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An injectable heparin-conjugated hyaluronan scaffold for local delivery of transforming growth factor beta 1 promotes successful chondrogenesis

机译:用于局部递送转化生长因子β1的可注射肝素 - 缀合的透明质石支架促进了促进了骨髓发生的成功

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摘要

Cartilage lacks basic repair mechanisms and thus surgical interventions are necessary to treat lesions. Minimally-invasive arthroscopic procedures require the development of injectable biomaterials to support chondrogenesis of implanted cells. However, most cartilage tissue engineering approaches rely on pre-culture of scaffolds in media containing growth factors (GFs) such as transforming growth factor (TGF)-beta 1, which are crucial for cartilage formation and homeostasis. GFs media-supplementation is incompatible with injectable approaches and has led to a knowledge gap about optimal dose of GFs and release profiles needed to achieve chondrogenesis. This study aims to determine the optimal loading and release kinetics of TGF-beta 1 bound to an engineered GAG hydrogel to promote optimal cartilaginous matrix production in absence of TGF-beta 1 media-supplementation. We show that heparin, a GAG known to bind a wide range of GFs, covalently conjugated to a hyaluronan hydrogel, leads to a sustained release of TGF-beta 1. Using this heparin-conjugated hyaluronan hydrogel, 0.25 to 50 ng TGF-beta 1 per scaffold was loaded and cell viability, proliferation and cartilaginous matrix deposition of the encapsulated chondroprogenitor cells were measured. Excellent chondrogenesis was found when 5 ng TGF-beta 1 per scaffold and higher were used. We also demonstrate the necessity of a sustained release of TGF-beta 1, as no matrix deposition is observed upon a burst release. In conclusion, our biomaterial loaded with an optimal initial dose of 5 ng/scaffold TGF-beta 1 is a promising injectable material for cartilage repair, with potentially increased safety due to the low, locally administered GF dose.
机译:软骨缺乏基本的修复机制,因此手术干预是治疗病变的必要条件。微创关节镜手术需要开发可注射的生物材料以支持植入细胞的软骨发生。然而,大多数软骨组织工程方法依赖于含有生长因子(GFS)的培养基中的支架预培养方法,例如转化生长因子(TGF)-Beta1,这对于软骨形成和稳态至关重要。 GFS介质补充与可注射方法不相容,导致了关于最佳剂量的GFS和释放曲线所​​需的知识差距,以实现有软骨菌。本研究旨在确定TGF-β1与工程GAG水凝胶结合的最佳载荷和释放动力学,以促进在不存在TGF-β1培养基的情况下最佳的软骨基质产生。我们表明肝素,已知粘合着众所周革的GFS,与透明质酸水凝胶共价缀合的GFS,导致TGF-β1的持续释放。使用该肝素 - 缀合的透明质酸水凝胶,0.25至50ng TGF-β1每支架被加载,并测量包封的软骨氢的细胞活力,增殖和软骨基质沉积。当使用每个支架和更高的β1和更高时,发现了优异的软骨发生。我们还证明了TGF-β1的持续释放的必要性,因为在爆发释放时没有观察到基质沉积。总之,我们的生物材料具有5 ng /支架TGF-β1的最佳初始剂量是用于软骨修复的有希望的可注射材料,由于低局部施用的GF剂量,潜在增加的安全性。

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