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Microbubble Infused Hydrogels for Cartilage Tissue Engineering

用于软骨组织工程的微泡注入水凝胶

基本信息

批准号：
8395972
负责人：
Mark Andrew Borden
金额：
$ 5.98万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2013-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In this potentially high-reward R21 proposal, we explore the novel application of lipid-shelled, gas-filled microbubbles (used clinically as ultrasound contrast agents) as a method for creating cell laden microporous hydogels for cartilage tissue engineering. Rather than classical techniques of porogen leaching (which are often toxic), microbubble dissolution can be triggered "on-demand" by applied hydrostatic pressure or ultrasound. The latter affords unique spatial control of micropore formation in the hydrogel, which we anticipate will promote culture development of mechanically functional, large (anatomically-shaped) engineered cartilage constructs to serve ultimately as clinical alternatives to large allografts or joint implants. The microbubble dissolution process generates micropores that are homogeneously distributed within the gels, while enabling the direct ab initio immobilization of cels within the gels. Importantly, preliminary data demonstrates a 2-fold increase in mechanical properties of chondrocyte-seeded hydrogels with microbubble- derived microporosity versus control gels. This effect is greater than we have observed with applied deformational loading using chondrogenic media. We also have evidence that microbubbles promote more homogeneous axial properties. The proposed research to fabricate patella constructs is guided by these Hypotheses (H) & Specific Aims (SA): H1: Microbubble-infused hydrogel scaffolds exhibit increasing solute permeability in a microbubble dose- dependent manner. SA1. Fabricate chondrocyte-seeded hydrogel constructs with microbubble concentrations yielding initially 25%, 50%, 100% greater permeability of transforming growth factor beta 3 (TGF-23), a critical chemical factor in engineering of functional cartilage, than the hydrogel without microbubbles (0%). Measure solute permeability (P) and material properties including Young's modulus (EY) and dynamic modulus (G*). H2: Chondrocyte-seeded, hydrogel scaffolds incorporated with microbubbles will yield engineered tissues with properties closer to the native tissue compared to the same scaffolds without microbubbles. H2a. The properties of constructs with microbubbles are dependent on timing of microbubble dissolution. H2b. Application of applied dynamic deformational loading enhances the beneficial effects of microbubble-infused hydrogels. SA2a. Using microbubble conditions of SA1 (25%, 50%, 100% increase in TGF-23 permeability), culture constructs for 56 days with triggered dissolution of gas-filled microbubbles on day 0 or day 14. Measure material and biochemical properties, solute permeability, and perform histology on day 0, 14, 28 and 56. SA2b. Repeat SA2a using the best responding groups for microbubbles triggered on day 0 and day 14, but with application of daily dynamic deformational loading (10% deformation at 1 Hz, 3 hours/day).

描述（由申请人提供）：在这一潜在的高回报R21提案中，我们探索了脂质壳的充气微泡（临床上用作超声造影剂）作为用于软骨组织工程的细胞负载微孔水凝胶的方法的新应用。与致孔剂浸出的经典技术（其通常是有毒的）不同，微泡溶解可以通过施加的流体静压力或超声“按需”触发。后者提供了独特的空间控制水凝胶中的软骨形成，我们预计这将促进机械功能，大型（解剖形状）工程化软骨结构的培养发展，最终作为大型同种异体移植物或关节植入物的临床替代品。微泡溶解过程产生均匀分布在凝胶内的微孔，同时使得能够在凝胶内直接从头固定化α-淀粉。重要的是，初步数据表明，与对照凝胶相比，具有微泡衍生的微孔性的软骨细胞接种的水凝胶的机械性质增加了2倍。这种效应大于我们在使用软骨形成介质施加变形载荷时观察到的效应。我们也有证据表明，微泡促进更均匀的轴向性能。提出的制造髌骨结构的研究由这些假设（H）和特定目的（SA）指导：H1：微泡灌注的水凝胶支架以微泡剂量依赖性方式表现出增加的溶质渗透性。SA 1.制造具有微泡浓度的软骨细胞接种的水凝胶构建体，与没有微泡的水凝胶（0%）相比，最初产生25%、50%、100%更高的转化生长因子β 3（TGF-23）渗透性，TGF-23是功能性软骨工程中的关键化学因子。测量溶质渗透率（P）和材料特性，包括杨氏模量（EY）和动态模量（G*）。H2：与没有微泡的相同支架相比，软骨细胞接种的水凝胶支架与微泡结合将产生具有更接近天然组织的性质的工程化组织。H2a。具有微泡的结构的性质取决于微泡溶解的时间。H2b。施加的动态变形载荷的应用增强了注入微泡的水凝胶的有益效果。SA2a。使用SA 1的微泡条件（TGF-23渗透性增加25%、50%、100%），培养构建体56天，在第0天或第14天触发充气微泡的溶解。在第0、14、28和56天测量材料和生化性质、溶质渗透性并进行组织学检查。SA2b.对于在第0天和第14天触发的微泡，使用最佳响应组重复SA 2a，但是施加每日动态变形负荷（在1Hz下10%变形，3小时/天）。