A fully biodegradable polydioxanone occluder for ventricle septal defect closure

Abstract

Ventricular septal defect (VSD) is one of the commonest congenital heart diseases (CHDs). Current occluders for VSD treatment are mainly made of nitinol, which has the risk of nickel allergy, persistent myocardial abrasion and fatal arrythmia. Herein, a fully biodegradable polydioxanone (PDO) occluder equipped with a shape line and poly-l-lactic acid PLLA membranes is developed for VSD closure without the addition of metal marker. PDO occluder showed great mechanical strength, fatigue resistance, geometry fitness, biocompatibility and degradability. In a rat subcutaneous implantation model, PDO filaments significantly alleviated inflammation response, mitigated fibrosis and promoted endothelialization compared with nitinol. The safety and efficacy of PDO occluder were confirmed in a canine VSD model with 3-year follow-up, demonstrating the biodegradable PDO occluder could not only effectively repair VSD, induce cardiac remodeling but also address the complications associated with metal occluders. Furthermore, a pilot clinical trial with five VSD patients indicated that all the occluders were successfully implanted under the guidance of echocardiography and no adverse events occurred during the 3-month follow-up. Collectively, the fully bioresorbable PDO occluder is safe and effective for clinical VSD closure and holds great promise for the treatment of structural CHDs.

Keywords: Biodegradable occluder; Congenital heart disease; Polymer; Tissue regeneration; Ventricle septal defect.

Graphical abstract

Fig. 1

Schematic diagram of the PDO occluder for VSD closure. (A) Biodegradable and biocompatible PDO occluder could significantly alleviate inflammation and promote endothelialization compared with NiTi alloy occluder. (B) The safety and effectiveness of PDO occluder was verified in a rat subcutaneous implantation model, a canine VSD model, and a pilot clinical application for 5 VSD patients. (C) 3-year follow-up of canine VSD model demonstrated the process of the occluder-induced cardiac repair.

Fig. 2

Design, characteristics, biocompatibility of PDO occluder. (A, B) Design of PDO occluder and delivery system. (C) Morphology of PDO occluder released from the sheath before (above) and after (below) the shape line was tightened. (D)¹H NMR; (E) XRD; (F) TGA; (G) GPC; (H) DSC of PDO. (I) Tensile test of PDO monofilament. (J) Microscopic image of right disc of PDO occluder after anti-fatigue test. (K) Cell viability determined by CCK-8 assay. (L) Hemolysis test of PDO monofilament.

Fig. 3

PDO monofilament causes less fibrosis and inflammation in a rat subcutaneous implantation model. (A) Schematic presentation for subcutaneous implantation of PDO monofilament and nitinol wire. (B) Masson staining of tissues of sham, PDO and nitinol group at 1 week, 1 and 3 months, respectively. (C) Statistical analysis of collagen volume fraction of control, PDO and nitinol groups (n = 3). (D) Representative images of H&E staining of control, PDO and nitinol groups. (E) Statistical analysis of inflammation area fraction of control, PDO and nitinol groups (n = 3). *P < 0.05. **P < 0.01. ***P < 0.001. ns, not significant. The black dotted lines indicated the interface between implants and tissue.

Fig. 4

PDO promotes pro-reparative macrophage polarization and endothelialization. (A) Representative immunofluorescence staining of CD206, CD68, iNOS at 1 month after implantation. Average optical density (AOD) was measured (n = 3). (B) Protein expression level of CD68, CD206 and iNOS in tissues determined by western blotting (n = 3). (C) CD31 immunofluorescence staining of tissues at 1 month (n = 3). (D) Protein expression level of CD31 in tissues (n = 3). *P < 0.05. **P < 0.01. ***P < 0.001. ns, not significant. The white dotted lines indicated the interface between implants and tissue.

Fig. 5

Safety and efficacy of PDO occluder implanted in a canine VSD model. (A) Macroscopic views of implanted PDO occluders in ventricular septum at 1, 3, 6, 12, 24 and 36 months. (B) H&E staining of implanted PDO occluder. (C) Masson staining of implanted PDO occluder. (D) The PDO residual area and endothelium coverage curves of PDO occluder. (E) SEM of implanted occluder harvested at 3 and 36 months and native ventricular septum tissue. (F) Illustration of the process of degradation and tissue regeneration.

Fig. 6

ECG, ultrasound and blood tests of canine VSD models. (A) Representative images of ECG and frequency of arrhythmia during follow-up. (B) TTE images and analysis of left and right disc area. The occluders are outlined with the white dotted line. (C–E) Quantification of LVEF, LVFS, LVEDV, LVEDS LVIDd and LVIDs by echocardiography (n = 3). (F–H) Quantification of ALT, AST, ALKP, WBC, RBC and HGB (n = 3). APB: atrial premature beat; AT: atrial tachyarrhythmia; VPB: ventricular premature beat; VT: ventricular tachyarrhythmia; AF: atrial fibrillation. LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; EDV: end-diastolic volume; ESV: end-systolic volume; LVIDd: left ventricular internal dimension in diastolic; LVIDs: left ventricular internal dimension in systole. ALT: alanine transaminase; AST: aspartate transaminase; ALKP: alkaline phosphatase; WBC: white blood cell; RBC: red blood cell; HGB: hemoglobin.

Fig. 7

Clinical application of PDO occluder in VSD patients. (A) Procedures of implantation of PDO occluders under the TTE guidance. (B) 3-month follow-up by TTE. TTE: transthoracic echocardiography. (C–H) Quantification of ALT, AST, TBIL, CRE, BUN, BUA, HGB and PLT (n = 5). ALT: alanine transaminase; AST: aspartate transaminase; TBIL: total bilirubin; CRE: creatinine; BUN: blood urea nitrogen; BUA: blood uric acid; HBG: hemoglobin; PLT: blood platelet.