Author + information
- Magdi H. Yacoub, MD∗ ()
- Imperial College, Harefield, United Kingdom; Aswan Heart Centre, Aswan, Egypt; and Qatar Cardiovascular Centre, Doha, Qatar
- ↵∗Reprint requests and correspondence:
Prof. Magdi H. Yacoub, Imperial College London, National Heart & Lung Institute, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, United Kingdom.
Biology is complex, messy and richly various like real life
—Peter Medawar (1)
Life imparts almost magical powers to the individual, organ, or tissue. Heart valves are no exception (2). It is now well established that the living valve performs extremely sophisticated functions that are dependent on the viability and interaction of its component parts. These functions including the capacity to adapt and grow, translate directly into clinically relevant end points such as survival and quality of life. These facts have stimulated the search for a living heart valve substitute. To date, the only clinical example of a living valve substitute is the Ross operation, which unfortunately is grossly underutilized, due to a variety of reasons, including the perceived complexity of the operative procedure (3). This highlights the need for developing a simple, off-the-shelf, living valve substitute.
To that end, several strategies have been used (4,5). Success of these efforts depends on reproducing or emulating the continuing cross talk between the extracellular matrix and specific cellular components, which characterize a living valve (2). In the past, the extracellular matrix (ECM) was thought to consist of inert substances, secreted by the cells with the sole function of acting as cement surrounding the cells and influencing the physical properties of the particular tissue. This view has been challenged by the findings that the ECM is metabolically active and can act as major regulator of cellular functions, including morphogenesis. These concepts are being explored in tissue engineering, with varying degrees of success (6,7). In this issue of the Journal, the report by Zafar et al. (8) is a welcome addition to the literature. The authors thoroughly investigated the use of an unstented tube scaffold made of an acellular scaffold manufactured from small intestinal submucosa, CorMatrix (CorMatrix Cardiovascular, Roswell, Georgia), for tricuspid valve replacement in a growing sheep model. The capacity of the valve to grow was documented over a period of 8 months. In addition, detailed histological examination, 8 months after implantation, showed what appeared to be almost complete replacement of the noncoapting part of the valve by host tissue, having a similar appearance to native cusp tissue. This excellent study represents a significant step towards the goal of producing a living valve substitute and raises several related issues to choice of material, valve design, and host responses.
Choice of a Smart Scaffold Material
The ideal scaffold material should be resorbable, nonimmunogenic, and capable of attracting, housing, and instructing cells to produce the particular phenotype. It should also reproduce the mechanical properties of the native valve, both in the short and long term. Two major types of scaffolds are currently being considered, the first are natural bioscaffolds prepared from decellularized non–cross-linked ECM, such as the one used in the report by Zafar et al. (8), and decellularized valves and whole organs (9). Other types of bioscaffolds are derived from amniotic membrane (10), or alginate manufactured from sea weed (11). The nature of the cytokines and growth factors secreted by bioscaffolds is being actively studied, but remains largely unknown. This applies to both allogenic and xenogeneic decellularized valves. In addition, removal of all cellular material does not render the matrix totally nonimmunogenic. Several components of the ECM such as collagen and elastin can be immunogenic, and could require specific processing. Interestingly, some biomaterials such as small intestinal submucosa stimulate TH2 response locally without affecting the host immune response to viruses (12).
The second type of intelligent scaffolds consist of synthetic polymers decorated by specific molecules (13), designed to enhance their capacity to attract and instruct the host cells, either from local or distant sources, and induce them to transdifferentiate to a tissue-specific phenotype (Figure 1). One major advantage of these materials is the fact that they can reproduce the anisotropic properties of the valve (14).
Valve design contributes to several important functions of the specific valve. These include optimal hemodynamic performance (15), smooth opening and closing characteristics, passive dynamism (2), and importantly, influencing ventricular function and coronary flow, in the case of the aortic valve. The tubular design used by Zafar et al. (8) have several advantages, which include being stent-less, have wide inlet and outlet orifices, and attach the annulus to the ventricular myocardium, thus enhancing the longitudinal ventricular function. However, any tubular design is subject to Poiseuille’s law and therefore increases the resistance to flow. In addition, it lacks the intercordal spaces. The fact that the coapting part of the valve substitute was not replaced by the host tissue is intriguing.
During valvulogenesisis in the embryo, there is close interaction between hemodynamics and valve development (16). The role of such interaction in tissue-engineered valves is still largely unknown, and deserves further study.
Personalized Behavior of Tissue Valves
Following insertion, all tissue valves develop an intimate type of interaction with the host (17). This is contributed to by many factors, which include the composition of the valve, the methods of processing, the technique of insertion, and importantly, by the genetic and epigenetic characteristics of the host. This should stimulate the development of a tailored, personalized approach to the use of tissue valves in the future.
Conclusions and Future Directions
The report of Zafar et al. (8) represents an important step towards the Holy Grail of developing a tissue-engineered living heart valve. It also highlights several issues that need to be addressed before this becomes a clinical reality. None of these issues is insuperable, and should be solved in the near future. This will enable valve replacement to achieve its full potential, particularly in children.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Prof. Yacoub has reported that he has no relationships relevant to the contents of this paper to disclose.
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