Valvular heart disease (VHD) occurs as the result of valvular malfunction, which can greatly reduce patient\'s quality of life and if left untreated may lead to death. Different treatment regiments are available for management of this defect, which can be helpful in reducing the symptoms. The global commitment to reduce VHD-related mortality rates has enhanced the need for new therapeutic approaches. During the past decade, development of innovative pharmacological and surgical approaches have dramatically improved the quality of life for VHD patients, yet the search for low cost, more effective, and less invasive approaches is ongoing. The gold standard approach for VHD management is to replace or repair the injured valvular tissue with natural or synthetic biomaterials. Application of these biomaterials for cardiac valve regeneration and repair holds a great promise for treatment of this type of heart disease. The focus of the present review is the current use of different types of biomaterials in treatment of valvular heart diseases.

OBJECTIVE: Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions.
METHODS: Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact.
RESULTS: Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (- 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2-€12.8 million (TAVI) for TEHV substitution rates of 25-100%.
CONCLUSIONS: Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

Ectopic calcification of native and bioprosthetic heart valves represents a major public health problem causing severe morbidity and mortality worldwide. Valve procalcific degeneration is known to be caused mainly by calcium salt precipitation onto membranes of suffering non-scavenged cells and dead-cell-derived products acting as major hydroxyapatite nucleators. Although etiopathogenesis of calcification in native valves is still far from being exhaustively elucidated, it is well known that bioprosthesis mineralization may be primed by glutaraldehyde-mediated toxicity for xenografts, cryopreservation-related damage for allografts and graft immune rejection for both. Instead, mechanical valves, which are free from calcification, are extremely thrombogenic, requiring chronic anticoagulation therapies for transplanted patients. Since surgical substitution of failed valves is still the leading therapeutic option, progressive improvements in tissue engineering techniques are crucial to attain readily available valve implants with good biocompatibility, proper functionality and long-term durability in order to meet the considerable clinical demand for valve substitutes. Bioengineered valves obtained from acellular non-valvular scaffolds or decellularized native valves are proving to be a compelling alternative to mechanical and bioprosthetic valve implants, as they appear to permit repopulation by the host\'s own cells with associated tissue remodelling, growth and repair, besides showing less propensity to calcification and adequate hemodynamic performances. In this review, insights into valve calcification onset as revealed by in vivo and in vitro procalcific models are updated as well as advances in the field of valve bioengineering.

UNASSIGNED: 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.

The future promises many technological advances in the field of heart valve interventions, like tissue-engineered heart valves (TEHV). Prior to introduction in clinical practice, it is essential to perform early health technology assessment. We aim to develop a conceptual model (CM) that can be used to investigate the performance and costs requirements for TEHV to become cost-effective.
After scoping the decision problem, a workgroup developed the draft CM based on clinical guidelines. This model was compared with existing models for cost-effectiveness of heart valve interventions, identified by systematic literature search. Next, it was discussed with a Delphi panel of cardiothoracic surgeons, cardiologists and a biomedical scientist (n=10).
The CM starts with the valve implantation. If patients survive the intervention, they can remain alive without complications, die from non-valve-related causes or experience a valve-related event. The events are separated in early and late events. After surviving an event, patients can experience another event or die due to non-valve-related causes. Predictors will include age, gender, NYHA class, left ventricular function and diabetes. Costs and quality adjusted life years are to be attached to health conditions to estimate long-term costs and health outcomes.
We developed a CM that will serve as foundation of a decision-analytic model that can estimate the potential cost-effectiveness of TEHV in early development stages. This supports developers in deciding about further development of TEHV and identifies promising interventions that may result in faster take-up in clinical practice by clinicians and reimbursement by payers.

OBJECTIVE: This study sought to evaluate long-term in vivo functionality, host cell repopulation, and remodeling of \"off-the-shelf\" tissue engineered transcatheter homologous heart valves.
BACKGROUND: Transcatheter valve implantation has emerged as a valid alternative to conventional surgery, in particular for elderly high-risk patients. However, currently used bioprosthetic transcatheter valves are prone to progressive dysfunctional degeneration, limiting their use in younger patients. To overcome these limitations, the concept of tissue engineered heart valves with self-repair capacity has been introduced as next-generation technology.
METHODS: In vivo functionality, host cell repopulation, and matrix remodeling of homologous transcatheter tissue-engineered heart valves (TEHVs) was evaluated up to 24 weeks as pulmonary valve replacements (transapical access) in sheep (n = 12). As a control, tissue composition and structure were analyzed in identical not implanted TEHVs (n = 5).
RESULTS: Transcatheter implantation was successful in all animals. Valve functionality was excellent displaying sufficient leaflet motion and coaptation with only minor paravalvular leakage in some animals. Mild central regurgitation was detected after 8 weeks, increasing to moderate after 24 weeks, correlating to a compromised leaflet coaptation. Mean and peak transvalvular pressure gradients were 4.4 ± 1.6 mm Hg and 9.7 ± 3.0 mm Hg, respectively. Significant matrix remodeling was observed in the entire valve and corresponded with the rate of host cell repopulation.
CONCLUSIONS: For the first time, the feasibility and long-term functionality of transcatheter-based homologous off-the-shelf tissue engineered heart valves are demonstrated in a relevant pre-clinical model. Such engineered heart valves may represent an interesting alternative to current prostheses because of their rapid cellular repopulation, tissue remodeling, and therewith self-repair capacity. The concept of homologous off-the-shelf tissue engineered heart valves may therefore substantially simplify previous tissue engineering concepts toward clinical translation.

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