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Chapter 15 - Computational Simulation of Cell Behavior for Tissue Regeneration

Cell migration, differentiation, proliferation, and morphology are vital processes in normal tissue development and morphogenesis of the human body and organ systems. Individual cell migration positions cells in tissues during morphogenesis and cancer, or allows them to pass through the tissue, as seen by immune cells. On the other hand, collective cell migration, such as neural crest, vasculature, and many epithelial cell migrations, is another fundamental form of cell translocation, which may relatively differ from individual cell migration while it is an important step in tissue generation. During cell migration, amoeboid movement causes frequent changes in cell shape due to the extension of protrusions in the cell front and retraction of cell rear. Regulation of intracellular mechanics and cell's physical interaction with its substrate relies on the control of cell shape during cell migration. Therefore, it is fundamental to understand this process in many biological processes ranging from morphogenesis to metastatic cancer cells. In addition to mechanical cue, cell migration can be also directed by chemical, thermal, and/or electrical stimuli. To achieve productive cell migration, each signaling passway may be temporally and spatially effective in particular regions of the cell substrate. Besides, experimental observations confirm that cells may undergo differentiation and/or proliferation due to mechanosensing process.

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Chapter 14 - Using 3-D Printing and Bioprinting Technologies for Personalized Implants

Implants and engineered artificial tissues have become widely used for replacement of damaged and injured tissues with a significant level of success. However, patient-to-patient variations in the 3-D architecture and physicochemical and mechanical properties of the tissue to be replaced necessitate methods that can ensure patient-specific implant/engineered tissue design and development. The recent advances in additive manufacturing techniques enable development of such implantable structures. In this chapter, we will first describe the available 3-D printing techniques used for medical purposes with a special focus on bioprinting techniques. This will be followed by a case study (silicone) of potential clinically relevant biomaterials to be 3-D printed with description of the clinical needs (the pathologies that will result in implant-based interventions), technical challenges, bottlenecks, and the required mechanical properties. In the particular example of silicone, the printing technique related mechanical property considerations were elaborated. Three-dimensional printing and bioprinting techniques have provided the basis of personalized implants and engineered tissues; however, the rheological and mechanical properties of the base materials need to be carefully considered for successful (bio)printing of highly complex structures with anatomical conformity from biocompatible materials.

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Chapter 18 - Cartilage Regeneration and Tissue Engineering

Articular cartilage in synovial joints is a hyaline cartilage highly hydrated with a rigorous order of cells and fibers and a specific content of proteoglycans and glycoproteins. It provides a low-friction surface, participates in the lubrication of the synovial joints, and distributes the forces to the underlying bone. It is an avascular and aneural tissue where small metabolites diffuse to and from cells. Unlike hyaline cartilage in other locations, articular cartilage lacks perichondrium, a layer of fibrous tissue around it that serves as the source of new cartilage cells. Thus, although extracellular matrix undergoes continuous remodeling throughout life, the ability to repair is limited, and often, degeneration in weight-bearing joints occurs by age or due to injuries, causing a reduction in mobility and increasing pain with joint movement, in a clinical profile called osteoarthritis, eventually progressing to long-term disability. Several medical and orthopedic treatments have been developed, but their long-term results are not usually satisfactory. New approaches point to tissue engineering techniques, where the combination of scaffolds made of biomaterials as artificial extracellular matrix, along with autologous or allogeneic cells and growth factors are used. Multiple scaffolds have been tested for articular cartilage regeneration, with different composition of biomaterial, conformations, and mechanical properties. With respect to the cellular source, autologous chondrocytes have been used, after an in vitro expansion, as well as mesenchymal stem cells from different origins (such as synovial membrane, bone marrow or adipose tissue), along with factors that induce the growth and cellular differentiation toward chondrogenic cells. We present our research in this field and summarize the advances obtained in the regeneration of articular cartilage.

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Chapter 17 - Skin Mechanobiology and Biomechanics: From Homeostasis to Wound Healing

Human skin represents the largest organ in the body by surface area, acting as a protective barrier from the environment. It constantly counteracts extrinsic and intrinsic mechanical forces during our daily lives. This is because the skin has remarkable biomechanical properties that are uniquely suited to its function. While it is relevant to know how skin tissue deforms and fails, it is even more important to understand how mechanical forces act on skin tissue to maintain tissue physiology and to regulate inherent biological processes such as wound healing. Skin contraction during wound healing is an example of how mechanical stimuli are important to wound closure. However, the scar formed after skin repair is a downside effect of skin mechanical contraction. Awareness of these processes has potentiated the creation of therapies to reduce scarring, but since the underlying mechanobiological mechanisms are not fully understood, there is still space for improvement. This chapter reviews the state of the art of skin biomechanics and mechanobiology at homeostasis and wound healing. The impact of the mechanical properties of the wounds on the rate and quality of wound healing are analyzed. The way this knowledge can improve wound healing and relieve scarring through new therapies is further discussed.

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Chapter 7 - Multiscale Numerical Simulation of Heart Electrophysiology

Mathematical modeling of the cardiac electrophysiology, and its simulation, is a great tool to understand the biological mechanisms that drive the observed response under physiological and pathological conditions. Modeling the electric activity of the heart, considering the structural complexities inherent to its tissue and having to account for the complex electric behavior of the cardiac cells, represents a great challenge. The cardiac electrophysiology is a multiscale problem that makes a numerical solution difficult, requiring temporal and spatial resolutions of 0.1ms and 0.2mm, respectively, for accurate simulations. This means models with millions of degrees of freedom that need to be solved for a thousand time steps. The solution to this problem requires the use of algorithms with higher levels of parallelism in multicore platforms. In this regard, the newer programmable graphic processing units (GPU) have become valid alternatives due to their tremendous computational horsepower. This chapter presents results obtained with novel electrophysiology simulation software entirely developed in compute unified device architecture. The software implements fully explicit and semiimplicit solvers for the monodomain model, using operator splitting and the finite element method for space discretization. Performance is compared with classical multicore message passing interface (MPI)-based solvers operating on dedicated high-performance computer clusters. Results obtained with the GPU-based solver show enormous potential for this technology, with accelerations of more than 50 times for three-dimensional (3D) problems. This technology has been applied to study proarrhythmic mechanisms during acute ischemia. In particular, how hyperkalemia affects the vulnerability window to reentry has been investigated as well as the reentry patterns in the heterogeneous substrate caused by acute regional ischemia using an anatomically and biophysically detailed human biventricular model. A 3D geometrically and anatomically accurate regionally ischemic human heart model was created. The ischemic region was located in the inferolateral and posterior side of the left ventricle, mimicking the occlusion of the circumflex artery, and the presence of a washed-out zone not affected by ischemia at the endocardium has been incorporated. Realistic heterogeneity and fiber anisotropy have also been considered in the model. A human highly electrophysiological detailed action potential model has been adapted to make it suitable for modeling ischemic conditions (hyperkalemia, hypoxia, and acidic conditions) by introducing a formulation of the adenosine triphosphate-sensitive K+ current. The model predicts the generation of sustained reentrant activity in the form of a single and a double circus around a blocked area within the ischemic zone for K+ concentrations bellow 9mM, with the reentrant activity associated with ventricular tachycardia in all cases. Results suggest the washed-out zone as a potential proarrhythmic substrate factor helping to establish sustained ventricular tachycardia. In addition, the implemented solver can be used to study proarrhythmic mechanisms during apnea by extending the hypoxia and hyperkalemia to the whole cardiac organ.

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