The majority of BRS that have been brought to the clinical trial stage have been based on lactate polymers. Other materials utilized include magnesium alloys, tyrosine copolymers, and iron. Table 1 out-lines some of the major BRS that have been brought to clinical trials. The following section outlines some of the key materials used in BRS and design features of the representative devices, with Table 2 outlining their clinical performance. The technologies used for BRS can be broadly categorized as polymeric resorbable scaffolds or metallic resorbable scaffolds (MRS).
Key Design Characteristics of Current Bioresorbable Scaffold Technologies.
Key Clinical Performance Measures of Selected Bioresorbable Scaffolds.
The majority of the data on BRS has been provided by lactate-based polymer systems, with poly-L-lactic acid (PLLA) the most commonly used polymer. The PLLA polymer is a thermoplastic aliphatic polyester that undergoes hydrolysis upon contact with the blood pool into lactate monomers and, ultimately, water and carbon dioxide when metabolized by the Krebs cycle.9,10
For many years PLLA has been used in a variety of other applications, such as resorbable sutures. Compared with metal alloys such as cobalt chromium and stainless steel, which are typically used in modern stents, PLLA has a lower tensile strength and, therefore, requires significantly thicker struts to provide comparable radial strength.11
Poly-D, L-lactic acid (PDLLA) undergoes a similar breakdown process to PLLA but at a faster rate because of a decreased crystalline structure compared to PLLA.
Several PLLA and PDLLA BRS exist at various stages of development, but the ABSORB clinical program has provided the majority of data on lactate-based BRS.
The Absorb BRS program. The Absorb BRS was the first BRS approved for use in the United States by the US Food and Drug Administration on the basis of several large, multicenter, randomized controlled trials. The ABSORB II, ABSORB III, ABSORB CHINA, ABSORB JAPAN, TROFI II, and EVERBIO III trials8,12–16 were all large-scale, multicenter, prospective trials comparing Absorb to a contemporary cobalt chromium everolimus-eluting stent (CoCr-EES) (Abbott Vascular, Santa Clara, CA, USA). Although individual trial-level results demonstrated similar performance characteristics and safety profiles between the two stents, subsequent analyses demonstrated increased rates of scaffold thrombosis at 1 year in the Absorb cohort.17,18 This trend appeared to continue to 3 years,19 with the additional worrisome finding of increased ischemia-driven target lesion revascularization (TLR) in the Absorb group.7 Longer-term follow-up to 4 and 5 years post-implantation demonstrated that the risk of adverse events appeared to stabilize after 3 years and was comparable to CoCr-EES,12 likely reflecting the complete resorption of the scaffold within the vessel wall.
The short- to medium-term concerns raised by the ABSORB program led to the withdrawal from the US market in 2018.4 However, the program provided some valuable lessons, in particular in BRS deployment techniques. Optimal deployment techniques that aimed at reducing inadequate vessel sizing, malposition, and scaffold underexpansion appeared, in smaller sub-studies, to reduce the rates of scaffold thrombosis, and the “PSP” technique (pre-dilation, proper sizing, and post-dilation) emerged. These findings were not consistent across all studies examining the effect of pre-dilation and post-dilation, and it remains unclear whether the risk of scaffold thrombosis related to the Absorb device or the deployment technique.20
Desaminotyrosine Polycarbonate-based BRS
Desaminotyrosine polycarbonate (DAT) is a polycarbonate copolymer of tyrosine analogues and is combined with biocompatible hydroxyesters when used in BRS. The DAT polymer has similar radial strength and recoil characteristics to metallic stents21
and has the added benefit of allowing combination with low levels (3%) of iodine to allow improved visualization under fluoroscopy.6,21
The FANTOM program. The Fantom stent (REVA Medical, San Diego, CA, USA), based on DAT, has a 125-μm strut and incorporates iodine into the scaffold to improve visualization. Upon breakdown, the stent elutes sirolimus, with 80% of strut degradation occurring in the first 12 months and complete resorption occurring at 36 months.21 Additionally, the strut design and DAT allow for single inflation.
The FANTOM II study enrolled 240 patients across 28 sites and demonstrated promising safety and efficacy at 12 months, with target lesion failure (TLF) occurring in 4.2% of patients, with only 1 event of scaffold thrombosis.21 Despite these initial successes, the company has been beset by financial difficulties. In early 2019 it voluntarily suspended trading,22 and filed for bankruptcy protection in early 2020.23
Magnesium in its pure elemental form does not have the radial strength required to prevent acute elastic recoil.6
When combined with zinc and manganese, however, the mechanical properties are comparable to stainless steel stents, with low elastic recoil (less than 8%), minimal shortening after inflation (less than 5%), and high collapse pressures (0.8 to 1.5 bar).24
Once deployed and in the body, the magnesium gradually breaks down into inorganic ions and is replaced by amorphous hydroxyapatite, a calcium-phosphorus compound. Additional processes, such as electropolishing of the alloy, can slow the degradation process, with complete degradation occurring by 12 months.25 Anti-neoproliferative agents are incorporated into an outer layer of PLLA to allow controlled drug elution. Interestingly, ex vivo models have demonstrated that the ionic properties of magnesium may have intrinsic antithrombotic effects, driven by decreased inflammatory cell and platelet deposition.26
The Magmaris program. The Magmaris program began with the AMS 1 stent (Biotronik AG, Bülach, Switzerland), which was bulky, hard to deliver, and limited by significant vessel recoil due to poor radial strength. This led to unacceptably high rates of TLR (45%) and major adverse cardiovascular events (26.7%) as demonstrated in the PROGRESS-AMS study.24 The AMS 2 and AMS 3 stents incorporated changes in the strut design, the magnesium alloy, and the outer polymer matrix, aimed at improving neointimal hyperplasia and vessel recoil. The best-performing of these early BRS—namely the AMS 3—was renamed Drug-Eluting AMS 1.0 (DREAMS),27 leading to the first-in-man BIOSOLVE-I28 clinical trial.
The BIOSOLVE-I trial demonstrated substantial improvements compared to the PROGRESS-AMS study, with TLR rates of 4.7% and TLF rates of 7% at 12 months, but still underperformed in comparison with contemporary stents.29 With further improvements in design—such as the incorporation of tantalum markers to enhance visualization, switching from a poly-D-lactc acid (PDLA) to a PLLA outer coating, and improved deployment technique—the DREAMS 2G scaffold was tested in the BIOSOLVE-II and BIOSOLVE-III trials.30 Both trials enrolled stable patients with simple de novo lesions. A recently presented pooled analysis of BIOSOLVE-II and BIOSOLVE-III demonstrated similar rates of TLF (6.4%, n=174) and clinically driven revascularization (3.7%, n=174) at 36 months’ follow-up when compared to second-generation drug-eluting stents (DES). No stent thrombosis events were reported.31 The ongoing BIOSOLVE-IV all-comers registry, with more than 1,000 patients enrolled, shows similar TLF rates to those of the earlier, smaller-scale BIOSOLVE-II and BIOSOLVE-III trials.32
Despite the DREAMS 2G (marketed as Magmaris) scaffold gaining CE mark approval in 2016, the lessons from the failure of the ABSORB program were at the forefront of operator’s experiences with BRS technology. Urging caution, a consensus paper by experts in the field recommended restricting the use of Magmaris in certain areas until further data became available, specifically recommending against the use of Magmaris in situations such as ST elevation myocardial infarction (STEMI), calcified lesions, poor medication compliance, or ostial lesions, restricting its use to stable patients with simple de novo lesions.33
The third generation of Magmaris, 3G, is ready to start clinical trials. This 3G platform utilizes Biomag as scaffold material, has thinner struts, markers enhancing visualization, and a large matrix of sizes and lengths to allow proper device selection.
Iron-based devices offer the advantage of being highly biocompatible with high radial strength but have been limited by a long corrosion period and clearance from the vessel.34
Previous in vitro
studies have shown that a 26-mm long, pure iron-based stent releases 41 mg/month of iron into the bloodstream, equivalent to the typical oral intake of dietary iron over the same period.35
Animal models up to 18 months have not shown evidence of iron toxicity.36
Pre-clinical porcine models have shown that the iron bioresorbable coronary scaffold (IBS) from Lifetech Scientific (Shenzhen, Guangdong, China) displays similar efficacy and safety profiles to current-generation everolimus DES,37
but no current data in humans are available.