User:Olalekan Usman/Mechanobiology

Mechanobiology

Mechanobiology is an emerging field of science at the interface of biology, engineering, and physics that focuses on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation, physiology, and disease. Mechanical forces are experienced and may be interpreted to give biological responses in cells. The movement of joints, compressive loads on the cartilage and bone during exercise, shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. A major challenge in the field is understanding mechanotransduction—the molecular mechanisms by which cells sense and respond to mechanical signals. While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics, extracellular matrix structure, or mechanotransduction may contribute to the development of many diseases, including atherosclerosis, fibrosis, asthma, osteoporosis, heart failure, and cancer. There is also a strong mechanical basis for many generalized medical disabilities, such as lower back pain, foot and postural injury, deformity, and irritable bowel syndrome.

Load Sensitive Cells

Fibroblasts

Skin fibroblasts are vital in development and wound repair and they are affected by mechanical cues like tension, compression and shear pressure[ ]. Fibroblasts synthesize structural proteins, some of which are mechanosensitive and form integral part of the extracellular Matrix (ECM) e. g collagen types I, III, IV, V VI, elastin, lamin etc. In addition to the structural proteins, fibroblasts make Tumor-Necrosis-Factor- alpha(TNF-α), Transforming-Growth-Factor-beta(TGF-β) and matrix metalloproteases that plays in tissue in tissue maintenance and remodeling [ ].

Chondrocytes

Articular cartilage is the connective tissue that protect bones of load-bearing joints like knee, shoulder by providing a lubricated surface. It deforms in response to compressive load, thereby reducing stress on bones. This mechanical responsiveness of articular cartilage is due to its biphasic nature; it contains both the solid and fluid phases. The fluid phase is made up of water -which contributes 80% of the wet weight – and inorganic ions e. g Sodium ion, Calcium ion and Potassium ion. The solid phase is made up of porous ECM. The proteoglycans and interstitial fluids interact to give compressive force to the cartilage through negative electrostatic repulsive forces. The ion concentration difference between the extracellular and intracellular ions composition of chondrocytes result in hydrostatic pressure. During development, mechanical environment of joint determines surface and topology of the joint. In adult, moderate mechanical loading is required to maintain cartilage; immobilization of joint leads to loss of proteoglycans and cartilage atrophy while excess mechanical loading results in degeneration of joint

Mechanobiology of Embryogenesis

The embryo is formed by self-assembly through which cells differentiate into tissues performing specialized functions. It was believed that only chemical signals give cues that control spatially oriented changes in cell growth, differentiation and fate switching that mediate morphogenetic controls. This is based on the assumptions that chemical signals are capable of inducing biochemical responses like tissue patterning in distant cells. However, it is now known that mechanical  forces generated within cells and tissues provide regulatory signals().

During the division of the fertilized oocyte , the cells aggregate compact and the compactness between cells increases with the help of actomyosin-dependent cytoskeletal traction forces and their application to adhesive receptors in  neighboring cells , thereby leading to formation of solid balls called Morula (). The spindle positioning within symmetrically and asymmetrically dividing cells are in the early embryo controlled by mechanical forces mediated by microtubules and actin microfilament system () . Also, local variation in physical forces and mechanical cues like stiffness of the ECM control the expression of gene that drive blastulation. The loss of stiffness-controlled transcription factor Cdx leads to  the ectopic expression of inner cell mass markers in trophectoderm() , and pluripotent transcription factor , Oct4 may be negatively expressed, thereby inducing lineage switching. This cell fate switching is regulated by the mechanosenstive hippo pathway().

The effectiveness of many of the mechanical therapies already in clinical use shows how important physical forces can be in physiological control. For example, pulmonary surfactant promotes lung development in premature infants; modifying the tidal volumes of mechanical ventilators reduces morbidity and death in patients with acute lung injury; expandable stents physically prevent coronary artery constriction; tissue expanders increase the skin area available for reconstructive surgery; and surgical tension application devices are used for bone fracture healing, orthodontics, cosmetic breast expansion and closure of non-healing wounds.

Insights into the mechanical basis of tissue regulation may also lead to development of improved medical devices, biomaterials, and engineered tissues for tissue repair and reconstruction.

Stretch-activated ion channels, caveolae, integrins, cadherins, growth factor receptors, myosin motors, cytoskeletal filaments, nuclei, extracellular matrix, and numerous other molecular structures and signaling molecules have been shown to contribute to cellular mechanotransduction. In addition, endogenous cell-generated traction forces contribute significantly to these responses by modulating tensional prestress within cells, tissues, and organs that govern their mechanical stability, as well as mechanical signal transmission from the macroscale to the nanoscale.

It is claimed all cells are mechanosensitive. Collectively cells respond to perturbations to their local mechanical environment resulting in tissue-level observations. For example, at the tissue-level an artery will either thicken or thin in response to changes in blood pressure above or below the healthy levels. That is, in the case of increased blood pressure (Hypertension) individual arterial cells experience greater circumferential stress (or tension). In order to alleviate this tension, they produce growth factors, which in turn stimulates proliferation. The net result is increased arterial wall thickness but the stress levels in the artery are restored to the normal levels.

Using mankind as a macroscopic example, in closed chain function, ground reactive forces, a dynamic architecture and a dynamic equilibrium of forces around joint axes impact the posture to produce tissue stress. This tissue stress can be both beneficial or harmful. Since gravity, hard, unyielding ground surfaces and other factors such as activity level, body weight and health state impact each of us differently there is no one plan of care that will work for every individual. This results in a lifetime of adaptation of tissues via Wolff's and Davis' Laws of Bone and Soft Tissue respectively that can unless compensated and/or corrected lead to breakdown, injury and reduced quality of life on a case to case basis.

As a further example, the foot has an inherited functional shape which when used will remodel and adapt in predictable manners. Theoretically programs can be establishing for prevention, performance enhancement and quality of life upgrading in addition to the treatment of pathology and pain. These interventions, some day, will cause positive remodeling of bone and soft tissue that will extend and possibly improve the mechanobiological timeline of ma