Preclinical research models for evaluating the biocompatibility of bioresorbable metallic cardiovascular stents: A comparative review

Figures

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  Fig. 1. Three main categories of cardiovascular stents. (i) Bare-metal stents, comprised of a metallic scaffold of corrosion resistant metals (such as stainless steel) or metallic alloys (such as platinum/cobalt-chrome alloys) were the first model of stent developed for use. These stents were associated with a high rate of complications post-implantation including the restenosis of vessels. To address this, (ii) drug-eluting stents, comprised of a metallic scaffold coated with a drug-eluting polymer (such as poly-lactic acid (PLA), polyvinylpyrrolidone (PVP), poly(vinylidencefluoride-cohexafluoropropenen) (PDF-HFP). Bioresorbable stents further provide an alternative to DES and BMS, comprised of either (iii) naturally degrading metals (such as magnesium, zinc or iron-based alloys), or (iv) polymers (such as poly-L-lactic acid or salicylic acid) due to their capability to degrade following implantation.

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  Fig. 2. In vitro models to evaluate the biocompatibility of metallic BRS. (A) Macroscopic (left) and high magnification image (right) of sample candidate metals are typically utilised in vitro. High (100X) magnification image obtained with scanning electron microscopy (conducted on a Zeiss EVO electron microscope) from unpublished data from our research team. (B) In vitro experimental models for evaluating biocompatibility consist primarily of (i) extract tests, where cells are cultured in media containing degradation products extracted from candidate metals; (ii) direct contact tests, where cells are cultured directly on the surface of candidate metals; or (iii) indirect contact test, where candidate metals are placed in inserts and positioned above cells to avoid direct contact, allowing degradation products to diffuse through the shared culture media and interact with the cells. S.

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  Fig. 3. Animal models utilised to evaluate the biocompatibility of metallic BRS in vivo. A combination of small and large animal models has been utilised to assess the biocompatibility of candidate metallic BRS. Small models, such as (i) rodent (i.e. rats or mice): and (ii) rabbit, have been used to initially assess the biocompatibility of metallic BRS. In these smaller models, candidate metals have been implanted in the abdominal aorta, subcutaneous tissue or iliac artery in the form of either samples of the metal (present as a disc or wire), or as a whole stent comprised of the candidate metal. (iii) Large animal models, such as pigs, have been utilised to assess the performance and biocompatibility of stents over prolonged periods. Due to the larger vasculature and organs, pig models allow stents to be implanted in locations similar to those in humans (i.e. the coronary arteries).

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  Fig. 4. Methods of implantation of bioresorbable metal samples within the aorta of murine animal models. Samples of candidate metals (typically as wires or rods) can be either implanted (i) within the aortic lumen whilst secured into the aortic wall or (ii) within the adventitial layer of the aortic wall. Alternatively, (iii) solutions containing degradation products released from candidate metals can be intraperitoneally injected to examine their systemic effects. The luminal implantation models enable investigators to examine interactions between candidate materials and blood components while simultaneously assessing metal degradation under continuous blood flow. Adventitial implantation models provide insight into the interactions between candidate metals and the tissue present within the medial and adventitial layers of the aortic wall.

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  Fig. 5. 3D Cardiovascular Cell Culture Models. (i) Cardiac spheroids consist of cardiac cells including fibroblasts, cardiomyocytes, endothelial or smooth muscle cells, grown into spherical. (ii) Cardiac organoids are similar to spheroids but instead rely on the use of stem cells to form self-assembling aggregates of cells. (iii) Organ-on-a-chip technology (consists of cardiac cells grown within artificial microfluidic structures that expose cells to a flow of liquid. (iv) 3D bioprinting involves the construction of artificial 3D printed tissues incorporating the use of cardiovascular cells and bioinks.