Large Animal Translational Validation of 3 Mitral Valve Repair Operations for Mitral Regurgitation Using a Mitral Valve Prolapse Model: A Comprehensive In Vivo Biomechanical Engineering Analysis.

BACKGROUND: Various mitral repair techniques have been described. Though these repair techniques can be highly effective when performed correctly in suitable patients, limited quantitative biomechanical data are available. Validation and thorough biomechanical evaluation of these repair techniques from translational large animal in vivo studies in a standardized, translatable fashion are lacking. We sought to evaluate and validate biomechanical differences among different mitral repair techniques and further optimize repair operations using a large animal mitral valve prolapse model. METHODS: Male Dorset sheep (n=20) had P2 chordae severed to create the mitral valve prolapse model. Fiber Bragg grating force sensors were implanted to measure chordal forces. Ten sheep underwent 3 randomized, paired mitral valve repair operations: neochord repair, nonresectional leaflet remodeling, and triangular resection. The other 10 sheep underwent neochord repair with 2, 4, and 6 neochordae. Data were collected at baseline, mitral valve prolapse, and after each repair. RESULTS: All mitral repair techniques successfully eliminated regurgitation. Compared with mitral valve prolapse (0.54±0.18 N), repair using neochord (0.37±0.20 N; P=0.02) and remodeling techniques (0.30±0.15 N; P=0.001) reduced secondary chordae peak force. Neochord repair further decreased primary chordae peak force (0.21±0.14 N) to baseline levels (0.20±0.17 N; P=0.83), and was associated with lower primary chordae peak force compared with the remodeling (0.34±0.18 N; P=0.02) and triangular resectional techniques (0.36±0.27 N; P=0.03). Specifically, repair using 2 neochordae resulted in higher peak primary chordal forces (0.28±0.21 N) compared with those using 4 (0.22±0.16 N; P=0.02) or 6 neochordae (0.19±0.16 N; P=0.002). No difference in peak primary chordal forces was observed between 4 and 6 neochordae (P=0.05). Peak forces on the neochordae were the lowest using 6 neochordae (0.09±0.11 N) compared with those of 4 neochordae (0.15±0.14 N; P=0.01) and 2 neochordae (0.29±0.18 N; P=0.001). CONCLUSIONS: Significant biomechanical differences were observed underlying different mitral repair techniques in a translational large animal model. Neochord repair was associated with the lowest primary chordae peak force compared to the remodeling and triangular resectional techniques. Additionally, neochord repair using at least 4 neochordae was associated with lower chordal forces on the primary chordae and the neochordae. This study provided key insights about mitral valve repair optimization and may further improve repair durability.

Biomechanical engineering analysis of neochordae length's impact on chordal forces in mitral repair.

OBJECTIVES: Artificial neochordae implantation is commonly used for mitral valve (MV) repair. However, neochordae length estimation can be difficult to perform. The objective was to assess the impact of neochordae length changes on MV haemodynamics and neochordal forces. METHODS: Porcine MVs (n = 6) were implanted in an ex vivo left heart simulator. MV prolapse (MVP) was generated by excising at least 2 native primary chordae supporting the P2 segments from each papillary muscle. Two neochordae anchored on each papillary muscle were placed with 1 tied to the native chord length (exact length) and the other tied with variable lengths from 2× to 0.5× of the native length (variable length). Haemodynamics, neochordal forces and echocardiography data were collected. RESULTS: Neochord implantation repair successfully eliminated mitral regurgitation with repaired regurgitant fractions of approximately 4% regardless of neochord length (P < 0.01). Leaflet coaptation height also significantly improved to a minimum height of 1.3 cm compared with that of MVP (0.9 ± 0.4 cm, P < 0.05). Peak and average forces on exact length neochordae increased as variable length neochordae lengths increased. Peak and average forces on the variable length neochordae increased with shortened lengths. Overall, chordal forces appeared to vary more drastically in variable length neochordae compared with exact length neochordae. CONCLUSIONS: MV regurgitation was eliminated with neochordal repair, regardless of the neochord length. However, chordal forces varied significantly with different neochord lengths, with a preferentially greater impact on the variable length neochord. Further validation studies may be performed before translating to clinical practices.

Chordal force profile after neochordal repair of anterior mitral valve prolapse: An ex vivo study.

Objective: This study aimed to biomechanically evaluate the force profiles on the anterior primary and secondary chordae after neochord repair for anterior valve prolapse with varied degrees of residual mitral regurgitation using an ex vivo heart simulator. Methods: The experiment used 8 healthy porcine mitral valves. Chordal forces were measured using fiber Bragg grating sensors on primary and secondary chordae from A2 segments. The anterior valve prolapse model was generated by excising 2 primary chordae at the A2 segment. Neochord repair was performed with 2 pairs of neochords. Varying neochord lengths simulated postrepair residual mitral regurgitation with regurgitant fraction at >30% (moderate), 10% to 30% (mild), and <10% (perfect repair). Results: Regurgitant fractions of baseline, moderate, mild, and perfect repair were 4.7% ± 0.8%, 35.8% ± 2.1%, 19.8% ± 2.0%, and 6.0% ± 0.7%, respectively (P < .001). Moderate had a greater peak force of the anterior primary chordae (0.43 ± 0.06 N) than those of baseline (0.19 ± 0.04 N; P = .011), mild (0.23 ± 0.05 N; P = .041), and perfect repair (0.21 ± 0.03 N; P = .006). In addition, moderate had a greater peak force of the anterior secondary chordae (1.67 ± 0.17 N) than those of baseline (0.64 ± 0.13 N; P = .003), mild (0.84 ± 0.24 N; P = .019), and perfect repair (0.68 ± 0.14 N; P = .001). No significant differences in peak and average forces on both primary and secondary anterior chordae were observed between the baseline and perfect repair as well as the mild and perfect repair. Conclusions: Moderate residual mitral regurgitation after neochord repair was associated with increased anterior primary and secondary chordae forces in our ex vivo anterior valve prolapse model. This difference in chordal force profile may influence long-term repair durability, providing biomechanical evidence in support of obtaining minimal regurgitation when repairing mitral anterior valve prolapse.

Biomechanics and clinical outcomes of various conduit configurations in valve sparing aortic root replacement.

Background: Several conduit configurations, such as straight graft (SG), Valsalva graft (VG), anticommissural plication (ACP), and the Stanford modification (SMOD) technique, have been described for the valve-sparing aortic root replacement (VSARR) procedure. Prior ex vivo studies have evaluated the impact of conduit configurations on root biomechanics, but the mock coronary artery circuits used could not replicate the physical properties of native coronary arteries. Moreover, the individual leaflet's biomechanics, including the fluttering phenomenon, were unclear. Methods: Porcine aortic roots with coronary arteries were explanted (n=5) and underwent VSARR using SG, VG, ACP, and SMOD for evaluation in an ex vivo left heart flow loop simulator. Additionally, 762 patients who underwent VSARR from 1993 through 2022 at our center were retrospectively reviewed. Analysis of variance was performed to evaluate differences between different conduit configurations, with post hoc Tukey's correction for pairwise testing. Results: SG demonstrated lower rapid leaflet opening velocity compared with VG (P=0.001) and SMOD (P=0.045) in the left coronary cusp (LCC), lower rapid leaflet closing velocity compared with VG (P=0.04) in the right coronary cusp (RCC), and lower relative opening force compared with ACP (P=0.04) in the RCC. The flutter frequency was lower in baseline compared with VG (P=0.02) and in VG compared with ACP (P=0.03) in the LCC. Left coronary artery mean flow was higher in SG compared with SMOD (P=0.02) and ACP (P=0.05). Clinically, operations using SG compared with sinus-containing graft was associated with shorter aortic cross-clamp and cardiopulmonary bypass time (P<0.001, <0.001). Conclusions: SG demonstrated hemodynamics and biomechanics most closely recapitulating those from the native root with significantly shorter intraoperative times compared with repair using sinus-containing graft. Future in vivo validation studies as well as correlation with comprehensive, comparative clinical study outcomes may provide additional invaluable insights regarding strategies to further enhance repair durability.

Optimization of Freeform Reversible Embedding of Suspended Hydrogel Microspheres for Substantially Improved Three-Dimensional Bioprinting Capabilities.

Three-dimensional (3D) bioprinting demonstrates technology that is capable of producing structures comparable to native tissues in the human body. The freeform reversible embedding of suspended hydrogels (FRESH) technique involves hydrogel-based bio-inks printed within a thermo-reversible support bath to provide mechanical strength to the printed construct. Smaller and more uniform microsphere sizes of FRESH were reported to aid in enhancing printing resolution and construct accuracy. Therefore, we sought to optimize the FRESH generation protocol, particularly by varying stir speed and stir duration, in hopes to further improve microsphere size and uniformity. We observed optimal conditions at a stir speed of 600 rpm and stir duration for 20 h that generated the smallest microspheres with the best uniformity. Comparison of using the optimized FRESH to the commercial FRESH LifeSupport to bioprint single filament and geometrical constructs revealed reduced single filament diameters and higher angular precision in the optimized FRESH bio-printed constructs compared with those printed in the commercial FRESH. Overall, our refinement of the FRESH manufacturing protocol represents an important step toward enhancing 3D bioprinting resolution and construct fidelity. Improving such technologies allows for the fabrication of highly accurate constructs with anatomical properties similar to native counterparts. Such work has significant implications in the field of tissue engineering for producing accurate human organ model systems. Impact statement Freeform reversible embedding of suspended hydrogels (FRESH) is a method of sacrificial three-dimensional (3D) bioprinting that offers support to reinforce bio-ink extrusion during printing. During FRESH generation, the stir speed and stir duration of the mixture can significantly impact FRESH microsphere characteristics. In this study, we optimized FRESH microspheres to significantly improve resolution and accuracy in bioprinting. This advancement in FRESH-based 3D bioprinting technologies allows for the fabrication of highly accurate constructs with anatomical properties similar to native counterparts and has significant implications in the field of tissue engineering and translational medicine.

Three-Dimensional Bioprinting with Alginate by Freeform Reversible Embedding of Suspended Hydrogels with Tunable Physical Properties and Cell Proliferation.

Extrusion-based three-dimensional (3D) bioprinting is an emerging technology that allows for rapid bio-fabrication of scaffolds with live cells. Alginate is a soft biomaterial that has been studied extensively as a bio-ink to support cell growth in 3D constructs. However, native alginate is a bio-inert material that requires modifications to allow for cell adhesion and cell growth. Cells grown in modified alginates with the RGD (arginine-glycine-aspartate) motif, a naturally existing tripeptide sequence that is crucial to cell adhesion and proliferation, demonstrate enhanced cell adhesion, spreading, and differentiation. Recently, the bioprinting technique using freeform reversible embedding of suspended hydrogels (FRESH) has revolutionized 3D bioprinting, enabling the use of soft bio-inks that would otherwise collapse in air. However, the printability of RGD-modified alginates using the FRESH technique has not been evaluated. The associated physical properties and bioactivity of 3D bio-printed alginates after RGD modification remains unclear. In this study, we characterized the physical properties, printability, and cellular proliferation of native and RGD-modified alginate after extrusion-based 3D bioprinting in FRESH. We demonstrated tunable physical properties of native and RGD-modified alginates after FRESH 3D bioprinting. Sodium alginate with RGD modification, especially at a high concentration, was associated with greatly improved cell viability and integrin clustering, which further enhanced cell proliferation.

A novel photosynthetic biologic topical gel for enhanced localized hyperoxygenation augments wound healing in peripheral artery disease.

Peripheral artery disease and the associated ischemic wounds are substantial causes of global morbidity and mortality, affecting over 200 million people worldwide. Although advancements have been made in preventive, pharmacologic, and surgical strategies to treat this disease, ischemic wounds, a consequence of end-stage peripheral artery disease, remain a significant clinical and economic challenge. Synechococcus elongatus is a cyanobacterium that grows photoautotrophically and converts carbon dioxide and water into oxygen. We present a novel topical biologic gel containing S. elongatus that provides oxygen via photosynthesis to augment wound healing by rescuing ischemic tissues caused by peripheral artery disease. By using light rather than blood as a source of energy, our novel topical therapy significantly accelerated wound healing in two rodent ischemic wound models. This novel topical gel can be directly translated to clinical practice by using a localized, portable light source without interfering with patients' daily activities, demonstrating potential to generate a paradigm shift in treating ischemic wounds from peripheral artery disease. Its novelty, low production cost, and ease of clinical translatability can potentially impact the clinical care for millions of patients suffering from peripheral arterial disease.