune microenvironment.

Combined with 3D cell spheroid and microfluidic technology, microneedles enable standardized preparation of high-activity cell preparations. The therapeutic goal of microneedles has evolved from simply flattening and softening scars to realizing full functional skin regeneration, including structural reconstruction and accessory organ recovery.

7. Summary, Challenges and Prospects

This systematic review confirms that microneedle technology has evolved from a single transdermal delivery tool into a multi-functional intelligent therapeutic platform integrating physical barrier penetration, mechanical stress regulation, precise multi-drug delivery, immune microenvironment modulation and tissue regeneration. It covers the delivery of small molecules, proteins, siRNA, cells and exosomes, adapting to the whole cycle of scar prevention, early intervention and mature scar repair.

Nevertheless, four core challenges restrict large-scale clinical transformation and industrialization:

• 1. Balance between drug loading and mechanical strength: High drug loading may weaken microneedle rigidity, causing insertion failure or breakage. Novel composite materials and microstructural optimization are urgently required;
• 2. Bioactivity stability: Biomacromolecules, siRNA, cells and exosomes are prone to inactivation during preparation, storage and delivery. Maintaining biological activity while ensuring mechanical performance remains a key bottleneck;
• 3. Individualized treatment deficiency: Scar thickness, hardness, location, maturity and inflammation status vary greatly among individuals. Future development requires AI evaluation, medical imaging and 3D printing to achieve personalized microneedle design;
• 4. Insufficient clinical evidence: Most current studies remain at animal experimental and preliminary exploratory stages. Large-sample, long-term follow-up and randomized controlled clinical trials are lacking for standardized clinical promotion.
• 1. Solubility modification: Cyclodextrin inclusion and nanoparticle loading improve the solubility and drug loading capacity of insoluble drugs while enhancing microneedle mechanical performance;