Chemical design and validation of ca 2+ -releasing platforms to promote vascularization in tissue regeneration

• Autores: Joan Martí Muñoz
• Directores de la Tesis: Óscar Castaño Linares (dir. tes.)
• Lectura: En la Universitat Politècnica de Catalunya (UPC) ( España ) en 2018
• Idioma: español
• Tribunal Calificador de la Tesis: Jesús Santamaría Ramiro (presid.), Carlos Alemán Llansó (secret.), Cameron D. Mackereth (voc.)
• Programa de doctorado: Programa de Doctorado en Ciencia e Ingeniería de Materiales por la Universidad Politécnica de Catalunya
• Materias:
  • Física
    • Física atómica y nuclear
      • Resonancia magnética nuclear
  • Ciencias tecnológicas
    • Tecnología de materiales
      • Vidrio
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• Resumen

  • An insufficient vascularization of the wound site is often the cause of failure in tissue regeneration. The use of cell therapy or growth factors has introduced promising results, nevertheless, they are risky, expensive and difficult to store. Synthetic biomaterials offer an alternative, reducing these limitations but also decreasing the positive effects. Among synthetic materials, degradable calcium phosphates have demonstrated an efficient bioactivity. Their partial dissolution towards the surrounding tissue induces several positive responses including cell migration, proliferation and even osteogenic differentiation. What is not so well understood is their angiogenic (formation of blood vessels from pre-existing ones) potential. Recent findings in our group indicates that their Ca2+ release is involved in the cell synthesis of angiogenic factors. Based on this finding, in this thesis, we synthesized binary (P205-Ca0) calcium phosphate glass (CPg) degradable nanoparticles by the sol-gel method and tested and validated their angiogenic potential. Interestingly, this is the first time that binary (P205-Ca0) CPg nanoparticles have been synthesized by the sol-gel method. We used ethylphosphate and calcium 2-methoxyethoxide as sol-gel precursors, and we catalyzed the precipitation of the particles using NH3(aq) in an ethanolic medium. Nuclear magnetic resonance supplemented with other characterization techniques, showed that the particles were a mixture of highly soluble amorphous calcium monoethylphosphate with the formation of portlandite or NH4H2P04 for an excess or the absence of Ca respectively. After a thermal treatment at 200 or 350°C, the highly soluble organic particles were converted into a more stable (but still degradable) inorganic amorphous calcium trimetaphosphate (ACTMP), pyrophosphate (ACPP), orthophosphate (ACP) and calcite as the Ca content of the particles increased respectively. We controlled the ion release of the particles under physiological conditions by modifying their Ca/P ratio and applying this moderately low thermal treatment. The CPg nanoparticles were combined with electrospun polylactic acid nanofibers to achieve an implantable scaffold. These Ca2+ releasing scaffolds showed promising results in angiogenesis, including a similar blood vessel formation than significant VEGF doses in the chick chorioallantioc membrane model. The scaffolds also induced a stronger osteogenic differentiation, and a significant skin ulcer reduction in diabetic and obese mice, that validates their use not only for bone but also for the healing of highly vascularized softer tissues such as the skin. Concluding, we demonstrated that the use of synthetic Ca2+ releasing scaffolds offers a cost-effective alternative for the regeneration of highly vascularized tissues.