可生物分解自組裝微胞型殼聚醣水凝膠平台用於中樞神經系統的客製化治療

Abstract

智能型可分解水凝膠（Smart biodegradable hydrogels）因具高含水性、生物相容性與多重環境響應特性（溫度、氧化還原、pH、濕度與光響應等），成為客製化醫材的理想候選材料之一。由天然高分子如殼聚醣、玻尿酸或明膠組成的自癒合水凝膠，可進一步提升生物降解性與相容性。具有異層級結構與刺激響應性的殼聚醣自癒合水凝膠，則特別適合用於原位藥物釋放與組織修復。然而，目前的材料設計仍面臨兩大挑戰：首先，針對多病理階段的疾病（如出血型腦中風），需要將多種藥物同時封裝於水膠網絡中，並達到對應的釋放順序；其次，於3D生物列印應用時，柔軟且具動態特性的化學交聯網絡容易造成列印結構坍塌與應變硬化（strain-stiffening）現象，導致列印解析度下降與細胞受損。因此，設計並調節「結構、功能與性質」之間的平衡，成為發展客製化殼聚醣自癒合水凝膠的核心課題。本研究開發了一款專為中樞神經系統客製化治療設計的可生物分解自組裝微胞型殼聚醣水凝膠平台，透過新型微胞交聯劑建構出異層級網絡結構，賦予該材料快速凝膠、組織黏附與抗自由基等優異的生醫特性。針對具多病理階段的臨床疾病（如腦中風或急性腦損傷），此水凝膠內部的疏水微胞網絡設計使其具備同時包封親水與疏水性藥物並達成異步釋放的能力，精準契合臨時腦部填充物的臨床迫切需求，展現出應用於微創腦手術的前瞻價值。此外，因應3D生物列印技術的發展，本研究亦將水凝膠的微結構與性能分析方法延伸，深入探討並評估其建構3D列印腦組織模塊的可行性。綜上所述，本論文基於此款軟基質異層級自癒合水凝膠進行全面的實驗分析，成功建立一個整合結構鑑定、複雜藥物輸送及腦組織工程應用的多功能創新材料平台。

Smart biodegradable hydrogels are ideal candidates for customized medical devices due to their high water content, biocompatibility, and multi-stimuli responsiveness (e.g., temperature, pH, and redox). Among these, chitosan-based self-healing hydrogels with hierarchical structures are particularly promising for in situ drug delivery and tissue repair. However, developing these materials presents two major challenges. First, treating diseases with multiple pathological stages, such as stroke, requires the simultaneous encapsulation and sequential release of various drugs. Second, in 3D bioprinting applications, the dynamic nature of soft chemical networks often causes structural collapse and strain-stiffening, which compromises printing resolution and cell viability. Thus, balancing "structure, function, and property" is a critical core challenge. To address these issues, this study develops a biodegradable, self-assembling micellar chitosan hydrogel platform tailored for customized central nervous system (CNS) treatments. By utilizing a novel micellar crosslinker, we constructed a hierarchical network that exhibits rapid gelation, tissue adhesion, and free-radical scavenging properties. Crucially, the internal hydrophobic micellar domains enable the co-encapsulation and asynchronous release of both hydrophilic and hydrophobic drugs. This precise capability meets the urgent clinical demands for temporary brain fillers in minimally invasive surgeries. Furthermore, alongside the advancement of 3D bioprinting, we extended our microstructural and performance analyses to evaluate the hydrogel's feasibility for constructing 3D-printed brain tissue modules. Ultimately, this thesis establishes a versatile soft-matrix hydrogel platform that successfully integrates structural characterization, complex drug delivery, and brain tissue engineering applications.