1

Introduction

The management of peripheral artery occlusive disease remains challenging, despite the advances and the shift toward less invasive endovascular techniques during the last decades. Recent studies have shown that primary stenting of infrapopliteal lesions produces similar results compared to balloon angioplasty alone , although modern drug-eluting stents are quite promising . Moreover, data so far seem to support stenting as a first-line treatment for symptomatic lesions in the femoropopliteal segment .

However, the implantation of traditional stents within arteries of the lower extremities is accompanied by major disadvantages. Therefore, in these cases where implants are expected to bear mechanical loads, application of biodegradable materials seem to be promising and challenging at the same time. Although the implantation of bioabsorbable stents in coronary arteries has been extensively evaluated , data regarding their application in peripheral arteries seem to be controversial. Therefore, aim of this study is to collect and present the results of trials testing bioabsorbable stents in patients with peripheral artery disease.

2

Problems associated with traditional stents

Clinical failure modes of stent procedures include restenosis due to intimal hyperplasia or thrombosis, as well as vessel closure due to stent fractures. Stenting itself predisposes to neointimal formation, although the overall luminal gain is maintained by limiting recoil . The initial expansion of the artery could result in disruption of the internal or external elastic laminae, both of which have been associated with higher risk for restenosis . Although stents of newer design have demonstrated promising results regarding primary patency and restenosis , the aforementioned risks remain still. Finally, stent fracture could cause mechanical restenosis through loss of the radial strength of the stent, and it could increase the probability of target lesion revascularization (TLR) .

Regarding long-term effects, a permanent implant (unlike angioplasty alone) remains a trigger for inflammation and vessel wall cellular proliferation long after the implantation procedure. Arteries are complex, non-homogeneous, and non-isotropic materials that undergo large deformations not encountered in most engineering materials. The amount and distribution of stress depends heavily on stent design, with more sparse mesh designs provoking less stress on the artery wall . This stress depends on the mechanical properties of the plaque as well . The degree of flow changes further depends on the degree of over-expansion, with larger post-procedure diameters being associated with lower wall shear stress and thicker neointima formation . However, recent data indicate that the phosphorylcholine groups could reduce tissue responses significantly both in vivo and in vitro, and bioabsorbable materials seem quite promising for preparing temporary cardiovascular stent devices .

2

Problems associated with traditional stents

Clinical failure modes of stent procedures include restenosis due to intimal hyperplasia or thrombosis, as well as vessel closure due to stent fractures. Stenting itself predisposes to neointimal formation, although the overall luminal gain is maintained by limiting recoil . The initial expansion of the artery could result in disruption of the internal or external elastic laminae, both of which have been associated with higher risk for restenosis . Although stents of newer design have demonstrated promising results regarding primary patency and restenosis , the aforementioned risks remain still. Finally, stent fracture could cause mechanical restenosis through loss of the radial strength of the stent, and it could increase the probability of target lesion revascularization (TLR) .

Regarding long-term effects, a permanent implant (unlike angioplasty alone) remains a trigger for inflammation and vessel wall cellular proliferation long after the implantation procedure. Arteries are complex, non-homogeneous, and non-isotropic materials that undergo large deformations not encountered in most engineering materials. The amount and distribution of stress depends heavily on stent design, with more sparse mesh designs provoking less stress on the artery wall . This stress depends on the mechanical properties of the plaque as well . The degree of flow changes further depends on the degree of over-expansion, with larger post-procedure diameters being associated with lower wall shear stress and thicker neointima formation . However, recent data indicate that the phosphorylcholine groups could reduce tissue responses significantly both in vivo and in vitro, and bioabsorbable materials seem quite promising for preparing temporary cardiovascular stent devices .

3

Characteristics and types of bioabsorbable stents

Main goals of bioabsorbable stenting (BRS) include potential reductions in stent/scaffold thrombosis. After biodegradation, there would potentially be no foreign materials present, such as uncovered stent struts or drug polymers that can persist long-term and trigger further thrombosis. Several authors have investigated the potential role of BRS in reducing late restenosis and neo-atherosclerosis although recent data indicate a need for long-term adjunct antithrombotic pharmacotherapy even for bioabsorbable scaffolds . Moreover, the absence of a rigid metallic cage could facilitate the restoration of the vessel vasomotor tone, adaptive shear stress, late luminal enlargement and beneficial late expansive remodeling. Recent studies on BRS of coronary vessels have concluded that this type of stents significantly lowers late lumen loss and late stent thrombosis rates .

In the long-term setting, BRS will potentially facilitate future treatment options such as percutaneous coronary interventions, coronary artery bypass grafting or pharmacologically induced plaque regression. BRS also appears to be compatible with noninvasive imaging such as computed tomography (CT) angiography or magnetic resonance imaging (MRI) . Finally, unlike permanent stents, bioabsorbable stents could be completely replaced by tissue, and may even allow for a positive vascular remodeling. Although current highly successful stent technology is based on permanent metallic stent platforms, it is clinical consensus that stents are only needed during the vascular healing period after stent implantation .

Numerous different materials are available, each with different chemical compositions, mechanical properties, and subsequently bioabsorption times ( Table 1 ). The most frequently used polymer in the current generation is Poly-L-lactide (PLLA), a biodegradable polymer whose molecular weight decreases over time due to cleavage of the ester linkage, degrading into small particles that can be phagocytosed . According to Grabow et al., the newly developed absorbable SIR-eluting PLLA/P4HB stent successfully fulfilled the requirements for peripheral ascular intervention under in vitro conditions . Additionally, metallic alloys are utilized for bioabsorbable stents, including iron and magnesium, with a combination of some other rare metals. Experimental data have shown that such metals halt smooth muscle cell proliferation and stimulate endothelial cell proliferation, which might translate into a beneficial effect in the setting of stent-associated vascular injury .

4

Trials on bioabsorbable stenting

4.2

Arteries below the knee

Only two trials are currently available regarding the use of bioabsorbable stents in infrapopliteal arterial lesions ( Table 2 ). Both studies utilize absorbable metal stents, namely magnesium alloy stents. Peeters et al. presented the results of BRS in patients with limb critical ischemia . In this observational study, mid-term results were quite promising, achieving high 3-month primary patency, limb salvage and survival rates. The AMS INSIGHT trial was the only trial randomizing patients with infrapopliteal lesions into two groups: those managed with percutaneous angioplasty only and those managed with PTA plus stenting . Although there was no difference between the two arms regarding the 30-day postoperative complications (amputation/death), patients managed with stenting showed worse 6-month primary patency and similar clinical improvement .

Table 2

Data of studies on bioabsorbable stenting in peripheral artery disease.

Trials	AMS INSIGHT (2009) [29]	PERSEUS study (2005) [30,31]	ESPRIT I (2013) [32]	GAIA study (2014) [34]	Belgian REMEDY study (2013) [33]	Linni et al (2014) [35]	BEST-BTK (2005) [28]
Design	Multicenter, randomized	Prospective, non-randomized, two-center	Prospective single arm, multi-center	Prospective, non-randomized, multi-center	Observational, multicenter study	Randomized, single-center	Single-center, observational
Type of Vessels	Infrapopliteal lesions	Superficial femoral	SFA, iliac arteries	SFA	SFA	CFA	Infrapopliteal
Number of patients	PTA plus AMS (60) vs PTA only (57)	103	35	30	100	bioabsorbable (40) vs CFE (40)	20
Type of bioabsorbable stent	Mg alloy	PLLA	ESPRIT BVS (PLLA)	Igaki-Tamai (PLLA)	REMEDY stent (PLLA)	REMEDY stent (PLLA)	Metal stent
Maximum follow-up	12 months	24 months	12 months	12 months	12 months	12 months	3 months
Inclusion criteria	> 50% stenosis or occlusion, < 15 mm length of lesion	Rutherford 2–3 Type A, B, C 6–7 cm lesion length limit	Rutherford 1–3, single lesion, length < 50 mm	Symptomatic < 7 cm SFA lesion	Symptomatic < 75 mm SFA lesions, Rutherford 2–5	CFA stenoses/occlusions	Critical limb ischemia (80–100% stenosis)
Main endpoints	30-day Major amputation/death, 6-month patency rate	Primary technical success, major adverse events 12 and 24-month Patency Number of interventions	Amputation, death (1-6-12 months) thrombosis, clinical improvement, ABI improvement	Technical success, restenosis rate, TLR rate, changes in ABI, and quality of life by evaluating the WIQ.	Technical success, freedom from TLR, primary patency	30-day primary patency, 1-year patency rates, limb salvage and survival	3 months patency, limb salvage
Main Results	No difference regarding complications, lower patency rate with AMS	100% technical success No major adverse events	6 month clinical improvement, ABI improvement, no major complications, 98% technical success	Comparable results to bare metal stents	High technical success, 100%	Similar technical success, worse short-term patency for bio-stents. Similar 1 year limb salvage and survival	High patency and limb salvage 3 months
30-day amputation	2/60 2/57 (NS)	0	0	0	0	0	0
30-day death	1/60 1/57 (NS)	0	0	0	0	0	0
6-month primary patency	AMS: 14/44 PTA: 29/50 (P = 0.013)	25% restenosis, no occlusions	100%	61.7%	70.2%	80% stent 100% open	N/A
6-month clinical improvement	27/39 27/41 (NS)	N/A	93.1%	ABI 53.6%	N/A	N/A	N/A 3-month limb salvage: 94.7% Survival 94%
6 month TLR	N/A	N/A	0	25%	18%	N/A	N/A

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