痤瘡（Acne vulgaris）是一種慢性發炎性皮膚疾病，主要由丙酸痤瘡桿菌（Cutibacterium acnes，C. acnes）過度生長、皮脂腺分泌旺盛及毛囊角質細胞過度增生等多重因素共同引起。傳統認為痤瘡好發於青春期族群，然而隨著現代生活壓力增加與作息型態改變，心理健康問題與生活品質下降已被證實為痤瘡的誘發或加重因素，使得痤瘡患者的年齡跨度逐漸擴大，成人型痤瘡的發生率亦呈上升趨勢，對患者的身心健康造成不容忽視的影響。雖然傳統外用療法中，以視黃酸類藥物如（阿達帕林，Adapalene）、抗生素及過氧化苯甲醯（Benzoyl Peroxide，BPO）具有一定的治療效果，但長期使用仍面臨諸多限制。外用抗生素的廣泛使用已導致 C. acnes 抗藥性菌株比例持續上升，降低療效並增加臨床治療困難；Adapalene 雖能有效調控角質細胞分化並抑制毛囊過度角化，卻常伴隨脫屑及皮膚刺激等副作用，影響患者的長期用藥順從性；BPO 則具有引發皮膚乾燥與刺激的風險。此外，現有製劑多為單一藥物設計，難以同時兼顧抗菌、抗角化與皮膚微生態平衡等多重治療需求。隨著皮膚微生物群（skin microbiome）研究的深入，痤瘡治療策略已逐漸轉向益生治療（probiotic therapy），著重於強化皮膚共生菌的功能。其中，表皮葡萄球菌（Staphylococcus epidermidis， S. epidermidis）能透過發酵特定碳源產生短鏈脂肪酸（Short-Chain Fatty Acids， SCFAs）、琥珀酸（Succinic acid）等酸性物質，藉由降低皮膚局部 pH 值及直接抑菌機制，有效抑制 C. acnes 的生長，從而維持皮膚微生態的自然拮抗平衡。本研究開發出一種新型複合溫感性水凝膠系統，以六亞甲基二異氰酸酯（Hexamethylene Diisocyanate，HDI）與泊洛沙姆407（Pluronic F127）反應合成之共聚物（HDI-PF127）為主要骨架，並摻入玻尿酸（Hyaluronic Acid， HA）以提升系統的生物相容性與皮膚保濕性能，同時載入Adapalene及聚六亞甲基雙胍（Polyhexamethylene Biguanide， PHMB）作為雙重活性成分。該水凝膠利用 Pluronic F127 之溫感特性，於室溫下呈液態，便於均勻塗抹施用；接觸皮膚後在體溫（約 37 °C）條件下迅速轉變為半固態凝膠，貼附於皮膚表面形成持續給藥之藥物儲庫。HDI 交聯改質進一步強化凝膠之機械強度與結構穩定性，並有效延緩藥物釋放速率，實現 Adapalene 與 PHMB 之持續可控釋放，降低用藥頻率與單次施用劑量。此系統旨在同時達成多重治療目標：透過 PHMB 直接抑制 C. acnes以及藉由 Adapalene 調控角質細胞過度增生與分化；並藉由水凝膠基質提供適合 S. epidermidis 定殖與發酵之微環境，促使酸性物質生成，強化共生菌對病原菌之自然拮抗作用。此整合性治療策略期望在降低抗菌劑與類視黃酸使用劑量的前提下提升整體療效，同時減少皮膚刺激與抗藥性風險，為痤瘡患者提供一種更安全、更有效且兼顧皮膚微生態平衡的新型治療策略。;Acne vulgaris is a chronic inflammatory skin disease primarily caused by the overgrowth of Cutibacterium acnes (C. acnes)， excessive sebaceous gland secretion， and follicular keratinocyte hyperproliferation. Although acne has traditionally been regarded as an adolescent condition， chronic psychological stress and disrupted lifestyle patterns have been increasingly recognized as triggering or exacerbating factors， broadening the affected age range and raising the prevalence of adult-onset acne， with considerable impact on patients′ physical and psychological well-being. Conventional treatments， including topical retinoids (e.g.， Adapalene)， antibiotics， and benzoyl peroxide (BPO)， offer clinical efficacy but are associated with notable limitations. Widespread antibiotic use has driven the emergence of resistant C. acnes strains， compromising treatment outcomes. Adapalene， while effective in regulating keratinocyte differentiation and suppressing follicular hyperkeratinization， frequently causes desquamation and skin irritation， reducing patient adherence. BPO carries additional risks of dryness and irritation. Moreover， most existing formulations target a single mechanism and fail to simultaneously address antibacterial activity， keratinization regulation， and cutaneous microecological balance. Growing understanding of the skin microbiome has shifted therapeutic focus toward probiotic-based strategies. Staphylococcus epidermidis (S. epidermidis)， a key skin commensal， produces short-chain fatty acids (SCFAs) through fermentation of specific carbon sources， suppressing C. acnes growth via local pH reduction and direct antimicrobial action， thereby maintaining the natural antagonistic balance of the skin microecosystem. In this study， a novel composite thermosensitive hydrogel was developed using hexamethylene diisocyanate (HDI)-modified Pluronic F127 (HDI-PF127) as the structural scaffold， incorporating hyaluronic acid (HA) to enhance biocompatibility and moisturization， and co-loading Adapalene and polyhexamethylene biguanide (PHMB) as dual active agents. The hydrogel remains liquid at room temperature for convenient application and undergoes rapid gelation upon contact with skin at physiological temperature (approximately 37 °C)， forming a sustained-release depot. HDI crosslinking reinforces mechanical strength and structural stability， prolonging drug release kinetics and enabling controlled co-delivery of Adapalene and PHMB， thereby reducing dosing frequency and per-application dose. This system simultaneously targets three therapeutic objectives: direct C. acnes inhibition via PHMB; suppression of keratinocyte hyperproliferation via Adapalene; and provision of a microenvironment conducive to S. epidermidis colonization and fermentation， promoting SCFA production and reinforcing commensal-pathogen antagonism. This integrated strategy aims to improve therapeutic efficacy while reducing antimicrobial and retinoid dosage， minimizing skin irritation and resistance risks， and offering a safer， more effective， and microbiome-conscious approach to acne treatment.
