Print this Article 
Send to a FriendThere is vivid debate - and speculation - over the future of cardiac surgeons and their business. One of the modules of transformation of our exciting profession is suggested to be diversification. The field will broaden to encompass innovative, and most naturally, less invasive techniques. Many of these techniques are in the stage of basic science or animal experimentation at the present time. The quest for novelty is so aggressive that many of the accomplished milestones are viewed with controversy by the conservatives of our profession. One of the fledgling -however rapidly expanding- methodologies which enter the stage of clinical study is tissue engineering and stem cell transfer. These techniques promise to provide tissue restoration or de-novo generation of heart muscle, valves and vessels. The clinical impact of the refined progeny of these innovations in the future is unimaginable.
Our surrounding disciplines of cardiology and radiology exhibit keen interest in novel cardiac therapies and the grey zone of shared therapeutic applications and indications is ever growing. We have to question ourselves, where the cardiac surgeon will place himself in this quest for the terra nova of the treatment of heart disease. Is there anything to be pursued by the cardiac surgeon, that a cardiologist cannot perform himself, even at a lower cost and with less invasiveness? While the clinical cake of myocardial restoration has not been defined yet, cardiologists and cardiac surgeons alike pursue similar paths in parallel. The research volume in myocardial restoration is equally shared by the two disciplines. When it comes to models of more advanced cardiac disease, the cardiac surgeons may keep a nose ahead. However, limits are becoming unclear, keeping in mind the percutaneously inserted valves, for instance.
Our first priority in order to keep pace with the current developments that may shape the future of cardiac surgery is to install a forum which will allow for permanent update and global flow of information as well as discussion, and pave the way for collaboration. Impressive activity is already going on, under lively participation of cardiac surgeons. Many issues need to be addressed: what is the progress in xenotransplantation? Is it reasonable to transplant cells clinically before we even understand their mechanism of action? Which type of cell is optimal for what disease model? When will we be able to produce the first human, totally bioartificial heart chamber? In the following, a brief survey over the most promising achievements in the field of cardiac restoration and tissue engineering of heart structures, but also a critical view of these will be provided.
Myocardial restoration: from vision to mission
The fundamental idea is to attempt to regenerate dead, injured or failing myocardium by transplanting robust and viable cells. These are preferably multipotent stem cells of autologous origin and are hoped to trans-differentiate to cardiomyocytes following engraftment into the damaged host heart. The spectrum of cells used is very heterogeneous, as are the routes of applications (Table 1).
|
Source |
Cell Types |
Routes of Administration |
|
Peripheral Blood |
Endothelial precursor cells |
Intracoronary infusion Cathether-based intramyocardial needle injection Direct intramyocardial injection during surgery
|
|
Bone Marrow |
Mesenchymal stem cells | |
|
Skeletal Muscle |
Satellite cells | |
|
Adipose Tissue |
Mesenchymal stem cells | |
|
Embryo |
Embryonic stem cells |
Table 1: Various sources of restorative stem cells and their routes of administration to the injured or failing heart muscle.
There is great controversy as to the potential of these cells to differentiate into functional cardiomyocytes [1]. Their application is often associated with adverse effects such as severe arrhythmias [2]. An emerging type of cell which bares true and strong potential for differentiation along the cardiac phenotype are embryonic stem cells [3,4]. These, however, are associated with in vivo tumor formation, rejection due to their allogeneic origin [5], and are subject of bioethical debate. The diversity and phantasy that evaded this scientific field seems never ending. There seems to be an emerging "star" of a cell, rising in regular short intervals, which often makes it to clinical application. With the most recently reported stem cell sources from fat tissue and menstruation blood, this trend raises concerns whether any limits to the human tissue recycling exist, before we understand the engraftment mechanism and microenvironmental niche of stem cells. Wollert et al. provided an updated list of clinical studies of cardiac stem cell applications, selected by the targeted disease, the type of cells utilized and the study outcomes (Table 2) [6]. A more critical research of the related literature reveals that appropriately randomized, double blind, prospective, placebo-controlled studies are on the way just recently. None of the studies included control groups with non-contractile cells, such as fibroblasts, so far.
Table 2:A representative list of clinical stem cell studies, the autologous cells involved, and the study outcomes. (by Wollert KC et al., Circ Res 2005;96:151-63).
 |
| Figure 1: Despite of enthusiastic reports of stem cell based myocardial restoration, its exact mechanism remains elusive. The analytical view of the fulminant events which occur in acute myocardial ischemia and infarction is very critical for the better understanding of the stem cell effect. Is the main benefit of the stem cells a true contribution to contractility, or rather a passive viability- and structure-support? |
The term "Tissue Engineering" was introduced by Professor Y.C. Fung at a National Science Foundation Meeting in 1987 and denotes a hybrid science of cell and matrix coculture in the Petri dish or in specially designed bioreactors, with the goal to manufacture tissue in vitro and replace diseased one in vivo. Even though the 8 year old prophecy that “humans will be able to produce the first bioartificial heart in 10 years” has not been fulfilled yet, the path of constructing human heart muscle is being pursued with relentless enthusiasm. Cardiac muscle equivalents have been produced using various solid and liquid scaffolds and a series of cell forms [7,8,9,10], (Video 1). Most of these 3-dimensional constructs contract in vitro after some time in culture. Following implantation many of these tissues are reported to support myocardial function. Even though this attractively surgical approach of myocardial restoration may harbor great clinical potential, we need to understand and share with the audience the fact that we are still far away from producing an efficient cardiac muscle in the petri dish. Why is the heart such as complex target to achieve by means of tissue engineering, the 3d-tissue-manufacture science? Simply, because the heart is far more than a 3-dimensional static organ, as it posesses more "dimensions", such as contractility and rhythm. All in vitro manufactured heart muscle is far less powerful than the native heart muscle. Doctor Buckberg has provided us with a great concept for understanding the complex structure and efficiency of this organ in his illuminating article "the helix and the heart" in 2002 (Figure 2), [11]. With referral to this work, I personally believe that it is time for a “reset” in the field of myocardial tissue engineering, for following particular reasons:
 |
 |
| Figure 2a: In Doctor Buckberg’s review, the helical structure of the heart and the band-like assembly (first described by F. Torrent-Guasp) is displayed. A. The heart’s muscular bands can be unfolded and reassembled as shown in the figure. | Figure 2b. The spiral assembly of the contractile elements of the heart in crucial for the development of the appropriate contractile force. A spherical assembly in contrast, would not suffice for an adequate Ejection Fraction (EF). |
I. The macro- and microstructure of the heart are highly asymmetric and anisotropic. However, all manufactured tissues are symmetric and isotropic, i.e. they do not resemble the helical assembly of the cardiac muscle bands; they rather display a uniform microstructure. In the best case of manufacture of an oval or cylindrical chamber, or even a simple patch, the construct will not be able to develop the vortex forces and the orchestrated sheer stress which is necessary for an effective production of cardiac work. The ingenious interplay of muscle fibers and "myocardial sheets" in the native heart muscle explains the increase of thickness of the left ventricular wall at a rate of 35-40% during systole, while the single myofiber only increases its thickness at a rate of 8%.
II. The heart accomplishes a total of 3 billion beats, propels 180 million liters of blood during a life-time and produces 100,000 Joules of work daily, with a weight of only 300 grams. In order to achieve this, the heart muscle has to rely on a dense network of vessels. Therefore the heart is highly angiotropic, in order to maintain viability and function of its components. In order to keep cell-scaffold compounds viable and functional, complex supply networks have to be included in any given 3-dimensional construct. This has not been achieved yet. Some fledgling innovative approaches of Vacanti et al. [12] and Langer et al. [13] are focusing on this issue and hold promise that bioartificial constructs could be engrafted and survive to play a true functional role.
III. Electrical conductivity and endocrine responsiveness of bioartificial cardiac tissues have to be addressed. Zimmermann et al. [14, 15], and Repel, Fleischmann et al. [16] report on promising approaches using overexpression of contact molecules between cells, complex electrophysiological studies and pharmacological preconditioning, prior to implantation.
IV. The heart constitutes a complex syncytium of cells, not only cardiomyocytes. In fact, only 20% of the hearts’ cells are myocytes. The vast majority of those are not replicative after birth. Consecutively, the optimal myocardial construct should involve a natural mixture of cardiac cells (cardiomyocytes, endothelial cells, fibroblasts etc) with the appropriate robustness and resistance to undersupply conditions. The optimal type of cell to be used is very controversial.
Still, all reported studies resulted in a symmetric "primitive" construct, which looks the same from the one end to the other. Such a construct may be beneficial for a targeted myocardial replacement of limited extend. When it comes to large scale myocardial replacement of diseased heart muscle, injectable, liquid myocardial tissue may be a more efficient tool [17]. It engrafts within the scar and expands under pressure-injection into the borderline and healthy areas of heart muscle, thereby bridging the core of the infarct with more viable parts of the heart from within, while it provides structural support (restoration of the thickness of the scar area for the Laplace law of the heart to become effective and generate more contractile force) and enriches the lesion with robust stem cells. This dual action can be applied on the beating heart, through minimal invasive or endoscopic approaches, and may be an attractive surgical, restorative option in the future.
It becomes obvious that in order to imitate nature with the highest possible fidelity, we need to break down the heart as a target for restoration to the components which compose it and to their specific function and assume a combined approach, with stem cells and structural matrix support simultaneously. In fact, we have found that there is significant functional improvement of the injured heart following injection of liquid matrix alone [17]. Therefore, the passive structural support should not be neglected to the favor of the quest for the "magic" cell for myocardial restoration.
In order to achieve the ambitious goals we announced years earlier, we need to welcome and utilize novel technologies, such as nanofabrication, molecular bioimaging and genetic reprogramming or cell fusion techniques. Most probably, an orchestration of these methods will result in a much more efficient and "biomimetic" product for large-scale myocardial replacement, as propagated by Gerecht-Nir, and Vunjak-Novakovic et al [18].
Tissue-engineered heart valves and vessels
The field of heart tissue engineering encompasses the production of bioartificial, tissue-engineered heart valves and vessels too. A plethora of promising achievements have been published in the recent years. There are two major concepts of bioartificial valve generation: the ex-situ decellularization of xenogeneic valves and subsequent implantation, and the in-vitro repopulation of decellularized donor valves with the recipients' own endothelial cells and fibroblasts [19,20,21]. These are both competing concepts, while polymer scaffolds are being increasingly utilized and seeded with stem cells for the same purpose [22,23]. First clinical implantations have been reported with promising short term results. The main challenges will be freedom of structural deterioration, freedom of in-vivo thrombosis of the implanted tissue engineered valves, and the maintenance of in vivo growth potential for an eventual use in congenital heart surgery.
The demand for bypass grafts for cardiac and vascular surgery is vast. In vitro manufacture of bioartificial vessels is booming [24]. L'Heureux et al produced tissue engineered blood vessels (TEBV) with sufficient mechanical properties to meet clinical demands and long term in vivo patency. The entire construct has been custom-fashioned from tiny skin biopsies of the later recipient [25]. It remains to evaluate how these constructs will perform as aortocoronary bypasses in the long term. Furthermore, in the author’s laboratory, efforts are being made to engineer bioartificial mitral valves. Also, the first bioartificial trachea has been generated and implanted clinically by Macchiarini et al, from the same institution [26,27].
It is more than natural, that Homo sapiens will seek and find ways to manufacture his own organic accessories. The cardiac surgeon of the future will be an active part of this process. However he will have to stay well informed about the rapid developments in the field, promote interdisciplinary synergy and learn from it. The anticipation of a more analytical approach on myocardial restoration, involving nanotechnology, cell science, matrix improvements, bioimaging, and integration of vascular and conductive networks within bioartificial tissues is exciting. The reorientation and definition of our future identity as cardiac surgeons will be served by stimulating collaboration and exchange, also in this advancing field- not least through our professional forum, the CTS-network. However, we need to proceed in a cautious, well controlled and patient-centered fashion, before we witness stem cell- and tissue engineering science abate and loose ground, as did growth factors and growth factor genes in various colors and combinations some 10 years ago (the growth factor “shotgun approach”). The new generation of heart surgeons may then witness the myth of the promethean organ regeneration turn to a panacea for heart disease.