軟骨是以無血管但有緻密胞外基質包覆疏密軟骨細胞所構成的組織，因受限軟骨組織的特性所以在缺損的狀態下難以進行自我修復。目前已有提出許多臨床治療的方式，然而其中卻沒有顯著長期修復的結果。組織工程可針對缺損軟骨或是缺損骨軟骨提供再生的可能性，即便如此，組織工程仍尙有一些挑戰。本研究是以發展可針對不規則的軟骨缺損處以較為優良的方式填入搭載細胞的支架，透過水膠材料聚乙二醇二丙烯酸酯並混和培養兔子脂肪幹細胞，以堆疊製備的方式形成支架，進而將製備完成的支架進行體內和離體系統的評估。
因應發展具備良好生物相容性的支架，透過直徑為3釐米與深度為3釐米的模子建立以光交聯堆疊製備的支架實驗，並以體外培養的方式進行材料的毒性測試試驗。將兔子內皮前驅幹細胞混入已帶有兔子脂肪幹細胞並與位在底部邊側的單層支架進行合成，此目的是要利用具備可令細胞提升分化能力與細胞活性的內皮前驅幹細胞來針對位於疊加製備支架他處的脂肪幹細胞進行刺激提升活性。藉由LIVE/DEAD染色結果可得知，培養至六天之支架內的細胞活性大多可不受光交聯的影響。光交聯過程中所產生會影響細胞毒性的危險因子則是透過ISO 10993-5與ISO 10993-12來評估，藉由3天的細胞存活率分析結果可知其因子對細胞的危害不大。綜合以上體外培養試驗結過發現，該支架的設計可藉由骨軟骨塞模型來發展具備軟骨修復能力的支架。
兩周的離體試驗中，藉由支架搭載不同細胞所設計的支架組別有ADSC組
，EPC/ADSC組以及3T3組。其中主要目的在於釐清並確定位在骨軟骨塞缺損處的內皮前驅幹細胞對於支架內部的脂肪幹細胞軟骨化影響。以上三組的支架堆疊製備形成於直徑為6釐米的骨軟骨塞中心缺損處(直徑為3釐米以及深度為3釐米)。其中較為特別設計的是EPC/ADSC組，骨軟骨塞缺損處靠近骨髓的地方所合成的支架是承載內皮前驅幹細胞，藉由先前已知的體外試驗結果，並結合利用內皮前驅細胞與骨髓間交互作用所產生特有的生物性分子來提升離體培養系統的效性。EPC/ADSC組位在軟骨缺損處的支架則是由承載脂肪幹細胞的支架進行疊加製備填補完成，而其他兩組不論是在骨髓缺損處抑或是軟骨缺損處則是透過承載該組設計使用的細胞，以同前述方式完成填補的製程。從組織染色結果得知，EPC/ADSC組可晚ADSC組一周在軟骨缺損處靠近表層附近發現似纖維軟骨的組織。不論是在第一周或是第二周的組織染色可發現EPC/ADSC組位在靠近缺損軟骨之支架處的脂肪幹細胞均有軟骨化的現象。每組的支架與軟骨組織之力學結合強度是透過Push-out試驗來評估。由力學分析結果與染色結果可知內皮前驅幹細胞可在離體培養一至二周的時間內提供作用，推估期間該細胞可輔助位於軟骨缺損與支架交界處的脂肪幹細胞軟骨化。然而，為期兩周的培養顯示每組支架與軟骨組織之力學結合強度呈現下降的趨勢，但在統計分析無顯著性差異，以上結果分析可支持支架於兩周的培養期間內可維持其穩定性。最後，未來可將此結合脂肪幹細胞並加以堆疊製備而成的支架，透過進階的快速模型製程來達到更加完善的軟骨組織印刷修復之訴求。

The avascular articular cartilage composed of low density chondrocytes embedded within a dense extracellular matrix, so its injury has limited self-repairing ability. Several clinical approaches have been proposed; however, none of them provide outstanding long term healing outcome so far. Tissue engineering provide the possibility to regenerate the damaged cartilage or osteochondral; nevertheless, there are still some challenges in the engineering cartilage. In this study, for better delivery of scaffold with cells to fill the irregular cartilage defect, the layer-by-layer poly (ethylene glycol) diacrylate (PEGDA) scaffold seeded with rabbit adipose-derived stem cells (ADSC) were evaluated in vitro and ex vivo.
To investigate cytotoxic response to photopolymerized PEGDA scaffold, which was combined with rabbit ADSC was fabricated in the layer-by-layer (LBL) fashion, rabbit endothelial progenitor cells (EPC) that were co-cultured with rabbit ADSC were incubated in vitro in the presence of differentiating and proliferating required growth factors for principle of stem cell simulation. The completed scaffold assembly was generated beyond a modified mold with multiple holes (Diameter, 3mm; height, 3mm). In PEGDA scaffold, the life-supporting function for most ADSC was proved through LIVE/DEAD staining after 6 days. The cell viability to photopolymerization was analyzed by MTS assay following the recommended procedures (ISO 10993-5 and ISO 10993-12), and the result has suggested that photocrosslinking process was not the risk factor for cytotoxicity in LBL assembly for 3 days. Taken together, these results showed that such scaffold assembly could have potential of forming repaired cartilage tissue with porcine osteochondral plug (OC plug).
For ex vivo study, the different cell distributions (ADSC, EPC/ADSC, and 3T3) were applied to LBL PEGDA scaffold to help deal with the ADSC chondrogenesis associated with EPC, then each scaffolds developed into 3-mm-diameter cylindrical cartilage defect (Depth, 3mm) in porcine, middle of 6-mm-diameter OC plug and culture ex vivo for 2 weeks. In EPC/ADSC group, the underlying scaffold was especially encapsulated with EPC in order to incorporate former findings into the introduction of bioactive factors from the bone marrow of OC plug in whole culture system. The rest layers combined with ADSC were fabricated by LBL assembly, and the other two groups (ADSC and 3T3 groups) of scaffolds were completely produced as well. According to results of histology, the fibrous-like tissue was appeared to cover the native cartilage in ADSC groups after a week as well as in EPC/ADSC group after two weeks. Under such ex vivo culture system in EPC/ADSC group, the LBL assembly could have the potential of fabricating repaired tissue with enhanced extracellular matrix deposition and structure to lesion site of OC plug for 2 weeks. The shear strength between scaffold and cartilage was examined though push-out test. Interestingly, the findings of histology and mechanical analyze were corroborated the concept that EPC could assist ADSC chondrogenesis, found in the interface of scaffold-cartilage, during the period of 1-2 week. Although the scaffold integrity to cartilage was decreased within each groups during 2 weeks, the statistic results showed that there was no statistical significance of difference. It was demonstrated that the shear strength within each groups was stable during 2 weeks of culture.
In summary, layer-by-layer PEGDA bioscaffold with ADSC can be a promising candidate for tissue engineering application with evenly distributed cell distribution and future cartilage tissue printing by advanced rapid prototyping.

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