Bioresorbable Scaffolds : The Revolution in Coronary Stenting ?

Bioresorbable scaffolds (BRS) represent the latest revolution in interventional cardiology. Thanks to their reabsorptive properties, they provide temporary scaffolding that helps stabilizing the plaque and promotes healing, and then disappear, thus restoring a functional endothelium and vasomotion. Several devices have been tested at the preclinical and clinical stage. Here we review the rationale, development, design and clinical data of the BRS platforms, providing a comprehensive review of the literature.


A Historical Perspective
In September 1977, Andreas Grüntzig, an ambitious young cardiologist from Zurich, performed the first coronary angioplasty on a severe stenosis of the left anterior descending artery in a conscious patient.The underlying concept was that the dilatation of the coronary stenosis using an inflatable balloon would allow redistribution of the atheroma (like "crushed snow"), and hence decrease in the degree of stenosis.The procedure was a complete success, and the patient-now asymptomatic-was soon discharged [1].
However, this technique was plagued by several problems, including the non-negligible risk of acute vessel closure (4-8%, due to occlusive dissection, and often requiring coronary artery bypass surgery, (CABG) [1,2] and high incidence of restenosis on mid-to-long term (≈30-60%, due to elastic recoil and constrictive remodeling) [3][4][5].These mechanical problems required a mechanical solution.In the late 1980's, different groups in both the U.S. and Europe independently developed metal "sleeves" that could be crimped onto balloon catheters, carried across the lesion and delivered by means of balloon expansion, in order to support vessel wall and prevent the collapse of the artery.
Since the development of the platform of these "bare-metal" stents (BMS) was approaching technical limits, the answer to these problems would come from a pharmacological approach, in the form of a surface coating and a drug delivery system.In particular, the addition of an antiproliferative compound, which would be released over the course of several months, would minimize the exuberant smooth muscle tissue growth within the stent.Indeed, the first-generation drug-eluting stents (DES)-sirolimus-eluting Cordis Cypher TM and paclitaxel-eluting Boston Scientific Taxus TM -showed very low rates of restenosis (≈10%).These promising results led to a widespread adoption of DES and an increase in clinical indications of percutaneous coronary intervention (PCI).The introduction of the novel drug-eluting concept uncovered a new type of complication: late and very late ST.In fact, the uncontrolled antiproliferative effect of firstgeneration DES was associated with delayed endothelialization and persistent inflammation, which in turn triggered ST at medium-to-long-term follow-up.All-comer registries showed a steady incidence of ST of 0.5% per year, which reached 3% at 4 years [16,17].Improvements in drug choice, release and concentration, as well as in the polymer delivering the drug and in strut thickness, led to a marked mitigation of this complication, with reassuring ST rates of 1% at 3 years [15].
Additionally, these second-generation DES (e.g., Abbott Vascular Xience V TM and Boston Scientific Promus Element TM Despite these improved results, the concept of metallic stenting has several intrinsic drawbacks.
Firstly, with the widespread increase in the volume of PCIs, together with the increasing life expectancy of the population, we have been witnessing an increase in the complexity of clinical scenarios where coronary stenting is now required.For example, it is not uncommon to encounter patients with a restenosed metallic stent, which had been in turn implanted to treat a first episode of restenosis.In this setting, the addition of a third layer of metallic stent does not look appealing.
Secondly, extensive stenting of distal vessels precludes further treatment with CABG (grafts cannot be anastomosed on metal-laden arteries).Thirdly, vasomotion tests have showed abnormal vasoconstriction in response to acetylcholine and exercise distally to the deployed metallic stent, suggesting that endothelium structure and function is abnormal following stent implantation [19,20].
Fourthly, metallic stenting of bifurcations has been associated with permanent jailing of side branches ostium.Finally, late lumen loss (LLL) and delayed endothelialization/persistent inflammation can still be improved beyond the limits reached with second-generation DES, thus reducing even further the risk of restenosis and ST [21].
The answer to all these limitations could be represented by temporary scaffolding of the diseased coronary segment by means of so-called "bioresorbable scaffolds" (BRS).Specifically, BRS could provide the advantages of metallic stents (i.e., plaque modification and stabilization, sealing of dissection, etc.) for several months, thus promoting vessel healing; when this is achieved, they would start the reabsorption process, leaving no trace of their previous presence behind (therefore avoiding the aforementioned long-term shortcomings of metallic stents).For these reasons, BRS have been considered the fourth revolution in the history of interventional cardiology [21,22].Reproduced with permission from [27].

History of the Development of BRS
The idea of developing a bioresorbable scaffold was conceived ≈25 years ago.The first efforts were devoted to identify and develop non-metallic compounds (e.g., polyester or other polymers) to build stents which would exhibit less inflammatory and prothrombotic behavior than conventional stainless steel stents [23].These experiments showed promising results in a swine model: the extent of neointimal proliferation was similar to that observed after placement of metal stents, despite the presence of a more pronounced inflammatory reaction [23].Subsequently, several biodegradable polymers-mounted on conventional metallic stents-were tested by Dutch and American researchers, in order to assess their biocompatibility in porcine coronary arteries.Unfortunately, all resulted in marked inflammation, leading to neointimal hyperplasia and/or thrombus formation [24].
Additional experiences demonstrated that a metallic stent coated with high-molecular weight poly-L-lactic acid (PLLA) was well tolerated in a porcine coronary injury model, exhibiting little inflammation, and also showed interesting properties as effective means of providing sustained, sitespecific drug delivery [25].Furthermore, Japanese researchers showed that a fully bioabsorbable PLLA scaffold eluting a tyrosine kinase inhibitor was able to efficiently suppress neointima hyperplasia induced by balloon injury in a swine model [26].The first device that was tested in humans was the Igaki-Tamai (Kyoto Medical), a fully bioresorbable scaffold made of poly-L-lactic acid (PLLA) without any drug coating.It required a 30-second inflation with a balloon filled with contrast heated at 70-80ºC to be implanted [27].The first-in-man trial (n = 15) was published in 2000, and showed no stent thrombosis or major adverse cardiac events (MACE) at 30 days, and one case of target lesion revascularization (TLR) at 6 months [28].Notwithstanding these promising results, this device did not become popular due to concerns about use of the heated contrast in coronary arteries.Despite these fast-paced advances during the 1990's, the development of what will be later known as BRS stagnated for a large part of the following decade, due to a combination of inability to manufacture an ideal polymer that could limit inflammation and restenosis, and because of the growing interest in metallic DES [21].

Current Clinically Tested BRS
Current, mature BRS technology relies on a bioresorbable polymer or metal (the "scaffold") that elutes an antiproliferative drug similar to metallic DES (most often, everolimus or sirolimus), although some devices lack any drug coating.Table 2 and Figure 1 show current BRS for which clinical data are available.

AIMS Medical Science
Volume 3, Issue 1, 126-146.Intravascular ultrasound data at 6 months demonstrated a significant (p < 0.001) increase in vessel area (17%), mean scaffold area (16%), and mean lumen area (9%).Moreover, only 1.2% of struts were left uncovered at 6 months (as opposed to 3.2% for Absorb TM TM ). Clinical outcomes were also promising, with an incidence of MACE of 3.3% at 6 months and 7.4% at 24 months, including a TLR rate of 1.6% and 4.1%, respectively, with no cases of definite ST [30,31].DESolve TM has obtained CE mark.[33].However, issues linked to the "slide and lock" delivery mechanism (which allowed the operator to ratchet open the device to a desired diameter during implantation) hampered the deliverability of this BRS, so that the new iteration of this scaffold will feature a conventional balloon expandable system.The ReZolve2 experience has contributed building data and knowledge for the development of the next generation device (Phantom), which is currently being tested in humans.Of note, to date no article publication on any of these BRS iterations has been released.

Biotronik DREAMS 2
Biotronik adopted a radically different approach for the development of it BRS platform.
Instead of a polymer, the company chose to use a bioabsorbable magnesium alloy.The first iteration of the device (AMS-1) was uncoated and did not elute any antiproliferative drug.Strut thickness was 165 µm.The radial support was lost within a few weeks after implantation (reabsorption was complete in < 4 months), resulting in a high rate of recoil and constrictive remodeling [27].AMS-1 was tested in the PROGRESS-AMS trial (n = 63), which showed marked LLL (1.08 ± 0.49 mm at 4 months), which determined a 24% TLR rate at 4 months.There were no cases of death, myocardial infarction or ST [34].The second iteration of this scaffold (DREAMS-1 TM TM ) featured thinner struts (125 µm), coating (poly-lactic-co-glycolic acid, PLGA) and drug elution (paclitaxel).The degradation process was longer (reabsorption was completed in 9 months).DREAMS-1 TM was tested in the BIOSOLVE-I trial (n = 46), which showed a LLL of 0.65 ± 0.50 mm at 6 months and 0.52 ± 0.39 mm at 12 months.TLR rate was 4% at 6 months and 7% at 12 months.No deaths or ST were observed [35].At 3-year follow-up, TLR rate was 4.5% and 2.3% of patients suffered a myocardial infarction.Again, no cases of death or ST were observed [36].Further refinement to the device has been performed: DREAMS-2 TM is a sirolimus-eluting scaffold that features PLLA coating.Strut thickness is 150 µm.Improved radiopacity is provided by metallic markers.Reabsorption is completed by 9 months.DREAMS-2 TM

Clinical Data for Abbott Vascular Absorb
is being tested in the ongoing BIOSOLVE-II trial.
As mentioned, the vast majority of clinical data available on BRS concerns Abbott Vascular Absorb TM TM (Table 3).

AIMS Medical Science
Volume 3, Issue 1, 126-146.The seminal ABSORB A trial (n = 30) tested the first version of the scaffold in a cohort of lesions of intermediate complexity.Two-year follow-up showed no cases of death or TLR, and a 3.6% of myocardial infarctions.No cases of ST were observed.LLL was 0.48 ± 0.28 mm at 2 years.At 2 years, 34.5% of strut locations presented no discernible features by optical coherence tomography (OCT).Additionally, vasomotion occurred at the stented site and adjacent coronary artery in response to vasoactive agents [29].At five-year, MACE rate remained unchanged (3.4%), and again no cases of ST [37].The second-generation device was tested in the ABSORB B trial (n = 101), showing a three-year MACE rate of 10.0% (3% of non-Q-wave MI, 7% of TLR, and no cardiac deaths), without any case of ST.LLL was 0.29 mm at 3 years [38].
ABSORB II was the first trial comparing a BRS with a DES [39].It randomized, in a 2:1 fashion, Absorb TM and Xience TM   The recently published ABSORB III [40] is to date the largest trial comparing a BRS to a metallic DES.It randomized n = 2008 patients to Absorb n = 501 patients with evidence of myocardial ischemia and one or two de-novo native lesions in different epicardial vessels.Patient population was somehow less selected than in previous trials (24% diabetes, 14% moderately or severely calcified lesions, 9% two or more lesions treated), even though type-C lesions were observed in only 1.5% of cases, bifurcations and acute coronary syndrome patients were excluded, lesions were on average quite short (13.8 ± 6.5 mm) and very few (15%) overlapping scaffolds were implanted.At 1 year, rates of first new or worsening angina were lower in the BRS group (22% vs. 30%, p = 0.04)-a finding that is believed to be due to the restored vasomotion-whereas performance during maximum exercise and angina status by a standardized questionnaire were similar.At one-year follow-up, MACE rate was 5% in the BRS group and 3% in the DES group (p = 0.35), with the most common adverse events being non-Q-wave myocardial infarction (4% vs 1%, p = 0.16) and clinically-indicated TLR (1% vs 2%, p = 0.69).Three patients (0.9%) in the BRS group had definite or probable ST (two definite early and one probable late), compared with no patients in the DES group (p = 0.55).
TM (n = 1322) or to Xience TM (n = 686) with stable or unstable angina.Patient population risk profile was intermediate: 32% diabetes, 70% type B2 or C lesions, but ST-elevation myocardial infarction (STEMI) and non-STEMI were exclusion criteria, so that only stable and unstable angina patients with one or two lesions were included.
Device success was 94% for Absorb TM and 99% for Xience TM .At 1 year, Absorb was non-inferior to Xience TM Additional randomized evidence on the safety and efficacy of Absorb in terms of MACE (7.8% vs. 6.1%, p = 0.007 for non-inferiority).Notably, there were no differences in stent thrombosis as well (1.5% vs. 0.7%, p = 0.13).
TM comes from the STEMI-TROFI II trial [41], which randomized n = 191 STEMI patients to either Absorb TM or Xience TM .The primary endpoint was the 6-month OCT "healing score".Healing was significantly improved in Absorb-treated patients, as compared with subjects randomized to Xience TM , thanks to better strut coverage and apposition.There were no differences in clinical endpoints.
Finally, ABSORB China, which again randomized n = 480 patients with stable coronary artery disease to either Absorb TM or Xience TM Beside randomized data, a large body of evidence on BRS comes from observational registries.
The largest of those is the GHOST-EU registry (n = 1189), which summarizes the European experience with BRS.Currently, 6-month follow-up is available [43].A total of 1731 Absorb , showed comparable outcomes in terms of angiographic insegment late loss at one year [42].
TM scaffolds were implanted, with a technical success rate of 99.7%, despite a large proportion of type-C lesions (28%).Clinical scenarios included: bifurcations (27%), STEMI (16%), in-stent restenosis (3%), ostial lesions (6%) and chronic total occlusions (CTO) (8%).Target lesion failure was 2.2% at 30 days and 4.4% at 6 months.At 6 months, the rates of cardiac death, target vessel myocardial infarction and TLR were 1.0%, 2.0% and 2.5%, respectively.Diabetes mellitus was found to be the only independent predictor of target lesion failure.Alarmingly (but not surprisingly, given the broad spectrum of indications of BRS in this study), the cumulative incidence of definite/probable ST was 1.5% at 30 days and 2.1% at 6 months, with 70% of cases occurring within the first month (at a median of 5 days).Based on these data, the rates of ST with Absorb TM Similar data comes from the ABSORB-EXTEND study, a registry that plans to enroll n = 800 patients from 100 sites worldwide.One of the strengths of this study is that an independent clinical events committee adjudicates all endpoint-related events.The one-year outcomes of n = 512 have recently been published [45].Patient population was of intermediate complexity (26% of patients had diabetes, 41% had type B2/C lesions).Clinical device success was 98.5%.At one year, the composite endpoints of ischemia-driven MACE and ischemia-driven target vessel failure were 4.3% and 4.9%, respectively.The rate of definite and probable ST was 0.8%.
resemble those of first-generation DES and do not compare favorably with the very low rates seen with secondgeneration DES [44].

Limitations of BRS
experienced users redacted consensus criteria for patient and lesion selection, BRS implantation and optimization, as well as the role of intravascular imaging guidance, approach to multiple patient and lesion scenarios, and management of complications [60].
One of the Achilles' heels of BRS appears to be its thrombogenicity, which likely results from rheological disturbances (abnormally low shear stress) observed in the vicinity of its thick struts [61].
As previously mentioned, the rate of ST in early large real-world registries is high (2.1% at 6 months in the GHOST-EU registry [43]).Additionally, the recent report of cases of very late BRS thrombosis [62,63] contributes debulking the belief that BRS were immune from this clinical entity, given the fact that reabsorption is at an advanced stage after one year since implantation, and is completed in most patients by 24 months.Suboptimal implantation (incomplete lesion coverage, underexpansion and malapposition) represents the main mechanism for both early and late BRS thrombosis, similar to metallic ST.Dual antiplatelet therapy discontinuation might also be a secondary contributor in several late events [64].
Similarly, BRS are also vulnerable to develop in-scaffold restenosis, as it has been highlighted by recent reports from the ABSORB B trial and the GHOST-EU registry [65,66].In the ABSORB B trial, the incidence of BRS restenosis was 6% (n = 6) at a median time-to-restenosis of 399 ± 248 days.For half of these cases the main mechanism of restenosis was shown to be significant intrascaffold tissue growth, whereas in the other half it was due to anatomical or procedural factors [65].
Similarly, in one of the centers participating in the GHOST-EU registry, the incidence of BRS restenosis was 3.6% (n = 12) at a median time-to-restenosis of 291 ± 101 days.In this case series, the most frequent mechanisms of restenosis were focal restenosis at the scaffold edge and underexpansion in BRS implanted in type-C lesions [66].Of note, unlike for metallic stent restenosis, there is very little information on how to deal with BRS restenosis.Since at the time of presentation (> 9-12 months) the scaffold has generally lost most of its mechanical properties, balloon angioplasty may disrupt the struts leading to adverse outcomes [66], so that additional stent/scaffold implantation may be unavoidable.A detailed dissertation on the risk factors and mechanisms of BRS failure, as well as possible strategies to deal with it, might be found elsewhere [67].
Another limitation of currently available BRS is their trackability and deliverability.To provide sufficient radial strength to oppose negative remodeling and minimize acute recoil, polymeric scaffolds have thicker struts (150-200 µm) than metallic stents ( ≈8 0 µm).This, together with challenges in the crimping process, results in worse crossing profile of BRS, which ranges between 1.4 mm (Absorb TM ) and 1.8 mm (first-generation ReZolve TM

Conclusions and Future Perspectives
), which is markedly worse than current DES (1.0 mm) [27].These technical limitations hamper the advancement of the BRS across tortuous segments of the coronary arteries and in calcified lesions, for example.Indeed, improvement in BRS crossing profile is one of the main goal of further upcoming iterations of these devices.
BRS have been hailed as the fourth revolution in the history of interventional cardiology [21,22], since they provide temporary scaffolding that helps stabilizing the plaque and promotes healing, and then disappear, leaving no trace behind.This has several advantages, as compared with metallic stents: e.g., the restoration of a functional endothelium and thus vasomotion, the ability to treat instent restenosis without delivering an additional layer of metal, the possibility of eventually performing a CABG anastomosis on the site of prior BRS implantation.

Figure 2 .
Figure 2. Reabsorption process of a polymeric bioresorbable scaffold.The encircled cartoons describe the progressive change in amorphous tie chains of poly-L-lactic acid (PLLA) and the progressive fragmentation of the crystal lamella.Reproduced with permission from [21].

Figure 3 .
Figure 3. Optical coherence tomography (OCT) and histology at 28 days and 2, 3, and 4 years after BRS implantation.At 28 days, OCT shows preserved "box" appearance (A), corresponding to the voids not stained by Alcian Blue (B and C).At 2 years, OCT still shows struts as preserved box (D), but the persistent voids (E) are now replaced by proteoglycan, which stained positively with Alcian Blue (F).At 3 years, only 2 struts at 6 o'clock remained detectable (G).Otherwise, connective tissue cells are now infiltrated in the strut footprints (H, hematoxylin and eosin staining; I, Alcian Blue).At 4 years, struts are no longer discernible by OCT (J); the strut footprints are hardly detectable in Movat staining (K) and Alcian Blue (L) and are characterized by paucity of connective tissue cells and a small amount of calcification.Reproduced with permission from [21].

Table 2 . Technical specifications of clinically tested bioresorbable scaffolds.
It allows traditional one-step implantation (as opposed with Absorb TM TM, which features an improved delivery system and crossing profile.It is an uncoated sirolimus-eluting BRS based on REVA's proprietary desaminotyrosine-derived polycarbonate platform.This interesting polymer is radiopaque, and thus enables complete visualization of the BRS, helping the operator minimizing geographic miss at implantation.