Mechanobiology

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Mechanobiology is an emerging field of science at the interface of biology, engineering, chemistry and physics. It 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, and shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. [1] 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. [2]

Contents

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. [3]

Chondrocytes

Articular cartilage is the connective tissue that protects 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. [4] 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. [5] During development, mechanical environment of joint determines surface and topology of the joint. [6] 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. [7]

Nuclear mechanobiology

The nucleus is also responsive to mechanical signals which are relayed from the extracellular matrix through the cytoskeleton by the help of Linker of Nucleoskeleton and Cytoskeleton LINC-associated proteins like KASH and SUN. [8] Examples of effect of mechanical responses in the nucleus involve:

Mechanobiology of embryogenesis

The embryo is formed by self-assembly through which cells differentiate into tissues performing specialized functions. It was previously 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 ability of chemical signals to induce biochemical responses like tissue patterning in distant cells. However, it is now known that mechanical  forces generated within cells and tissues provide regulatory signals. [10]

During the division of the fertilized oocyte, cells aggregate 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. [11] The spindle positioning within symmetrically and asymmetrically dividing cells in the early embryo is controlled by mechanical forces mediated by microtubules and actin microfilament system. [12] Local variation in physical forces and mechanical cues such as stiffness of the ECM also control the expression of genes that give rise to the embryonic developmental process of blastulation. The loss of stiffness-controlled transcription factor Cdx leads to the ectopic expression of inner cell mass markers in the trophectoderm, and the pluripotent transcription factor, Oct-4 may be negatively expressed, thereby inducing lineage switching. This cell fate switching is regulated by the mechanosensitive hippo pathway [13]

Applications

The effectiveness of many of the mechanical therapies already in clinical use shows how important physical forces can be in physiological control. Several examples illustrate this point. 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. [14] Surgical tension application devices are used for bone fracture healing, orthodontics, cosmetic breast expansion and closure of non-healing wounds. [ citation needed ]

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. [15]

Known contributors to cellular mechanotransduction are a growing list and include stretch-activated ion channels, caveolae, integrins, cadherins, growth factor receptors, myosin motors, cytoskeletal filaments, nuclei, extracellular matrix, and numerous other signaling molecules. Endogenous cell-generated traction forces also 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. [16] [17]

See also

Related Research Articles

<span class="mw-page-title-main">Tendon</span> Type of tissue that connects muscle to bone

A tendon or sinew is a tough, high-tensile-strength band of dense fibrous connective tissue that connects muscle to bone. It is able to transmit the mechanical forces of muscle contraction to the skeletal system without sacrificing its ability to withstand significant amounts of tension.

<span class="mw-page-title-main">Cytoskeleton</span> Network of filamentous proteins that forms the internal framework of cells

The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is composed of similar proteins in the various organisms. It is composed of three main components, microfilaments, intermediate filaments and microtubules, and these are all capable of rapid growth or disassembly dependent on the cell's requirements.

<span class="mw-page-title-main">Cartilage</span> Resilient and smooth elastic tissue in animals

Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans, but also in cyclostomes, it may constitute a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

<span class="mw-page-title-main">Synovial membrane</span> Connective tissue present within and around synovial joints

The synovial membrane is a specialized connective tissue that lines the inner surface of capsules of synovial joints and tendon sheath. It makes direct contact with the fibrous membrane on the outside surface and with the synovial fluid lubricant on the inside surface. In contact with the synovial fluid at the tissue surface are many rounded macrophage-like synovial cells and also type B cells, which are also known as fibroblast-like synoviocytes (FLS). Type A cells maintain the synovial fluid by removing wear-and-tear debris. As for the FLS, they produce hyaluronan, as well as other extracellular components in the synovial fluid.

Mechanotaxis refers to the directed movement of cell motility via mechanical cues. In response to fluidic shear stress, for example, cells have been shown to migrate in the direction of the fluid flow. Mechanotaxis is critical in many normal biological processes in animals, such as gastrulation, inflammation, and repair in response to a wound, as well as in mechanisms of diseases such as tumor metastasis.

Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients.

<span class="mw-page-title-main">Hyaluronic acid</span> Anionic, nonsulfated glycosaminoglycan

Hyaluronic acid, also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.

<span class="mw-page-title-main">Chondrocyte</span> Cell that makes up cartilage

Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.

<span class="mw-page-title-main">Focal adhesion</span>

In cell biology, focal adhesions are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More precisely, focal adhesions are the sub-cellular structures that mediate the regulatory effects of a cell in response to ECM adhesion.

<span class="mw-page-title-main">Mechanotransduction</span> Conversion of mechanical stimulus of a cell into electrochemical activity

In cellular biology, mechanotransduction is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of senses and physiological processes in the body, including proprioception, touch, balance, and hearing. The basic mechanism of mechanotransduction involves converting mechanical signals into electrical or chemical signals.

<span class="mw-page-title-main">Chondroblast</span> Mesenchymal progenitor cell that forms a chondrocyte

Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.

<span class="mw-page-title-main">Aggrecan</span>

Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ACAN gene. This gene is a member of the lectican (chondroitin sulfate proteoglycan) family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage.

Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.

Mechanotherapy is a type of medical therapeutics in which treatment is given by manual or mechanical means. It was defined in 1890 as “the employment of mechanical means for the cure of disease”. Mechanotherapy employs mechanotransduction in order to stimulate tissue repair and remodelling.

Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanoreceptors, are responsible for the sense of touch. Tiny cells in the inner ear, called hair cells, are responsible for hearing and balance. States of neuropathic pain, such as hyperalgesia and allodynia, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.

Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

<span class="mw-page-title-main">Nanobiomechanics</span>

Nanobiomechanics is an emerging field in nanoscience and biomechanics that combines the powerful tools of nanomechanics to explore fundamental science of biomaterials and biomechanics.

Lori Ann Setton is an American biomechanical engineer noted for her research on mechanics and mechanobiology of the intervertebral disc, articular cartilage mechanics, drug delivery, and pathomechanisms of osteoarthritis. She is currently the Department Chair as well as the Lucy and Stanley Lopata Distinguished Professor of Biomedical Engineering at Washington University in St. Louis.

Physical oncology (PO) is defined as the study of the role of mechanical signals in a cancerous tumor. The mechanical signals can be forces, pressures. If we generalize we will speak of "stress field" and "stress tensor".

References

  1. ↑ Wang, J. H.-C.; Thampatty, B. P. (March 2006). "An introductory review of cell mechanobiology". Biomechanics and Modeling in Mechanobiology. 5 (1): 1–16. doi:10.1007/s10237-005-0012-z. ISSN   1617-7959. PMID   16489478. S2CID   5017641.
  2. ↑ Smit, Theodoor H. (2020). "Adolescent idiopathic scoliosis: The mechanobiology of differential growth". JOR Spine. 3 (4): e1115. doi: 10.1002/jsp2.1115 . ISSN   2572-1143. PMC   7770204 . PMID   33392452. S2CID   225497216.
  3. ↑ Tracy, Lauren E.; Minasian, Raquel A.; Caterson, E.J. (March 2016). "Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound". Advances in Wound Care. 5 (3): 119–136. doi:10.1089/wound.2014.0561. ISSN   2162-1918. PMC   4779293 . PMID   26989578.
  4. ↑ Korhonen, R.K; Laasanen, M.S; Töyräs, J; Rieppo, J; Hirvonen, J; Helminen, H.J; Jurvelin, J.S (July 2002). "Comparison of the equilibrium response of articular cartilage in unconfined compression, confined compression and indentation". Journal of Biomechanics. 35 (7): 903–909. doi:10.1016/s0021-9290(02)00052-0. ISSN   0021-9290. PMID   12052392.
  5. ↑ Ateshian, G.A.; Warden, W.H.; Kim, J.J.; Grelsamer, R.P.; Mow, V.C. (November 1997). "Finite deformation biphasic material properties of bovine articular cartilage from confined compression experiments". Journal of Biomechanics. 30 (11–12): 1157–1164. doi: 10.1016/s0021-9290(97)85606-0 . ISSN   0021-9290. PMID   9456384.
  6. ↑ Wong, M; Carter, D.R (July 2003). "Articular cartilage functional histomorphology and mechanobiology: a research perspective". Bone. 33 (1): 1–13. doi:10.1016/s8756-3282(03)00083-8. ISSN   8756-3282. PMID   12919695.
  7. ↑ Haapala, Jussi; Arokoski, Jari P.A.; Hyttinen, Mika M.; Lammi, Mikko; Tammi, Markku; Kovanen, Vuokko; Helminen, Heikki J.; Kiviranta, Ilkka (May 1999). "Remobilization Does Not Fully Restore Immobilization Induced Articular Cartilage Atrophy". Clinical Orthopaedics and Related Research. 362: 218–229. doi:10.1097/00003086-199905000-00031. ISSN   0009-921X.
  8. ↑ Stroud, Matthew J; Banerjee, Indroneal; Veevers, Jennifer; Chen, Ju (31 January 2014). "Linker of Nucleoskeleton and Cytoskeleton Complex Proteins in Cardiac Structure, Function, and Disease". Circulation Research. 114 (3): 538–548. doi: 10.1161/circresaha.114.301236 .
  9. ↑ Xia, Yuntao; Pfeifer, Charlotte R.; Cho, Sangkyun; Discher, Dennis E.; Irianto, Jerome (2018-12-21). del Río Hernández, Armando (ed.). "Nuclear mechanosensing". Emerging Topics in Life Sciences. 2 (5): 713–725. doi:10.1042/ETLS20180051. ISSN   2397-8554. PMC   6830732 . PMID   31693005.
  10. ↑ Mammoto, Akiko; Mammoto, Tadanori; Ingber, Donald E. (2012-07-01). "Mechanosensitive mechanisms in transcriptional regulation". Journal of Cell Science. 125 (13): 3061–3073. doi:10.1242/jcs.093005. ISSN   0021-9533. PMC   3434847 . PMID   22797927.
  11. ↑ Ou, Guangshuo; Stuurman, Nico; D’Ambrosio, Michael; Vale, Ronald D. (2010-09-30). "Polarized Myosin Produces Unequal-Size Daughters During Asymmetric Cell Division". Science. 330 (6004): 677–680. Bibcode:2010Sci...330..677O. doi:10.1126/science.1196112. ISSN   0036-8075. PMC   3032534 . PMID   20929735.
  12. ↑ Ingber, D. E. (October 1997). "Tensegrity: The Architectural Basis of Cellular Mechanotransduction". Annual Review of Physiology. 59 (1): 575–599. doi:10.1146/annurev.physiol.59.1.575. ISSN   0066-4278. PMID   9074778.
  13. ↑ Niwa, Hitoshi; Toyooka, Yayoi; Shimosato, Daisuke; Strumpf, Dan; Takahashi, Kadue; Yagi, Rika; Rossant, Janet (December 2005). "Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation". Cell. 123 (5): 917–929. doi: 10.1016/j.cell.2005.08.040 . ISSN   0092-8674. PMID   16325584. S2CID   13242763.
  14. ↑ Buganza Tepole, A; Ploch, CJ; Wong, J; Gosain, AK; Kuhl, E (2011). "Growing skin - A computational model for skin expansion in reconstructive surgery". J. Mech. Phys. Solids. 59 (10): 2177–2190. Bibcode:2011JMPSo..59.2177B. doi:10.1016/j.jmps.2011.05.004. PMC   3212404 . PMID   22081726.
  15. ↑ Ingber, DE (2003). "Mechanobiology and diseases of mechanotransduction". Annals of Medicine. 35 (8): 564–77. doi:10.1080/07853890310016333. PMID   14708967. S2CID   22753025.
  16. ↑ Ingber, DE (1997). "Tensegrity: the architectural basis of cellular mechanotransduction". Annu. Rev. Physiol. 59: 575–599. doi:10.1146/annurev.physiol.59.1.575. PMID   9074778.
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