Layered dissolving microneedle containing a three-drug combination on the treatment of hypertrophic scar

Hypertrophic scar (HS), one of the most common types of scars, is often associated with symptoms such as pruritus, contracture, limited joint mobility, deformity, and disfigurement [[1], [2], [3]], causing physical and psychological sequelae that seriously impair the quality of patient life [4].

HS is generally caused by fibroblast hyperproliferation and collagen overproduction due to deep burns, trauma, and acne [[5], [6], [7], [8]]. Currently, various treatments, including surgical resection, radiotherapy, corticosteroid injection, and laser therapy, are used for HS [9,10]. However, these methods do not achieve satisfactory results, and their long-term use may even cause complications in patients. Therefore, it is necessary to develop economic and simple treatment strategies for patients with HS [11,12].

Natural herbal medicines are abundant and show good potential for treating scars. Among them, both Asiaticoside (AS) and ginsenoside are used as drug candidates for the treatment of HS. AS is an active ingredient extracted from the medicinal plant, Centella asiatica, that exerts strong biological effects. AS accelerates the cell cycle, promotes collagen synthesis in fibroblasts [13], prevents scarring by inhibiting inflammation and transforming growth factor (TGF)-β1 secretion, and enhances the activity of SMAD7 (a negative regulator of TGF-β signaling) [14]. Currently, AS is available in China as a commercial drug, including AS tablets and AS cream ointment, AS has been used commonly as a dermatologic agent for the treatment of wound healing and HS [15]. Ginsenoside Rb1, a saponin component of ginseng, promotes wound healing and prevents skin degeneration via multiple pathways. Research has reported that ginsenoside Rb1 inhibits HS in rabbit ears by inhibiting MMP2, TIMP1, α-SMA, and TGF-β1 [16].

However, the poor absorption and low bioavailability of orally administered drugs make the use of medicine often less than ideal for therapeutic effects [17,18]. The compact structure of natural skin barriers such as the stratum corneum and scar tissue limits the penetration and efficiency of herbal medicines for skin diseases [19,20]. Therefore, development of a convenient, effective, and painless treatment method for HS remains challenging.

Microneedles (MNs) are needle-like structures that are typically several hundred microns in length and form micron-sized holes in the skin to enhance drug delivery [21,22]. They do not irritate the nerves associated with pain, thereby increasing patient compliance and reducing their pain [23]. Adjustments and changes in MN geometry and composition can facilitate controlled drugs [24,25]. Dissolving MNs (DMNs) have attracted attention owing to their high biocompatibility and biodegradability, cost-effectiveness, and high drug payload [26].

In this study, DMNs loaded with multi-component drugs for effective HS treatment were designed. Due to its anti-inflammatory and antioxidant effects, L-carnosine is also added as an active ingredient to the needle tip solution of DMNs [27]. Tip layer of DMNs was made of sodium carboxymethyl cellulose (CMC) loaded with AS–GRb1–carnosine (A–G–C), and the base layer was made of low-viscosity CMC to improve the mechanical strength of MNs. Additionally, we investigated the properties of fabricated DMNs, including their physical morphology, puncture properties, and solubility. Histological analysis revealed the mutual enhancement of the therapeutic effects of the three drugs, with the MN group achieving a therapeutic effect comparable to that of the triamcinolone acetonide (TA) injection group.

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