Substrates for cardiovascular tissue engineering☆
Graphical Abstract
Introduction
Most human tissues have a limited regeneration potential. In the case of tissue damage, the recovery of tissue structure and function is often incomplete, usually leading to scar tissue and impaired functionality. For fully differentiated, load-bearing cardiovascular tissues, such as heart valves, arteries and myocardium, complete regeneration is unlikely and replacement therapy is frequently applied in end-stage pathologies. Current treatment modalities include the use of autografts (e.g. coronary artery bypass graft with autologous vein, Ross operation), allografts (donor valve or heart transplantations), xenografts (bovine or porcine heart valves) and artificial prostheses (synthetic vascular grafts, mechanical valves, cardiac assist devices). However, each of these methods has its limitations, which include shortage of donor tissue, immune rejection, pathogen transfer, anticoagulation therapy, and limited durability. More importantly, they do not allow full regeneration and functional recovery and hence reduce the patient's life expectancy as compared to that of age-matched healthy subjects [1], [2].
The emerging field of regenerative medicine tries to find solutions for the incomplete regeneration of tissues in the human body. It employs living cells, biomaterials, soluble mediators of tissue regeneration, or a combination of these to recapitulate normal tissue structure and function [3], [4], [5]. Examples are: the in vitro or in vivo construction of tissues (tissue engineering) to replace damaged structures or the in vivo introduction or enhancement of cells (cell therapy) to replace lost host cells or to induce endogenous tissue regeneration. In case of cardiovascular regeneration cell therapy mainly applies to the myocardium, while tissue engineering strategies have been widely explored to create heart valves and vessels and to a lesser extent to create cardiac tissue. The degree of success of these strategies is generally evaluated from the improvement of tissue function following implantation in preclinical studies and from structural similarities with ’the original’ or native tissue.
Apart from the creation of tissue replacements, tissue engineering provides powerful living model systems of tissues and organs. From a physiological point of view these three-dimensional (3D) models are far more realistic than existing cell culture models and can be used to study or test a specific aspect of interest with a higher degree of experimental control and with less ethical considerations than animal models. Tissue models find their application in studying normal and pathological tissue development and the associated testing of potential therapies [6], [7], [8], [9]. In addition, they represent useful tools for technology development for regenerative medicine, early diagnosis and tissue screening [10], [11]. Engineered cardiac tissue models have for instance been used to systematically investigate the influence of mechanical stimulation, electrical stimulation and mass transport on neo-tissue formation [12], [13], [14]. These and similar studies underscore the importance to consider not only tissue structure and function in an engineered cardiovascular tissue (model), but also the relevant hemodynamic and electrophysiological environment of the tissue.
With recent advances in developmental and (stem) cell biology, tissue engineering is also becoming increasingly oriented towards designing biologically inspired cellular microenvironments, aimed to guide cell growth, differentiation and functional tissue organization [15], [16]. The premise is that in order to unlock the full potential of the cells, at least some aspects of the 3D tissue environment associated with their renewal, differentiation and organization needs to be mimicked in the applied scaffold materials. The selection of the (bio)material, as well as the assembly or processing of the material into a 3D structure, therefore becomes increasingly important to achieve both microscopic and macroscopic environments relevant for cell fate and tissue development (Fig. 1). In addition, at the nanometer length scale molecular interactions within the biomaterial, between the material and the cells, and within the newly deposited extracellular matrix, determine the final outcome of the engineered tissues, and therefore are important subjects of research. These molecular interactions are based on specific non-covalent bonds in which dynamics play an important role.
This review aims to provide an up-to-date overview of cardiovascular tissue engineering with an emphasis on the synthetic and biological substrates used as scaffolds for these tissues. After discussing the key properties of native tissue to be considered in the design of their engineered counterparts, we review current substrates used for heart valve, vessel and cardiac tissue engineering as well as directions for substrate requirements for next generation regenerative therapies. Next, we focus on specific substrate properties to meet these requirement and methods to evaluate and model their contribution both in vitro and in vivo. Finally, we indicate future challenges in substrate development and potential hurdles that may interfere with the progression in this area.
Section snippets
Key properties of cardiovascular tissues
Structure-function properties of native cardiovascular tissue pose strong design criteria to the substrates required to engineer their living counterparts or to be used in endogenous repair. When designing these substrates one should consider the macroscopic (organ level, geometry), the microscopic (cell and tissue level), and molecular properties relevant for tissue morphogenesis and function. In addition, developmental aspects, such as growth, differentiation, migration and maturation should
Engineered cardiovascular tissues
The classical in vitro tissue engineering paradigm comprises the isolation and expansion of autologous cells, subsequent seeding of the cells into an appropriate substrate, conditioning of the cell-substrate construct to allow for tissue formation (e.g. in bioreactors), and implantation back into the patient, ideally after testing the tissue. Other tissue engineering approaches usually omit one or more steps of this scheme. For example, cells sheets without substrates [70] or substrates without
Substrate properties
Compared to other engineered tissues, engineered cardiovascular tissues have distinct challenges as they are in direct contact with the blood, in case of blood vessels and valves, or in close proximity to the blood stream, in case of cardiac tissue. The latter also requires high rates of oxygen and nutrient exchange for proper metabolic functioning. Further, these tissues are subjected to ongoing cyclic stresses and strains, requiring substrates with targeted mechanical properties in terms of
Novel substrate designs
In their natural extracellular matrix environment cells are provided with a complex combination of factors that contribute to the overall control of cell fate and hence tissue morphogenesis, both through physical and molecular interactions. These environmental factors, which together constitute the so-called ‘cellular niche’, include: the presence and density of cell adhesion molecules, growth factors and morphogens, the micro-mechanical properties of the surrounding matrix, and the local
Testing, modeling, and imaging
The application of existing and newly developed substrates requires extensive testing of the material as well as the engineered tissue outcome under circumstances that mimic the physiological environment of the cardiovascular system and incorporate tissue neo-formation. Next to more general screenings of e.g. toxicity, mechanical robustness, and biocompatibility of the substrate and degradation products, this involves the assessment of substrate properties in relation to tissue development and
Future challenges
In the past few decades substrates for tissue engineering have significantly progressed from being initially biologically inert structural supports to multifunctional systems capable of orchestrating the formation and regeneration of complex tissue architectures. It has become possible to recapitulate, at least partially, the molecular, structural, and mechanical properties of the native ECM to mimic the native cellular environment [328], [329]. For cardiovascular tissue engineering future
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This review is part of the Advanced Drug Delivery Reviews theme issue on “From Tissue Engineering To Regenerative Medicine – The Potential And The Pitfalls”.