Resumen de Stimulation of wound healing and vascularization with calcium-releasing biomaterials
Chronic skin wounds are a major socioeconomic burden in developed societies, affecting specially elder and diabetic people. It is estimated that 1 to 2% of the population will suffer a chronic wound in their lifetime and, as global population ages and adopts a sedentary lifestyle, the incidence of these wounds will continue its upward trend. Chronic injuries are characterized for presenting a complicated and diverse pathophysiology that make them resistant to current therapies. For this reason, novel therapeutic strategies based on the release of growth factors and the use of tissue engineered constructs are being investigated and show promising results. However, very few biologically based products reach the market, mainly due to regulatory, economic and stability constraints, amplifying the need for easily translational novel treatments.
Recently, inorganic biomaterials known as bioceramics have been acknowledged for their wound healing and vascularization capability, mainly due to their ion release. Based on this concept, the present thesis project was dedicated to investigate the potential application of novel bioceramics on wound healing and soft tissue regeneration. More specifically we focused on the role of the calcium ion and its release from newly designed bioceramics to stimulate wound healing and blood vessel formation in both in vitro and in vivo systems.
Although it is known that calcium affects all the phases of wound healing, the concentrations and release profile that can improve the healing process has not been described. For this reason, we evaluated the effect of different concentrations of extracellular calcium in vitro on dermal fibroblast, a crucial cell type in the skin and the healing process, and found stimulation of relevant biological responses at specific concentrations. In addition, we compared whether similar effects could be obtained with the ion release of newly designed bioceramic particles containing equivalent calcium concentrations. Interestingly, while stimulating most of the effects, the ion release inhibited some responses triggered by calcium alone that are not desired in the context of chronic wound healing.
Then, we investigated the cellular mechanism mediating some of the responses stimulated by calcium, focusing on the implication of the calcium-sensing receptor (CaSR). Several agonists of the receptor stimulated similar effects than calcium, suggesting the relevance of the CaSR on fibroblasts behavior, and opening a window to the design of novel bioceramics that release CaSR-agonists.
In order to test the healing capability of the above mentioned bioceramic particles in vivo, they were incorporated in a mat of poly(lactic acid) (PLA) fibers. This novel dressing was applied on a model of chronic wounds in vivo, and compared with a mat of particle-free PLA and to a frequently used commercially available dressing. We found that the PLA-bioceramic mat accelerated wound closure and increased vasculature at the injured site at initial time-points. Thus, improved healing was achieved with the newly designed dressing.
Finally, a different composite material was synthesized combining bioceramic particles and human mesenchymal stromal cells (hMSC) in a degradable hydrogel, and its vasculogenic potential was evaluated in soft tissue. This material supported hMSC survival and stimulated the release of the angiogenic factor IGF-1 from these cells in vitro. In addition, when implanted in soft tissue of immunocompromised mice, the composite construct improved hMSC survival and generated a more mature vasculature at the site of implantation.
In conclusion, this thesis shows that calcium-releasing bioceramics can successfully contribute to the treatment of chronic wounds and soft tissue regeneration.
