Evaluating Calcification in Tissue-Engineered Heart Valves: Much More Complicated Than Expected?
Ontology highlight
ABSTRACT:
SUBMITTER: Motta SE
PROVIDER: S-EPMC10264561 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
Publications
Evaluating Calcification in Tissue-Engineered Heart Valves: Much More Complicated Than Expected?
Motta Sarah E SE Breuer Christopher K CK Zilla Peter P Hoerstrup Simon P SP Emmert Maximilian Y MY
JACC. Basic to translational science 20230522 5
Similar Datasets
Project description:Heart valve disease is a major health burden, treated by either valve repair or valve replacement, depending on the affected valve. Nearly 300,000 valve replacements are performed worldwide per year. Valve replacement is lifesaving, but not without complications. The in situ tissue-engineered heart valve is a promising alternative to current treatments, but the translation of this novel technology to the clinic still faces several challenges. These challenges originate from the variety encountered in the patient population, the conversion of an implant into a living tissue, the highly mechanical nature of the heart valve, the complex homeostatic tissue that has to be reached at the end stage of the regenerating heart valve, and all the biomaterial properties that can be controlled to obtain this tissue. Many of these challenges are multidimensional and multiscalar, and both the macroscopic properties of the complete heart valve and the microscopic properties of the patient's cells interacting with the materials have to be optimal. Using newly developed in vitro models, or bioreactors, where variables of interest can be controlled tightly and complex mixtures of cell populations similar to those encountered in the regenerating valve can be cultured, it is likely that the challenges can be overcome.
| S-EPMC5545463 | biostudies-other
Project description:The limitations of the current clinical options for valve replacements have inspired the development of enabling technologies to create a tissue engineered heart valve (TEHV). Poly(ethylene glycol) diacrylate (PEGDA) hydrogel scaffolds permit greater biological and biomechanical customization than do non-woven mesh scaffold technologies. However, the material characterization of PEGDA hydrogels has been predominantly limited to compression and tension, as opposed to bending. Since large flexural deformations result in points of maximum stress in native valves as well as TEHVs, it is crucial to evaluate any potential scaffold material in this mode. The effect of formulation parameters on the bending mechanics of cell-seeded PEGDA hydrogels were investigated with a custom designed bending tester. Three molecular weights (3.4, 6, and 8 kDa) and three weight fractions (5%, 10%, and 15%, w/v) were subjected to three-point bending tests and the flexural stiffness was calculated. Manipulating the composition of the hydrogels resulted in flexural stiffnesses comparable with native tissues (15-220 kPa) with varied mesh sizes and swelling ratios. Hydrogels containing encapsulated valve cells, methacrylated heparin (Hep-MA), or both were substantially less stiff than acellular hydrogels. In conclusion, PEGDA hydrogels are an attractive potential scaffold system for TEHVs because they are not only cytocompatible and modifiable but can also withstand bending deformations. These studies are the first to explore the encapsulation of valvular interstitial cells in pure PEGDA hydrogels as well as to investigate the bending properties of PEGDA gels.
| S-EPMC4667841 | biostudies-literature
Project description:In situ tissue engineering that uses resorbable synthetic heart valve scaffolds is an affordable and practical approach for heart valve replacement; therefore, it is attractive for clinical use. This study showed no consistent collagen organization in the predefined direction of electrospun scaffolds made from a resorbable supramolecular elastomer with random or circumferentially aligned fibers, after 12 months of implantation in sheep. These unexpected findings and the observed intervalvular variability highlight the need for a mechanistic understanding of the long-term in situ remodeling processes in large animal models to improve predictability of outcome toward robust and safe clinical application.
| S-EPMC7775962 | biostudies-literature
Project description:Regenerative tissue-engineered matrix-based heart valves (TEM-based TEHVs) may become an alternative to currently-used bioprostheses for transcatheter valve replacement. We recently identified TEM-based TEHVs-geometry as one key-factor guiding their remodeling towards successful long-term performance or failure. While our first-generation TEHVs, with a simple, non-physiological valve-geometry, failed over time due to leaflet-wall fusion phenomena, our second-generation TEHVs, with a computational modeling-inspired design, showed native-like remodeling resulting in long-term performance. However, a thorough understanding on how TEHV-geometry impacts the underlying host cell response, which in return determines tissue remodeling, is not yet fully understood. To assess that, we here present a comparative samples evaluation derived from our first- and second-generation TEHVs. We performed an in-depth qualitative and quantitative (immuno-)histological analysis focusing on key-players of the inflammatory and remodeling cascades (M1/M2 macrophages, α-SMA+- and endothelial cells). First-generation TEHVs were prone to chronic inflammation, showing a high presence of macrophages and α-SMA+-cells, hinge-area thickening, and delayed endothelialization. Second-generation TEHVs presented with negligible amounts of macrophages and α-SMA+-cells, absence of hinge-area thickening, and early endothelialization. Our results suggest that TEHV-geometry can significantly influence the host cell response by determining the infiltration and presence of macrophages and α-SMA+-cells, which play a crucial role in orchestrating TEHV remodeling.
| S-EPMC7669851 | biostudies-literature
Project description:The creation of living heart valve replacements via tissue engineering is actively being pursued by many research groups. Numerous strategies have been described, aimed either at culturing autologous living valves in a bioreactor (in vitro) or inducing endogenous regeneration by the host via resorbable scaffolds (in situ). Whereas a lot of effort is being invested in the optimization of heart valve scaffold parameters and culturing conditions, the pathophysiological in vivo remodeling processes to which tissue-engineered heart valves are subjected upon implantation have been largely under-investigated. This is partly due to the unavailability of suitable immunohistochemical tools specific to sheep, which serves as the gold standard animal model in translational research on heart valve replacements. Therefore, the goal of this study was to comprise and validate a comprehensive sheep-specific panel of antibodies for the immunohistochemical analysis of tissue-engineered heart valve explants. For the selection of our panel we took inspiration from previous histopathological studies describing the morphology, extracellular matrix composition and cellular composition of native human heart valves throughout development and adult stages. Moreover, we included a range of immunological markers, which are particularly relevant to assess the host inflammatory response evoked by the implanted heart valve. The markers specifically identifying extracellular matrix components and cell phenotypes were tested on formalin-fixed paraffin-embedded sections of native sheep aortic valves. Markers for inflammation and apoptosis were tested on ovine spleen and kidney tissues. Taken together, this panel of antibodies could serve as a tool to study the spatiotemporal expression of proteins in remodeling tissue-engineered heart valves after implantation in a sheep model, thereby contributing to our understanding of the in vivo processes which ultimately determine long-term success or failure of tissue-engineered heart valves.
| S-EPMC6104173 | biostudies-literature
Project description:The development of cardiovascular implants is abundant, yet their clinical adoption remains a significant challenge in the treatment of valvular diseases. Tissue-engineered heart valves (TEHV) have emerged as a promising solution due to their remodeling capabilities, which have been extensively studied in recent years. However, ensuring reproducible production and clinical translation of TEHV requires robust longitudinal monitoring methods.Cardiovascular magnetic resonance imaging (MRI) is a non-invasive, radiation-free technique providing detailed valvular imaging and functional assessment. To facilitate this, we designed a state-of-the-art metal-free bioreactor enabling dynamic MRI and ultrasound imaging. Our compact bioreactor, tailored to fit a 72 mm bore 7 T MRI coil, features an integrated backflow design ensuring MRI compatibility. A pneumatic drive system operates the bioreactor, minimizing potential MRI interference. The bioreactor was digitally designed and constructed using polymethyl methacrylate, utilizing only polyether ether ketone screws for secure fastening. Our biohybrid TEHV incorporates a non-degradable polyethylene terephthalate textile scaffold with fibrin matrix hydrogel and human arterial smooth muscle cells.As a result, the bioreactor was successfully proven to be MRI compatible, with no blooming artifacts detected. The dynamic movement of the TEHVs was observed using gated MRI motion artifact compensation and ultrasound imaging techniques. In addition, the conditioning of TEHVs in the bioreactor enhanced ECM production. Immunohistology demonstrated abundant collagen, α-smooth muscle actin, and a monolayer of endothelial cells throughout the valve cusp. Our innovative methodology provides a physiologically relevant environment for TEHV conditioning and development, enabling accurate monitoring and assessment of functionality, thus accelerating clinical acceptance.
| S-EPMC11805768 | biostudies-literature
Project description:Heart valve tissue engineering requires biocompatible and hemocompatible scaffolds that undergo remodeling and repopulation, but that also withstand harsh mechanical forces immediately following implantation. We hypothesized that reversibly stabilized acellular porcine valves, seeded with endothelial cells and conditioned in pulsatile bioreactors would pave the way for next generations of tissue engineered heart valves (TEHVs). A novel valve conditioning system was first designed, manufactured and tested to adequately assess TEHVs. The bioreactor created proper closing and opening of valves and allowed for multiple mounting methods in sterile conditions. Porcine aortic heart valve roots were decellularized by chemical extractions and treated with penta-galloyl glucose (PGG) for stabilization. Properties of the novel scaffolds were evaluated by testing resistance to collagenase and elastase, biaxial mechanical analysis, and thermal denaturation profiles. Porcine aortic endothelial cells were seeded onto the leaflets and whole aortic roots were mounted within the dynamic pulsatile heart valve bioreactor system under physiologic pulmonary valve pressures and analyzed after 17 days for cell viability, morphology, and metabolic activity. Our tissue preparation methods effectively removed cells, including the potent α-Gal antigen, while leaving a well preserved extra-cellular matrix scaffold with adequate mechanical properties. PGG enhanced stabilization of extracellular matrix components but also showed the ability to be reversible. Engineered valve scaffolds encouraged attachment and survival of endothelial cells for extended periods and showed signs of widespread cell coverage after conditioning. Our novel approach shows promise toward development of sturdy and durable TEHVs capable of remodeling and cellular repopulation.
| S-EPMC3039844 | biostudies-literature
Project description:Optimal antimicrobial treatment of infective endocarditis requires identification and susceptibility patterns of pathogens. Sonication of explanted heart valves could increase the identification and culture of pathogens, as shown in prosthetic joint and pacemaker/ICD infections. We tested 26 explanted heart valves from 20 patients with active definite endocarditis for added diagnostic value of sonication to the standard microbiological workup in a prospective diagnostic proof of concept study. Two sonication protocols (broth enrichment vs. centrifugation) were compared in an additional 35 negative control valves for contamination rates. We selected sonication/centrifugation based on acceptable false positive rates (11.4%; 4/35). Sonication/enrichment yielded many false positive results in negative controls (28.6%; 10/35), mainly Propionibacterium acnes (next-generation sequencing excluded technical problems). Compared to direct culture only, adding sonication/centrifugation (including molecular testing) significantly increased the diagnostic yield from 6/26 to 17/26 valves (p = 0.003). Most importantly, culture positives almost doubled (from 6 to 10), providing unique quantitative information about antimicrobial susceptibility. Even if direct molecular testing was added to the standard workup, sonication/centrifugation provided additional diagnostic information in a significant number of valves (8/26; 31%; p = 0.013). We concluded that sonication/centrifugation added relevant diagnostic information in the workup of heart valves with infective endocarditis, with acceptable contamination rates.
| S-EPMC6113321 | biostudies-literature
Project description:The development of a novel artificial heart valve with outstanding durability and safety has remained a challenge since the first mechanical heart valve entered the market 65 years ago. Recent progress in high-molecular compounds opened new horizons in overcoming major drawbacks of mechanical and tissue heart valves (dysfunction and failure, tissue degradation, calcification, high immunogenic potential, and high risk of thrombosis), providing new insights into the development of an ideal artificial heart valve. Polymeric heart valves can best mimic the tissue-level mechanical behavior of the native valves. This review summarizes the evolution of polymeric heart valves and the state-of-the-art approaches to their development, fabrication, and manufacturing. The review discusses the biocompatibility and durability testing of previously investigated polymeric materials and presents the most recent developments, including the first human clinical trials of LifePolymer. New promising functional polymers, nanocomposite biomaterials, and valve designs are discussed in terms of their potential application in the development of an ideal polymeric heart valve. The superiority and inferiority of nanocomposite and hybrid materials to non-modified polymers are reported. The review proposes several concepts potentially suitable to address the above-mentioned challenges arising in the R&D of polymeric heart valves from the properties, structure, and surface of polymeric materials. Additive manufacturing, nanotechnology, anisotropy control, machine learning, and advanced modeling tools have given the green light to set new directions for polymeric heart valves.
| S-EPMC9967268 | biostudies-literature
Project description:Background and purposeCalcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H2 S) may exert anti-calcific actions. Here we investigated H2 S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis.Experimental approachEffects of H2 S on osteoblastic transdifferentiation of valvular interstitial cells (VIC) isolated from samples of human aortic valves were studied using immunohistochemistry and western blots. We also assessed H2S on valvular calcification in apolipoprotein E-deficient (ApoE-/- ) mice.Key resultsIn human VIC, H2 S from donor compounds (NaSH, Na2 S, GYY4137, AP67, and AP72) inhibited mineralization/osteoblastic transdifferentiation, dose-dependently in response to phosphate. Accumulation of calcium in the extracellular matrix and expression of osteocalcin and alkaline phosphatase was also inhibited. RUNX2 was not translocated to the nucleus and phosphate uptake was decreased. Pyrophosphate generation was increased via up-regulating ENPP2 and ANK1. Lowering endogenous production of H2 S by concomitant silencing of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) favoured VIC calcification. analysis of human specimens revealed higher Expression of CSE in aorta stenosis valves with calcification (AS) was higher than in valves of aortic insufficiency (AI). In contrast, tissue H2 S generation was lower in AS valves compared to AI valves. Valvular calcification in ApoE-/- mice on a high-fat diet was inhibited by H2 S.Conclusions and implicationsThe endogenous CSE-CBS/H2 S system exerts anti-calcification effects in heart valves providing a novel therapeutic approach to prevent hardening of valves.Linked articlesThis article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
| S-EPMC7024713 | biostudies-literature