Periodic Reporting for period 1 - 4D STENT (4D shape memory polymers via microstereolithography for production of thermally responsive stents)
Reporting period: 2018-04-01 to 2020-03-31
Cardiovascular disease (CVD), which includes coronary artery disease and peripheral artery disease, is the narrowing or occluding of arteries and veins; this condition affects nearly 18 million people globally in 2015 (World Health Organization) as a result of heart attacks and strokes.1 The current treatment for CVD includes opening the occluded vessel through the use of stenting using a cylindrical tube typically made of a biocompatible metal or polymer that is compressed and delivered by a catheter to the implant site 1-2 Once at the blocked vessel, the stent is threaded into the narrowing section and expanded. However, while the vessel will ideally remain open indefinitely afterward, there are a number of complications associated with the long-term stent presence, including: thrombogenesis, restenosis (30% of cases), plaque build-up, infection, and perforation of the artery, all of which have significant long-term impact on European society. 3 Metallic stents, which are the most commonly used, are primarily nondegradable, limited by poor surface biocompatibility and poor tissue-material mismatch, which may also result in thrombus formation and vessel restenosis. 4 However, metallic stents are also simple to manufacture, with approximately 50 µm struts achievable. 6 Polymer stents, made of polylactic acid (PLA) and poly ε-caprolactone (PCL), are degradable and are known for biocompatibility, but are produced through costly, time consuming laser cutting.4-7,10-12 Polymeric struts are 200 µm, with contacting surface area percentage up to 90%, compared with 25% for metallic stents, primarily due to manufacturing limitations. 6 Hence, a significant hurdle for cardiovascular surgery is the development of stents that match the tissue mechanical properties, degrade, allow for cellular remodeling, and have similar physical dimensions to current metallic devices. 7 Superior stents require novel materials that can be processed using additive manufacturing, which will allow for greater resolution of struts and surface features while simultaneously improving long-term clinical outcomes without sacrificing biocompatibility. 3D printed materials are gaining significant interest in both the academic and industrial sectors due to their reproducible structures and rapid production throughput.13 Microstereolithography, one such method, allows for the production of features on the order of 50 µm reproducibly and rapidly.14-15 However, the limitation of this and other additive manufacturing methods is that only a few polymeric compositions can be used without processing limitations, or are limited by the manufacturing method itself (as is the case with some fusiform filament deposition methods).5 Shape memory materials, which undergo extreme geometry changes without compromising other material properties, offer the opportunity to revolutionize biomaterials. Currently, most shape memory materials cannot be processed by additive manufacturing to provide controlled morphology, or possess the capability for spatially-defined surface functionalization by additional post polymerization modifications. So-called 4D materials (materials possessing a response after printing), present a unique opportunity to print a complex part that can either then be deformed or may undergo deformation during use, after which it may be returned to its printed geometry through application of an external stimuli.6 Owing to the enormous potential of printing this family of materials, significant research has been directed towards the development of new 4D materials with specific responses, as well as tunable properties.5 In 4D Stent, novel polymeric resins possessing clinically relevant thermomechanical and degradation properties will be utilized to print stents whose surfaces can then be tailored to prevent biofouling (thrombosis) on the interior face as well as recruit endothelial cells for better healing on the exterior face.
Research methodology:
Our novel approach will yield 4D functional materials for CVD stenting. To accomplish this, the project is comprised of three specific aims:
• Synthesis of functional polymer resins: Utilizing ring opening polymerization (ROP), reproducible, controlled printing resins, with tailorable material properties, were be synthesized; COMPLETED and published as a UK patent application (Patent Application - GB1906987.1 “Bio-orthogonal functionalization of polymer systems)
• Materials characterization: Thermomechanical properties, degradation, and biocompatibility will be assessed as a function of composition; COMPLETED and published as a UK patent application (see above)
• Printing of medical device protoytpes: A porous tissue scaffold was printed and tested, including cellular proliferation with spatiotemporal surface composition control. Partially completed. Biological analysis of the prototypes was completed, as well printing of stent models and other 3D objects that display 4D behavior.
This funding was also used as part of the following publications: Terpene- and terpenoid-based polymeric resins for stereolithography 3D printing† Andrew C. Weems, Kayla R. Delle Chiaie, Joshua C. Worch, Connor J. Stubbs and Andrew P. Dove. Polym. Chem., 2019, 10, 5959 (Open Access); Selective Reactivity of Myrcene for Vat Photopolymerization 3D Printing and Postfabrication Surface Modification Andrew C. Weems,† Kayla R. Delle Chiaie,† Rachel Yee,†,‡ and Andrew P. Dove. Biomacromolecules 2020, 21, 163−170
Our novel approach will yield 4D functional materials for CVD stenting. To accomplish this, the project is comprised of three specific aims:
• Synthesis of functional polymer resins: Utilizing ring opening polymerization (ROP), reproducible, controlled printing resins, with tailorable material properties, were be synthesized; COMPLETED and published as a UK patent application (Patent Application - GB1906987.1 “Bio-orthogonal functionalization of polymer systems)
• Materials characterization: Thermomechanical properties, degradation, and biocompatibility will be assessed as a function of composition; COMPLETED and published as a UK patent application (see above)
• Printing of medical device protoytpes: A porous tissue scaffold was printed and tested, including cellular proliferation with spatiotemporal surface composition control. Partially completed. Biological analysis of the prototypes was completed, as well printing of stent models and other 3D objects that display 4D behavior.
This funding was also used as part of the following publications: Terpene- and terpenoid-based polymeric resins for stereolithography 3D printing† Andrew C. Weems, Kayla R. Delle Chiaie, Joshua C. Worch, Connor J. Stubbs and Andrew P. Dove. Polym. Chem., 2019, 10, 5959 (Open Access); Selective Reactivity of Myrcene for Vat Photopolymerization 3D Printing and Postfabrication Surface Modification Andrew C. Weems,† Kayla R. Delle Chiaie,† Rachel Yee,†,‡ and Andrew P. Dove. Biomacromolecules 2020, 21, 163−170
Importantly, in good accordance with the Horizon 2020-Framework Programme, this proposal was designed to align with the EU societal challenge focused on Piloting demand-driven collaborative innovation models in Europe to enable Europe to become “the most competitive and dynamic knowledge-based economy in the world”. The development of novel, functional medical devices has significant innovation potential to be exploited in the consumer market, and early and open collaboration with clinical partners is crucial for developing useful medical devices via proof-of-concept demonstrations. As a part of that, the company 4D Medicine Ltd was spun out of the University of Birmingham, licensing the patents and intellectual property developed from this work. The 4D Stent project work and the spinout company 4D Medicine were the recipients of the 2018 Royal Society of Chemistry Emerging Technology Award (Runner Up) in Healthcare, a measure of the great potential of this technology. This work has further been the focus of two articles in Chemistry World and in Medical Devices (forth coming).
Regarding the results of this work upon the conclusion of the project, a final series of open access manuscripts is anticipated, focusing further on the biocompatibility and utility of these 4D materials in biological applications. This will further demonstrate the translational potential of this work.
Regarding the results of this work upon the conclusion of the project, a final series of open access manuscripts is anticipated, focusing further on the biocompatibility and utility of these 4D materials in biological applications. This will further demonstrate the translational potential of this work.