Department of Biomedical and Applied Sciences, Indiana University School of Dentistry, Indianapolis, IN 46202, United States of America.
Biomed Mater. 2019 Feb 27;14(2):025015. doi: 10.1088/1748-605X/aafffa.
Pyk2 is a non-receptor tyrosine kinase that belongs to the family of focal adhesion kinases. Studies from our laboratory and others demonstrated that mice lacking the Pyk2 gene (Ptk2B) have high bone mass, which was due to increased osteoblast activity, as well as decreased osteoclast activity. It was previously reported that a chemical inhibitor that targets both Pyk2 and its homolog FAK, led to increased bone formation in ovariectomized rats. In the current study, we developed a hydrogel containing poly(ethylene glycol) diacrylate (PEGDA) and gelatin which was curable by visible-light and was suitable for the delivery of small molecules, including a Pyk2-targeted chemical inhibitor. We characterized several critical properties of the hydrogel, including viscosity, gelation time, swelling, degradation, and drug release behavior. We found that a hydrogel composed of PEGDA1000 plus 10% gelatin (P1000:G10) exhibited Bingham fluid behavior that can resist free flowing before in situ polymerization, making it suitable for use as an injectable carrier in open wound applications. The P1000:G10 hydrogel was cytocompatible and displayed a more delayed drug release behavior than other hydrogels we tested. Importantly, the Pyk2-inhibitor-hydrogel retained its inhibitory activity against the Pyk2 tyrosine kinase, and promoted osteoblast activity and mineral deposition in vitro. Overall, our findings suggest that a Pyk2-inhibitor based hydrogel may be suitable for the treatment of craniofacial and appendicular skeletal defects and targeted bone regeneration.
Pyk2 是一种非受体酪氨酸激酶，属于粘着斑激酶家族。我们实验室和其他实验室的研究表明，缺乏 Pyk2 基因（Ptk2B）的小鼠骨量增加，这是由于成骨细胞活性增加，以及破骨细胞活性降低所致。先前有报道称，一种针对 Pyk2 和其同源物 FAK 的化学抑制剂可导致去卵巢大鼠骨形成增加。在本研究中，我们开发了一种含有聚乙二醇二丙烯酸酯（PEGDA）和明胶的水凝胶，该水凝胶可通过可见光固化，适用于小分子的递送，包括针对 Pyk2 的化学抑制剂。我们对水凝胶的几个关键性质进行了表征，包括粘度、凝胶时间、溶胀、降解和药物释放行为。我们发现，由 PEGDA1000 加 10%明胶（P1000:G10）组成的水凝胶表现出宾汉流体行为，在原位聚合之前可以抵抗自由流动，使其适合用作开放性伤口应用中的可注射载体。P1000:G10 水凝胶具有细胞相容性，并表现出比我们测试的其他水凝胶更延迟的药物释放行为。重要的是，Pyk2 抑制剂水凝胶保留了其对 Pyk2 酪氨酸激酶的抑制活性，并在体外促进成骨细胞活性和矿化沉积。总体而言，我们的研究结果表明，基于 Pyk2 抑制剂的水凝胶可能适用于治疗颅面和四肢骨骼缺陷和靶向骨再生。
