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Reviews

Myocardial tissue engineering: the extracellular matrix

^a Department of Cardiac Surgery, University Clinic Heidelberg, Heidelberg, Germany
^b Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany

Received 23 December 2007; received in revised form 25 March 2008; accepted 27 March 2008.

^_* Corresponding author. Address: Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel.: +49 6221 56 6272; fax: +49 6221 56 5585. (Email: Payam.Akhyari{at}med.uni-heidelberg.de).

	Abstract

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
More than a decade after the first reports on successful three-dimensional cardiac cell culture for experimental and potential therapeutic application, the interest and experimental efforts in the field of myocardial tissue engineering continues to grow. The hope that tissue cultures may one day act as graft substitute for malfunctioning myocardium continues to drive current scientific activity. Against this background interest seem to have progressively shifted towards the aim of engineering single tissue components. Accordingly, elements of the extracellular matrix (ECM) have gained increasing attention as potentially crucial mediators in developing and maintaining the characteristics of three-dimensional cardiac cell cultures. The ECM is now no longer regarded as merely a scaffold for developing tissue, a concept that is widely acknowledged in modern tissue engineering. The understanding of the role of precursor and stem cells has highlighted new complicated aspects of cell proliferation and differentiation and ECM proves to play an important role in providing essential signals to influence major intracellular pathways such as proliferation, differentiation and cell metabolism. Furthermore, progress in biochemical engineering has provided the perspective of application of synthetic ECM-linked molecules with bioactive potential. With the advent and continuous refinement of cell removal techniques, a new class of native acellular ECM has emerged with some striking advantages. The presently available ECM materials aim to closely resemble the in vivo microenvironment by acting as an active component of the developing tissue construct. It is therefore not surprising that most of the focus in myocardial tissue engineering has been on cell–matrix interaction, for both naturally derived and synthetic ECM. This article provides a review of established models of myocardial tissue engineering with respect to the employed ECM materials including current frontiers in material development.

Key Words: Tissue engineering: Extracellular matrix • Myocardial regeneration • Bioartificial tissue • Biological scaffold • Degradable polymer

	1. Introduction

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
More than a decade after the first reports on the successful three-dimensional culture of cardiac cells for experimental and potential therapeutic application [1,2], today, the general interest and experimental efforts in the field of myocardial tissue engineering still represent an emerging scientific area. The vision that engineered tissue may one day act as a substitute for malfunctioning myocardium keeps driving current scientific activity. Over time, experimental focus has shifted progressively away from the efforts of one stage organ development towards the improvement of single tissue components with the capacity of growth and integration under in vivo conditions. Along with this process, elements of the extracellular matrix (ECM) have gained increasing attention as crucial elements in directing the development and maintaining the characteristics of three-dimensional cardiac cell aggregates. This is in line with the general trend in other scientific fields [3]. The ECM is now no longer regarded as a mere tissue conductive mechanical scaffold for developing tissue, but with an important tissue inductive function. With this concept in mind, the focus has been on the various components and their careful proportional composition of the ECM.

There are several good reasons for the increasing recognition of the central role of ECM in maintaining physiological tissue balance. As an early finding, the role of the ECM in the translation of external physical forces into intracellular pathways was described [4]. More recently, precursor and stem cells have been employed in tissue engineering concepts, which has raised new questions related to guided cell proliferation and differentiation in vitro and in vivo [5]. Experimental efforts to increase control over the tissue maturation process led to an extensive search for tools to enhance the control of precursor and stem cells. The ECM was found to be a helpful means to provide some crucial physical signals to influence major intracellular pathways and thereby directing proliferation, differentiation and cell metabolism [6]. Furthermore, progress in biochemical engineering has introduced the perspective of ECM-linked bioactive molecules [7,8]. Among the possible candidates for the latter entity, growth factors and cytokines are of major interest, as the key to turning basic ECM into a more custom made, tissue specific template that promotes tissue regeneration actively, thus changing the features of the current in vitro employed ECM to resemble the ideal microenvironment more in vivo presentation, by enhancing the interaction of the developing tissue construct with the seeded in vitro cells. As a result of this concept, most experimental efforts in the field of myocardial tissue engineering have been focusing on the cell–matrix interaction, for both naturally extracted and synthetically developed ECM components. The following section intends to review established models of myocardial tissue engineering with respect to the employed ECM materials including current frontiers in material development.

	2. Native myocardial extracellular matrix

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
The heart is a unique organ with dynamic functional properties that require a sophisticated tissue architecture involving specialized cellular and extracellular components [9]. One of the key characteristics to enable the heart as the circulatory motor to meet variable demands during rest and exercise lies in the asymmetrical, helical architecture of the myocardial structure [10]. With each excitation–contraction cycle the physical forces that are developed on the cellular level have to congregate to develop the macroscopic contraction force of the heart. This process of upscale merging of physical forces is mediated by the delicate arrangement of the cardiac ECM [11]. As a result a significant dynamic change of the three-dimensional arrangement of all active and passive myocardial elements takes place accordingly. There are a number of implications of the mechanical events involved in every excitation and contraction cycle for the extracellular matrix of the heart. Besides a flexible and elastic design, a close link to the contractile elements is essential during both the contraction phase and the relaxation period. The link between mechanical function and macroscopic architecture of the heart has been described [12], and a better understanding of the microscopic and ultrastructural elements involved in the mechanical function of the myocardium has underlined the importance of the ECM [13]. Recent studies suggest a more significant involvement of the ECM in all aspects of the electromechanically active myocardium than previously believed [14,15]. Beside these findings on native myocardium, further insight into the regulatory role of the ECM was gained through experimental studies on primary cardiac cells and cardiac cells derived from progenitor or stem cells [16–18]. In summary, there is increasing consensus on the pivotal role of the ECM for cell survival, differentiation, proliferation, metabolism, and integrative function, both under in vivo and in vitro conditions [19–22].

Based on the current understanding, the ideal ECM for tissue engineering purposes can be characterized by a catalogue of properties that, to date, has not been satisfactorily achieved in any of the available ECM models. However, based on the current ECM models a substantial improvement in terms of viability, survival, function and differentiation of the resulting bioengineered myocardial structures have been reported, a summary of which will be presented in the following section. The involved models of ECM can be classified into those with biologically derived components, synthetic ECM materials and de novo synthesized ECM deriving from cultured cell populations. More recently, composite solutions of a mixture of biologically derived and synthetic materials have been favored for their more advantageously balanced physical and biological characteristics [23].

	3. Biological ECM models

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
3.1 Collagen and gelatin
Biologically derived ECM materials appear attractive for the reason of their natural origin and native proportional constitution of various ECM proteins. Also the natural arrangement and microarchitecture speak in favor of natural ECM materials. Hence, myocardial tissue engineering has been studied in numerous culture models employing a variety of biological ECM compositions. One of the most simple biological ECM materials, porous dry collagen has a history of extensive clinical application as a hemostatic agent to control diffuse hemorrhage in tissue injuries, long before it has been considered as a regenerative tool [24]. Due to the industrial manufacturing and standardization as well as to the highly biocompatible characteristics, porous collagen sheets are user-friendly and efficient ECM components for the three-dimensional cell culture and have been successfully employed for myocardial tissue engineering [25]. Similar in vitro results have been demonstrated for a porous matrix based on gelatine [26,27]. Although collagen and its chemically denatured product gelatin, are both considered as biodegradable materials, the latter can provoke an unspecific inflammatory response. Under certain circumstances this may be desired due to the concomitant proangiogenic events at the site of implantation [28]. On the other hand a negative impact on the survival and function of the inoculated cells inside the implanted bioengineered graft has to be considered. Using matrigel, a collagen-based, multicomponent mixture of ECM proteins and growth factors, Eschenhagen et al. have established one of the currently most convincing models of three-dimensional cardiac cell cultures, where differentiation status and functional parameters reach a quality close to that of native myocardium. Matrigel is a liquid basement membrane extract derived from a sarcoma cell line and contains a broad range of ECM proteins, such as collagens, and bioactive substances including growth factors, that can promote cell growth and beneficial remodelling of three-dimensional cell culture in vitro as well as in vivo [1,29–31]. Further experimental evolution of this model that was coined engineered heart tissue (EHT) includes the evaluation of different cell populations and the effort of the investigators to replace certain components of their protocol in order to adhere with requirements existing in the clinical setting [1,29]. There has been some controversy about Matrigel and the question of the growth factor content within Matrigel has been partially regarded as a potential contaminant. This can be explained by levels of individual growth factors varying from one manufacturing batch of Matrigel to another. Furthermore, some of these components have no regulatory approval for use in human patients. The latter fact might be rather a secondary dilemma at the moment, but it surely will gain further importance as the tissue engineering field comes into age and the first applications may soon find their way into clinical trials. Finally, in an experimental setting exploring mechanistic issues, the presence of a mixture of different substances interfering with the development of the culture can be disturbing to the evaluation process. As a consequence, Matrigel has become available in different compositions, e.g. as a growth factor reduced type. Reports on a combination of Matrigel with other ECM materials underline its versatility. Another advantage of Matrigel lies in its liquid application form that allows for a casting of cell cultures in an experimentally desired shape, with an even spatial distribution of the cells within the matrix [32]. Due to the conveniently long gelation time a simultaneous injection of Matrigel together with a cell suspension to form a cell–matrix combination at the targeted in vivo site has been proven as surgically feasible [33]. Another approach to achieve suitable tissue microarchitecture that supports cell infiltration and growth lies in mimicking ECM fiber density and orientation of native organs. Faradj et al. report on a collagen processing protocol that involves specific freezing steps and selected solvents to yield accurately predicted fiber orientation patterns. Interestingly, different patterns of collagen fiber orientation, including parallel, networked or alveolar-like micro-configuration were produced. The result of ultrastructural analysis strikingly demonstrates the close relation to native ECM configuration in distinct organs [34] (Fig. 1C–F). This concept achieves a biological ECM with desired microstructure. It could be enhanced further by increasing the number of the involved ECM types, e.g. by adding glycosaminoglycans to the collagen component [35] (Fig. 1G). Although ultrastructural analysis of these ECM is remarkable due to the parallelism to native tissue [34], the superior suitability of such tailored microarchitecture for spatial cell seeding warrants future evaluation by in vitro and in vivo studies. This might disclose the need of further improvement, as many practical drawbacks of ECM materials for the first time appear in cell culture or in vivo studies.

View larger version (167K): [in this window] [in a new window]   Fig. 1. Targeted alteration of ECM microarchitecture. Scanning electron micrographs. Fibrin-based ECM with interconnected alveolar-like micropores (A and B), collagen matrix modification and design of tissue specific microarchitecture by alternation of chemical solvent solution (C–F), porous biological (G) and synthetic (H) composite ECM with controlled biomechanical and biodegradation characteristics.

3.3 Hyaluronic acid
Another member of the native ECM that has been successfully applied to TE models is hyaluronic acid (HA). HA is a polysaccharide that functions as an efficient space filler and also has a significant impact on the mechanical properties of a tissue by binding proteoglycans and maintaining hydration [49]. While HA macromolecules maintain the biomechanical properties of tissue, its fragments prove as strong bioactive molecules that are involved in many regulatory events, including cellular function and development, tumor progression, angiogenesis, inflammation, wound healing and regeneration [50,51]. Also, a supportive effect on differentiated cell phenotype has been reported for adult cardiomyocytes grown on a HA containing substrate [52]. Due to its viscoelastic properties HA has been employed in experimental and clinical studies on soft tissue repair, mostly involving cartilage, but also other tissues including heart valves [53–56]. In most applications it appears attractive to support the HA matrix by adding other biological or synthetic ECM components [57,58] to yield the desired combination of compressive and tensile characteristics and at the same time beneficial bioactivity of the resulting ECM [6,42,59]. However, only very limited implementation of HA for myocardial tissue engineering has been documented to date [52], and whenever in use, the support of further ECM components appears mandatory [42].

3.4 Alginate and cellulose
In vitro cell culture models based on alginate gels have been known for almost two decades [60]. Alginate is a polysaccharide consisting of mannuronic acid and guluronic acid with a variable three-dimensional molecular structure that is determined by the sequential appearance of these two acids. The main advantage of alginate lies in the capacity of gelation upon addition of calcium or its salts. Due to a general pro-proliferative effect, calcium alginate has been extensively evaluated as a substrate for chondrocyte culture and tissue engineering of cartilage [61–63]. Alginate encapsulation of cells of varying type and function has also been established in numerous models [64–66]. Leor et al. [67] have described a model of three-dimensional cardiac cell culture within an alginate based ECM. Besides a convincing level of cell viability after an in vitro culture period of up to several weeks, the resulting grafts survived in vivo and explanted hearts showed the alginate as almost completely absorbed after 9 weeks in vivo. In this study sodium alginate was employed to form a solid porous matrix where the cell suspension was applied. These promising results with alginate as an ECM material were supplemented by others who introduced further ECM components to achieve more control over the matrix microarchitecture and degradation behavior in vivo [68]. Although as a single component not widely acknowledged in the field of cardiac tissue engineering, alginate might yet gain further recognition as an interesting element of a desired ECM. Similarly, cellulose, another polysaccharide that builds the major structural component of plants, has been used as ECM for three-dimensional culture of cardiac and other cells [69,70]. As with many other materials, in case of cellulose an industrial manufacture has become feasible. Also, particular topological characteristics can be designed in order to fulfil certain tissue specific requirements. Although mammalians do not have the enzymatic repertoire to digest cellulose, in vivo experiments have demonstrated a slow degradation upon implantation [71]. However, further studies with focus on in vivo degradation pathways and functional benefits are needed to assess the value of plant-originated biomaterials in myocardial tissue engineering.

3.5 Native tissue derived ECM
Almost two decades ago Badylak and co-workers reported on the feasibility of vascular replacement by small intestinal submucosa (SIS) in a large animal model. Likewise animal derived SIS has been clinically used as a biological material to fill substantial tissue defects [72]. The superior in vivo performance and integrative capacity of this native biological material has inspired many groups in their efforts to create tissue implants on the structural base of native organs. Although Badylak's model as well as similar works at that time were successfully performed due to an autologous model and often included chemical fixation steps of the grafts, a new trend in replacement therapy was evident, which was refined by introducing decellularization techniques. Hereafter allogenous and xenogenous models could be established. Decellularization can be performed via various methods, e.g. physical, chemical or enzymatic treatment [73] and today, many tissue specific methods of decellularization have been evaluated [74–78]. The main obvious advantage of a naturally grown ECM lies in its balanced composition of all physiologically appearing protein components. With respect to myocardial repair, in vivo studies have proven the suitability of native ECM in terms of regional compatibility and support of local cell ingrowth, although with the use of the ECM of the urinary bladder a heterotopic ECM transplantation was performed [79]. Similar effects of general support of tissue development have gained exceptional interest along with recent experimental attempts to culture premature cardiomyocytes or to differentiate cardiac progenitor cells [16]. Providentially, from the evolutionary point of view major components of the ECM are relatively well preserved across the mammalian species. Hence, the immunological barrier may be regarded as a secondary issue. Based on current evidence, there is a chance that even a xenogenic implantation of a decellularized ECM might provoke an immunological response that is only of minor relevance [80].

The challenge lies in the effectiveness of the decellularization process. This might ultimately turn out as big a task as the promised benefits, however tempting. The ideal decellularization procedure pertains a total and exclusive removal of all cellular components that are responsible for the immunological rejection upon implantation. At the same time all ECM components have to be preserved in their quantity and native configuration. Many decellularization techniques have been described in the literature [81] and many of them were primary designed for the application to cardiovascular structures [79,82,83]. Although due to technical reasons the ideal decellularization product, that is a totally preserved ECM without any cellular residues, might never become available, existing protocols have proven to be highly effective in producing an ECM that shows remarkable in vitro and in vivo performance [79]. A few reports describe a decellularization technique under preservation of the functionally relevant morphology, e.g. heart valves or vascularized intestine segments [84,85] (Fig. 2E). The latter one, named biological vascularized matrix (BioVAM) has a broad application capacity and has also been used for myocardial tissue engineering [86,87]. Preliminary results suggest that native ECM might deliver sufficient growth promoting signals, even in the heterotopic application, e.g. application of intestinal ECM for tissue engineering of cardiac structures [88]. The very most recent report by Ott et al. delivers an excellent example of the high potential of native ECM for in vitro engineering of a bioartificial tissue. By decellularizing a complete heart under preservation of the anatomical architecture of the ECM a template to build a new heart was generated. All native cells could be removed, the ECM exhibited a high degree of preservation (intact basal lamina, high content of glycosaminoglycans, etc.) and the native vascular network could be preserved. Most interestingly, neonatal rodent cardiomyocytes regained contractile activity upon seeding on the decellularized matrix. The authors report on the possibility of applying this technology on organs of the size of a human or a pig heart [89]. This might be a milestone in myocardial tissue engineering on the ECM level opening new avenues towards preclinical studies. Hence, from the current perspective, tissue engineering concepts that involve native ECM components appear promising due to their strong biocompatibility, their preserved bioactivity and most prominently, due to the option of an integrated functional vascular network, which will be in focus later on in this manuscript.

View larger version (77K): [in this window] [in a new window]   Fig. 2. ECM models with pre-existing perfusion pathways. (A) In vivo vascularized chamber, macroscopic in situ image; (B) bioreactor with central perfusion vessel; H&E staining of cross section (top) and FDG-PET demonstration of increasing tissue viability in close proximity to a central perfusion vessel (lower image); (C) channelled scaffold for tissue perfusion; (D) macroscopic image of BioVAM, decellularized intestinal submucosa with preserved vascular network; (E) dil-labeling of endothelial lining after luminal reseeding of BioVAM).

	4. Synthetic extracellular matrix

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
4.1 Polyesters
Among the synthetic biodegradable materials the polyester family has been the most frequently explored group, including the prominent polymers poly(lactic acid) (PLA) and poly(glycolic acid) (PGA). As the two latter materials have been among the first ones subjected to tissue engineering applications, today numerous reports on a successful application of these materials in different organ systems exist. Their use is supported by the exact control of polymer composition, the density and porosity of the resulting scaffold and also by the chemical production pathway that excludes pathogen transmission risks adhering to some biological matrices. On the other hand, generally spoken, all synthetic ECM materials lack an adequate and elaborate physiological recognition system and need more sophisticated modification steps in order to obtain a bioactive ECM.

PGA is a thermoplastic material that has been in clinical use for many years as suture material (Dexon). It can also be processed into porous scaffolds to home seeded cells. The major advantages lie in a biocompatible degradation fate resulting in a natural metabolite, glycolic acid. However, localized excess acid production is known to result in a hostile environment for cell growth and differentiation and this has been a concern of some investigators [95]. In early pioneering stages of cardiac tissue engineering PGA has proven to provide the basic necessary characteristics to allow for cell infiltration and survival. However, upon implantation foreign body reaction and tissue destruction as a possible adverse reaction have been reported [96,97]. However, Carrier and colleagues as well as other groups have used porous PGA matrices for cardiac and cartilage tissue engineering and could demonstrate cardiac cell phenotype preservation and electrophysiological performance after seeding of neonatal cells and subsequent in vitro culture [98–101]. Similarly, PLA has been used for three-dimensional culture of cells [102]. PLA has, to some extent, a higher resistance to hydrolytic degradation that may be explained by a higher hydrophobicity. It also provides a higher plasticity that may be used to support structural integrity of three-dimensional cell cultures. Copolymers containing lactic and glycolic acid (PLGA, poly(lactic-glycolic acid)) also have a long-term history of clinical use as suture material (Vicryl), more recently also as porous ECM for tissue engineering purposes [103,104]. Besides generally acknowledged factors such as porosity, molecular weight, cross linking rate and implantation site, the relative amount of each monomer also has an impact on the degradation rate in vitro and upon implantation [104]. First generation polymers that were initially applied in tissue engineering experiments have been widely replaced by novel ECM polymers containing bioactive components or an improved biochemical composition.

4.2 Polylactones
Another group of synthetic materials is built by polylactones, where Poly(epsilon-caprolactone) (PCL) is the most frequently employed member [105]. PCL is considered as a biocompatible polymer with a significantly longer degradation time as compared to the above mentioned materials, lasting to over a year in vitro. Copolymers of PCL are used in various biomedical applications, again also as suture material (Monocryl). In the tissue engineering field copolymers including other materials are preferred, most probably due to higher versatility of the material characteristics [106–108]. However, recently the successful introduction of cardiac cell cultures in a porous PCL matrix has been reported [109,110]. The results of these few reports describe an ECM that could be an alternative to more sophisticated composite ECM solutions (see below).

4.3 Polyurethanes
The class of polyurethanes (PU) comprises biocompatible synthetic materials that are in wide biomedical and industry use. From the chemical point of view, PU is made by a polymerization process involving dioles and diisocyanates. Depending on the specific configuration of these two components, the resulting PU material may expose extremely varying mechanical characteristics and biological degradability. It is possible to produce PU materials with extreme durability lasting life-long under in vivo conditions and gaining their adequate function as vascular prosthesis, etc. At the same time a PU based material may be manufactured with an in vivo integrity of only up to a few days. With recent technological progress chemical engineering has expanded the freedom of degree of novel synthetic materials. Similarly, PU-based ECM materials have remarkably improved, actually becoming available as smart materials with selective incorporation of peptides or other bioactive molecules [111,112]. In the cardiovascular field, laminin coated PU has been used to pattern cardiomyocyte cultures [113], where the suitability of PU as a substrate for cardiomyocyte culture was demonstrated. The improvement of a PU matrix by addition of laminin has also been used by Siepe et al. [114]. In this model, the authors employed a three-dimensional, porous elastomeric PU matrix with a coating of laminin or fibronectin for tissue engineering purposes. The seeded skeletal myoblasts were cultured for several weeks. Remarkably, cell survival and the spatial distribution of myogenic cells were maintained throughout the in vitro culture period and even survived in vivo remodelling after epicardial implantation on ischemic myocardium [115]. Although the authors did not observe any evidence for differentiation of the inoculated myoblasts, (e.g. myotubes), the presence of numerous microvessels speaks in favor of PU-based tissue engineering models. An improvement of PU by addition of cell differentiation promoting agents may further encourage the use PU based ECM for myocardial tissue engineering.

	5. Composite ECM

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
The promotion of cell differentiation is one of the pivotal functional roles of an ideal ECM. Cell attachment, proliferation and cell type specific activity (e.g. contraction, secretion of ECM proteins or secretion of messenger molecules) are further characteristics defining a tissue growth-promoting environment. As many of the above mentioned ECM models, be it biological or synthetic, consist of one major component, in many of these models it appears beneficial to introduce other ECM elements with complementary characteristics to improve mechanical performance or bioactive mimicry of a native microenvironment. This might have been the inspiration of several groups to develop composite ECM materials that contain more than one biological or synthetic material. Many of these models combine biological with synthetic elements. Boublik et al. [23] have established a model of composite ECM by seeding cardiac cells suspended in a polymerizing fibrin gel on a knitted hyaluronan matrix (Fig. 1H). Fibrin serves as an initial cell immobilizer and also as a template upon which a new ECM can be synthesized and secreted by the embedded cells. After implantation fibrin represents the natural target for host derived remodelling that involves vascularization via angiogenesis and deposition of native ECM components. During the in vitro culture and the initial in vivo maturation the elastomeric hyaluronan compartment determines the mechanical properties of the growing tissue and will be susceptible to slow degradation in later stages, when a mechanically competent de novo synthesized ECM will be present. Consistent with the results of other studies employing fibrin, in this study after in vitro culture as well as after in vivo evaluation a preservation of cardiomyogenic phenotype could be demonstrated [23]. Other groups have combined PGA [116] or PGLA with natural products such as alginate [117] to achieve an ECM with improved mechanical and biocompatible characteristics. Numerous reports depict the suitability of synthetic materials like PCL when an adequate biological co-material is simultaneously used. As a co-ECM, candidate materials should have a high potential to mimic the native microenvironment of the seeded cells. In this context, few convincing models of tissue engineering are based on PCL linked to collagen [106], fibrin [118], chitosan [107], gelatine [119] or fibronectin [118].

To this point the large number of the single ECM components more or less suitable for myocardial tissue engineering becomes evident. The even larger number of combinatory options accounts for the recent exciting developments in this field. In every one of the above mentioned models the rational for the ECM composition is based on a number of criteria, such as influence on the fate of the inoculated cells, resulting tissue mechanics, predicted tissue remodelling in vivo, etc. Some of these aspects warrant complementary comments.

	6. Biomechanics

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
Most of the myocardial tissue engineering studies aim at constructing a myogenic tissue fragment that can be used as a patch to replace malfunctioning or congenitally malformed cardiac tissue. Hence, active and passive mechanical performance of a bioartificial myocardial tissue is regarded as a principal characteristic. Various mechanical aspects have been described and quoted as crucial in existing studies, where active operation generally relies on cell type and culture conditions [120]. In contrast, passive mechanical features are mainly determined by the ECM [23,27]. Ideally, tissue elasticity and maximum strength can allow for a long-term contractile function and at the same time tissue strength will withstand external forces imposed upon the tissue by alternating pressures of the ventricles or the great vessels. In almost all of the established models the initial mechanical properties of the bioartificial grafts are the immediate result of the ECM mechanics. Future concepts designing improved ECM scaffolds will deliver initial characteristics close to those of the native tissue. In the ideal setting, the speed of the subsequent scaffold degradation is controlled and adopted to the velocity with which a de novo matrix is established. Today, this process may appear straightforward for an in vitro model when a homogenous population of differentiated cells is used. However, cell (de-) differentiation, change in the relative composition of the involved cell types, changing cell proliferation and alternating conditions of oxygen and nutrition supply are interfering and interactively linked factors. These factors make the underlying calculation difficult. On the other hand, under in vivo conditions a large battery of additional elements with an impact on tissue development becomes active, hindering the manufacture of the ideal ECM based on a theoretical calculation. To this point most of the manuscripts describing the creation of tailored ECM materials involve limited cell culture and in vivo evaluation steps [42,106,107,118,119]. Hence, more data on long-term performance of bioartificial myocardial tissue is needed to determine the value of each one of the currently designed ECM materials.

	7. Vascularization

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
Contractile activity provides evidence of intact myogenic function, and as such it can only effectively operate when necessary metabolic resources are supplied in an adequate quantity. In pathology as well as in tissue-engineered constructs, oxygen and nutrition supply to the working cardiomyocytes may fall below the minimum quantities necessary for physiological function or even under the limits of mere cell survival. Regardless of an ongoing discussion concerned with the maximum depth of vital tissue under diffusion conditions [121,122], there is an obvious need for an intact vascular network embedded in a tissue-engineered unit that provides the anatomical infrastructure for tissue perfusion. Successful tissue engineering of myocardium will need an entire concept for oxygen and nutrition supply to the cells inside the growing tissue. Several studies have addressed the current shortage of supply that is adhering to most of tissue engineering models [37,123,124]. The choice of the ECM is closely linked to the question of vascularization. In this matter, one of the best examples may be given by Bar et al. [87]. Their model, named biological vascularized matrix (BioVAM), a decellularized segment of porcine small intestine may represent a superior ECM for three-dimensional cardiomyocyte culture (Fig. 2E and F). It provides an intact native vascular network, including capillaries as well as a pair of central arterial and venous vessels that are suitable for surgical anastomosis. This exciting model of a vascularized biological matrix has been adopted by groups from other regenerative disciplines to engineer urological and skeletal elements upon [85,125]. However, drawbacks may lie in the donor-depending variety of the vascular quality, as donor animals may be prone to vascular malformation or pathology. Despite ongoing debate, biohazard concerns have been widely resolved by several studies [126,127] and the xenogenic origin might be of minor relevance in this context.

Other examples of vascularized tissue involve large volume vessels of macroscopic dimensions that are placed in the center of the growing tissue [25,128] (Fig. 2A–C). Hereby, perfusion of the tissue-engineered constructs via angiogenesis and microscopic neovascularization can be stimulated in vitro [37] or in vivo [128]. The latter concept is developed in vivo and utilizes in situ vessels from the recipient around which the combination of cells and ECM are implanted and grown (Fig. 2A). This approach, also referred to as guided tissue engineering, is preferable due to the use of autologous native vasculature with minimal risk of thrombosis or immunological adverse reactions. Nevertheless, there is a major disadvantage of a two stage procedure involving the implantation of the culture chamber in a first step followed by the transfer of the cellular component into the vascularized chamber in a second procedure. According to the other in vitro concept by Kofidis et al. (Fig. 2B and C) a liquid cell–ECM mixture is casted around a macroscopic donor vessel (that also can be harvested from the tissue recipient, hence becoming autologous) and cultured in a bioreactor system. Perfusion with circulating medium and growth factors is maintained through the tissue embedded vessel for up to several weeks, enhancing cell survival and tissue maturation. In these and other in vitro experiments on tissue-engineered myocardium, in contrast, have been capable of merely proving superior cell viability, tissue organization and differentiation [37,129,130] without demonstration of significant vasculogenesis. Sprouting neo vessels as an evidence of angiogenesis have only been documented for in vivo incubated constructs [28,115,128,131], and this phenomena may be significantly depending on the ECM material and ECM microarchitecture. For in vitro studies, one solution to the problem of missing capillary size vessels may lie in the concept of channelled ECM scaffolds [132] (Fig. 2D). Here, constructs are built by seeding cardiac cells on scaffolds that include microscopic channels. Subsequent culture in a bioreactor with constant medium flow through the channels resembles tissue perfusion and improves viability and functional parameters. Synthetic oxygen carriers that are administered as a supplement of the culture medium, significantly increase the benefit of perfusion. Other groups report on co-culture techniques utilizing endothelial progenitor cells or on the use of embryonic stem cells, both resulting in formation of microscopic structures of capillary like morphology within the tissue-engineered cardiac tissue [133,134]. However, further improvement, most probably involving a co-ordinated progress of cellular components, ECM design and bioactive factors, is warranted before a surgical anastomosis of these microscopic vascular networks to the blood circulation of a recipient organism becomes feasible. The question of intact endoluminal endothelial lining to avoid thrombosis of the ECM vascular network in blood circulation deserves further consideration when in vivo tests are planned.

	8. Smart biomaterials

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
Finally, a scaffold might be precisely structured (e.g. via micro patterning) and well organized surrounding the desired cell population in a three-dimensional culture, and yet the development of a differentiated tissue depends on further factors that ideally mimic the native ECM. The recognition of important ECM bound factors in native tissues has led to the development of ECM materials that harbor bioactive molecules. The resulting entity of ECM materials was soon called smart, as these materials are capable of interaction with the embedded cells. Vascular endothelial growth factor (VEGF) was one of the factors that was recognized early for their potent impact on tissue remodelling in vitro as well as in vivo. Consequently ECM bound VEGF has become an attractive tool to induce vascularization of bioengineered tissue substitutes [135]. In parallel other growth factors or peptides with bioactive potency have been employed as ECM bound mediators of angiogenesis, cell proliferation and differentiation [136,137]. Other concepts of biologically interactive ECM materials were soon to follow. Jefferey A. Hubbel and his research group have extensively explored bioresponsive polymer materials for biomedical research and therapeutics [138,139]. Modified poly(ethylene glycol) (PEG) hydrogels with specific susceptibility to enzymatic degradation were engineered by introducing peptide sequences that represent specific targets of various matrix metalloproteinases (MMP). The authors showed that an increasing enzyme specificity of ECM may be converted in an increased level of control over cell migration and differentiation. And this in turn resembles a powerful ECM-based tool for engineering of complex tissues [140,141]. Besides growth factors or protease specific peptides the introduction of matrix bound ribonuclease molecules for gene therapeutical purposes in a tissue-engineered construct denotes another option in directing cell and tissue development at the implant site [142,143]. Target gene sequences may be delivered as DNA or RNA [144], and additional vectors can be installed to enhance local expression rate and duration while the harboring scaffold may serve as protecting barrier against recipient immune response and enzymatic degradation of the ribonuclease molecules [145]. Furthermore, linkage to the ECM provides additional spatial control of gene release while elaborated immobilization techniques may improve temporal control of gene release [146], both leading to superior guidance of the in vivo tissue maturation upon implantation of the construct. Another tool to improve targeted activity may be installed by introducing inducible promoter sequences that serves as an on–off switch that is triggered and driven by the local in vivo milieu and the involved cells. In vivo models have already proven the feasibility of ECM based gene delivery and demonstrated the versatile options in terms of regulation of local microenvironment at the targeted site [147]. Using this principal, crucial tissue remodelling events may be influenced at various stages of the respective signalling cascade [148].

With the focus on myocardial tissue engineering and regeneration a number of genes that play a central role in angiogenesis, protection of the myocardium from ischemic injury cardiomyocyte differentiation and survival appear to be promising candidates for an ECM bound gene delivery system [149], some preliminary data already support actual optimism. Recent advances in chemical engineering have paved new avenues for custom made, multifunctional materials. In an interesting approach to overcome the oxygen shortage in ischemic tissue, the implementation of synthetic oxygen carriers bound to an ECM template has been tested in an in vivo model [150,151]. The promising results predispose such an oxygen-delivering biomaterial for cardiac tissue engineering, where working myocytes demand a relatively large amount of oxygen supply. Other novel ECM preparations containing self-assembling peptides undergo a gelation process after initiation of the assembly to form a nanoscale fiber network in vivo. In an in vivo trial the hereby achieved microenvironment was capable of attracting endothelial and smooth muscle cells and supported the survival of engrafted cardiomyocytes [152]. The number of new developments in this field has been growing progressively in the past years and today smart ECM materials respond to various chemical or physical stimuli or even to specific physiological messengers [153,154].

These novel materials provide mechanical support to the inoculated cells while simultaneously specific bioactive signals drive tissue formation and targeted differentiation. Although some of the most recent innovations have yet not been applied to myocardial tissue engineering, the underlying principles clearly support main aspects of the culture conditions that today are known as crucial for optimal tissue formation and growth. Therefore, it appears most likely that some of the above mentioned protocols will find their way in future studies concerned with myocardial tissue engineering.

	9. Bioprinting

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
A very recent development that already has raised high expectations among the material scientists and biomedical engineers is called micro patterning or bioprinting. The best simple way to describe this method is essentially to compare it with the process of inkjet printing by regular desktop printers. Instead of the ink, bio printing involves biological materials, suspended cells or cell–matrix preparations that hereby can be transferred onto a culture substrate in a precise spatial order and distribution [155]. This way multilayer sandwiches of cell and biopolymer layers could be printed and this process can, theoretically, be expanded to larger scales of tissue fragments or even whole organs [156]. Although a long way off many optimization steps have to be taken in order to adopt this technique to the requirements of viable cells of a large size, e.g. cardiomyocytes, the potentially high merits of this technology aren’t entirely known at this early stage of development. Barriers encountered today on the way to a micro patterned tissue fragment appear to be of a technical nature and there is a good chance that in this matter significant progress will be achieved in the near future [157].

	10. Summary

Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 
Tissue engineering has entered the next level, where simple addition of cells on top or into an extracellular matrix material with rather random localization and subsequent development of the three-dimensional product is widely overcome. Biocompatible scaffolds providing considerable mechanical support are already available in a broad range of biological or synthetic composition. Today, polymer engineering and processing technology can provide a novel quality of synthetic products for the implementation in tissue-engineered constructs. Besides electrospinning technology [104], the utilization of protein self-assembly [158] has also thoroughly changed the prospects of both biological and synthetic ECM materials in the field of tissue engineering. Actual frontiers surround the question of how to direct tissue remodelling in vitro as well as in vivo. Matrix linked growth factors, cytokines, cell surface receptors and other bioactive components build the base of a novel class of ECM materials that are designed to develop a biomimetic microenvironment for organ specific tissue development. Finally, focusing on the heart and thinking of myocardial tissue replacement, all the above mentioned aspects have to be considered in a single ECM solution. This ideal solution has the necessary macroscopic physical properties for surgical handling (e.g. suture strength) and sufficient strength to resist pressure gradients that are present in systemic circulation. At this time, in vitro and animal studies of recent innovative concepts have awoken the hope for a breakthrough in tissue engineering in the near future. Concerns about biological safety and standardization issues of bioactive materials have already attracted the interest of scientists and clinicians and will be among the upcoming topics on the agenda of the tissue engineering community.

	Footnotes

 
Presented at the Postgraduate Course of the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16, 2007.

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Top Abstract 1. Introduction 2. Native myocardial... 3. Biological ECM models 4. Synthetic extracellular... 5. Composite ECM 6. Biomechanics 7. Vascularization 8. Smart biomaterials 9. Bioprinting 10. Summary References

 

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