Advances in tissue engineering are evident, and the application of this technology to the regeneration of myocardium has been increasingly explored, and presented encouraging results. The main approach of this scientific field is the creation of scaffolds, which contain cells that can be applied as cardiac grafts in the body, to have the desired recovery. This review briefly presents the most widely used techniques in cardiac tissue engineering spanning two decades: from the late s, when this tissue engineering application saw its first studies, to nowadays, when grafts with a broad potential for cardiac regeneration are sought.
The techniques used to obtain cardiac grafts focus on four important issues Figure 1 : 1 scaffold material selection; 2 scaffold material production; 3 cell selection; and 4 in vitro cell culture. Biomaterials have been the focus of materials for use in tissue engineering, as traditional biomaterials or development of tissue engineering-specific variants. The approach usually taken into account is since biomaterials are able to positively interact with biological systems, they should then seek to improve the regeneration of the damaged tissue or effectively replacing it.
One of the most important classes of biomaterials comprises polymers, which are available with different compositions and properties. This review focuses on the application of polyurethane in cardiac tissue engineering, considering that this biopolymer is one of the most used.
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There is a variety of biomedical applications for PU, from durable devices to biodegradable scaffolds. However, long-term biostability has proved to be an obstacle for this type of application. In contrast, cardiac tissue engineering strategies focus on temporary polymer scaffolds with adjustable degradation rates, good porosity, biocompatibility and elastomeric properties, which can mechanically favor the tissue contraction inherent to the cardiac function.
These properties are met in polyurethane-based scaffolds 11 Figure 2 , and different approaches using polyurethane have therefore been investigated, demonstrating the different possibilities and the versatility of polyurethane as a material for porous scaffolds in myocardial regeneration. Fujimoto et al. Natural polymers for scaffolds are inspired by the extracellular matrix ECM that holds the cells together in a native tissue.
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Therefore, some materials, such as collagen mainly type I and III are found in the heart and fibrin, have been extensively investigated in cardiac tissue engineering for their properties of natural interaction with cells. Considering the often poor mechanical characteristics of natural polymers, the combination of synthetic and natural polymers has been proposed to improve the weakness of each material to create a scaffold with better properties.
Alperin et al. An important issue that has been the object of investigation for groups involved in tissue engineering of the myocardium is the delivery method of the cells to the damaged site. One of the first technologies developed for cardiac regeneration was cellular cardiomyoplasty.
This technology was very important for the study of cell types, their application and effects in cardiac regeneration. However, the delivery methods of the cells in the myocardial tissue used in this technology, such as the transvenous, endomyocardial and intracoronary routes, have not proven themselves satisfactory and had many disadvantages leading to inefficiencies. Many techniques have been investigated in order to create grafts to be implanted in the heart, and include fiber production methods, such as electrospinning 7 , 8 , 20 and rotary-jet spinning, 21 as well as cell-sheet engineering.
Decellularization is a process that consists of removing all cells from tissues or organs and maintaining the ECM intact Figure 3 , through different physical, chemical and enzymatic methods. This technique is widely used to obtain biologic scaffolds for clinical applications. The process of perfusion decellularization has been shown to be efficient in preserving the three-dimensional geometry of organs while eliminating the cells with a more even distribution of decellularization agents.
The choice of conduit for the perfusate is also important, and different conduits of vascular or parenchymal nature are viable alternatives for certain organs e. A whole heart may be human, e.
Over a period of time, usually 1 or more days of continuous application of decellularization solution, the heart gradually whitens, indicative of the cell constituent of the tissue being washed away, largely leaving behind the collagen and other connective tissue substance and preserving to a great extent the original organs anatomical architecture with respect to vasculature and parenchyma C. The cellular cardiomyoplasty technology is based on cell transplantation, consisting of supplying cells to the injured myocardial tissue aiming for the regeneration of the cardiac function that has been compromised.
The next topic critical for creating a cardiac graft, following cellular selection, is the cell culture.
From dishes to specialized cell culture facilities bioreactors , research has been made to study how to promote cell proliferation, alignment, differentiation and maturation in vitro, before the implantation in vivo. The potential for alignment of cells on the scaffold has been shown in some studies with polyurethane and in vitro cell culture in dishes. McDevitt et al. To promote increased cellular proliferation, differentiation and maturation, the in vitro cell culture of the chosen cell types is performed in specialized cell culture facilities, be it in academia or industry.
The standard infrastructure comprises clean rooms, carbon dioxide incubators, biological safety cabinets, sterile cell culture consumables, cell counters, and other standard equipment. In some cases, 56 it may be warranted the use of cell bioreactors, based solely on the purpose of improving, refining and optimizing the quality and yield expansion of the cell itself. Looking more broadly on the instrument category as a whole, bioreactors may be described as systems with controlled conditions and parameters that enable the stimulation of cell growth or biotransformation of substrate into products of interest by living cells or its components, such as enzymes or organelles.
Many types of bioreactors have been used for different applications in bioprocesses. The diversity of bioreactor design alternatives is based on specific parameters and conditions, such as heat or gas transfer and homogeneity, required for each application. Some examples of bioreactor designs are the stirred tank and the airlift reactors. The possibility of creating a dynamic environment with mechanical, physical and biochemical control makes tissue bioreactors a widely used technology in tissue engineering, due to the necessity of providing suitable stimuli for appropriate cellular differentiation and proliferation, and ECM properties for a tissue in development.
Cardiovascular tissue engineering studies applying bioreactors involve blood vessels, 63 heart valves 57 , 64 and cardiac tissue culture. Carrier et al. The same bioreactor may be employed for tissue cultivation, using cell culture media instead of decellularization solutions e. The heart is an extremely complex organ and the techniques influencing its regeneration depend on many variables of non-trivial character. These techniques generally focus on the scaffold material selection, scaffold material production, cellular selection and cellular cultivation in vitro.
Many studies in this field have already made enormous progress, either looking for a graft or an entire bioartificial heart. However, much work remains to be done to better understand and solve the challenges of experimental technologies, improving on existing techniques and developing new techniques, protocols and methods. For the material selection and structure, firstly, it is important to define the best material synthetic, natural or hybrid for cardiac applications. Some desired properties for these materials are adjustable degradation rates, good porosity, biocompatibility, hemocompatibility, good cell adhesion, mechanical and elastic properties compatible with the heart, and that the material permits an electrical coupling between cells and between the scaffold and the native tissue.
Future perspectives in this field focus on obtaining a scaffold from the threedimensional structure of an entire heart. In addition to decellularization, which is promising for cardiac tissue engineering application, another technology in vogue is three-dimensional bioprinting of tissues and organs. For cell selection and expansion in vitro , the first essential step is to determine the best cell type for the application bone marrow-derived stem cells, cardiomyocytes, iPSC, among others , considering the availability and concerns about each cell type.
After that, the cultivation of these cells in vitro is needed before seeding and subsequent tissue implantation. The most efficient technology to provide the proliferation and differentiation of these cells is the bioreactor. Many different types of bioreactors for cardiac tissue engineering applications have been studied, but it remains to be determined what approaches are the most suitable, with an ideal balance of advantages and disadvantages, appreciating that no single approach may tick all boxes. Other opportunities for myocardial tissue engineering include finding the best combination of different techniques described herein, to achieve an ideal bioengineered myocardium for clinical applications and to study the influence of other aspects, such as the best period of time for implantation, with increased engraftment of cells at the recipient's tissue, after an acute myocardial infarction.
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