A Composite Tissue-engineered Aortic Valve Prosthesis

描述（由申请人提供）：主动脉瓣疾病通过用机械或动物组织人工心脏瓣膜置换患病瓣膜进行治疗。不幸的是，这两种设备都不能提供良好的生活质量。组织工程技术提供了无限供应活组织的希望，例如替换心脏瓣膜。传统的组织工程方法包括将细胞接种在可生物降解的基质上，将其植入患者体内，并期望随着基质的缓慢降解而再生新的瓣膜。 到目前为止，这种方法还不是很成功，因为心血管组织很复杂，自我修复的能力很低。我们一直在研究一种我们认为更适合于主动脉瓣的替代方法-在体外用适当的基质分子制造整个小叶的微结构。我们已经能够制造（i）胶原纤维束，直链和支链，（ii）弹性蛋白管和片，和（iii）粘弹性糖胺聚糖（GAG）矩阵。这样的组织工程方法（i）不需要形态复杂的组织的再生长，（ii）提供可以在植入后立即承受心脏负荷的基质，和（iii）可以使用常规工程原理设计和制造。GAG基质基于二乙烯砜交联透明质酸（hylan），胶原纤维束使用定向胶原凝胶收缩制造，弹性蛋白片和管在hylan和胶原纤维束上生长。我们的下一步是（i）改进这些组件的制造工艺，（ii）提高其机械性能，以及（iii）组装组件以生产具有适当机械性能的主动脉瓣尖。为此，我们将（i）利用动态细胞培养来增加基质合成并改善我们构建体的机械性能，以及（ii）使用UV和γ辐照使hylan凝胶质地化以改善细胞渗透和基质粘附。 一旦瓣叶组件的材料性能得到改善，将其组装成复合主动脉瓣尖并进行机械评价。通过本项目，我们的目的是证明，组织工程瓣尖可以通过操纵生物分子在体外使用传统的生物化学和细胞培养方法制造。

DESCRIPTION (provided by applicant): Aortic valve disease is treated by replacing the diseased valve with either a mechanical or an animal tissue-based artificial heart valve. Unfortunately, neither device can provide good quality of life. Tissue engineering technologies offer the promise of a limitless supply of living tissues, such as replacement heart valves. The conventional approach to tissue engineering involves seeding cells on a biodegradable matrix, implanting it into the patient, and expecting a new valve to regrow as the matrix slowly degrades. Thus far, this approach has not been very successful because cardiovascular tissues are complex and have a low capacity for self-repair. We have been working on an alternative approach that we think is more appropriate for the aortic valve - the fabrication of the entire leaflet microstructure in vitro from the appropriate matrix molecules. We have been able to fabricate (i) collagen fiber bundles, both straight and branched, (ii) elastin tubes and sheets, and (iii) a viscoelastic glycosaminoglycan (GAG) matrix. Such an approach to tissue engineering (i) does not require regrowth of morphologically complex tissues, (ii) provides a matrix that can withstand cardiac loads immediately upon implantation, and (iii) can be designed and fabricated using conventional engineering principles. The GAG matrix is based on divinylsulfone-crosslinked hyaluronan (hylan), the collagen fiber bundles are fabricated using directed collagen gel shrinkage, and the elastin sheets and tubes have been grown on both the hylan and the collagen fiber bundles. Our next steps are to (i) improve the fabrication process of each of these components, (ii) improve their mechanical properties, and (iii) assemble the components to produce an aortic valve cusp with the appropriate mechanical properties. To this end we will (i) make use of dynamic cell culture to increase matrix synthesis and improve the mechanical properties of our constructs, and (ii) texturize hylan gels using UV and gamma irradiation to improve cell penetration and matrix adhesion. Once the material properties of the leaflet components are improved, they will be assembled into a composite aortic valve cusp and evaluated mechanically. Through this project, we aim to demonstrate that a tissue engineered valve cusp can be fabricated by manipulating biologic molecules in vitro using conventional biochemical and cell culture methodologies.