小管徑的人工血管(<6釐米)取代通常應用於冠狀動脈旁路移植、周邊血管置換以及洗腎廔管。為了預防小管徑血管置換後再栓塞，自體內乳動脈和隱靜脈通常被拿來當作移植血管。但自體血管的數量和合適的尺寸有限，以及自體靜脈和旁路移植處之間因力學性質的差異而有形成動脈瘤的傾向。因此，合成高分子材料因為可調整的力學性質，例如Dacron和expanded polytetrafluoroethylene (ePTFE)而被用於血管取代移植物。然而因為內壁缺乏完整的內皮化以及順應性的差異導致小管徑高分子材料人工血管取代後的通透性不如預期。所以置備小管徑人工血管的相關研究持續在發展中。而本研究主要設計了有種植脂肪幹細胞的自體生物膜管，並進行兔子頸動脈的取代觀察，以對照力學性質類似人體動脈的合成材料組別，聚乙烯醇(poly(vinyl alcohol), PVA)，並比較兩者在取代1個月及5個月的實驗結果。
1. 自體生物膜管
生物膜管是藉由植入管狀物至皮下後產生自體的人工血管組織。而在本研究中，會在兔子背部皮下植入直徑2毫米的矽膠管1個月。接著在生物膜管上種植脂肪幹細胞，並植入兔子的頸動脈1個月及5個月的時間，觀察脂肪幹細胞是否促進內壁內皮化。兔子犧牲後進行組織切片檢查，以螢光染色分別進行內皮細胞抗體CD31和vWF的觀察以及平滑肌細胞抗體α-SMA以及Myosin Heavy Chain (MHC)的觀察。同時也進行Masson和Van Gieson染色，觀察生物膜管的纖維組織及彈性纖維組織分佈構造。最後，也利用材料拉伸測試機進行生物膜管的力學性質測試。
實驗結果顯示，生物膜管的彈性係數雖然小於頸動脈，但順應性大於頸動脈。另外，在種植脂肪幹細胞的生物膜管植入取代頸動脈的1個月後，從螢光染色結果觀察到脂肪幹細胞開始遷移至內管壁，並開始分化成類內皮細胞。而在5個月後，種植脂肪幹細胞的生物膜管中，內壁有連續排列的類內皮細胞以及管壁中層的平滑肌細胞和彈性纖維組織。然而，沒有種植脂肪幹細胞的生物膜管，觀察在1個月時，縫合處開始有阻塞的狀況發生。
2. 合成材料，聚乙烯醇 (PVA)
聚乙烯醇(PVA)水凝膠具有與人體動脈類似的力學性質，所以被應用於血管移植物。血管內皮生長因子(VEGF)常用於刺激血管內皮細胞的血管生成、增殖和遷移。因此在本研究中，將血管內皮生長因子(VEGF)固定在PVA的內表面，以增強體內內皮細胞的遷移和增殖進而改善合成材料缺乏內壁內皮化的狀況。
在本研究中，7.5％(w/v）的PVA溶液經過三次來回的冷凍-室溫的循環交聯後，製備出內徑2毫米，管壁厚度1毫米的PVA管。然後，利用聚多巴胺將VEGF固定在PVA管的內壁上。接著，將PVA/VEGF管植入兔子的頸動脈進行取代1個月及5個月的時間，並利用超音波系統觀察血管取代的通暢性。
實驗結果顯示，PVA管的彈性係數小於頸動脈，可承受的爆破壓約為165毫米汞柱，並在植入取代1個月及5個月後仍保持通暢。然而，在PVA管的組別中，縫合部位有部分的凝血塊。另外，與植入1個月後的PVA管不同，利用標記內皮細胞的螢光染色中，PVA/VEGF管的內壁觀察到類內皮細胞。但PVA/VEGF管在植入5個月後，內壁上的類內皮細胞的覆蓋率並沒有增加。
比較兩者的實驗結果，生物膜管及PVA管的彈性係數都小於兔子的頸動脈，但順應性都相較於市售的合成材料更接近動脈的順應性。而在血管內皮化的結果中，有種植脂肪幹細胞的生物膜管在取代5個月後，有形成類似動脈的結構，推論在更長期的植入下，可以血管再栓塞的狀況；反之，PVA/VEGF管的管壁內類內皮細胞的螢光表現沒有明顯的增加。在未來，生物膜管可藉由結合生物可降解的材料，增加管壁厚度，進一步進行大型動物的血管取代實驗，觀察在不同動物模型中，血管通透性及內皮化的狀況。

Small-sized vascular replacements (<6 mm) are usually applied in coronary artery bypass, peripheral vascular replacement and dialysis fistula. In order to prevent restenosis after vascular replacement, autologous internal mammary arteries and saphenous veins are often used as donor grafts, but the numbers of suitable donor sites and blood vessels with matching size are limited. Also, autologous grafts from a venous site have a tendency for aneurysm formation because of a difference in mechanical integrity between the donor venous and recipient sites. Therefore, synthetic graft materials, such as Dacron and ePTFE have been considered for vascular replacement due to their ease of tailoring mechanical properties. However, the lack of functional endothelium and a compliance mismatch for small-sized vascular grafts result in a poor patency rate. Therefore, the study designed two types of small-sized vascular grafts, autologous biotube and synthetic poly(vinyl alcohol) graft for their potential applications as vascular graft.
1. Autologous biotube:
Biotube is an in vivo tissue engineered approached to grow autologous graft by implanting a rod subcutaneously. In this study, we embedded 2mm-diameter silicone rod into New Zealand white rabbits’ dorsal subcutaneous to grow biotubes for 4weeks. Then, the formation of functional endothelium alignment on the inner wall surface was accessed by seeding with adipose stem cells (ADSCs). These two groups, biotube and ADSCs-seeded biotube were implanted into the carotid artery for more than 1 month, respectively. The patency rates are observed by angiography, and the remodeling of endothelial cells are observed by the immunofluorescence staining.
The results showed the mechanical properties of biotube could withstand the blood pressure in vivo. On the other hand, the ADSCs started differentiated into endothelial cell in the inner wall surface at 1 month implantation. Moreover, ADSCs-seeded biotube showed patency after 5 months implantation. The fluorescence staining results showed that ADSCs not only differentiated into the endothelial cells but also smooth muscle cells, which fabricated the complete construction of small sized vascular graft. However, the biotube groups were showed occlusion at the suture site after 3 months implantation. It could be speculated that the ADSCs-seeded small sized biotube vascular could decrease the rate of intimal hyperplasia for longer time implantation.

2. Synthetic graft materials, Poly(vinyl alcohol) (PVA)
Poly(vinyl alcohol) (PVA) hydrogel has mechanical properties that are similar to those of human arteries. It has thus been considered for vascular graft. Vascular endothelial growth factor (VEGF) is usually used to stimulate angiogenesis, proliferation and migration of vascular endothelial cells (ECs) in the previous studies. This study immobilized vascular endothelial growth factor (VEGF) on the inner surface of PVA to enhance the migration and proliferation of endothelial cells (ECs) in vivo.
In this study, 7.5% (w/v) PVA was cross-linked via three freeze-thaw cycles to fabricate a PVA graft. Then, polydopamine was used to immobilize VEGF on the inner surface of the PVA graft. The PVA/VEGF graft was implanted in the carotid artery of a rabbit for 1 month. Patency was observed using an ultrasound system.
The results show that the burst pressure of PVA/VEGF was 165 mmHg, and the graft remained patent for 1 month and 5 months post-implantation. However, there was some blood clots at the suture site in PVA graft group. Unlike PVA graft at 1 month post-implantation, EC markers were observed on the PVA/VEGF graft using fluorescence staining. However, the coverage of ECs on the inner surface of PVA/VEGF graft were not increased.

Compared the results of both approaches, the elastic modulus of biotube and PVA graft are smaller than carotid artery. However, the compliance were higher than commercial synthetic materials. For the endothelialization results, ADSCs-seeded biotube was similar to artery structure after 5 months implantation. It speculated that the rate of restenosis would decrease for longer period implantation. Otherwise, the endothelial-like cell couldn’t increase at 5 months post-implantation. Therefore, biotube could combine with biodegradable materials to increase the wall thickness in the future. Further, biotube will implant in large animal models to investigate the patency and endothelialization.

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