Application situation of degradable coronary stents

doi:10.3969/j.issn.2095-4344.2014.08.020

Abstract

Abstract:

BACKGROUND: The appearance of biodigradable stents brings a new dawn for the fourth coronary intervention revolution. They not only can solve the problem of postoperative acute occlusion of blood vessels, but also can be completely absorbed after a certain time.
OBJECTIVE: To summarize the application status of biodegradable coronary stents.
METHODS: PubMed, CBM and embase were searched for articles related to biodegradable intravascular stents.
RESULTS AND CONCLUSION: Biodegradable polymer stents, biodegradable magnesium stents and biodegradable iron stents are currently the three major research biodegradable stent systems. Numerous clinical trials have demonstrated the long-term safety and reliability of the biological degradation stents, and in the near future they will replace the existing drug-eluting stents as the primary means of percutaneous coronary intervention. Biodegradable stents currently still have their limitations, which are reflected in the relationship between mechanical properties and degradation rate and cannot be applied to complicated coronary patients temporarily. It takes 6-12 months to restore normal physiological function of blood vessels, and it can be considered reasonable that degradation of stents is completed in 12-24 months. Poly(lactic-co-glycolic) produced by polylactic acid and polyglycolic acid is currently widely recognized as the stent’s framework. We can get a more appropriate balance between the mechanical properties of the stent and the degradation rate by adjusting the ratio of polylactic acid and polyglycolic acid. This stent not only has good mechanical properties, but also can be completely biodegradable after the restoration of normal function of blood vessels, which has a broad research space.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: biocompatible materials, stents, coronary stenosis, review

CLC Number:

R318

Li Lu-feng, Liu Huan-yun, Zhao Xiao-hui. Application situation of degradable coronary stents[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(8): 1270-1276.

Figures/Tables 3

聚羟基乙酸、聚乳酸、聚对二氧环己酮、聚己内酯及聚三亚甲基碳酸酯。其中的聚乳酸有右旋和左旋之分。因只有左旋聚乳酸能被人体降解吸收，故一般选用左旋聚乳酸。在这些可降解材料中，综合考虑机械性能、生物相容性及可降解性，左旋聚乳酸，聚羟基乙酸尤其是它们的共聚物PLGA较适合作为支架材料。聚乳酸结晶度较高，硬度较大，生物降解需时较长，聚羟基乙酸则结晶度较低，硬度较小，生物降解需时较短，将这两种材料按照不同比例共聚得到的不同的PLGA将会具有不同降解速度，从而实现对完全降解时间的调控。Lincoff 等[8]通过实验证实高分子左旋聚乳酸支架(相对分子质量321 000)相比于低分子左旋聚乳酸支架与血管壁的生物相容性更好。Yamawaki等[9]第一次研制出一种由左旋聚乳酸和酪氨酸及酶抑制剂构成的完全的生物可降解支架。通过在猪模型上做实验说明了这个支架的有效性和安全性并支持应用于人。 2.1.2 Igaki-Tamai(IT)支架 IT 支架是第一种在人体内进行临床评估的完全可降解生物支架，由左旋聚乳酸组成，完全降解需要18-24个月。第一代IT支架采用螺旋曲折设计，该支架被安置在一个标准的血管成形的球囊上，随着球囊的扩张进行自我热膨胀。自1998至2012年，在大量动物实验证明左旋聚乳酸支架具有良好的生物相容性及支撑性能后[3]，人们对IT支架开展了一系列临床研究[10]，FIM(First-in-man)研究表明：IT支架(15例患者，19处病变，25个支架)在30 d内没有发生主要心血管不良事件或支架血栓形成事件，并且与裸金属支架相比，损耗指数为0.48(后期亏损/急性增益)，这是生物可降解支架第一次没有引起内膜增生过多。目前Nishio等[11-12]报道了一个前瞻性观察研究对的长期随访结果(>10年)，有50例患者(63处病变)共植入84枚IT支架，10年全因死亡、心源性死亡、主要心血管不良事件的累积存活率分别是87%、98%和90%；靶病变血运重建率分别为第1年16%，第5年18%，第10年28%。尽管短期和长期随访结果很不错，但IT支架没能继续取得研究进展，主要是由于植入需要的引导管太大(8F)及需要使用热诱导促使自我膨胀，这可能会引起动脉壁坏死进而导致内膜过度增生或者增加血小板黏附，故难以将其用于临床应用。新一代IT支架整逐渐克服这些缺点，可以使用6F的引导管且不需要再膨胀过程中加热。目前此支架正在进行预临床评估。 2.1.3 BVS支架 BVS支架由美国的雅培公司开发，是一种以左旋聚乳酸为骨架，右旋聚乳酸为涂层，依维莫司为抗增殖药物的生物可降解支架。在猪模型上进行组织学为基础的研究表明：支架植入后3年被完全吸收[13]。第一代BVS支架(图1A)直径 1.4 mm，厚度150 µm，由细而直的桥连接的锯齿状圈状物构成，进行了ABSORB cohort A试验[14]。该试验的目的是为了评估在单支冠状动脉病变患者置入这种支架的可行性与安全性，选择了30例有稳定或不稳定的冠状动脉缺血患者，主要心血管不良事件的终点是心源性死亡、心肌梗死、缺血性靶病变血运重建。4年跟踪随访显示主要不良心血管事件发生率为3.3%，仅有1例患者发生没有病理性Q波的心肌梗死[15]。造影显示术后6个月和12个月的支架内管腔丢失率没有显著差异。血管内超声显像说明管腔面积的变化是由于支架早期回缩导致内膜增生所致[16]。因为以上的缺陷，BVS支架经过重新设计，新一代BVS拥有更多的支柱能对血管壁提供"

更有力的支撑[17]。第二代BVS支架(图1B)通过ABSORB cohort B试验进行测试。 ABSORB cohort B试验选择101例患者分别植入3.0 mm×18 mm 可吸收BVS支架，分为B1组(n=45)，B2组(n=56)[18-19]。B1组在半年和第2年，B2组在第1年和第3年行血管内造影及血管内超声等侵入性检查，两组在随访第18个月是均性断层冠脉造影。发现与第一代BVS支架相比，晚期支架回缩基本消失。6个月时的晚期管腔丢失为(0.19±0.18) mm，3年后随访管腔丢失为(0.27±0.32) mm，与Xience V依维莫司洗脱支架晚期丢失(0.23±0.29) mm相似。除了ABSORB cohort B试验，还有ABSORB physiology、ABSORB 2、ABSORB EXTEND三个试验正在进行。Muramatsu等[20]进行了有关 BVS 支架植入后分支血管阻塞的ABSORB-EXTEND 试验。结果显示BVS比依维莫司洗脱支架能提供更持久的血管支持及将药物输送到血管内皮，没有晚期支架内血栓和未来很难进行外科手术恢复血运重建等问题。该试验还表明：与依维莫司洗脱金属支架相比，BVS有更高的小分支闭塞发生率。随着支架厚度的增加，小分支闭塞的发生率还会进一步增加，此问题有待通过改进支架工艺解决。 2.1.4 REVA支架是由美国 REVA医药公司研发的多聚(碘化酪氨酸烷基)碳酸酯支架，降解产物有水、二氧化碳、乙醇及碘化酪氨酸烷基，最后均可被人体吸收或排出体外，完全降解需要36个月。第一代REVA支架(图2A)未负载抗增殖药物，采用独特的“滑动和锁定”设计，能在支架置入后提供不错的径向支撑力[22]。第一代REVA支架的长期试验(55个月)在健康猪模型上进行，试验指出：一系列血管超声表明随访期间管腔面积逐渐增大[23]。REVA支架的临床表现通过RESORB研究评价。血管造影显示25例有单支冠脉病变的患者植入此支架后最小管腔直径由(0.88±0.39) mm增加到(2.76± 0.36) mm，与目前金属支架的急性增益相似。然而在随访的4-6个月之间靶病变血运重建率增大，为了解决这一问题，科学家对支架结构进行了重新设计[24]。改进后的第二代ReZolve支架(图2B，抗增殖药物为西罗莫司)，药物完全洗脱需要超过30 d，支架完全降解需要1年，通过提高聚合物强度及改进的“螺旋的滑动和锁定”设计进一步提高径向支撑力，以减少支架弹性回缩。REsolve 西罗莫司洗脱可降解冠状动脉支架正在进行RESORB试验，计划选择50例患者调查它的有效性和安全性。目前第二代ReZolve支架已经有了更高剂量的西罗莫司及更慢的药物释放系统，并且支架制作工艺得到了改进，在保证机械性能的前提下减小支架横截面积及厚度，大规模的临床试验即将展开。 2.1.5 IDEAL支架 IDEAL支架是由美国生物吸收治疗公司研发的可完全生物吸收的球囊扩张支架，骨干是聚酐酯和水杨酸，雷帕霉素是涂层药物。预临床试验表明水杨酸有潜在的抗炎和抗血小板的特性，在聚合物洗脱时可以减少狭窄，促进血管恢复正常的生理功能[26-27]。有研究对第一代BTI支架进行了“WHISPER”研究，11例患者参与了这一研究[28]。血管内超声提示由于药物携带量不足和药物释放过快导致了内膜形成增加。故第二代IDEAL支架优化了支架结构，增加携带药物剂量，减慢药物释放，目前新一代的IDEAL支架正在进行预临床试验，不久的将来即将开展临床试验。 2.1.6 DESolve支架 DESolve支架以左旋聚乳酸为骨架，聚乳酸为聚合物涂层，Myolimus和Novolimus 为抗增殖药物。这种支架的径向支撑力可以与Elixir的裸金属支架相比，完全降解吸收需要二三年[29]。为了证明其安全性和有效性，Verheye[30]在16例单支病变长度小于1 cm的冠状动脉病变患者血管内植入直径3 mm的DEsolve支架，1例冠脉旁路移植患者在30 d随访时发生了靶血管血运重建，1例患者在30-180 d的随访时间内发生了靶病变血运重建，而在6个月随访期间没有心源性死亡、心肌梗死、支架内血栓的发生。在总结以上数据后，DEsolve NX试验展开。这个试验计划选取120例患者，随访6个月，终点事件为晚期支架内病变消失。DEsolve NX 2试验计划纳入更多的患者来证实该支架"

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