J. of Cardiovasc. Trans. Res. (2014) 7:413–425 DOI 10.1007/s12265-014-9571-7
The Effects of Novel, Bioresorbable Scaffolds on Coronary Vascular Pathophysiology Michael J. Lipinski & Ricardo O. Escarcega & Thibault Lhermusier & Ron Waksman
Received: 18 March 2014 / Accepted: 21 April 2014 / Published online: 7 May 2014 # Springer Science+Business Media New York 2014
Abstract Percutaneous coronary intervention (PCI) has rapidly evolved over the past 30 years as technology has sought to improve clinical outcomes by addressing pathophysiologic complications arising from the intervention. Stents were designed to resolve the drawbacks of balloon angioplasty by providing radial support to prevent vessel recoil, by sealing coronary dissections, and by preventing abrupt vessel closure. The conceptualization of an ideal drug-eluting fully bioresorbable scaffold (BRS), whether metallic or polymeric, would theoretically address the adverse aspects of permanent metallic stents. In this review of the literature, we will discuss the impact these novel fully BRS platforms have on vascular pathophysiology following PCI. Keywords Percutaneous coronary intervention . Bioresorbable scaffold . Smooth muscle cells
Introduction Percutaneous coronary intervention (PCI) has rapidly evolved over the past 30 years as technology has sought to improve clinical outcomes by addressing pathophysiologic complications arising from the intervention. Following balloon angioplasty, the vessel undergoes negative remodeling with shrinkage of the external elastic lamina at the site of dilation compared with the proximal vessel [1]. Furthermore, vessel injury can result in a maladaptive healing process characterized by neointimal hyperplasia [2] and eventual restenosis [3]. Immediately following balloon angioplasty, the platelets Associate Editor Angela Taylor oversaw the review of this article M. J. Lipinski : R. O. Escarcega : T. Lhermusier : R. Waksman (*) MedStar Cardiovascular Research Network, MedStar Heart Institute, MedStar Washington Hospital Center, 110 Irving St., NW, Suite 4B-1, Washington, DC 20010, USA e-mail: [email protected]
present in thrombus lining the vessel wall may help contribute to the process of restenosis [4]. The injured vessel then experiences inflammatory cell infiltration initially with neutrophils [5] and later with mononuclear cells [6, 7]. This stimulates infiltration of smooth muscle cells (SMCs) into the intima and deposition of proteoglycan matrix, which ultimately contribute to restenosis [8]. Stents were designed to resolve the drawbacks of balloon angioplasty by providing radial support to prevent vessel recoil, [9] by sealing coronary dissections, and by preventing abrupt vessel closure. The introduction of bare metal stents (BMSs) was associated with early stent thrombosis, highlighting the need for dual antiplatelet therapy, and restenosis from intimal proliferation remained a significant limitation of percutaneous intervention. Drug-eluting stents (DESs) utilize an antiproliferative drug that elutes from a polymer coating the metallic scaffold. Though they reduced the restenosis rate requiring target lesion revascularization (TLR) to approximately 6 % [10], the slow effusion of antiproliferative drug delays healing, reendothelialization, and coverage of the stent struts, increasing risk of late stent thrombosis, which demanded prolong duration of dual antiplatelet therapy (DAPT) to 12 months [11]. In addition, the polymer coating can also induce acute and chronic inflammation, endothelial dysfunction, and vessel hypersensitivity at the site of the stent, which can lead to late neoatherosclerosis and clinical events [12]. Furthermore, metallic stents are permanent implants and do not allow the vessel to remodel or adapt to neointima formation and can also jail the side branch. The conceptualization of an ideal drug-eluting fully bioresorbable scaffold (BRS), whether metallic or polymeric, would theoretically address the adverse aspects of permanent metallic stents. The presence of a vascular scaffold will seal intimal dissection following balloon angioplasty and provide radial support to prevent vessel recoil, the elution of antiproliferative drug will abate neointimal hyperplasia, and degradation of the stent/scaffold will enable appropriate
414
reendothelialization, allowing the vessel to regain its vasoreactivity and eliminate late effects seen after metallic stents. Figure 1 illustrates the proposed benefits of BRS in relation to vessel pathology. In this review of the literature, we will discuss the impact these novel fully BRS platforms have on vascular pathophysiology following PCI.
Metallic Bioresorbable Scaffolds Stent Corrosion Rather than utilizing inert metal alloys as is seen in traditional BMS, such as stainless steel, cobalt chromium, or platinum chromium, metallic BRSs that are absorbed by the body following serving the role as a vascular scaffold have been developed. This requires that the metallic BRSs meet certain mechanical and corrosion characteristics pertaining to safety and efficacy. There is debate regarding the safety of aluminum-based BRS, and this alloy has not been pursued in humans [13, 14]. A major issue pertaining to metallic BRS is corrosion, as this can impact metal strength and result in BRS fracture. Pure magnesium has low strength [15], and alloy composition is critically important as the presence of nickel, iron, and copper increases the rate of magnesium corrosion [16]. These elements also have important biological effects, as nickel is also known to induce apoptosis through oxidative stress [17], while essential biological trace metals such as manganese and zinc, which strengthen the alloy and reduce corrosion, are critical in multiple biological functions such as protein synthesis [16]. Furthermore, magnesium ions can induce local tissue injury and result in tissue calcification in these regions through stimulation of osteoblastic cell response [18]. The addition of a hydroxyapatite coating to magnesium was shown to also decrease the rate of corrosion and reduced cytotoxicity [19]. Corrosion studies raised concern whether iron is acceptable for use in BRS [20, 21]. Studies of iron BRS in porcine coronary arteries demonstrated evidence of iron BRS degradation at 28 days without fracture [22]. Another small study of iron BRS (Lifetech Scientific) implanted in porcine coronary arteries demonstrated considerable iron staining at 28 days in the tissue surrounding the iron BRS, suggesting iron degradation [23]. While there was no difference in local inflammation surrounding the stent struts compared with pigs that received VISION cobalt chromium BMS (Abbott Vascular, CA, USA), there was a significant reduction in platelet count for pigs that received the iron BRS, raising a question of toxicity [23]. First-generation magnesium BRS (BIOTRONIK AG, Switzerland) in porcine coronary arteries demonstrated BRS degradation as early as 28 days [24]. High-magnification photomicrographs of magnesium BRS at 28 days in porcine coronaries demonstrate intact struts, color changes, and
J. of Cardiovasc. Trans. Res. (2014) 7:413–425
minute cracks at 52 days and large cracks consistent with complete degradation at 3 months [25]. In humans, the firstgeneration magnesium BRS (BIOTRONIK AG, Switzerland) was shown on intravascular ultrasound (IVUS) follow-up to have strut degradation by 4 months in the temporary scaffolding of coronary arteries with bioabsorbable magnesium stents (PROGRESS-AMS) study [26, 27]. The addition of biodegradable sirolimus-eluting poly(lactic acid-co-trimethylene carbonate) polymer to a Chinese magnesium BRS (Institute of Metal Research, Chinese Academy of Sciences) that was deployed in the infrarenal aorta of rabbits resulted in gradual degradation with total biocorrosion in approximately 4 months [28]. The drug-eluting absorbable metallic stent (DREAMS)1 BRS, a paclitaxel-eluting polylactic-co-glycolic acid (PLGA) polymer-coated refined magnesium BRS (BIOTRONIK, Switzerland), has degradation of the refined magnesium scaffold over 9 12 months with resorption of the PLGA and release of paclitaxel over the first 3 months, enabling improved radial support while incorporating drugeluting polymer to combat restenosis [29]. The DREAMS-2 stent, a sirolimus-eluting poly-L-lactic acid (PLLA) polymercoated refined magnesium BRS, is currently under investigation in a large multicenter randomized controlled trial (BIOSOLVE-II). Medtronic Corporation also has a magnesium BRS that is currently being studied, but data are not yet publicly available. Vessel Recoil and Remodeling Vessel recoil and negative remodeling were major reasons for the development of stents. The presence of a durable scaffold to maintain a large lumen following PCI is critical to enable adequate blood flow to the distal vessel. Even if the lesion does not have significant restenosis with neointimal hyperplasia, vessel recoil and negative vessel remodeling can result in a small enough luminal area to cause ischemia. Thus, metallic BRS requires adequate radial strength to resist vessel recoil to prevent negative remodeling. When assessing the artery for in-scaffold area and remodeling following scaffold degradation, it is important to note that the vessel can shrink by 20– 30 % with histopathological processing [30]. Therefore, assessment of vessel remodeling should also be based on in vivo assessment with intracoronary imaging modalities. Firstgeneration magnesium BRS had a significantly smaller vessel area, intimal area, and intimal thickness after 28 days compared with stainless steel stents deployed in the porcine coronary arteries [24]. Though the vessel area of the magnesium BRS was significantly smaller, the increased intimal area and intimal thickness of the stainless steel stent resulted in no significant difference in luminal area for stainless steel stent or magnesium BRS groups [24]. Another study assessing magnesium BRS in porcine coronaries with optical coherence tomography (OCT)
J. of Cardiovasc. Trans. Res. (2014) 7:413–425
415
Fig. 1 Cartoon illustrating the major limitations of percutaneous coronary intervention (PCI) and potential benefit of metallic or polymeric bioresorbable scaffold (BRS). In a, there is a focal atherosclerotic lesion within a coronary artery. The lesion is treated with balloon angioplasty (b), which can result in intimal dissection with subsequent thrombus formation (c, left) or acute vessel recoil (c, right). The lesion can then be treated with placement of a bare metal stent (BMS), drug-eluting stent (DES), or BRS (d). In the case of BMS, neointimal hyperplasia with
restenosis remains a significant problem (e, left). In the case of DES, the risk of restenosis is significantly reduced but stent thrombosis due to inadequate endothelialization remains a major concern (e, center). In the case of a BRS (e, right), the scaffold helps seal intimal dissection and prevent acute vessel recoil, but degradation of the scaffold prevents late stent thrombosis, and incorporation of antiproliferative drug within the biodegradable polymer helps prevent restenosis
demonstrated that both vessel minimal luminal area and mean in-scaffold vessel area at 28-day follow-up (1.68 and 2.48 mm2, respectively) were significantly reduced compared with post-implantation (7.12 and 8.02 mm2, respectively) [25]. These findings suggest negative remodeling and vessel recoil. However, these values increased to 2.99 and 5.90 mm2, respectively, at 3-month follow-up. IVUS demonstrated similar findings for mean lumen cross-sectional area. Negative vascular remodeling was also confirmed in pigs by Maeng and colleagues who compared magnesium BRS with BMS and DES [31]. While neointimal formation was again smallest in the magnesium BRS group, the external elastic lamina area measurement by IVUS was smallest in the magnesium BRS group compared with the BMS and DES groups. IVUS data at 4 months from the PROGRESS-AMS study demonstrated negative remodeling or recoil in 42 % of patients [27] with late lumen loss of 1.08 mm [26]. Implantation of magnesium BRS was characterized by less expansion and less scaffold volume when compared with stainless steel metallic stents, which may be due to the lower radial force with the magnesium BRS [27]. Given that the BRS was nearly completely degraded at 4 months, this raised the question of whether slower degradation of magnesium BRS was necessary to provide greater radial support to prevent vessel recoil and negative remodeling. Improvements in design led to the DREAMS-1 refined magnesium BRS (BIOTRONIK), which was shown to have improved radial support through alteration of the alloy. The BIOSOLVE-I trial demonstrated that there was a decrease in minimal luminal diameter, minimal luminal area, and mean lumen area at 6- and 12-month follow-up with
a non-significant increase in lumen area stenosis after the procedure of 28.8 to 46.1 % at 12-month follow-up [29]. There was evidence of 9.2 % acute recoil following the procedure [29]. Importantly, angiographic late lumen loss decreased to 0.65 mm at 6 months and 0.52 mm at 12 months in BIOSOLVE-I [29] compared with 1.08 mm at 4 months as previously seen in PROGRESS-AMS [26], demonstrating that the improvements in magnesium alloy composition have resulted in better performance in regard to vessel recoil and remodeling. Endothelialization and Neointimal Hyperplasia Following scaffold deployment, a balance must be reached between providing endothelial coverage over the scaffold struts and neointimal hyperplasia with proliferation of SMC. Ideally, there will be rapid endothelial coverage of the scaffold struts to prevent thrombosis with minimal neointimal hyperplasia and no in-scaffold restenosis. Additionally, BRS strut thickness may predict the degree of coverage and endothelialization, as prior data regarding BMS in rabbits demonstrated an inverse correlation between strut thickness and strut coverage [32]. This is important since the number of uncovered struts is predictive of late stent thrombosis [33]. When compared with cobalt-chromium BMS, iron BRS in porcine coronary arteries demonstrated no significant differences in thrombosis, inflammation surrounding the stents, or parastrut fibrin deposition, with a trend toward benefit regarding intimal thickness and area [22]. Another study compared iron BRS (Lifetech Scientific) implanted in porcine coronary
416
arteries with VISION cobalt chromium BMS (Abbott Vascular) [23]. Histopathology demonstrated no significant difference in neointimal area, mean neointimal thickness, and percent area stenosis between iron BRS and BMS. Importantly, six iron BRS had mild to moderate fibrous intimal hyperplasia at 28 days, and two stents had severe hyperplasia [23], suggesting that iron BRS had no benefit in terms of restenosis compared with BMS. Thus, iron BRS do not seem to have benefit when compared with already available BMS, in which there is an established safety and efficacy profile. In vitro studies have that suggested magnesium BRS may be beneficial, as magnesium suppressed vascular SMC proliferation while enhancing endothelial cell proliferation [34]. This raises the hope for reduced restenosis with reduced risk of stent thrombosis. Early studies in porcine coronary arteries demonstrated that magnesium BRS showed no difference compared with stainless steel stents in regard to vessel inflammation, adventitial fibrosis, intimal SMC content, intimal vascularization, endothelialization, or intimal fibrin deposition at 28 days within the stented segment [24]. Importantly, there were no differences between the groups in the non-stented segments. However, the magnesium stents had a significantly smaller intimal area (2.4 vs 5.0 mm2, p
The Effects of Novel, Bioresorbable Scaffolds on Coronary Vascular Pathophysiology Michael J. Lipinski & Ricardo O. Escarcega & Thibault Lhermusier & Ron Waksman
Received: 18 March 2014 / Accepted: 21 April 2014 / Published online: 7 May 2014 # Springer Science+Business Media New York 2014
Abstract Percutaneous coronary intervention (PCI) has rapidly evolved over the past 30 years as technology has sought to improve clinical outcomes by addressing pathophysiologic complications arising from the intervention. Stents were designed to resolve the drawbacks of balloon angioplasty by providing radial support to prevent vessel recoil, by sealing coronary dissections, and by preventing abrupt vessel closure. The conceptualization of an ideal drug-eluting fully bioresorbable scaffold (BRS), whether metallic or polymeric, would theoretically address the adverse aspects of permanent metallic stents. In this review of the literature, we will discuss the impact these novel fully BRS platforms have on vascular pathophysiology following PCI. Keywords Percutaneous coronary intervention . Bioresorbable scaffold . Smooth muscle cells
Introduction Percutaneous coronary intervention (PCI) has rapidly evolved over the past 30 years as technology has sought to improve clinical outcomes by addressing pathophysiologic complications arising from the intervention. Following balloon angioplasty, the vessel undergoes negative remodeling with shrinkage of the external elastic lamina at the site of dilation compared with the proximal vessel [1]. Furthermore, vessel injury can result in a maladaptive healing process characterized by neointimal hyperplasia [2] and eventual restenosis [3]. Immediately following balloon angioplasty, the platelets Associate Editor Angela Taylor oversaw the review of this article M. J. Lipinski : R. O. Escarcega : T. Lhermusier : R. Waksman (*) MedStar Cardiovascular Research Network, MedStar Heart Institute, MedStar Washington Hospital Center, 110 Irving St., NW, Suite 4B-1, Washington, DC 20010, USA e-mail: [email protected]
present in thrombus lining the vessel wall may help contribute to the process of restenosis [4]. The injured vessel then experiences inflammatory cell infiltration initially with neutrophils [5] and later with mononuclear cells [6, 7]. This stimulates infiltration of smooth muscle cells (SMCs) into the intima and deposition of proteoglycan matrix, which ultimately contribute to restenosis [8]. Stents were designed to resolve the drawbacks of balloon angioplasty by providing radial support to prevent vessel recoil, [9] by sealing coronary dissections, and by preventing abrupt vessel closure. The introduction of bare metal stents (BMSs) was associated with early stent thrombosis, highlighting the need for dual antiplatelet therapy, and restenosis from intimal proliferation remained a significant limitation of percutaneous intervention. Drug-eluting stents (DESs) utilize an antiproliferative drug that elutes from a polymer coating the metallic scaffold. Though they reduced the restenosis rate requiring target lesion revascularization (TLR) to approximately 6 % [10], the slow effusion of antiproliferative drug delays healing, reendothelialization, and coverage of the stent struts, increasing risk of late stent thrombosis, which demanded prolong duration of dual antiplatelet therapy (DAPT) to 12 months [11]. In addition, the polymer coating can also induce acute and chronic inflammation, endothelial dysfunction, and vessel hypersensitivity at the site of the stent, which can lead to late neoatherosclerosis and clinical events [12]. Furthermore, metallic stents are permanent implants and do not allow the vessel to remodel or adapt to neointima formation and can also jail the side branch. The conceptualization of an ideal drug-eluting fully bioresorbable scaffold (BRS), whether metallic or polymeric, would theoretically address the adverse aspects of permanent metallic stents. The presence of a vascular scaffold will seal intimal dissection following balloon angioplasty and provide radial support to prevent vessel recoil, the elution of antiproliferative drug will abate neointimal hyperplasia, and degradation of the stent/scaffold will enable appropriate
414
reendothelialization, allowing the vessel to regain its vasoreactivity and eliminate late effects seen after metallic stents. Figure 1 illustrates the proposed benefits of BRS in relation to vessel pathology. In this review of the literature, we will discuss the impact these novel fully BRS platforms have on vascular pathophysiology following PCI.
Metallic Bioresorbable Scaffolds Stent Corrosion Rather than utilizing inert metal alloys as is seen in traditional BMS, such as stainless steel, cobalt chromium, or platinum chromium, metallic BRSs that are absorbed by the body following serving the role as a vascular scaffold have been developed. This requires that the metallic BRSs meet certain mechanical and corrosion characteristics pertaining to safety and efficacy. There is debate regarding the safety of aluminum-based BRS, and this alloy has not been pursued in humans [13, 14]. A major issue pertaining to metallic BRS is corrosion, as this can impact metal strength and result in BRS fracture. Pure magnesium has low strength [15], and alloy composition is critically important as the presence of nickel, iron, and copper increases the rate of magnesium corrosion [16]. These elements also have important biological effects, as nickel is also known to induce apoptosis through oxidative stress [17], while essential biological trace metals such as manganese and zinc, which strengthen the alloy and reduce corrosion, are critical in multiple biological functions such as protein synthesis [16]. Furthermore, magnesium ions can induce local tissue injury and result in tissue calcification in these regions through stimulation of osteoblastic cell response [18]. The addition of a hydroxyapatite coating to magnesium was shown to also decrease the rate of corrosion and reduced cytotoxicity [19]. Corrosion studies raised concern whether iron is acceptable for use in BRS [20, 21]. Studies of iron BRS in porcine coronary arteries demonstrated evidence of iron BRS degradation at 28 days without fracture [22]. Another small study of iron BRS (Lifetech Scientific) implanted in porcine coronary arteries demonstrated considerable iron staining at 28 days in the tissue surrounding the iron BRS, suggesting iron degradation [23]. While there was no difference in local inflammation surrounding the stent struts compared with pigs that received VISION cobalt chromium BMS (Abbott Vascular, CA, USA), there was a significant reduction in platelet count for pigs that received the iron BRS, raising a question of toxicity [23]. First-generation magnesium BRS (BIOTRONIK AG, Switzerland) in porcine coronary arteries demonstrated BRS degradation as early as 28 days [24]. High-magnification photomicrographs of magnesium BRS at 28 days in porcine coronaries demonstrate intact struts, color changes, and
J. of Cardiovasc. Trans. Res. (2014) 7:413–425
minute cracks at 52 days and large cracks consistent with complete degradation at 3 months [25]. In humans, the firstgeneration magnesium BRS (BIOTRONIK AG, Switzerland) was shown on intravascular ultrasound (IVUS) follow-up to have strut degradation by 4 months in the temporary scaffolding of coronary arteries with bioabsorbable magnesium stents (PROGRESS-AMS) study [26, 27]. The addition of biodegradable sirolimus-eluting poly(lactic acid-co-trimethylene carbonate) polymer to a Chinese magnesium BRS (Institute of Metal Research, Chinese Academy of Sciences) that was deployed in the infrarenal aorta of rabbits resulted in gradual degradation with total biocorrosion in approximately 4 months [28]. The drug-eluting absorbable metallic stent (DREAMS)1 BRS, a paclitaxel-eluting polylactic-co-glycolic acid (PLGA) polymer-coated refined magnesium BRS (BIOTRONIK, Switzerland), has degradation of the refined magnesium scaffold over 9 12 months with resorption of the PLGA and release of paclitaxel over the first 3 months, enabling improved radial support while incorporating drugeluting polymer to combat restenosis [29]. The DREAMS-2 stent, a sirolimus-eluting poly-L-lactic acid (PLLA) polymercoated refined magnesium BRS, is currently under investigation in a large multicenter randomized controlled trial (BIOSOLVE-II). Medtronic Corporation also has a magnesium BRS that is currently being studied, but data are not yet publicly available. Vessel Recoil and Remodeling Vessel recoil and negative remodeling were major reasons for the development of stents. The presence of a durable scaffold to maintain a large lumen following PCI is critical to enable adequate blood flow to the distal vessel. Even if the lesion does not have significant restenosis with neointimal hyperplasia, vessel recoil and negative vessel remodeling can result in a small enough luminal area to cause ischemia. Thus, metallic BRS requires adequate radial strength to resist vessel recoil to prevent negative remodeling. When assessing the artery for in-scaffold area and remodeling following scaffold degradation, it is important to note that the vessel can shrink by 20– 30 % with histopathological processing [30]. Therefore, assessment of vessel remodeling should also be based on in vivo assessment with intracoronary imaging modalities. Firstgeneration magnesium BRS had a significantly smaller vessel area, intimal area, and intimal thickness after 28 days compared with stainless steel stents deployed in the porcine coronary arteries [24]. Though the vessel area of the magnesium BRS was significantly smaller, the increased intimal area and intimal thickness of the stainless steel stent resulted in no significant difference in luminal area for stainless steel stent or magnesium BRS groups [24]. Another study assessing magnesium BRS in porcine coronaries with optical coherence tomography (OCT)
J. of Cardiovasc. Trans. Res. (2014) 7:413–425
415
Fig. 1 Cartoon illustrating the major limitations of percutaneous coronary intervention (PCI) and potential benefit of metallic or polymeric bioresorbable scaffold (BRS). In a, there is a focal atherosclerotic lesion within a coronary artery. The lesion is treated with balloon angioplasty (b), which can result in intimal dissection with subsequent thrombus formation (c, left) or acute vessel recoil (c, right). The lesion can then be treated with placement of a bare metal stent (BMS), drug-eluting stent (DES), or BRS (d). In the case of BMS, neointimal hyperplasia with
restenosis remains a significant problem (e, left). In the case of DES, the risk of restenosis is significantly reduced but stent thrombosis due to inadequate endothelialization remains a major concern (e, center). In the case of a BRS (e, right), the scaffold helps seal intimal dissection and prevent acute vessel recoil, but degradation of the scaffold prevents late stent thrombosis, and incorporation of antiproliferative drug within the biodegradable polymer helps prevent restenosis
demonstrated that both vessel minimal luminal area and mean in-scaffold vessel area at 28-day follow-up (1.68 and 2.48 mm2, respectively) were significantly reduced compared with post-implantation (7.12 and 8.02 mm2, respectively) [25]. These findings suggest negative remodeling and vessel recoil. However, these values increased to 2.99 and 5.90 mm2, respectively, at 3-month follow-up. IVUS demonstrated similar findings for mean lumen cross-sectional area. Negative vascular remodeling was also confirmed in pigs by Maeng and colleagues who compared magnesium BRS with BMS and DES [31]. While neointimal formation was again smallest in the magnesium BRS group, the external elastic lamina area measurement by IVUS was smallest in the magnesium BRS group compared with the BMS and DES groups. IVUS data at 4 months from the PROGRESS-AMS study demonstrated negative remodeling or recoil in 42 % of patients [27] with late lumen loss of 1.08 mm [26]. Implantation of magnesium BRS was characterized by less expansion and less scaffold volume when compared with stainless steel metallic stents, which may be due to the lower radial force with the magnesium BRS [27]. Given that the BRS was nearly completely degraded at 4 months, this raised the question of whether slower degradation of magnesium BRS was necessary to provide greater radial support to prevent vessel recoil and negative remodeling. Improvements in design led to the DREAMS-1 refined magnesium BRS (BIOTRONIK), which was shown to have improved radial support through alteration of the alloy. The BIOSOLVE-I trial demonstrated that there was a decrease in minimal luminal diameter, minimal luminal area, and mean lumen area at 6- and 12-month follow-up with
a non-significant increase in lumen area stenosis after the procedure of 28.8 to 46.1 % at 12-month follow-up [29]. There was evidence of 9.2 % acute recoil following the procedure [29]. Importantly, angiographic late lumen loss decreased to 0.65 mm at 6 months and 0.52 mm at 12 months in BIOSOLVE-I [29] compared with 1.08 mm at 4 months as previously seen in PROGRESS-AMS [26], demonstrating that the improvements in magnesium alloy composition have resulted in better performance in regard to vessel recoil and remodeling. Endothelialization and Neointimal Hyperplasia Following scaffold deployment, a balance must be reached between providing endothelial coverage over the scaffold struts and neointimal hyperplasia with proliferation of SMC. Ideally, there will be rapid endothelial coverage of the scaffold struts to prevent thrombosis with minimal neointimal hyperplasia and no in-scaffold restenosis. Additionally, BRS strut thickness may predict the degree of coverage and endothelialization, as prior data regarding BMS in rabbits demonstrated an inverse correlation between strut thickness and strut coverage [32]. This is important since the number of uncovered struts is predictive of late stent thrombosis [33]. When compared with cobalt-chromium BMS, iron BRS in porcine coronary arteries demonstrated no significant differences in thrombosis, inflammation surrounding the stents, or parastrut fibrin deposition, with a trend toward benefit regarding intimal thickness and area [22]. Another study compared iron BRS (Lifetech Scientific) implanted in porcine coronary
416
arteries with VISION cobalt chromium BMS (Abbott Vascular) [23]. Histopathology demonstrated no significant difference in neointimal area, mean neointimal thickness, and percent area stenosis between iron BRS and BMS. Importantly, six iron BRS had mild to moderate fibrous intimal hyperplasia at 28 days, and two stents had severe hyperplasia [23], suggesting that iron BRS had no benefit in terms of restenosis compared with BMS. Thus, iron BRS do not seem to have benefit when compared with already available BMS, in which there is an established safety and efficacy profile. In vitro studies have that suggested magnesium BRS may be beneficial, as magnesium suppressed vascular SMC proliferation while enhancing endothelial cell proliferation [34]. This raises the hope for reduced restenosis with reduced risk of stent thrombosis. Early studies in porcine coronary arteries demonstrated that magnesium BRS showed no difference compared with stainless steel stents in regard to vessel inflammation, adventitial fibrosis, intimal SMC content, intimal vascularization, endothelialization, or intimal fibrin deposition at 28 days within the stented segment [24]. Importantly, there were no differences between the groups in the non-stented segments. However, the magnesium stents had a significantly smaller intimal area (2.4 vs 5.0 mm2, p
