In Vitro Comparison of a Closed and Semi-closed Leaflet Design for Adult and Pediatric Transcatheter Heart Valves.

Transcatheter heart valve replacements (TVR) are mostly designed in a closed position (c) with leaflets coaptating. However, recent literature suggests fabricating valves in semi-closed (sc) position to minimize pinwheeling. With about 100,000 children in need of a new pulmonary valve each year worldwide, this study evaluates both geometrical approaches in adult as well as pediatric size and condition. Three valves of each geometry were fabricated in adult (30 mm) and pediatric (15 mm) size, using porcine pericardium. To evaluate performance, the mean transvalvular pressure gradient (TPG), effective orifice area (EOA), and regurgitation fraction (RF) were determined in three different annulus geometries (circular, elliptic, and tilted). For both adult-sized valve geometries, the TPG (TPGC = 2.326 ± 0.115 mmHg; TPGSC = 1.848 ± 0.175 mmHg)* and EOA (EOAC = 3.69 ± 0.255 cm2; EOASC = 3.565 ± 0.025 cm2)* showed no significant difference. Yet the RF as well as its fluctuation was significantly higher for valves with the closed geometry (RFC = 12.657 ± 7.669 %; RFSC = 8.72 ± 0.977 %)*. Recordings showed that the increased backflow was caused by pinwheeling due to a surplus of tissue material. Hydrodynamic testing of pediatric TVRs verified the semi-closed geometry being favourable. Despite the RF (RFC = 7.721 ± 0.348 cm2; RFSC = 5.172 ± 0.679 cm2), these valves also showed an improved opening behaviour ((TPGC = 20.929 ± 0.497 cm2; TPGSC = 15.972 ± 1.158 cm2); (EOAC = 0.629 ± 0.017 cm2; EOASC = 0.731 ± 0.026 cm2)). Both adult and pediatric TVR with semi-closed geometry show better fluiddynamic functionality compared to valves with a closed design due to less pinwheeling. Besides improved short-term functionality, less pinwheeling potentially prevents early valve degeneration and improves durability. *Results are representatively shown for a circular annulus geometry.

A Glutaraldehyde-Free Crosslinking Method for the Treatment of Collagen-Based Biomaterials for Clinical Application.

Biological bioprostheses such as grafts, patches, and heart valves are often derived from biological tissue like the pericardium. These bioprostheses can be of xenogenic, allogeneic, or autologous origin. Irrespective of their origin, all types are pre-treated via crosslinking to render the tissue non-antigenic and mechanically strong or to minimize degradation. The most widely used crosslinking agent is glutaraldehyde. However, glutaraldehyde-treated tissue is prone to calcification, inflammatory degradation, and mechanical injury, and it is incapable of matrix regeneration, leading to structural degeneration over time. In this work, we are investigating an alternative crosslinking method for an intraoperative application. The treated tissue's crosslinking degree was evaluated by differential scanning calorimetry. To confirm the findings, a collagenase assay was conducted. Uniaxial tensile testing was used to assess the tissue's mechanical properties. To support the findings, the treated tissue was visualized using two-photon microscopy. Additionally, fourier transform infrared spectroscopy was performed to study the overall protein secondary structure. Finally, a crosslinking procedure was identified for intraoperative processing. The samples showed a significant increase in thermal and enzymatic stability after treatment compared to the control, with a difference of up to 22.2 °C and 100%, respectively. Also, the tissue showed similar biomechanics to glutaraldehyde-treated tissue, showing greater extensibility, a higher failure strain, and a lower ultimate tensile strength than the control. The significant difference in the structure band ratio after treatment is proof of the introduction of additional crosslinks compared to the untreated control with regard to differences in the amide-I region. The microscopic images support these findings, showing an alteration of the fiber orientation after treatment. For collagen-based biomaterials, such as pericardial tissue, the novel phenolic crosslinking agent proved to be an equivalent alternative to glutaraldehyde regarding tissue characteristics. Although long-term studies must be performed to investigate superiority in terms of longevity and calcification, our novel crosslinking agent can be applied in concentrations of 1.5% or 2.0% for the treatment of biomaterials.

Genetic knockout of porcine GGTA1 or CMAH/GGTA1 is associated with the emergence of neo-glycans.

BACKGROUND: Pig-derived tissues could overcome the shortage of human donor organs in transplantation. However, the glycans with terminal α-Gal and Neu5Gc, which are synthesized by enzymes, encoded by the genes GGTA1 and CMAH, are known to play a major role in immunogenicity of porcine tissue, ultimately leading to xenograft rejection. METHODS: The N-glycome and glycosphingolipidome of native and decellularized porcine pericardia from wildtype (WT), GGTA1-KO and GGTA1/CMAH-KO pigs were analyzed by multiplexed capillary gel electrophoresis coupled to laser-induced fluorescence detection. RESULTS: We identified biantennary and core-fucosylated N-glycans terminating with immunogenic α-Gal- and α-Gal-/Neu5Gc-epitopes on pericardium of WT pigs that were absent in GGTA1 and GGTA1/CMAH-KO pigs, respectively. Levels of N-glycans terminating with galactose bound in ß(1-4)-linkage to N-acetylglucosamine and their derivatives elongated by Neu5Ac were increased in both KO groups. N-glycans capped with Neu5Gc were increased in GGTA1-KO pigs compared to WT, but were not detected in GGTA1/CMAH-KO pigs. Similarly, the ganglioside Neu5Gc-GM3 was found in WT and GGTA1-KO but not in GGTA1/CMAH-KO pigs. The applied detergent based decellularization efficiently removed GSL glycans. CONCLUSION: Genetic deletion of GGTA1 or GGTA1/CMAH removes specific epitopes providing a more human-like glycosylation pattern, but at the same time changes distribution and levels of other porcine glycans that are potentially immunogenic.

Bioengineered percutaneous heart valves for transcatheter aortic valve replacement: a comparative evaluation of decellularised bovine and porcine pericardia.

Glutaraldehyde-treated, surgical bioprosthetic heart valves undergo structural degeneration within 10-15 years of implantation. Analogous preliminary results were disclosed for percutaneous heart valves (PHVs) realized with similarly-treated tissues. To improve long-term performance, decellularised scaffolds can be proposed as alternative fabricating biomaterials. The aim of this study was to evaluate whether bovine and porcine decellularised pericardia could be utilised to manufacture bioengineered percutaneous heart valves (bioPHVs) with adequate hydrodynamic performance and leaflet resistance to crimping damage. BioPHVs were fabricated by mounting acellular pericardia onto commercial stents. Independently from the pericardial species used for valve fabrication, bioPHVs satisfied the minimum hydrodynamic performance criteria set by ISO 5840-3 standards and were able to withstand a large spectrum of cardiac output conditions, also during extreme backpressure, without severe regurgitation, especially in the case of the porcine group. No macroscopic or microscopic leaflet damage was detected following bioPHV crimping. Bovine and porcine decellularized pericardia are both suitable alternatives to glutaraldehyde-treated tissues. Between the two types of pericardial species tested, the porcine tissue scaffold might be preferable to fabricate advanced PHV replacements for long-term performance. CONDENSED ABSTRACT: Current percutaneous heart valve replacements are formulated with glutaraldehyde-treated animal tissues, prone to structural degeneration. In order to improve long-term performance, bovine and porcine decellularised pericardia were utilised to manufacture bioengineered replacements, which demonstrated adequate hydrodynamic behaviour and resistance to crimping without leaflet architectural alteration.