Material Safety of Styrene-Block-Ethylene/Butylene-Block-Styrene Copolymers Used for Cardiac Valves: 6-Month In Vivo Results from a Juvenile Sheep Model

Abstract

Objectives: To assess the in vivo 6-month safety of styrene-block-ethylene/butylene-block-styrene (SEBS) block copolymers material used to make cardiac valves.

Methods: Research-grade mitral valve prototypes made from SEBS29/SEBS20 copolymers (n = 7; 3 with heparin-coating) were implanted in juvenile sheep under cardiopulmonary bypass and kept for 6 months. No vitamin K antagonists were used. Anticoagulation included enoxaparin 1 mg/kg SC twice/day from day 1 until day 120 along with clopidogrel 300 mg once/day with food from day 1 until sacrifice. Safety measures included SEBS-related calcification, degradation, haemolysis, cytotoxicity, clinical pathology (biochemistry, complete blood count, coagulation), structural integrity, damage to surrounding tissue, overall animal health, and device embolization and function.

Results: Surgery was feasible in all cases. Four animals reached the final 180 ± 5 days timepoint, while 1 needed non-SEBS related sacrifice on day 2, 1 suffered non-SEBS related death on day 81, and 1 needed sacrifice on day 169 due to prototype dysfunction. High-resolution X-ray, spectroscopy and histology showed absence of SEBS calcification, while gel permeation chromatography confirmed no SEBS degradation at 6 months. At histology, there was no SEBS-related calcification, thrombosis, cytotoxic or neoplastic degeneration, and no damage of the cardiac and downwards organs. Blood testing showed no haemolysis, while clinical pathology and animal health remained within normal reference intervals. The function of the research-grade mitral prototypes was clinically acceptable. The use of heparin-coating did not add benefit.

Conclusions: This preclinical in vivo study in juvenile sheep confirms the 6-month safety of SEBS29/SEBS20 material used to make cardiac valves. A future early feasibility study is warranted to confirm long-term durability, haemocompatibility, and function in humans.

Keywords: SEBS co-polymers; calcification; cardiac valves; material safety; preclinical testing.

Graphical abstract

Figure 1.

Macroscopy of SEBS29: Representative Image of 11704 Prototype. Inflow (A) and outflow (B) views showing no calcification, thrombosis, pannus, or structural abnormalities of the SEBS29 material or the interfaced cardiac tissue

Figure 2.

Macroscopy of SEBS20. Inflow views of all leaflets; black arrows show tiny trace of pannus; purple arrow shows a small fibrin deposit on 1 leaflet; yellow arrows show small tears; orange arrow shows large tears; grey dot shows a missing part in 1 leaflet. Scale bar: 0.5 cm. L: Lateral cusp; C: Cranial cusp; M: Medial cusp. Legends report study animal, termination day, weight at surgery, N (normal) or HC (heparin-coated) sub-groups

Figure 3.

High-resolution X-ray (Faxitron) Images. No calcification seen on any SEBS29/SEBS20 parts. Legends report study animal, termination day, weight at surgery, N (normal) or HC (heparin-coated) sub-groups

Figure 4.

SEBS29 Degradation. Triple detector chromatograms of SEBS29 samples from all explanted valves and the non-implanted raw material (G1650)