Degree of bioresorbable vascular scaffold expansion modulates loss of essential function

Abstract

Drug-eluting bioresorbable vascular scaffolds (BVSs) have the potential to restore lumen patency, enable recovery of the native vascular environment, and circumvent late complications associated with permanent endovascular devices. To ensure therapeutic effects persist for sufficient times prior to scaffold resorption and resultant functional loss, many factors dictating BVS performance must be identified, characterized and optimized. While some factors relate to BVS design and manufacturing, others depend on device deployment and intrinsic vascular properties. Importantly, these factors interact and cannot be considered in isolation. The objective of this study is to quantify the extent to which degree of radial expansion modulates BVS performance, specifically in the context of modifying device erosion kinetics and evolution of structural mechanics and local drug elution. We systematically varied degree of radial expansion in model BVS constructs composed of poly dl-lactide-glycolide and generated in vitro metrics of device microstructure, degradation, erosion, mechanics and drug release. Experimental data permitted development of computational models that predicted transient concentrations of scaffold-derived soluble species and drug in the arterial wall, thus enabling speculation on the short- and long-term effects of differential expansion. We demonstrate that degree of expansion significantly affects scaffold properties critical to functionality, underscoring its relevance in BVS design and optimization.

Statement of significance: Bioresorbable vascular scaffold (BVS) therapy is beginning to transform the treatment of obstructive artery disease, owing to effective treatment of short term vessel closure while avoiding long term consequences such as in situ, late stent thrombosis - a fatal event associated with permanent implants such as drug-eluting stents. As device scaffolding and drug elution are temporary for BVS, the notion of using this therapy in lieu of existing, clinically approved devices seems attractive. However, there is still a limited understanding regarding the optimal lifetime and performance characteristics of erodible endovascular implants. Several engineering criteria must be met and clinical endpoints confirmed to ensure these devices are both safe and effective. In this manuscript, we sought to establish general principles for the design and deployment of erodible, drug-eluting endovascular scaffolds, with focus on how differential expansion can modulate device performance.

Keywords: Bioresorbable vascular scaffolds; Computational modeling; Drug delivery; Radial expansion.

Figure 1. A schematic of the employed BVS synthesis procedure

Three scaffold variants with an increasing degree of radial expansion (E-1, E-2, or E-3) were created for subsequent studies. Constant surface area was maintained for all scaffolds, implying a variation in length in the expanded states.

Figure 2. SEM images of scaffold microstructure

SEM images were used to assess the morphology of the scaffold surface as a function of in-vitro incubation time and the imposed degree of radial expansion.

Figure 3. Evolution in scaffold structure and composition

The degree of radial expansion modulates in-vitro scaffold (A) porosity, (B) water absorption kinetics, (C) degradation kinetics as indicated by loss of weight-average molecular weight (MW_w), and (D) erosion kinetics as indicated by mass loss. The total amount of absorbed water, MW_w , and mass loss at any point are normalized with respect to the scaffolds concurrent dry mass, initial MW_w, and initial dry mass, respectively. *indicates statistically significant differences between groups (p<0.05).

Figure 4. Evolution in scaffold function

The degree of radial expansion modulates in-vitro scaffold (A) compressive force response and (B) linearized compressive moduli. Compressive force vs. displacement curves correspond to the 4 day incubation time point. Forces are normalized with respect to the corresponding scaffolds length. (C) The degree of radial expansion also affects in-vitro release kinetics of Paclitaxel in PBS solution at 37°C. The drug release amount is normalized with respect to the initial drug content.* indicates statistically significant differences between groups (p<0.05).

Figure 5. Computational predictions of arterial wall concentrations

(A) A representative surface plot of the soluble degradation species concentration (after 30 days degradation for expansion case E-2) predicted by a two-dimensional computational model consisting of a square scaffold strut fully-embedded in the arterial wall. (B) Computational predictions indicate that peak arterial wall soluble species concentration is influenced by the degree of radial expansion. Initial soluble species diffusion coefficient of-1 × 10⁻¹³ m²/s and hydrolytic degradation rate of 4.0 × 10⁻⁸ m³/mol − s, 4.3 × 10⁻⁸ m³/mol − s, and 4.6 × 10⁻⁸ m³/mol − s were used for E-1, E-2, and E-3, respectively. Color bars represent soluble species concentrations in corresponding domains. (C) A representative Paclitaxel concentration surface plot (after 30 days degradation for expansion case E-2). Color bars represent Paclitaxel concentrations in corresponding domains. Computational predictions indicate that average arterial wall (D) bound and (E) free paclitaxel concentrations kinetics are largely independent of radial expansion. Paclitaxel initial bulk diffusion coefficient in the scaffold of 3.5 × 10⁻¹⁹ m²/s and the diffusion coefficient change rate of 3.75 × 10⁻⁶ m²/s, 4.00 × 10⁻⁶ m²/s, and 4.05 × 10-⁶m²/s were used for E-1, E-2, and E-3, respectively. Arterial wall Paclitaxel diffusivity of 5.71 × 10⁻¹⁰ m²/s, net tissue-binding capacity of 13 mol/m³, association and dissociation rate constants of 21.97 mol/m³ −s and 2.98798 1/s, respectively were used for all illustrated simulated results. (F) Scaffold erosion affects arterial wall Paclitaxel pharmacokinetics. Paclitaxel bulk diffusion coefficient in the scaffold of 5.71 × 10⁻¹⁰ m²/s and 3.5 × 10⁻¹⁹ m²/s were considered for limiting (extreme) cases of scaffold erosion.

Figure 6. Scaled-evolution in scaffold function

(A) For a given degree of expansion, scaffold compressive modulus exhibits linear correlation (R² = 0.99,0.79, 0.99 for E − 1,E − 2,E−3,respectively) with normalized MW_w. (B) For all degrees of expansion, the fraction of cumulative Paclitaxel release from the scaffold exhibits linear correlation (R² = 0.92) with scaffolds mass loss (A)