Periodic Reporting for period 2 - Bi-Stretch-4-Biomed (BIaxial STRETCHing of PLLA-WS2 nanocomposites FOR thinner and stronger BIOMEDical scaffolds)
Période du rapport: 2018-02-01 au 2020-01-31
Toward the goal of guiding blood vessels to regenerate into a healthy state after heart disease, our team is creating new materials with the combination of strength, biocompatibility and bioresorption that could revolutionize treatment of coronary heart disease (CHD).
Metal stents have become the standard cure for patients suffering from CHD. However, the presence of a permanent metal structure places mechanical restrictions as it alters the arterial vasomotion of the coronary artery giving rise to fatal complications such as late stent thrombosis. In recent years, a revolution in the treatment of CHD has pointed a bioresorbable device that works as well as metal stents by restoring the regular flow of blood and guiding tissue regeneration but is resorbed by the body thus eliminating long-term complications.
Our project contributed to the innovative research on bioresorbable scaffolds by 1) developing new compositions that combine biocompatible inorganic nanomaterials for strength with polymers that have demonstrated success in transient implants, 2) understanding the way the structure in the new materials responds to processes that are used to form the bioresorbable vascular scaffold (BVS), and 3) guiding the unified design of materials and processes to enable thinner scaffolds that are easier for surgeons to implant and provide better outcomes for patients.
The project fully achieved the initial objectives and the results place the project itself in a pilot phase ready for next steps including in vivo testing of the nanocomposite and manufacturing of a BVS prototype.
Metal stents have become the standard cure for patients suffering from CHD. However, the presence of a permanent metal structure places mechanical restrictions as it alters the arterial vasomotion of the coronary artery giving rise to fatal complications such as late stent thrombosis. In recent years, a revolution in the treatment of CHD has pointed a bioresorbable device that works as well as metal stents by restoring the regular flow of blood and guiding tissue regeneration but is resorbed by the body thus eliminating long-term complications.
Our project contributed to the innovative research on bioresorbable scaffolds by 1) developing new compositions that combine biocompatible inorganic nanomaterials for strength with polymers that have demonstrated success in transient implants, 2) understanding the way the structure in the new materials responds to processes that are used to form the bioresorbable vascular scaffold (BVS), and 3) guiding the unified design of materials and processes to enable thinner scaffolds that are easier for surgeons to implant and provide better outcomes for patients.
The project fully achieved the initial objectives and the results place the project itself in a pilot phase ready for next steps including in vivo testing of the nanocomposite and manufacturing of a BVS prototype.
"Toward the objective of creating stronger BVS materials by combining nanofillers with poly(Llactide) (PLLA), experiments at Caltech with ENEA staff evaluated biocompatibility in vitro with two types of cells relevant to vasculature (endothelial cells that line blood vessel walls and smooth muscle cells). When tungsten disulfide nanotubes are incorporated into PLLA, the material remains well tolerated. This is true in ""direct contact"" experiments and in experiments that expose cells to medium that has leached constituents of the nanocomposite. These represent significant steps in the preclinical evaluation of biocompatibility. Also toward the objective of creating stronger BVS, ENEA and Warwick collaboration with Caltech through reciprocal secondments showed that the addition of WS2 nanotubes does accelerate nucleation of crystallization in PLLA and the resulting interactions make the material stronger and more ductile.
Progress toward the objective of understanding the processing-structure-property relationships of new BVS materials has focused on developing methods, initially using PLLA alone as our foundation and later PLLA-WS2 nanocomposites. All four institutions have contributed significantly. The ENEA-Caltech collaboration created an apparatus that imposes elongation in ""tube expansion,"" corresponding to an essential step in producing BVS. The instrument is the first of its kind and brings innovative measurement capabilities to see structure development in situ during stretch blow moulding. Exciting results were obtained when the instrument was used for the first time for real-time synchrotron X-ray measurements: deformation proceeds in distinct steps, first dominated by the glassy character of the pre-formed tube and the later stage that is marked by a sudden appearance of oriented crystals. Successively, an upgraded version of the instrument enabled data acquisition with optimized measurement conditions, easier sample interchange and enhanced stretching modalities.
Warwick established the ability to extrude samples in the form of sheets that were used at Queens in biaxial extensional measurements revealing strong effects of temperature and elongation rate. With these input parameters, we developed computational tools to predict the macroscopic mechanical properties of PLLA-WS2 (constitutive models developed by Queens) from the molecular and nanoscopic scale (multiscale modelling by Warwick). Both constitutive and multiscale modelling started from the PLLA-based model and then the nanofillers were incorporated: constitutive modelling firstly captured the behaviour of PLLA during stretch blow moulding and then incorporated the features due to WS2; similarly, the multiscale modelling studied the composite system as interaction of the nanotubes with the PLLA polymer previously modelled alone. Finally, the two models linked: the underlying molecular and nanoscopic mechanisms (validated by in situ x-ray measurements) provided the parameters for a predictive constitutive model (validated by biaxial elongation measurements).
Multiple dissemination activities were directed both to expert academic audiences and to the general public. Dissemination resulted from presentations in international webinars, academic seminars, lectures, and through publications on peer-reviewed journals and conference communications. Additional forms of promotion took place through publishing in each institution webpages, newsletters, periodic journals and national newspapers.
The dissemination activities fostered the development of a consolidated networking that became a launch pad for collaborations with academic and industrial companies mainly involved in biomedical. Exploitation of the acquired knowledge throughout the conducted research also targeted new R&D projects by monitoring open calls especially focusing on bilateral cooperative actions (see UK-US and IT-US)."
Progress toward the objective of understanding the processing-structure-property relationships of new BVS materials has focused on developing methods, initially using PLLA alone as our foundation and later PLLA-WS2 nanocomposites. All four institutions have contributed significantly. The ENEA-Caltech collaboration created an apparatus that imposes elongation in ""tube expansion,"" corresponding to an essential step in producing BVS. The instrument is the first of its kind and brings innovative measurement capabilities to see structure development in situ during stretch blow moulding. Exciting results were obtained when the instrument was used for the first time for real-time synchrotron X-ray measurements: deformation proceeds in distinct steps, first dominated by the glassy character of the pre-formed tube and the later stage that is marked by a sudden appearance of oriented crystals. Successively, an upgraded version of the instrument enabled data acquisition with optimized measurement conditions, easier sample interchange and enhanced stretching modalities.
Warwick established the ability to extrude samples in the form of sheets that were used at Queens in biaxial extensional measurements revealing strong effects of temperature and elongation rate. With these input parameters, we developed computational tools to predict the macroscopic mechanical properties of PLLA-WS2 (constitutive models developed by Queens) from the molecular and nanoscopic scale (multiscale modelling by Warwick). Both constitutive and multiscale modelling started from the PLLA-based model and then the nanofillers were incorporated: constitutive modelling firstly captured the behaviour of PLLA during stretch blow moulding and then incorporated the features due to WS2; similarly, the multiscale modelling studied the composite system as interaction of the nanotubes with the PLLA polymer previously modelled alone. Finally, the two models linked: the underlying molecular and nanoscopic mechanisms (validated by in situ x-ray measurements) provided the parameters for a predictive constitutive model (validated by biaxial elongation measurements).
Multiple dissemination activities were directed both to expert academic audiences and to the general public. Dissemination resulted from presentations in international webinars, academic seminars, lectures, and through publications on peer-reviewed journals and conference communications. Additional forms of promotion took place through publishing in each institution webpages, newsletters, periodic journals and national newspapers.
The dissemination activities fostered the development of a consolidated networking that became a launch pad for collaborations with academic and industrial companies mainly involved in biomedical. Exploitation of the acquired knowledge throughout the conducted research also targeted new R&D projects by monitoring open calls especially focusing on bilateral cooperative actions (see UK-US and IT-US)."
BVS are promising new treatment for CHD, a major societal problem that accounts for 40% of all deaths worldwide and claims more than 2 million lives per year in EU and USA.
The standard care of CHD is the implant of a permanent metal stent, a tubular mesh that is expanded in the artery through angioplasty procedure and keeps the artery open. In contrast to metal stents, BVS are transient implants that keep the artery open for 6 months allowing the repair of the vasodilation and vasoconstriction functionalities of the vessels and their original anatomy and then are completely resorbed by the body in 2-3 years leaving a healthy artery.
This new technology represents a great therapeutic outlook of vascular repair eliminating long-term side effects such as late stent thrombosis.
The BVS device that obtained clinical approval both in Europe (2011) and in the USA (2016) , made of bioresorbable polylactide (PLLA) polymer, was recently withdrawn from the market after longer clinical trials that showed increase of stent thrombosis despite the initial success. Thickness and radio-opacity are the main factors that limit safe BVS implantation and functionality. Our research has focused on developing a new nanocomposite-based material to enable thinner devices, visible under X-rays guidance to facilitate the scaffold implantation so reducing risk factors. This aim addresses the request strongly demanded by the doctors who feel high responsibility when inserting a device and enlarges the BVS also into the tiny, delicate arteries of the patients.
The EU and USA scientists involved in this Marie Curie RISE action jointly contributed to the experimental, theoretical and modelling research activities enabling rational design of a new material made of PLLA reinforced with radio-opaque tungsten disulfide (WS2) nanotubes and processes adequate for thinner yet strong scaffolds.
The standard care of CHD is the implant of a permanent metal stent, a tubular mesh that is expanded in the artery through angioplasty procedure and keeps the artery open. In contrast to metal stents, BVS are transient implants that keep the artery open for 6 months allowing the repair of the vasodilation and vasoconstriction functionalities of the vessels and their original anatomy and then are completely resorbed by the body in 2-3 years leaving a healthy artery.
This new technology represents a great therapeutic outlook of vascular repair eliminating long-term side effects such as late stent thrombosis.
The BVS device that obtained clinical approval both in Europe (2011) and in the USA (2016) , made of bioresorbable polylactide (PLLA) polymer, was recently withdrawn from the market after longer clinical trials that showed increase of stent thrombosis despite the initial success. Thickness and radio-opacity are the main factors that limit safe BVS implantation and functionality. Our research has focused on developing a new nanocomposite-based material to enable thinner devices, visible under X-rays guidance to facilitate the scaffold implantation so reducing risk factors. This aim addresses the request strongly demanded by the doctors who feel high responsibility when inserting a device and enlarges the BVS also into the tiny, delicate arteries of the patients.
The EU and USA scientists involved in this Marie Curie RISE action jointly contributed to the experimental, theoretical and modelling research activities enabling rational design of a new material made of PLLA reinforced with radio-opaque tungsten disulfide (WS2) nanotubes and processes adequate for thinner yet strong scaffolds.