Abstract
Fully bioresorbable vascular scaffolds (BVSs) aim to overcome the limitations of metallic drug-eluting stents (DESs). However, polymer-based BVSs, such as Abbott's Absorb, the only US FDA-approved BVS, have had limited use due to increased strut thickness (157 μm for Absorb), exacerbated tissue inflammation, and increased risk of major cardiac events leading to inferior clinical performance when compared to metallic DESs. Herein we report the development of a drug-eluting BVS (DE-BVS) through the innovative use of a photopolymerizable, citrate-based biomaterial and a high-precision additive manufacturing process. BVS with a clinically relevant strut thickness of 62 μm can be produced in a high-throughput manner, i.e. one BVS per minute, and controlled release of the anti-restenosis drug everolimus can be achieved by engineering the structure of polymer coatings to fabricate drug-eluting BVS. We achieved the successful deployment of BVSs and DE-BVSs in swine coronary arteries using a custom-built balloon catheter and BVS delivery system and confirmed BVS safety and efficacy regarding maintenance of vessel patency for 28 days, observing an inflammation profile for BVS and DE-BVS that was comparable to the commercial XIENCE™ DES (Abbott Vascular).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 195-206 |
| Number of pages | 12 |
| Journal | Bioactive Materials |
| Volume | 38 |
| DOIs | |
| State | Published - Aug 2024 |
Funding
We tackle the aforementioned challenges via the implementation of a two-fold strategy. To address the inflammatory responses to PLLA, we investigate the use of citrate-based polymers, such as polydiolcitrates, to fabricate BVSs. Polydiolcitrates have demonstrated intrinsic antioxidant properties that reduce chronic inflammatory responses associated with PLLA [13]. Of note, polydiolcitrates have been recently used for the fabrication of FDA-cleared biodegradable implantable medical devices currently used in musculoskeletal surgeries [14,15]. Furthermore, we and others have shown that polydiolcitrates have intrinsic thromboresistant properties and support the formation of a functional endothelium [16\u201318]. To address the adverse impact of increased strut thickness, we refined the high-precision additive manufacturing process flow to fabricate drug-eluting BVSs (DE-BVSs) with a clinically relevant strut thickness of less than 100 \u03BCm.DESs consisting of a metal stent with a thin polymer coating as the carrier of anti-stenosis drugs have been developed to combat intimal hyperplasia. Current approaches to control the release of a drug from a stent have challenges that impact endothelial tissue recovery. Here, we applied mPOC as the drug-carrying polymer coating for 3D-printed BVSs and show that the controlled release of everolimus is achieved (Fig. 2). Drug-eluting BVSs (DE-BVSs) were fabricated by sequentially depositing a polymer-drug layer (mPOC with everolimus) and a barrier layer (mPOC only) with an ultrasonic sprayer (Fig. 2A). A conformal and uniform coating with a smooth surface finish was obtained on both luminal and abluminal surfaces of the DE-BVSs, as shown by scanning electron microscopy (SEM) images (Supporting InformationFig. S2). The strut thickness was increased from 62 \u00B1 3 \u03BCm for the bare BVS to 99 \u00B1 4 \u03BCm for the DE-BVS (drug layer and barrier layer). The successful incorporation of everolimus within the coating was confirmed by ATR-FTIR analysis (Supporting Information Fig. S3). The characteristic peaks for pure everolimus, including 1643 cm\u22121 (C=O), 1451 cm\u22121 (C\u2013H), and 990 cm\u22121 (C\u2013H) [19], were detected in the spectra of DE-BVS (drug and drug + barrier), but they were not visible in the spectra of BVS with pure polymer coating not containing the drug.Both BVSs and DE-BVSs induced similar levels of arterial narrowing to that induced by XIENCE DES as measured by IVUS over 28 days (Fig. 5A). The Movat's pentachrome and hematoxylin and eosin (H&E) stained tissue sections showed that: 1) the lumen remained patent without any evidence of thrombosis; and 2) all scaffold/stent struts were fully covered by neointima tissue with well-organized structures (Fig. 5B). Quantitative analyses showed that there were no statistically significant differences in luminal area, neointimal area, neointimal thickness, and area stenosis when comparing the BVS or DE-BVS with the XIENCE DES (Fig. 5C and Supporting InformationTable S1). The mean values of neointimal area and area restenosis induced by the XIENCE DES were lower than those induced by BVS and DE-BVS, which was mainly ascribed to the significant arterial remodeling response to the implantation in 2 out of 8 swine. The neointima area of DE-BVS and XIENCE DES groups were 4.6 \u00B1 4.4 and 2.6 \u00B1 1.2 mm2, respectively, which were not significantly different from that of the BVS group, i.e. 3.8 \u00B1 2.2 mm2 and p > 0.46. Similarly, there was no statistically significant difference in the area restenosis among these three groups, i.e. BVS (62.0 \u00B1 23.8 %), DE-BVS (61.8 \u00B1 17.5 %), and XIENCE DES (48.6 \u00B1 22.1 %); p > 0.49. These results suggest that vascular responses to BVS and DE-BVS observed in this study are largely comparable to those of the commercial XIENCE DES for all key measures at 28 days post-implantation. Interestingly, the bare polymer BVS displayed comparable levels of restenosis to the DE-BVS.This work was supported by the National Institutes of Health, United States (Grant: R01HL141933). Y. Ding was supported in part by the Center for Advanced Regenerative Engineering and American Heart Association Career Development Award (AHA, Grant: 852772). The authors gratefully acknowledge Connor Alexander Moore and Casey Tan for their technical support in schematic illustration and data analysis, respectively.
ASJC Scopus subject areas
- Biotechnology
- Biomaterials
- Biomedical Engineering
