Conception et évaluation in vivo de prothèses vasculaires compliantes de petit diamètre par électrofilage avec revêtement bioactif

Abstract

For the treatment of cardiovascular diseases, the use of synthetic prostheses is currently limited due to severe clinical complications, particularly for the replacement of small diameter vessels (< 6 mm). The low compliance of the implants and their inadequate surface properties are the causes of the lack of endothelialisation and biological processes leading to an unacceptable rate of occlusion for the conduits. The underlying premise of this project is that the combination of a compliant tubular structure with a non-thrombogenic inner layer with the ability to promote the formation of an endothelial cell monolayer would have the potential to improve clinical outcomes. In this context, the electrospinning technique has been selected because it allows the production of modulable fibrous structures in order to reproduce the morphology of the extracellular matrix from the native vessels and to mimic their mechanical properties. Besides, a bioactive coating, made of a primary amine-rich plasma polymerized layer (L-PPE:N) on which is grafted chondroitin sulfate (CS), has demonstrated a potential for reducing the adsorption of proteins involved in thrombus formation, while promoting the endothelialisation of surfaces. This thesis proposes then to develop a new generation of vascular prostheses in order to improve the in vivo patency of implants, by the design of compliant electrospun tubular materials, and their in vivo evaluation in a sheep model following their combination with a bioactive coating. Due to the lack of guidelines in vascular implant design practices, we first used an analytical model to select a material that could achieve a similar compliance and burst pressure than small diameter native arteries (0.0725 %/mmHg and 2031 mmHg, respectively). In order to establish the proof of concept, we demonstrated that an electrospun polyurethane (PU) and polycaprolactone (PCL) structure was more compliant than a commercial expanded polytetrafluoroethylene (ePTFE) implant. With the selection of a 145 μm-thickness it was then possible to build a small diameter vascular prosthesis with an adequate balance between the following important properties: compliance, burst pressure, blood permeability and handling ability. Following the transfer of the bioactive coating based on L-PPE:N and CS on the electrospun PU/PCL implants, animal experiments have demonstrated their inferiority compared to ePTFE implants, with the observation of stenoses and occlusions within our conduits. The causes of these failures concern, on one hand, structural parietal alterations for thrombosed electrospun implants, and on the other hand, the thrombogenicity of the luminal surface of the prostheses potentially caused by poor grafting of CS. The benefit of the compliance of our conduits could not be verified. Recommendations have been proposed for each of the hypotheses of failure to target future work improvements. For this purpose, a peel test was adapted to characterize the adhesion force at their interface to optimize the cohesion between two electrospun mats, and different parameters were explored. In particular, this work highlighted the increase of the adhesive strength between two electrospun mats with their fiber diameter. These results bring fruitful insights for the optimization of the implants and the development of multilayer prostheses. This project led to the development of a new electrospun PU/PCL implant, according to a simple design approach that is the analytical model, and with better mechanical properties than ePTFE commercial implants. Despite the unsatisfactory results of the animal study on these conduits with bioactive coating, this work establishes an advance of knowledge on the combination of these types of materials and active molecules in a large animal model. The exploratory study on adhesive strength also advances the understanding of adhesion properties between electrospun matrices. The potential of the electrospinning technique is thus highlighted in this project and paves the way for the development of a new generation of small diameter vascular prostheses.

Date	20 Feb 2020
Original language	French
Awarding Institution	École de technologie supérieure
Supervisor	Sophie Lerouge (Supervisor) & Abdellah Ajji (Co-supervisor)