Bioabsorbable stent quo vadis: a case for nano-theranostics

Abstract

Percutaneous coronary intervention (PCI) is one of the most commonly performed invasive medical procedures in medicine today. Since the first coronary balloon angioplasty in 1977, interventional cardiology has seen a wide array of developments in PCI. Bare metal stents (BMS) were soon superseded by the revolutionary drug-eluting stents (DES), which aimed to address the issue of restenosis found with BMS. However, evidence began to mount against DES, with late-stent thrombosis (ST) rates being higher than that of BMS. The bioabsorbable stent may be a promising alternative, providing vessel patency and support for the necessary time required and thereafter degrade into safe non-toxic compounds which are reabsorbed by the body. This temporary presence provides no triggers for ST, which is brought about by non-endothelialized stent struts and drug polymers remaining in vivo for extended periods of time. Likewise, nano-theranostics incorporated into a bioabsorbable stent of the future may provide an incredibly valuable single platform offering both therapeutic and diagnostic capabilities. Such a stent may allow delivery of therapeutic particles to specific sites thus keeping potential toxicity to a minimum, improved ease of tracking delivery in vivo by embedding imaging agents, controlled rate of therapy release and protection of the implanted therapy. Indeed, nanocarriers may allow an increased therapeutic index as well as offer novel post-stent implantation imaging and diagnostic methods for atherosclerosis, restenosis and thrombosis. It is envisioned that a nano-theranostic stent may well form the cornerstone of future stent designs in clinical practice.

Keywords: bioabsorbable stent; drug-eluting stent; nanotechnology; theranostics.

Figure 1

(A) The progression of atherosclerosis and various therapeutic approaches. Such therapies involve lipid modulation of the blood, decreasing intra-plaque inflammation, thrombosis and angiogenesis. (B) Pro-healing and anti-restenosis approaches post PCI. Anti-inflammatory and anti-proliferative drug delivery as well as light-activated ablation, both of which use nanoparticles can be used to prevent restenosis. Nanofibrous scaffolds emulating extracellular matrix and magnetic nanoparticles delivering endothelial cells can be used to enhance stent strut endothelialization. Copyright © 2013 Elsevier B.V. Reproduced with permission from .

Figure 2

(A) PLLA and citric acid-crosslinked gelatin matrices demonstrated in pictures and (B) scanning electron microscope images. Such composites have been used as DES coating material which allows antithrombogenic and drug-eluting properties. The composite has varying ratios of PLLA to citric acid-crosslinked gelatin: 100/0 (a), 80/20 (b), 60/40 (c), 40/60 (d), 20/80 (e), 0/100 (f). Copyright © 2012 Wiley Periodicals, Inc. Reproduced with permission from .

Figure 3

Hydrolytic degradation of the PLA polymer family. Copyright © 2013 Europa Digital & Publishing. Reproduced with permission from .

Figure 4

(A and C) BVS 1.0, the first generation BVS with out-of-phase zig-zag loops and (B, D and E) BVS 1.1, the second generation with in-phase zig-zag loops. (C) The red circular and green outlines demonstrate the unsupported cross sectional areas which are larger in BVS 1.0 than in (D) BVS 1.1. (E) Illustration the newer in-phase zig-zag loops which allow more uniform vessel support and increased consistency of drug application. Copyright © 2013 Nature Publishing Group, a division of Macmillan Publishers Limited. Copyright © 2013 Europa Digital & Publishing. Reproduced with permission from .

Figure 5

A graphical representation of the 3 BVS (1.1) stent phases. The phases are revascularisation, restoration and resorption which all coincide with various physiological responses. 80% of everolimus-elution (green curve) occurs within 28 days of implantation and luminal support (red curve) is provided for at least 3 months. Copyright © 2013 Europa Digital & Publishing. Reproduced with permission from .

Figure 6

The maximum compressive load needed to bend the ABSORB Cohort B device (BVS 1.1) and XIENCE V (a metallic DES), which is an indication of flexibility. The BVS 1.1 has greater flexibility at a statistically significant level, where p = 0.004. Copyright © 2013 Europa Digital & Publishing. Reproduced with permission from .

Figure 7

Acute radial strength of the ABSORB Cohort B device (BVS 1.1) compared to metallic DES such as XIENCE V, Cypher Select and Taxus Liberte. Data obtained using MSI RX550 radial expansion force gauge. Copyright © 2013 Europa Digital & Publishing. Reproduced with permission from .

Figure 8

Depiction of a theranostic nanoparticle. Such multi-functionalized nanoparticles may be used for carrying a drug payload, molecular imaging, drug delivery, visualisation using fluorescence probes, X-ray imaging, contrast reagents, ultrasonic assistance and specific targeting of ligands. Copyright © 2013 Ivyspring International Publisher. Reproduced with permission from .

Figure 9

Classes of various nanoparticles with theranostic properties, compositions and sizes included. Copyright © 2013 Elsevier B.V. Reproduced with permission from .

Figure 10

Paclitaxel (PTX) and Ceramide (CER) chemical structures and a scanning electron micrograph of poly(ethylene oxide)-modified poly(epsilon caprolactone) NP (PEO-PCL NP). Copyright © 2008 Springer Science+Business Media, LLC. Reproduced with permission from .

Figure 11

Microscopy images demonstrating fluorescent liposomal uptake (orange) into vessel walls 24 hours after balloon injury. Lower row is of higher magnification. Liposomes are taken up following injury and with treatment of liposomal bisphosphonates, the vessel wall size is substantially reduced. L = lumen. FL = fluorescent liposomes. BP FL = bisphosphonate fluorescent liposomes. Copyright © 2013 Elsevier B.V. Reproduced with permission from , .

Figure 12

Detection of inflammatory foci using PET imaging tracers. The most widely used tracer in PET is considered to be ¹⁸F-FDG (2-deoxy-2-¹⁸F-fluoro-D-glucose). Copyright © 2013 Ivyspring International Publisher. Reproduced with permission from .

Figure 13

Diagram illustrating numerous nanoparticles that may be used for molecular imaging. PEG: polyethylene glycol. apoAI: apolipoprotein A I. Gd: gadolinium. CE: cholesteryl ester. TG: triglyceride. Copyright © 2010 John Wiley & Sons, Inc. Reproduced with permission from .

Figure 14

Dextran polymeric NPs present in various plaques. (A) Immunohistochemical stain visualising CD11b+ myeloid cells. (B) Fluorescence microscopy of A showing NP presence. (C) Autofluorescence image of B. (D) Immunofluorescence microscopy of CD11b under higher magnification. (E) Immunofluorescence microscopy of NPs (see arrows), same image as (D). (F) Images D and E combined where cells staining positive for CD11b show DNP presence inside. Scale bar = 20 µm. Copyright: © 2013 American Heart Association, Inc. Reproduced with permission from .

Figure 15

(A) Light and fluorescence microscopic pictures of stented intraluminal coronary artery segments of the FITC-NP-Eluting stent and dip-coated FITC stent (polymer-based FITC-eluting stent). Yellow scale bar = 1 mm. (B) Expanded image of yellow box in A. Image B reveals distinct regions of fluorescence which indicate local uptake of FITC-NPs. (C) Cross-section fluorescence microscopic pictures of FITC-NP-Eluting stent and dip-coated FITC stent. *Stent strut region. Copyright © 2013 Elsevier B.V. Reproduced with permission from .

Figure 16

(A) In vitro human coronary artery SMCs visualised using fluorescence microscopy. Cells were incubated with non-encapsulated FITC, blank PLGA-NP and FITC-PLGA NP for one hour at a concentration of 0.1mg/ml. Green indicates FITC fluorescence and red indicates nuclei. FITC-PLGA NP demonstrates the most fluorescence. (B) In vitro human coronary artery SMCs incubated with FITC-NP at 0.1mg/ml visualized using confocal fluorescence microscopy (left image showing XY-axis and right image showing Z-axis of the left image). (C) Percentage of FITC-NP uptake of SMCs over a 24 hour period. (D) Cross-section of SMC visualized transmission electron microscopy. Arrows show FITC-NP uptake. N = nucleus. Copyright © 2013 Elsevier B.V. Reproduced with permission from .