陈宜婷,胡海波

• 1:国家心血管病中心北京协和医学院中国医学科学院阜外医院结构性心脏病中心

摘要(Abstract)：

先天性心脏病是一类常见的先天性畸形疾病。临床上常见的先天性心脏病有室间隔缺损、房间隔缺损、动脉导管未闭、卵圆孔未闭等，以镍钛金属封堵器为主流的经导管封堵术为目前一线治疗方案，但术后面临着如心脏穿孔、镍离子过敏、残余分流、心脏侵蚀、房室传导阻滞等并发症的发生风险。因此，可降解封堵器成为近十年来的研究热点，其发展已从“部分可吸收”演进至“完全可吸收”，多种可降解装置在人体试验中展现出初步的安全性和有效性。然而，置入引发的免疫/炎症反应及降解副产物，仍是影响其封堵可靠性和长期安全性的关键挑战。因此本文系统综述生物可降解封堵器体内炎症反应机制、研究进展与临床转化挑战，重点探讨提升生物相容性的材料改性策略及最新成果，并展望其从实验室到临床应用的情况。

关键词(KeyWords)： 生物可降解封堵器;炎症反应;生物相容性;先天性心脏病;临床转化

Abstract:

Keywords:

基金项目(Foundation): 北京市科学技术委员会“首都临床特色诊疗技术研究与转化应用”专项基金项目（Z201100005520075）;; 中国医学科学院阜外医院国家高水平医院临床科研项目（2022-GSP-GG-18）

作者(Author): 陈宜婷,胡海波

参考文献(References)：

• [1]Liu Y,Chen S,Zühlke L,et al.Global birth prevalence of congenital heart defects 1970-2017:updated systematic review and metaanalysis of 260 studies[J].Int J Epidemiol, 2019,48(2):455-463.DOI:10.1093/ije/dyz009.
• [2]Chessa M,Carminati M,Butera G,et al.Early and late complications associated with transcatheter occlusion of secundum atrial septal defect[J].J Am Coll Cardiol,2002,39(6):1061-1065. DOI:10.1016/s0735-1097(02)01711-4.
• [3]Xu Q,Fa H,Yang P,et al.Progress of biodegradable polymer application in cardiac occluders[J].J Biomed Mater Res B Appl Biomater,2024,112(1):e35351. DOI:10.1002/jbm.b.35351.
• [4]Nyska A,Schiffenbauer YS,Brami CT,et al.Histopathology of biodegradable polymers:challenges in interpretation and the use of a novel compact MRI for biocompatibility evaluation[J].Polym Adv Technol,2014,25(5):461-467. DOI:10.1002/pat.3238.
• [5]Ramot Y,Haim-Zada M,Domb AJ,et al.Biocompatibility and safety of PLA and its copolymers[J].Adv Drug Deliv Rev,2016,107:153-162. DOI:10.1016/j.addr.2016.03.012.
• [6]Luttikhuizen DT,Harmsen MC,Van Luyn MJ.Cellular and molecular dynamics in the foreign body reaction[J].Tissue Eng,2006,12(7):1955-1970. DOI:10.1089/ten.2006.12.1955.
• [7]Tang L,Jennings TA,Eaton JW.Mast cells mediate acute inflammatory responses to implanted biomaterials[J].Proc Natl Acad Sci U S A,1998,95(15):8841-8846. DOI:10.1073/pnas.95.15.8841.
• [8]Nicolete R,dos Santos DF,Faccioli LH.The uptake of PLGA micro or nanoparticles by macrophages provokes distinct in vitro inflammatory response[J].Int Immunopharmacol,2011,11(10):1557-1563.DOI:10.1016/j.intimp.2011.05.014.
• [9]Yoon SJ,Kim SH,Ha HJ,et al.Reduction of inflammatory reaction of poly(d,l-lactic-co-glycolic Acid)using demineralized bone particles[J].Tissue Eng Part A,2008,14(4):539-547. DOI:10.1089/tea.2007.0129.
• [10]Zhu H,Yang F,Tang B,et al.Mesenchymal stem cells attenuated PLGA-induced inflammatory responses by inhibiting host DC maturation and function[J].Biomaterials,2015,53:688-698.DOI:10.1016/j.biomaterials.2015.03.005.
• [11]Amini AR,Wallace JS,Nukavarapu SP.Short-term and longterm effects of orthopedic biodegradable implants[J].J Long Term Eff Med Implants,2011,21(2):93-122. DOI:10.1615/jlongtermeffmedimplants.v21.i2.10.
• [12]Spiller KL,Nassiri S,Witherel CE,et al.Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds[J].Biomaterials,2015,37:194-207. DOI:10.1016/j.biomaterials.2014.10.017.
• [13]Caires HR,Barros da Silva P,Barbosa MA,et al.A co-culture system with three different primary human cell populations reveals that biomaterials and MSC modulate macrophage-driven fibroblast recruitment[J].J Tissue Eng Regen Med,2018, 12(3):e1433-e1440.DOI:10.1002/term.2560.
• [14]Ma S,Feng X,Liu F,et al.The pro-inflammatory response of macrophages regulated by acid degradation products of poly(lactide-co-glycolide)nanoparticles[J].Eng Life Sci,2021,21(10):709-720. DOI:10.1002/elsc.202100040.
• [15]Li Z,Kong P,Liu X,et al.A fully biodegradable polydioxanone occluder for ventricle septal defect closure[J].Bioact Mater,2022,24:252-262. DOI:10.1016/j.bioactmat.2022.12.018.
• [16]Garg K,Pullen NA,Oskeritzian CA,et al.Macrophage functional polarization(M1/M2)in response to varying fiber and pore dimensions of electrospun scaffolds[J].Biomaterials,2013,34(18):4439-4451. DOI:10.1016/j.biomaterials.2013.02.065.
• [17]Abebayehu D,Spence AJ,McClure MJ,et al.Polymer scaffold architecture is a key determinant in mast cell inflammatory and angiogenic responses[J].J Biomed Mater Res A,2019,107(4):884-892. DOI:10.1002/jbm.a.36605.
• [18]Pineda Molina C,Giglio R,Gandhi RM,et al.Comparison of the host macrophage response to synthetic and biologic surgical meshes used for ventral hernia repair[J].Journal of Immunology and Regenerative Medicine,2019,3:13-25. DOI:10.1016/j.regen.2018.12.002.
• [19]Pineda Molina C,Hussey GS,Liu A,et al. Role of 4-hydroxybutyrate in increased resistance to surgical site infections associated with surgical meshes[J].Biomaterials,2021,267:120493. DOI:10.1016/j.biomaterials.2020.120493.
• [20]Keridou I,Franco L,del Valle LJ,et al.Hydrolytic and enzymatic degradation of biobased poly(4-hydroxybutyrate)films. Selective etching of spherulites[J].Polymer Degradation and Stability,2021,183:109451. DOI:10.1016/j.polymdegradstab.2020.109451.
• [21]Kyriakides TR,Kim HJ,Zheng C,et al.Foreign body response to synthetic polymer biomaterials and the role of adaptive immunity[J].Biomed Mater,2022,17(2). DOI:10.1088/1748-605X/ac5574.
• [22]Jux C,Bertram H,Wohlsein P,et al.Interventional atrial septal defect closure using a totally bioresorbable occluder matrix:development and preclinical evaluation of the BioSTAR device[J].J Am Coll Cardiol,2006,48(1):161-169. DOI:10.1016/j.jacc.2006.02.057.
• [23]Pavcnik D,Tekulve K,Uchida BT,et al.Double BioDisk:a new bioprosthetic device for transcatheter closure of atrial septal defects-a feasibility study in adult sheep[J].Radiol Oncol,2012,46(2):89-96. DOI:10.2478/v10019-012-0029-8.
• [24]周广泰,周超,张海军.卵圆孔未闭封堵器材料研究进展[J].中国介入心脏病学杂志,2024,32(12):709-716. DOI:10.3969/j.issn.1004-8812.2024.12.008.
• [25]Lin C,Liu L,Liu Y,et al.Recent developments in next-generation occlusion devices[J].Acta Biomater,2021,128:100-119.DOI:10.1016/j.actbio.2021.04.050.
• [26]Ping Ooi C,Cameron RE.The hydrolytic degradation of polydioxanone(PDSII)sutures.PartⅠ:morphological aspects[J].J Biomed Mater Res,2002,63(3):280-290. DOI:10.1002/jbm.10180.
• [27]Sun Y,Zhang X,Li W,et al.3D printing and biocompatibility study of a new biodegradable occluder for cardiac defect[J].J Cardiol,2019,74(2):182-188. DOI:10.1016/j.jjcc.2019.02.002.
• [28]Li Y,Xie Y,Li B,et al.Initial clinical experience with the biodegradable AbsnowTM device for percutaneous closure of atrial septal defect:a 3-year follow-up[J].J Interv Cardiol,2021,2021:6369493. DOI:10.1155/2021/6369493.
• [29]Bartnikowski M,Dargaville TR,Ivanovski S,et al.Degradation mechanisms of polycaprolactone in the context of chemistry,geometry and environment[J].Progress in Polymer Science,2019,96:1-20. DOI:0.1016/j.progpolymsci.2019.05.004.
• [30]Liu SJ,Peng KM,Hsiao CY,et al.Novel biodegradable polycaprolactone occlusion device combining nanofibrous PLGA/collagen membrane for closure of atrial septal defect(ASD)[J].Ann Biomed Eng, 2011,39(11):2759-2766. DOI:10.1007/s10439-011-0368-4.
• [31]Cagli B,Gratteri M,Cimmino AA,et al.Innovative application of Gala FLEX poly-4-hydroxybutyrate scaffold in breast reduction/mastopexy with inferiorly based dermo-adipose flap[J]. Plast Reconstr Surg Glob Open,2024,12(3):e5676. DOI:10.1097/GOX.0000000000005676.
• [32]Weber B,Schoenauer R,Papadopulos F,et al.Engineering of living autologous human umbilical cord cell-based septal occluder membranes using composite PGA-P4HB matrices[J].Biomaterials,2011,32(36):9630-9641. DOI:10.1016/j.biomaterials.2011.07.070.
• [33]Mohammadi Nasr S,Rabiee N,Hajebi S,et al.Biodegradable nanopolymers in cardiac tissue engineering:from concept towards nanomedicine[J].Int J Nanomedicine,2020,15:4205-4224.DOI:10.2147/IJN.S245936.
• [34]Lu Y,Cheng D,Niu B,et al.Properties of poly(lactic-co-glycolic acid)and progress of poly(lactic-co-glycolic acid)-based biodegradable materials in biomedical research[J]. Pharmaceuticals(Basel),2023,16(3):454. DOI:10.3390/ph16030454.
• [35]Sittinger M,Reitzel D,Dauner M,et al.Resorbable polyesters in cartilage engineering:affinity and biocompatibility of polymer fiber structures to chondrocytes[J].J Biomed Mater Res,1998,33(2):57-63.DOI:10.1002/(SICI)1097-4636(199622)33:2<57::AID-JBM1>3.0.CO;2-K.
• [36]Mahar R,Chakraborty A,Nainwal N,et al.Application of PLGA as a biodegradable and biocompatible polymer for pulmonary delivery of drugs[J].AAPS PharmSciTech,2023,24(1):39. DOI:10.1208/s12249-023-02502-1.
• [37]陈怡峰,郝鸿业,王聪,等.心血管植介入器械原位内皮化策略——内皮细胞选择性[J].中国医学前沿杂志(电子版),2023,15(9):61-68. DOI:10.12037/YXQY.2023.09-09.
• [38]Grewe PH,Deneke T,Machraoui A,et al.Acute and chronic tissue response to coronary stent implantation:pathologic findings in human specimen[J].J Am Coll Cardiol,2000,35(1):157-163.DOI:10.1016/s0735-1097(99)00486-6.
• [39]Kong P,Liu X,Li Z,et al.Biodegradable cardiac occluder with surface modification by gelatin-peptide conjugate to promote endogenous tissue regeneration[J].Adv Sci(Weinh),2024,11(2):e2305967. DOI:10.1002/advs.202305967.
• [40]Bonou M,Lampropoulos KM,Barbetseas J.Thrombus formation 10years after placement of an atrial septal secundum defect closure device[J].Eur Heart J,2012,33(6):704. DOI:10.1093/eurheartj/ehr313.
• [41]Li BN,Xie YM,Xie ZF,et al. Study of biodegradable occluder of atrial septal defect in a porcine model[J].Catheter Cardiovasc Interv,2019,93(1):E38-E45. DOI:10.1002/ccd.27852.
• [42]Roh JD,Sawh-Martinez R,Brennan MP,et al.Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling[J].Proc Natl Acad Sci U S A,2010,107(10):4669-4674. DOI:10.1073/pnas.0911465107.
• [43]Qin Y,Zhu Y,Lu L,et al.Tailored extracellular matrix-mimetic coating facilitates reendothelialization and tissue healing of cardiac occluders[J].Biomaterials,2025,313:122769. DOI:10.1016/j.biomaterials.2024.122769.
• [44]Chu B,Li X,Fan S,et al.CD34 antibody-coated biodegradable fiber membrane effectively corrects atrial septal defect(ASD)by promoting endothelialization[J].Polymers(Basel),2022, 15(1):108.DOI:10.3390/polym15010108.
• [45]田认,陈铀.可降解材料在心血管介入治疗中的应用进展[J].临床医学进展,2022,12(10):9037-9043. DOI:10.12677/ACM.2022.12101307.
• [46]Coronel-Meneses D,Sánchez-Trasvi??a C,Ratera I,et al. Strategies for surface coatings of implantable cardiac medical devices[J].Front Bioeng Biotechnol,2023,11:1173260. DOI:10.3389/fbioe.2023.1173260.
• [47]东南大学,东南大学苏州医疗器械研究院.一种具有药物缓释功能的可降解封堵器及其制备方法和应用:CN202510478973.4[P].2025-07-11.
• [48]Ouyang W,Jiang H,Yan X,et al.Bioresorbable vs metallic occluders for transcatheter atrial septal defect closure:a randomized clinical trial[J].JAMA,2025. DOI:10.1001/jama.2025.17639.
• [49]Sun Y,Xia Y,Zhang X,et al.An innovative occluder for cardiac defect:3D printing and a biocompatibility research based on self-developed bioabsorbable material-LA-GA-TMC[J].J Biomed Mater Res B Appl Biomater,2020,108(5):2108-2118.DOI:10.1002/jbm.b.34550.
• [50]Lin C,Lv J,Li Y,et al.4D-printed biodegradable and remotely controllable shape memory occlusion devices[J].Advanced Functional Materials,2019,29(51):1906569. DOI:10.1002/adfm.201906569.
• [51]Xiang Z,Zhang J,Zhou C,et al.Near-infrared remotely controllable shape memory biodegradable occluder based on poly(l-lactide-co-ε-caprolactone)/gold nanorod composite[J].ACS Appl Mater Interfaces,2023,15(36):42341-42353. DOI:10.1021/acsami.3c09852.
• [52]Zhang F,Dong J,Wei P,et al Transcatheter closure of patent foramen ovale with a novel biodegradable device:a prospective, multicenter,randomized controlled clinical trial[J].Circulation,2026,153(2):71-81.DOI:10.1161/CIRCULATIONAHA.125.074609.
• [53]栗政伟,胡海波,潘湘斌.经导管缝合卵圆孔未闭的研究进展[J].中国介入心脏病学杂志,2025,33(2):106-110. DOI:10.3969/j.issn.1004-8812.2025.02.007.