Ulceration is a common symptom of many oral cavity diseases and has various etiologic factors, including heredity, immunity, infection, psychological factors, and systemic disorders [1], [2], [3], [4]. It leads to discomfort and difficulties with swallowing, speaking, and eating, ultimately affecting a patient's quality of life [5]. The primary aim of treatment is to reduce discomfort, accelerate healing, decrease ulcer size, minimize recurrence rates, and prolong the time between episodes. These can be achieved with systemic corticosteroids and immunosuppressants; topical anti-inflammatory, analgesic, and antimicrobial agents; or local drug injections [6]. However, these drug delivery technologies encounter several challenges, including difficulty in crossing the pseudomembrane barrier, the requirement for frequent administration, poor patient compliance, and limited residence time in the oral cavity. Especially, the severe pain caused by local injections can lead to reduced patient compliance and the worsening of chronic pain [7], [8]. Moreover, long-term use of immunosuppressants and oral corticosteroids can result in adverse effects, such as myelosuppression and renal damage [9]. Therefore, a delivery system that can easily pass through the pseudomembrane to ensure sustained drug release is urgently required. This is particularly challenging because of the complex conditions in the oral cavity, such as moisture, saliva washout, as well as movement of the tongue and buccal mucosa during swallowing or speaking. This study aimed to address these challenges and facilitate ulcer healing by investigating innovative medications and improved drug administration methods.

Microneedle is an advanced drug delivery system receiving considerable attention in recent years, which has been used to deliver drugs or vaccines across the oral mucosal barrier for oral mucositis treatment, topical anesthesia, and vaccination [10], [11]. Microneedle patches can penetrate physiological barriers in the oral mucosa and deliver drugs directly into the submucosa [12]. Compared with traditional transmucosal drug delivery systems, microneedle patches can improve drug permeability and achieve effective local or systemic drug delivery [13], [14], [15]. It has the advantages of low cost, convenient use, strong transdermal ability, painless application, and high efficiency, demonstrating significant potential in transdermal drug delivery [16], [17]. Among the various microneedle patches, soluble or degradable microneedle patch is fabricated from cuticle-penetrating materials with good mechanical properties, biocompatibility, and degradability and are more suitable for application in the oral mucosa [18], [19]. Considering this, keratin was selected in this study as the needle tip material loaded with hop extract for antimicrobial and antioxidant activity. Keratin, the main component of wool, hair, nails, hooves, feathers, and horns, is one of the most abundant and underutilized sources of protein [20]. Keratin has good biocompatibility, biodegradability [13], [21], and mechanical strength, and can be applied in various fields, including wound healing, hemostasis, tissue repair, nerve regeneration, and collagen synthesis [22], [23]. Alternatively, to avoid the risk of immunosuppressant and corticosteroid overuse, hop extract is integrated into the needle tips. Hops are medicinal and food homologous plants whose extracts have good biological activities, including antimicrobial, antioxidant, antiviral, antitumor, sedative, and hypnotic properties [24], [25]. Previous reports have confirmed the robust antimicrobial properties of hop extract against common oral pathogens, thereby establishing it as a promising candidate agent for loading into the needle tips [26], [27]. For the backing layers, hyaluronic acid (HA) is chosen, which is a glycosaminoglycan of glucuronic acid N-acetylglucosamine disaccharide with wound-healing ability and has been widely applied in the management of various oral and systemic inflammatory conditions, suitable for the backing layer of microneedle patch [28], [29]. Therefore, microneedle patches prepared based on these materials are envisaged to offer a promising approach to effectively eliminate bacterial infections and promote ulcer healing.

In this study, a keratin and hyaluronic acid-based degradable microneedle patch loaded with hop extract (KMNs@HE) has been developed, aiming for the efficacious treatment of oral ulcer. Innovatively, hop extract was incorporated into keratin as the needle tip while HA was used as the backing layer. The designed microneedle patches exhibited good mechanical properties, biocompatibility, antimicrobial and antioxidant activity, with sustained release profiles. Furthermore, in vivo studies with a rat model of oral ulcers demonstrated that this microneedle patch significantly accelerated oral ulcer healing by ameliorating inflammation and promoting collagen formation, offering a promising therapeutic approach for oral diseases.