Biosafety and efficacy evaluation of a biodegradable magnesium-based drug-eluting stent in porcine coronary artery

Abstract

Although the drug-eluting stent (DES) has become the standard for percutaneous coronary intervention (PCI)-based revascularization, concerns remain regarding the use of DES, mainly due to its permanent rigid constraint to vessels. A drug-eluting bioresorbable stent (BRS) was thus developed as an alternative to DES, which can be absorbed entirely after its therapeutic period. Magnesium (Mg)-based BRSs have attracted a great deal of attention due to their suitable mechanical properties, innovative chemical features, and well-proven biocompatibility. However, the primary disadvantage of Mg-based BRSs is the rapid degradation rate, resulting in the early loss of structural support long before the recovery of vascular function. Recently, a new type of patented Mg–Nd–Zn-Zr alloy (JDBM) was developed at Shanghai Jiao Tong University to reduce the degradation rate compared to commercial Mg alloys. In the present investigation, a poly(d,l-lactic acid)-coated and rapamycin eluting (PDLLA/RAPA) JDBM BRS was prepared, and its biosafety and efficacy for coronary artery stenosis were evaluated via in vitro and in vivo experiments. The degree of smooth muscle cell adhesion to the PDLLA/RAPA coated alloy and the rapamycin pharmacokinetics of JDBM BRS were first assessed in vitro. JDBM BRS and commercial DES FIREHAWK were then implanted in the coronary arteries of a porcine model. Neointimal hyperplasia was evaluated at 30, 90, and 180 days, and re-endothelialization was evaluated at 30 days. Furthermore, Micro-CT and optical coherence tomography (OCT) analyses were performed 180 days after stent implantation to evaluate the technical feasibility, biocompatibility, and degradation characteristics of JDBM BRS in vivo. The results show the ability of a PDLLA/RAPA coated JDBM to inhibit smooth muscle cell adhesion and moderate the drug release rate of JDBM BRS in vitro. In vivo, low local and systemic risks of JDBM BRS were demonstrated in the porcine model, with preserved mechanical integrity after 6 months of implantation. We also showed that this novel BRS was associated with a similar efficacy profile compared with standard DES and high anti-restenosis performance. These findings may confer long term advantages for using this BRS over a traditional DES.

Adaptation of Vascular Smooth Muscle Cell to Degradable Metal Stent Implantation

“…Transformation-modulating agents are usually applied for DMSs and are no doubt good for conciliating VSMCs’ adverse adaptive responses to DMSs. Those antiproliferative or phenotypic modulating drugs have been proven and even utilized in stent products for clinical use, and their pharmacology directly focuses on VSMCs. − Good examples are the above-mentioned JDBM stents. Their PDLLA/RAPA coatings not only inhibited SMC proliferation and intimal hyperplasia restenosis by regulating the rapamycin release but also greatly slowed stent degradation simultaneously and thus enabled JDBM stents to support the arterial wall radially for up to six months, helping JDBM stents achieve efficacy spectrum comparable to and antirestenosis better than standard DMSs .…”

“…Those antiproliferative or phenotypic modulating drugs have been proven and even utilized in stent products for clinical use, and their pharmacology directly focuses on VSMCs. − Good examples are the above-mentioned JDBM stents. Their PDLLA/RAPA coatings not only inhibited SMC proliferation and intimal hyperplasia restenosis by regulating the rapamycin release but also greatly slowed stent degradation simultaneously and thus enabled JDBM stents to support the arterial wall radially for up to six months, helping JDBM stents achieve efficacy spectrum comparable to and antirestenosis better than standard DMSs . Similarly, creating rapamycin-loaded and poly­(lactic- co -glycolic acid) (PLGA)-coated Fe 2 O 3 nanotubes on the surface of pure iron was shown to accelerate the corrosion and reendothelialization of iron materials and inhibit VSMC proliferation .…”

“…Their PDLLA/RAPA coatings not only inhibited SMC proliferation and intimal hyperplasia restenosis by regulating the rapamycin release but also greatly slowed stent degradation simultaneously and thus enabled JDBM stents to support the arterial wall radially for up to six months, helping JDBM stents achieve efficacy spectrum comparable to and antirestenosis better than standard DMSs. 102 Similarly, creating rapamycin-loaded and poly(lactic-co-glycolic acid) (PLGA)-coated Fe 2 O 3 nanotubes on the surface of pure iron was shown to accelerate the corrosion and reendothelialization of iron materials and inhibit VSMC proliferation. 103 Such surface-modified iron stents demonstrate elegant hemocompatibility.…”

Preliminary Studies for One-Step Fabrication of Metallic Iron-Based Coatings on Magnesium as Temporary Protection in Biodegradable Medical Application

“…The most well-known metallic biomaterials are high corrosion-resistant materials, such as 316 stainless steel (Tan et al, 2003;Shih et al, 2004;Patnaik et al, 2020), cobalt-chromium alloys (Ducheyne and Healy, 1988;Que and Topoleski, 2000;Kereiakes et al, 2003;Watanabe et al, 2021), titanium and its alloys (Helary et al, 2009;Huang et al, 2010;Niinomi et al, 2012;Jin et al, 2015;Lourenço et al, 2020), tantalum alloys (Miyazaki et al, 2000;Shimko et al, 2005;Zhou et al, 2007;Rodriguez-Contreras et al, 2021), as well as precious alloys (O'Brien, 1997;Chen et al, 2005;Niinomi et al, 2015). Another group of metals consists of biodegradable materials, such as pure iron and a variety of Fe-based alloys as well as pure magnesium and Mg alloys (Wu et al, 2016;Mao et al, 2017;Yang et al, 2018;Gorejová et al, 2019;Costantino et al, 2020;Zhu et al, 2021).…”

“…Therefore, various surface modification and coating methods (Rajabalizadeh and Seifzadeh, 2014;Seifzadeh and Farhoudi, 2016;Nezamdoust et al, 2019;Abdi-Alghanab et al, 2020;Ouyang et al, 2020;Chen et al, 2021) are applied to tailor the undesired fast degradation rate into a moderate one to fulfill the therapeutic tasks. For instance, Zhu (Zhu et al, 2021) prepared a poly (d,llactic acid)-coated magnesium alloy-based rapamycin drugeluting bioresorbable stent. In vivo and in vitro studies showed that the polymeric coatings provided a suitable degradation rate of magnesium alloy stents.…”