title: Nanoparticulate delivery of agents for induced elastogenesis in three-dimensional collagenous matrices.
abstract: The degradation of elastic matrix in the infrarenal aortic wall is a critical parameter underlying the formation and progression of abdominal aortic aneurysms. It is mediated by the chronic overexpression of matrix metalloprotease (MMP)-2 and MMP-9, leading to a progressive loss of elasticity and weakening of the aortic wall. Delivery of therapeutic agents to inhibit MMPs, while concurrently coaxing cell-based regenerative repair of the elastic matrix represents a potential strategy for slowing or arresting abdominal aortic aneurysm growth. Previous studies have demonstrated elastogenic induction of healthy and aneurysmal aortic smooth muscle cells and inhibition of MMPs, following exogenous delivery of elastogenic factors such as transforming growth factor (TGF)-β1, as well as MMP-inhibitors such as doxycycline (DOX) in two-dimensional culture. Based on these findings, and others that demonstrated elastogenic benefits of nanoparticulate delivery of these agents in two-dimensional culture, poly(lactide-co-glycolide) nanoparticles were developed for localized, controlled and sustained delivery of DOX and TGF-β1 to human aortic smooth muscle cells within a three-dimensional gels of type I collagen, which closely simulate the arterial tissue microenvironment. DOX and TGF-β1 released from these nanoparticles influenced elastogenic outcomes positively within the collagen constructs over 21 days of culture, which were comparable to that induced by exogenous supplementation of DOX and TGF-β1 within the culture medium. However, this was accomplished at doses ~20-fold lower than the exogenous dosages of the agents, illustrating that their localized, controlled and sustained delivery from nanoparticles embedded within a three-dimensional scaffold is an efficient strategy for directed elastogenesis. Copyright © 2014 John Wiley & Sons, Ltd.
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.|Department of Bioengineering, Clemson University, Clemson, SC, USA.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Venkataraman
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Sivaraman
authors.affiliation: Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, USA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Vaidya
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.|Department of Bioengineering, Clemson University, Clemson, SC, USA.|Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Ramamurthi
mesh_terms: D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D004318:Doxycycline / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D011098:Polyglactin 910 / Q000737:chemistry*; D053773:Transforming Growth Factor beta1 / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D011098:Polyglactin 910; D004318:Doxycycline
keywords: MMP inhibitor; elastic matrix; elastogenic factors; nanoparticles; three-dimensional tissues; vascular smooth muscle cells
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