Strategies to induce vascularization: angiogenesis stimulation and tissue engineering blood vessels
Angiogenesis, which results in a capillary network formation, is one of the crucial events that take place when there is tissue damage, being critical for successful tissue regeneration. It does not only allow the arrival of oxygen, nutrients and waste removal, but it also allows the arrival of prog...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/670474 |
| Acceso en línea: | http://hdl.handle.net/10803/670474 |
| Access Level: | acceso abierto |
| Palabra clave: | Bioingeniería 573 62 |
| Sumario: | Angiogenesis, which results in a capillary network formation, is one of the crucial events that take place when there is tissue damage, being critical for successful tissue regeneration. It does not only allow the arrival of oxygen, nutrients and waste removal, but it also allows the arrival of progenitor cells necessary to induce tissue restoration. However, when there is an excessive damage, tissues are unable to regenerate by themselves. During the last decades, tissue engineering emerged as an alternative to improve tissue regeneration, with the combination of biomaterials (which serves as scaffolds), cells and/or stimulatory molecules. Therefore, one of the aims of tissue engineering is to incorporate stimulatory molecules within scaffolds to promote blood vessel formation for successful tissue regeneration and integration. Alternatively, there are some clinical situations in which high caliber vessels are needed instead of capillary network formation. An example would be with cardiovascular diseases (CVD), such as atherosclerosis or aneurysms, in which blood vessel replacement is needed. Autologous and xenogeneic grafts present some limitations, mainly risk of disease transmission and shortage of donors. Therefore, tissue engineered blood vessels (TEBVs) emerged as a promising alternative. Regarding angiogenesis, generally, growth factors have been incorporated within scaffolds as molecules of choice to stimulate blood vessel formation. Although they have demonstrated a proper angiogenic response, they present some limitations, such as delicate handling properties and short half-life. As naturally found in human body, ions have demonstrated to be a promising alternative, being able to stimulate cellular functions, such as blood vessel formation. However, sometimes there is no consensus about the appropriate non-toxic and therapeutic doses, due to a lack of concentration screening studies before introducing them into the scaffolds. Regarding TEBVs, different approaches have been described for their development. However, they usually include several manufacturing steps and additional biomaterial patterning or additional stimulus to acquire native vascular cell alignment. This thesis is focused on angiogenesis stimulation and TEBVs, divided in two main blocks: i) development of a drug delivery system (DDS) with the incorporation of ions to stimulate early phases of bone regeneration, including angiogenesis; ii) development of TEBVs through extrusion-based approach. In the first part, an initial screening of different concentrations of therapeutic ions was performed to assess non-toxic and therapeutic concentrations in angiogenesis and osteogenesis, with endothelial cells (ECs) and human mesenchymal stem cells (hMSCs), respectively. Results allowed establishing therapeutic doses of both ions for blood vessel formation, although they showed impairment when tested for osteogenic differentiation. These ions were then incorporated within a biomaterial to allow forming a DDS, showing that the incorporated therapeutic ions could have antibacterial and angiogenic potential, allowing a sequential delivery of both ions. The designed DDS consisted of a fiber like structure incorporating hydroxyapatite based microparticles which could potentially be used for bone tissue regeneration. In the second part, TEBVs were successfully developed with extrusion-based approach in one single step procedure. Moreover, specific vascular cell types were incorporated, with high cell survival and presenting native cell alignment and some vasoactive functionality. Furthermore, we could improve their mechanical properties by extruding TEBVs with high concentrations of collagen, allowing their perfusion with arterial shear stress. Further studies are required to prove their functionality and maturation, with the potential to be used as blood vessel replacement or even vascular disease modeling |
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