Sokic S, Christenson M C, Larson J C, Appel A A, Brey E M, Papavasiliou G
Department of Biomedical Engineering, Illinois Institute of Technology, 3255 South Dearborn Street, Wishnick Hall Room 314, Chicago, IL, 60616-3793, USA. Tel: (312) 567-5959; Fax (312) 567-5770.
Research Service, Hines Veterans Administration Hospital, Hines, IL.
Biomater Sci. 2014 Oct 1;2(10):1343-1354. doi: 10.1039/C4BM00088A. Epub 2014 Jul 7.
Controlled vascular response in scaffolds following implantation remains a significant clinical challenge. A critical biomaterial design criterion is the synchronization of the rates of scaffold degradation and vascularized tissue formation. Matrix metalloproteinases (MMPs) are key enzymes that regulate neovascularization and extracellular matrix remodelling. Synthetic protease-sensitive hydrogels offer controllable environments for investigating the role of matrix degradation on neovascularization. In this study, PEG hydrogels containing MMP-sensitive peptides with increased catalytic activity for MMPs expressed during neovascularization were investigated. Scaffolds were functionalized with MMP-2-, MMP-14- or general collagenase-sensitive peptides and with varying peptide concentration using crosslinkers containing one (SSite) or multiple (TSite) repeats of each protease-sensitive sequence. Increasing peptide concentration enhanced the degradation kinetics of scaffolds functionalized with MMP-specific sequences while 80% of the collagenase-sensitive scaffolds remained upon exposure to MMP-2 and MMP-14. neovascularization was consistent with tissue invasion with significantly increased invasion occurring within SSite MMP-specific as compared to collagenase-sensitive hydrogels and with further invasion in TSite as compared to SSite hydrogels regardless of peptide specificity. All scaffolds supported neovascularization; however, this was not dependent on peptide specificity. These findings demonstrate that peptide concentration and specificity regulate scaffold degradation, neovascularization and matrix remodelling.
植入后支架中可控的血管反应仍然是一个重大的临床挑战。一个关键的生物材料设计标准是支架降解速率与血管化组织形成速率的同步。基质金属蛋白酶（MMPs）是调节新血管形成和细胞外基质重塑的关键酶。合成的蛋白酶敏感水凝胶为研究基质降解在新血管形成中的作用提供了可控环境。在本研究中，对含有对新血管形成过程中表达的MMPs具有增强催化活性的MMP敏感肽的聚乙二醇水凝胶进行了研究。使用含有每个蛋白酶敏感序列的一个（SSite）或多个（TSite）重复序列的交联剂，用MMP-2、MMP-14或一般胶原酶敏感肽对支架进行功能化，并改变肽浓度。增加肽浓度可增强用MMP特异性序列功能化的支架的降解动力学，而80%的胶原酶敏感支架在暴露于MMP-2和MMP-14后仍保留。新血管形成与组织侵袭一致，与胶原酶敏感水凝胶相比，在SSite MMP特异性水凝胶中侵袭显著增加，与SSite水凝胶相比，在TSite水凝胶中侵袭进一步增加，而与肽特异性无关。所有支架都支持新血管形成；然而，这并不依赖于肽特异性。这些发现表明，肽浓度和特异性调节支架降解、新血管形成和基质重塑。
