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Full-Text Articles in Biomedical Engineering and Bioengineering
Cathepsin K Targeting Matrix Regenerative Nanoparticles For Small Abdominal Aortic Aneurysm Repair, Jonathan M. Fox
Cathepsin K Targeting Matrix Regenerative Nanoparticles For Small Abdominal Aortic Aneurysm Repair, Jonathan M. Fox
ETD Archive
Abdominal aortic aneurysms (AAAs) are characterized by the loss of elasticity in the aorta wall leading to a chronic increase in diameter and resulting in rupture. This is due to the lack of regeneration of elastic fibers and chronic proteolytic breakdown of elastic fibers within the aorta mediated by matrix metalloproteinases (MMPs), specifically MMP-2 and -9. Previous studies in our lab have shown cationic amphiphile-surface functionalized poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with doxycycline (DOX) to inhibit MMP activity and stimulate elastic matrix synthesis, effects we attributed to both low doses (< 10 mg/ml) of DOX released and independent effects of cationic amphiphile pendant groups on the NP surface. This promises application of these NPs to arrest or regress AAA growth since high oral DOX dosing inhibits new elastic matrix formation in the AAA wall and has undesirable side effects. In this study, we investigated feasibility of antibody-based active targeting of intravenously infused NPs to the AAA wall. Cathepsin K, a cysteine protease, is a biomarker for AAA and overexpressed in abdominal aortic aneurysm tissue making it an ideal target moiety. We have shown using a covalent conjugation method of modifying the surface of the NPs with a cathepsin K antibody resulted in a more robust antibody attachment which did not affect the DOX release profile. Cathepsin K expression was confirmed to be localized on the cell surface and utilizing cathepsin K Ab-conjugated NPs, we demonstrated an increased NP localization to the cathepsin K overexpressing cells in vitro and ex vivo. Importantly, the DOX-loaded NPs demonstrated pro-elastogenic and anti-proteolytic effects in aneurysmal smooth muscle cells supporting their use as regenerative therapies to arrest and regress AAA growth. Preliminary data has been collected indicating cathepsin K Ab-conjugated NP targeting to AAAs in elastase-injured rat models. The study outcomes support the feasibility of using cathepsin K Ab-conjugated NPs as a targeted therapy for elastic matrix regeneration in AAA tissue and will serve as a basis for already initiated follow up studies to assess NP biodistribution, in situ retention in the AAA wall, and safety as a function of time.
C-Jun N-Terminal Kinase Inhibitory Nanotherapeutics For Regenerative Elastic Matrix Repair In Abdominal Aortic Aneurysms, Andrew T. Camardo
C-Jun N-Terminal Kinase Inhibitory Nanotherapeutics For Regenerative Elastic Matrix Repair In Abdominal Aortic Aneurysms, Andrew T. Camardo
ETD Archive
Abdominal aortic aneurysms (AAA) are localized expansions of the aorta wall that continue to grow until they reach a critical size and fatally rupture. This growth is driven by the chronic disruption, degradation, and subsequent loss of aortal wall elastic fibers by matrix metalloproteinases (MMPs) secreted by inflammatory cells recruited to the aorta wall following an injury stimulus, and the inherent inability of vascular smooth muscle cells (SMCs) to naturally repair or regenerate elastic fibers. This leads to a net loss of elastic matrix and the continuing weakening of the aortal wall until eventual rupture. Current treatments seek to reinforce …
Design And Control Of A Powered Rowing Machine With Programmable Impedance, Jose Humberto De La Casas Zolezzi
Design And Control Of A Powered Rowing Machine With Programmable Impedance, Jose Humberto De La Casas Zolezzi
ETD Archive
Due to the rise of obesity, diabetes and cardiovascular disease, research in human performance and physical activity has received increased attention. Rowing machines are used for performance improvements through concentric exercises, however a combination of concentric and eccentric actions is known to improve the effectiveness of training. In this work, a conventional rowing machine was modified to include an electric motor and a robust impedance control system, enabling programmable impedance with concentric and eccentric capabilities. Eccentric exercises are known to contribute significantly to the efficacy of training and to diminish the detrimental effects of humans operating in microgravity for long …