Modulation of the inflammatory response using a guided bone regeneration membrane with dual drug delivery capacity
Bone is a complex and dynamic tissue that fulfills several critical functions such as protecting vital organs including the brain, heart and lungs; providing sites of attachment for muscles to allow movement and maintaining ion homeostasis. Moreover, bone has a remarkable regenerative capacity which...
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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:10803/671867 |
| Acceso en línea: | http://hdl.handle.net/10803/671867 |
| Access Level: | acceso abierto |
| Palabra clave: | Macrophage Inflammation Guided Bone Regeneration Ion Drug Release Bioingeniería 61 |
| Sumario: | Bone is a complex and dynamic tissue that fulfills several critical functions such as protecting vital organs including the brain, heart and lungs; providing sites of attachment for muscles to allow movement and maintaining ion homeostasis. Moreover, bone has a remarkable regenerative capacity which allows the complete healing of the tissue upon damage. However, this capacity can be exceeded when the size of the defect is too large due to clinical procedures such as tumor resection or the presence of traumatic fracture or osteolysis, which constitute a significant clinical challenge nowadays. Autologous grafts, as well as allografts and xenografts present several limitations to their clinical application such as limited bone supply, disease transmission and ethical issues. Therefore, tissue engineering combining biomaterials and stimulatory molecules to guide bone regeneration presents as an alternative to these methods. Recent advances in bone biology have shown that osteogenesis occurs due to the interaction of multiple systems and not only by the actions of the bone tissue. In this sense, the immune system has gained great importance since the inflammatory response promoted by either tissue damage or the immune recognition of the implanted biomaterial can direct the outcome of the bone healing response. More precisely, macrophages have been described to have a central role in bone regeneration. Their differentiation to a pro-inflammatory phenotype (M1) phenotype can lead to the development of chronic inflammation, which impairs bone healing, whereas their differentiation to an anti-inflammatory phenotype (M2) can lead to enhanced biomaterial integration and improved bone regeneration. Therefore, the design of biomaterials has focused on modulating macrophage differentiation to M2 phenotype to improve bone regeneration. One of the approaches to modulate macrophage response has been the release of antiinflammatory modulators such as cytokines, viral vectors or siRNAs. However, their short half-life and concerns in their efficiency in cellular uptake, as well as long term safety limit VI their clinical application. Ions have risen as a promising alternative since they are stable cues which are present at low concentrations in the body and have already shown benefits on angiogenesis and bone regeneration when delivered from scaffolds. However, there are limited evidences showing their immunomodulatory potential. This thesis is focused on modulating macrophage response by developing a dual drug delivery system with the ability to release ions, as well as small drugs, to promote the M2 macrophage phenotype. First, an initial screening of three bioactive ions was performed to determine the cytotoxic and therapeutic concentrations in macrophages. Those concentrations that induced macrophage differentiation towards the M2 phenotype were tested in presence of different concentrations of a pro-inflammatory stimulus, which allowed to determine the anti-inflammatory potential of these ions. Then, the effect of the ions combined with an anti-inflammatory drug was tested in macrophages to observe a possible synergistic effect between both molecules, although no major differences were observed compared to the effect of the drug alone. Following these assays, the dual drug delivery system was developed, which consisted of a collagen film with ion loaded microparticles and drug loaded microspheres. The results showed that these films not only were able to release controlled concentrations of the ion, but they were also able to perform a sustained release of the drug. Finally, macrophages and mesenchymal stem cells (MSCs) were exposed to the films, showing that they were able to induce M2 macrophage differentiation and osteogenesis. Moreover, treating MSCs with conditioned media from film-induced M2 macrophages further improved the osteogenic differentiation. |
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