利用積層製造法製備明膠/泊洛沙姆之互穿網路水膠應用於高生物相容性之人工角膜材料

Abstract

本研究開發一種可結合積層製造法(3D列印技術)的生物相容性高分子水膠配方作為仿生人工角膜材料。透過使用泊洛沙姆高分子(Poloxamer 407或P407)做為水膠主要材料。基於泊洛沙姆高分子具有低臨界溶液溫度(lower critical solution temperature, LCST)之特性，其在低溫時能於水互溶，當溶液溫度升高超過LCST時則由液態轉換成凝膠態，故可透過改變溫度從而調整泊洛沙姆水溶液黏度使其可應用於3D列印以客製化製造仿生人工角膜。本實驗透過改質泊洛沙姆高分子使其末端接上丙烯醯基團(P407DA)，讓高分子具有雙鍵，能在紫外光下激發起始劑產生自由基後進行自由基聚合反應形成一個三維的網路結構。利用小角度x光散射實驗(SAXS)，我們可以了解此溶液態/凝膠態的轉化，來自於三嵌段之P407DA高分子的自組裝特性的轉化所產生。 但由於泊洛沙姆水膠的機械強度較弱，不足以達到人工角膜的需求，本實驗透過加入明膠並使其在泊洛沙姆水膠裡交聯形成明膠網路使水膠成為互穿網路(interpenetrating network)系統增加水膠的機械強度。隨後便對水膠進行透光度、含水量、機械強度進行測試，根據水膠的物理試驗之實驗結果評估是否適合作為人眼角膜。隨後利用塗佈明膠包覆水膠增加生物相容性，根據實驗結果發現此水膠具有與人眼角膜相似的物性而且生物相容性方面也有改善，為一具有潛力的仿生人工角膜材料。最後，我利用實驗室製作之3D列印機，以加熱在30°C的溫度，以擠壓之方式將泊洛沙姆水膠/明膠之互穿網路列印成具備有弧度之角膜，並利用調節溫度以減小列印之紋路，因此驗證此類水膠可做為日後利用3D列印的方式製備客製化人工角膜之水膠材料。

In this study, a method to fabricate biocompatible soft artificial cornea hydrogels by using additive manufacturing method, capable of 3D printing corneas with customized biometric, was developed. In order to synergistically maintain the mechanical integrity for building dome-shaped cornea with a soft gel during layer printing and the flexibility of easy adjustment of gel solution formulation for biocompatibility, thermos-reversible hydrogels of Poloxamer triblock copolymer (P407), capable of undergoing a sol-gel transition to exhibit dramatic viscosity variation upon temperature changes, was used as the main material composition. This morphological transition, based on the self-assembling behavior of P407, was investigated by using small-angle x-ray scattering (SAXS) technique. Photosensitive P407 (P407DA) was first synthesized by modifying both of its hydroxyl chain ends with double bonds, preparing for crosslink reaction of the double bonds upon UV light exposure after 3D printing to fixate their final structure with free radical polymerization. For the purpose of further enhancing their mechanical property, transparent corneas with interpenetrating network (IPN) structure were made by mixing various amount of gelatin into P407DA as the final ingredient for 3D printing. The formulation was optimized so that similar sol-gel transition could be preserved to facilitate 3D printing. Afterwards, the IPN hydrogel was tested for its optical transparency, water content, and mechanical strength to compare with those of human cornea. To improve its biocompatibility, the IPN hydrogel was coated on its surfaces with another thin layer of different gelatin types. It was found that the hybrid hydrogels developed in this study had the physical properties similar to those of human cornea and their biocompatibilities were also significantly improved, showing its potential to be used as a future biocompatible artificial corneas for 3D printing manufacturing.