| Author: | Rao, Jingdong |
| Title: | Biomedical applications of nitric oxide production system in the promotion of cardiovascular homeostasis and bone regeneration |
| Advisors: | Zhao, Xin (BME) |
| Degree: | Ph.D. |
| Year: | 2024 |
| Department: | Department of Biomedical Engineering |
| Pages: | xiv, 124 pages : color illustrations |
| Language: | English |
| Abstract: | Nitric oxide (NO) is a ubiquitous, bioactive gas that plays a crucial role in various biological systems. However, inadequate NO levels are associated with various disease complications. Therefore, the introduction of NO into a therapeutic system has great potential for disease treatment. In this dissertation, we propose three projects focused on cardiovascular stent and bone scaffold with NO-generating and releasing capabilities. The first project aimed to address the inadequate NO donors (RSNO) in vivo, which may impair catalytic NO generation by glutathione peroxidase (GPx)-like substances such as copper (Cu). GPx has peroxidase activity and can decompose endogenous RSNO to NO. Similarly, Cu(II) can be reduced into Cu(I) to then decompose RSNO. Therefore, Cu has GPx-like properties in catalyzing NO production. To maintain cardiovascular homeostasis, we constructed an endothelium-mimicking coating (DCAH) on the surface of cardiovascular stent. The nanometer-thin coating consisted of a dopamine-copper (DC) network with immobilized L-arginine and glycocalyx heparin. The coating could catalyze NO generation in the presence of endogenous RSNO. The arginine served as an NO precursor to release NO by endothelial nitric oxide synthase (eNOS), guaranteeing sufficient NO supply when RSNO were not present. Furthermore, the introduction of heparin could increase the eNOS level, which facilitated arginine decomposition into NO. The long-term and sufficient NO production could inhibit smooth muscle cells (SMC) growth as well as platelet adhesion, combating stent thrombosis and restenosis. The second project aimed to address the slow re-reendothelialization after stenting. Building on the results of the first project, we found that a sufficient number of (endothelial cells) ECs grown on the material could spontaneously produce NO. Moreover, the pathological progression after endothelial destruction also calls for rapid EC adhesion to facilitate re-reendothelialization. Therefore, we grafted vascular endothelial growth factor (VEGF) onto DCAH to prepare an AHV coating. In this system, VEGF promoted EC adhesion at the early stage, which spontaneously produced NO and formed an uncompromised endothelium on the stent surface. The AHV stent coating targeted vascular repair phases to further promote rapid reendothelialization, long-term inhibition of platelet adhesion and SMC migration and proliferation. The third project addressed the challenge of coordinating both osteogenesis and angiogenesis as well as rebuilding a bone microenvironment rich in various active molecules such as VEGF, NO, and bone morphogenetic protein-2 (BMP-2). Inspired by the second project, where a stent could capture cells for reendothelialization, we designed a triply periodic minimal surface (TPMS) scaffold with N-Cadherin (N-CAD) and TPSLEQRTVYAK peptide (TPS) coatings to attract endothelial progenitor cells (EPCs) and bone mesenchymal stem cells (BMSCs), respectively. This scaffold recreated a bone-friendly environment by spontaneously producing NO, VEGF and BMP-2 from the adherent cells through paracrine effects. The captured cells could undergo differentiation to promote osteogenesis and angiogenesis, thus facilitating bone regeneration. In summary, we have developed a series of NO production platforms based on the bio-functions of NO in the cardiovascular system and bone tissues. These platforms aim to reshape a healthy microenvironment and ultimately improve therapeutic outcomes in cardiovascular intervention and bone tissue engineering. |
| Rights: | All rights reserved |
| Access: | open access |
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