© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Tissue engineering of aortic heart valves
Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
*Corresponding author. Tel.: +49-40-42803-3180; fax: +49-40-42803-4876. Email address: w.zimmermann{at}uke.uni-hamburg.de
Received 1 October 2003; accepted 7 October 2003
See article by Schenke-Layland et al. (pages 497–509) in this issue.
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1. Introduction |
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 Top 1. Introduction 2. Decellularization and cell...3. In vitro conditioning...4. ConclusionReferences |
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Valve replacement is the most common surgical procedure in patients with advanced valvular heart disease [1]. Extensive experience has been gained with mechanical and decellularized biological valve prostheses since their clinical implementation in 1965 [2]. In the year 2000, 87,000 valve replacement procedures were performed in the US (www.americanheart.org). Despite its indisputable clinical value, currently employed concepts are hampered by thromboembolic complications, infections, limited durability, and lack of growth potential. Tissue engineering approaches hold the promise of generating completely biological, autologous "living" valves with functional features of their native counterparts that may overcome the present limitations [3,4].
Two main concepts are being pursued in tissue engineering of heart valves: (i) engineering of completely artificial valves from biocompatible and degradable synthetic polymers or biomaterials [5–7] and (ii) decellularization of native heart valves from xenogeneic/allogeneic donors [8–10], an extension of clinically employed biological valves. A drawback of purely (bio-)material-based approaches is the pronounced thrombogenicity of the currently employed polymers and biological matrix components. Seeding of the entire thrombogenic surfaces with endothelial cells would possibly solve this problem but is severely compromised by cell detachment, especially under high pressure aortic flow conditions. Another crucial issue in cardiac valve engineering is the design of stable, strain-resistant and at the same time pliable constructs with functional leaflets [7]. An improvement of valve stability has been achieved by seeding acellular valve constructs with fibroblasts and exposing constructs to pulsatile flow in bioreactors [11]. First studies in sheep have demonstrated the general feasibility of current tissue engineering concepts to replace heart valves in pulmonary valve position [7].
In this issue of Cardiovascular Research, Schenke-Layland and colleagues have combined decellularization techniques, sequential cell seeding with myofibroblasts and endothelial cells, and in vitro conditioning under pulsatile flow and pressure to engineer heart valves with some properties of aortic heart valves. A key finding of the current study is the well-organized cellular repopulation of decellularized porcine pulmonary valves. Most notable is the observation of a complete and sustained endothelial cell lining on inflow and outflow sides of the tissue-engineered valves under moderate physical load (60/40 mm Hg at 1 Hz).
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2. Decellularization and cell seeding |
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Top1. Introduction2. Decellularization and cell...3. In vitro conditioning...4. ConclusionReferences |
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As a principal advantage over polymer-based strategies, decellularization approaches make use of the native matrix environment to support cellular repopulation and physiological heart valve function [8,10]. In the current study, Schenke-Layland and colleagues have decellularized porcine pulmonary valve conduits by trypsin-EDTA treatment [8]. A general problem of decellularization is to retain the structure of the native heart valve and at the same time dispose of all cellular components. Schenke-Layland and co-workers clearly demonstrate the successful preservation of matrix structure and the nearly complete eradication of cellular components after the decellularization procedure by comprehensive morphological and biochemical analyses. Importantly, the native biomatrix appeared to promote repopulation with myofibroblasts and endothelial cells.
The concept of sequential cell seeding of tissue-engineered heart valves with fibroblasts, to improve mechanical strength, and endothelial cells, as a surface lining to reduce thrombogenicity, was previously established by Steinhoff et al. [8] and Hoerstrup et al. [6]. However, neither group could demonstrate the suitability of their tissue engineering techniques for valve repair in a high-pressure environment. Consequently, most approaches in valve replacement have so far focused on pulmonary valve replacement. Schenke-Layland and colleagues propose that dynamic conditioning under pulsatile flow would lead to superior construct stability, rendering engineered valves suitable for aortic valve replacement. Indeed, testing of tensile strength indicated that radial and circumferential strength of bioreactor-conditioned tissue-engineered valves was superior to static cultures and comparable to native porcine valves. Whether this holds true for prolonged exposure to physiological aortic flow conditions has not been assessed in the current study and remains to be demonstrated.
The availability of cell material from vascular biopsies, bone marrow, umbilical cord, and peripheral blood cells [12,13] opens the door for autologous tissue engineering approaches. However, aside from the cellular components, it is in our view imperative to develop a completely autologous or non-immunogenic tissue engineering concept in order to fulfill the promise of a clinically applicable valve replacement procedure devoid of immunorejection and foreign body reactions. Schenke-Layland et al. employed a potentially mixed approach by utilization of ovine cells (autologous) on porcine decellularized valves (xenogenic) for later implantation in lambs. Whether decellularization by trypsin/EDTA treatment and subsequent repopulation with autologous cells will lead to a complete masking of antigens or assimilation of xenogenic extracellular matrix components remains to be demonstrated in vivo.
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3. In vitro conditioning and testing |
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Top1. Introduction2. Decellularization and cell...3. In vitro conditioning...4. ConclusionReferences |
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Beneficial effects of pulsatile flow and strain on tissue engineered heart valves have been described earlier by Hoerstrup et al. [6] and Mol et al. [14]. Accordingly, Schenke-Layland et al. observed superior mechanical properties of tissue-engineered valves that were exposed to dynamic, pulsatile flow when compared to static controls. The dynamic culture also led to increased accumulation of matrix proteins. At this point, it is difficult to judge whether or not matrix protein accumulation will be beneficial or detrimental for valve stability and function. On one hand, matrix accumulation is expected to improve stability of the tissue-engineered valve. On the other hand, pliability is expected to decrease with increasing matrix rigidity, possibly leading to impaired functional properties. Unfortunately, data on flow parameters (pressure gradients, valve closure in diastole) have not been reported by Schenke-Layland and colleagues. Thus, before advancing into an expensive large animal model, it may be worthwhile to test the stability of the valve itself and of the surface cell lining under more physiologic (high pressure) conditions in vitro.
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4. Conclusion |
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Top1. Introduction2. Decellularization and cell...3. In vitro conditioning...4. ConclusionReferences |
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Tissue engineering holds the promise of an autologous and physiological restoration of impaired heart valves (restitutio ad integrum). However, despite considerable efforts, convincing proof of the in vivo applicability of tissue-engineered heart valves is sparse. Notably, a recent study on the implantation of FDA-approved engineered heart valves, based on decellularized porcine valves, has failed, leading to the death of three out of four patients [15]. Rejection/inflammation, degeneration, and graft rupture were cited as causes for the recent failure. Whether or not this could have been foreseen by more rigorous preclinical testing must be thoroughly analyzed to avoid future setbacks. Nevertheless, the concept of engineering an autologous heart valve for a clinical application remains intriguing and the contribution by Schenke-Layland and co-workers extends previous findings in heart valve engineering by combining decellulariziation, cell seeding, and dynamic conditioning. In our view, tissue engineering based on decellularization will bring about immunological concerns associated with inflammation, rejection, and eventually malfunction and might necessitate the development of a completely autologous approach. Eventually, rigorous in vitro testing under physiological conditions followed by long-term animal studies will decide whether or not the concept of engineering an aortic valve by dynamic cell seeding and conditioning of decellularized valves can become a clinical reality.
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References |
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