IJCM  Vol.10 No.3 , March 2019
Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (I) Basics and the Diseases of Tendon
Abstract: We analyze the crucial biochemical and biophysical properties of the basic constituents—connective tissues (CT), and interstitial fluid (IF) constituting the non-cellular part of the fascia. We provide ample evidence that the resident cells and cells in transit in the fascia are continuously interacting with the non-cellular constituents to form an active organ with well-defined functions. We show evidence that pathological states of diseases of internal organs, as well as that of the constituents of the fascia itself, manifest in certain CTIF domains of the fascia. Numerous diseases originate from imbalance of the digestion and synthesis of the native collagen triple helices. Review on the scanning electron microscopy examination of cross-section of tendons indicates that micro-fibrils of collagen I form regular geometrical structures, supporting the hypothesis that the collagen fibrils assemble like liquid crystals. Information on the age of Achilles tendons has been reported, based on dating of the 14C atoms generated from the nuclear bomb tests in 1955-1963. The causes of spontaneous tendon rupture and tendinopathy are analyzed. Plausible clinical measures to treat tendinopathy are briefly discussed, including the application of synthetic mechano-growth factor, glyceryl trinitrate patch (to supply nitric oxide), platelet rich plasma, proteomic profile analysis and microRNA 29a therapy.
Cite this paper: Fung, P. and Kong, R. (2019) Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (I) Basics and the Diseases of Tendon. International Journal of Clinical Medicine, 10, 183-249. doi: 10.4236/ijcm.2019.103018.

[1]   Ingber, D.E. (1997) Tensegrity: The Architectural Basis of Cellular Mechanotransduction. Annual Review of Physics, 59, 575-599.

[2]   Fung, P.C.W. (2009) Probing the Mystery of Chinese Medicine Meridian Channels with Special Emphasis on the Connective Tissue Interstitial Fluid System, Mechanotransduction, Cells Durotaxis and Mast Cell Degranulation. Chinese Medicine, 4, 10.

[3]   Fung, P.C.W. (2013) Chapter 5. Plausible Biomedical Consequences of Acupuncture Applied at Sites Characteristic of Acupoints in the Connective-Tissue-Interstitial-Fluid System. In: Chen, L.L. and Cheng, T.O., Eds., Acupuncture in Modern Medicine, IntechOpen, Rijeka, 95-131.

[4]   Liu, X., Zhao, Y., Gao J, Pawlyk, B., Starcher, B., Spemcer, J.A., Yanagisawa, H., Zuo, J. and Li, T. (2004) Elastic fiber Homeostasis Requires Lysyl Oxidase-Like 1 Protein. Nature Genetics, 36, 178-182.

[5]   Ushiki, T. (2002) Collagen Fibers, Reticular Fibers and Elastic Fibers. A Comprehensive Understanding from a Morphological Viewpoint. Archives of Histology and Cytology, 65, 109-126.

[6]   Page, K.E. (1952) The Role of the Fascia in the Maintenance of Structural Integrity Newark. Academy of Applied Osteopathy Yearbook, Newark, 70.

[7]   Yuan, L., Yao, D.W., Tang, L., Huang, W.H., Jiao, P.F., Lu, Y.T., Dai, J.X., Zhang, H., He, Z.Q. and Zhong, S.Z. (2004) A Study on Morphological Basis of Chinese Acupuncture and Moxibustion from Digital Human Body. Acta Anatomica Sinica, 35, 337-343.

[8]   Ross, R. (1975) Connective Tissue Cells, Cell Proliferation and Synthesis of Extracellular Matrix—A Review. Philosophical Transactions of the Royal Society of London. Series B, 271, 247-259.

[9]   Wilke, J., Schleip, R., Yucesoy, C.A. and Banzer, W. (2017) Not Merely a Protective Packing Organ? A Review of Fascia and Its Force Transmission Capacity. Journal of Applied Physiology, 124, 234-244.

[10]   Lo, C.M., Wang, H.B., Dembo, M. and Wang, Y.L. (2000) Cell Movement Is Guided by the Rigidity of the Substrate. Biophysical Journal, 79, 144-152.

[11]   Fung, P.C.W. and Kong, R.K.C. (2016) The Integrative Five-Fluid Circulation System in the Human Body. Open Journal of Molecular and Integrative Physiology, 6, 45-97.

[12]   Sastry, S.K. and Burridge, K. (2000) Focal Adhesions: A Nexus for Intracellular Signaling and Cytoskeletal Dynamics. Experimental Cell Research, 261, 25-36.

[13]   Katsum, A., Naoe, T., Matsushita, T., Kaibuchi, K. and Schwartz, M.A. (2006) Integrin Activation and Matrix Binding Mediate Cellular Responses to Mechanical Stretch. The Journal of Biological Chemistry, 280, 16546-16549.

[14]   Wang, N., Tytell, J.D. and Ingber, D.E. (2009) Mechanotransduction at a Distance: Mechanically Coupling the Extracellular Matrix with the Nucleus. Nature Reviews/Molecular Cell Biology, 10, 75-82.

[15]   Bershadsky, A.D., Balaban, N.Q. and Geiger, B. (2003) Adhesion-Dependent Cell Mechanosensitivity. Annual Review of Cell & Development Biology, 19, 677-695.

[16]   Nicholson, B.J. (2003) Gap Junctions—From Cell to Molecule. Journal of Cell Science, 116, 4479-4481.

[17]   Kumar, N.M. and Gilula, N.B. (1996) The Gap Junction Communication. Cell, 84, 381-388.

[18]   Delma, M., Coombs, W., Sorgen, P., Duffy, H.S. and Taffet, S.M. (2004) Structural Bases for the Chemical Regulation of Connexin43 Channels. Cardiovascular Research, 62, 268-275.

[19]   Boot-Handford, R.P. and Tuckwell, D.S. (2003) Fibrillar Collagen: The Key to Vertebrate Evolution? A Tale of Molecular Incest. BioEssays, 25, 142-151.

[20]   Exposito, J.Y., Cluzel, C., Garrone, R. and Lethias, C. (2002) Evolution of Collagens. The Anatomical Record, 268, 302-316.

[21]   Aumailley, M. and Gayraud, B. (1998) Structure and Biological Activity of the Extracellular Matrix. Journal of Molecular Medicine, 76, 253-265.

[22]   Linsenmayer, T.F. (1987) Collagen. In: Hay, E.D., Ed., Cell Biology of the Extracellular Matrix, 2nd Edition, Plenum Press, New York, 7-44.

[23]   Wilson, S.L., Guilbert, M., Sulé-Suso, J., Torbet, J., Jeansson, P., Sockalingum, G.D. and Yang, Y. (2012) The Effect of Collagen-Ageing on Its Structure and Cellular Behavior. Proceedings of SPIE, 8222, Article ID: 822210.

[24]   Kuhn, K. (1987) The Classical Collagens: Types I, II and III. In: Mayne, R. and Burgeson, R.E., Eds., Structure and Function of Collagen Types, Academic Press, Orlando, 1-42.

[25]   Kielty, C.M. and Grant, M.E. (2003) Chapter 2. The Collagen Family: Structure, Assembly, and Organization in the Extracellular Matrix. In: Royce, P.M. and Steinmann, B., Eds., Connective Tissue and Its Heritable Disorders, Wiley, New York, 159-221.

[26]   Fung, P.C.W. and Kong, R.K.C. (2017) The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines. Journal of Cancer Therapy, 8, 962-1029.

[27]   Buevich, A.V., Silva, T., Brodsky, B. and Baum, J. (2004) Transformation of the Mechanism of Triple-Helix Peptide Folding in the Absence of a C-Terminal Nucleation Domain and Its Implications for Mutations in Collagen Disorders. The Journal of Biochemistry, 279, 46890-46895.

[28]   Nagata, K. (1996) Hsp47: A Collagen-Specific Molecular Chaperone. Trends in Biochemical Sciences, 21, 23-26.

[29]   Silver, F.H. (2009) The Importance of Collagen Fibers in Vertebrate Biology. Journal of Engineered Fibers and Fabrics, 4, 9-17.

[30]   Veis, A. and Yuan, L. (1975) Structure of the Collagen Microfibril. A Four-Strand Overlap Model. Biopolymers, 14, 895-900.

[31]   Liu, J-.F. and He, J.-H. (2010) Hierarchical Structure and Fractal Dimensions of Tendon. Materials Science and Technology, 26, 1317-1319.

[32]   Werner, S. and Grose, R. (2003) Regulation of Wound Healing by Growth Factors and Cytokines. Physiological Reviews, 83, 835-870.

[33]   Ge, Z., Goh, J.C.H. and Lee, E.H. (2005) The Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Fascia Wrap Application to Anterior Cruciate Ligament Tissue Engineering. Cell Transplantation, 14, 763-773.

[34]   Mistriotis, P. and Andreadis, S.T. (2013) Hair Follicle: A Novel Source of Multipotent Stem Cells for Tissue Engineering and Regenerative Medicine. Tissue Engineering Part B: Reviews,19, 265-278.

[35]   Gattazzo, F., Urciuolo, A. and Bonaldo, P. (2014) Extracellular Matrix: A Dynamic Microenvironment for Stem Cell Niche. Biochimica et Biophysica Acta (BBA)-General Subjects, 1840, 2506-2519.


[37]   Seeman, E. (2006) Chapter 13. Bone Structure and Strength. In: Seibel, M.J., Robins, S.P. and Bilezikian, J.P., Eds., Dynamics of Bone and Cartilage Metabolism: Principles and Clinical Applications, 2nd Edition, Academic Press, London, 213-220.

[38]   Histology Guide © Faculty of Biological Sciences, University of Leeds.

[39]   Pittenger, M.F., Mackay, A.M., Beck, S.C., Jaiswal, R.K., Douglas, R., Mosca, J.D., Moorman, M.A., Simonetti, D.W., Craig, S. and Marshak, D.R. (1999) Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science, 284, 143-147.

[40]   Arana-Chavez, V.E., Soares, A.M. and Katchburian, E. (1995) Junctions between Early Developing Osteoblasts of Rat Calvaria as Revealed by Freeze-Fracture and Ultrathin Section Electron Microscopy. Archives of Histology and Cytology, 58, 285-292.

[41]   Blair, H.C., Sun, L. and Kohanski, R.A. (2007) Balanced Regulation of Proliferation, Growth, Differentiation, and Degradation in Skeletal Cells. Annals of the New York Academy of Sciences, 1116, 165-173.

[42]   Gurish, M.F., Tao, H., Abonia, J.P., Arya, A., Friend, D.S., Parker, C.M. and Austen, K.F. (2001) Intestinal Mast Cell Progenitors Require CD49dβ7 (α4β7 Integrin) for Tissue-Specific Homing. The Journal of Experimental Medicine, 194, 1243-1252.

[43]   Rodewald, H.R., Dessing, M., Dvorak, A.M. and Galli, S.J. (1996) Identification of a Committed Precursor for the Mast Cell Lineage. Science, 271, 818-822.

[44]   Metcalfe, D.D., Baram, D. and Mekori, Y.A. (1997) Mast Cells. Physiological Reviews, 77, 1033-1079.

[45]   Artuc, M., Steckelings, U.M. and Henz, B.M. (2002) Mast Cell-Fibroblast Interactions: Human Mast Cells as Source and Inducers of Fibroblast and Epithelial Growth Factors. Journal of Investigative Dermatology, 118, 391-395.

[46]   Dioguardi, N., Grizzi, F., Bossi, P. and Roncalli, M. (1999) Fractal and Spectral Dimension Analysis of Liver Fibrosis in Needle Biopsy Specimens. Analytical and Quantitative Cytology and Histology, 21, 262-266.

[47]   Magnusson, S.P., Qvortrup, K., Larsen, J.O., Rosager, S., Hanson, P., Aagaard, P., Krogsgaard, M. and Kjaer, M. (2002) Collagen Fibril Size and Crimp Morphology in Ruptured and Intact Achilles Tendons. Matrix Biology, 21, 369-377.

[48]   Silver, F.H., Freeman, J.W. and Gwinder, P.S. (2003) Collagen Self-Assembly and the Development of Tendon Mechanical Properties. Journal of Biomechanics, 36, 1529-1553.

[49]   Ho, M.W. and Saunders, P.T. (1994) Liquid Crystalline Mesophases in Living Organisms. In: Ho, M.W., Popp, F.A. and Warnke, U., Eds., Bioelectrodynamcis and Biocommunications, World Scientific, Singapore, 213-227.

[50]   Martin, R., Farjanel, J., Eichenberger, D., Colige, A., Kessler, E., Hulmes, D.J.S. and Giraud-Guille, M.M. (2000) Liquid Crystalline Ordering of Procollagen as a Determinant of Three-Dimensional Extracellular Matrix Architecture. Journal of Molecular Biology, 301, 11-17.

[51]   Snedeker, J.G. and Foolen, J. (2017) Tendon Injury and Repair—A Perspective on the Basic Mechanisms of Tendon Disease and Future Clinical Therapy. Acta Biomaterialia, 63, 18-36.

[52]   Guilak, F., Cohen, D.M., Estes, B.T., Gimble, J.M., Liedtke, W. and Chen, C.S. (2009) Control of Stem Cell Fate by Physical Interactions with the Extracellular Matrix. Cell Stem Cell, 5, 17-26.

[53]   Itoh, M., Lin, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R.J. and Cotsarelis, G. (2005) Stem Cells in the Hair Follicle Bulge Contribute to Wound Repair but Not to Homeostasis of the Epidermis. Nature Medicine, 11, 1351-1354.

[54]   Liu, C.-F., Aschbacher-Smith, L., Barthelery, N.J., Dyment, N., Butler, D. and Wylie, C. (2011) What We Should Know before Using Tissue Engineering Techniques to Repair Injured Tendons: A Developmental Biology Perspective. Tissue Engineering Part B: Reviews, 17, 165-176.

[55]   Ackermann, P.W., Franklin, S.L., Dean, B.J., Carr, A.J., Salo, P.T. and Hart, D.A. (2014) Neuronal Pathways in Tendon Healing and Tendinopathy—Update. Frontiers in Bioscience (Landmark Ed), 19, 1251-1278.

[56]   Ackermann, P.W., Salo, P. and Hart, D.A. (2016) Tendon Innervation. In: Ackermann, P. and Hart, D., Eds., Metabolic Influences on Risk for Tendon Disorders. Advances in Experimental Medicine and Biology, Vol. 920, Springer, Cham, 35-51.

[57]   Franchi, M., Fini, M., Quaranta, M., Pasquale, V.D., Raspanti, M., Giavaresi, G., Ottani, V. and Ruggeri, A. (2007) Crimp Morphology in Relaxed and Stretched Rat Achilles Tendon. Journal of Anatomy, 210, 1-7.

[58]   Franchi, M., Ottani, V., Stagni, R. and Ruggeri, A. (2010) Tendon and Ligament Fibrillar Crimps Give Rise to Left-Handed Helices of Collagen Fibrils in Both Planar and Helical Crimps. Journal of Anatomy, 216, 301-309.

[59]   Icardo, J.M., Elvira Colvee, E. and Revuelta, J.M. (2013) Structural Analysis of Chordae Tendineae in Degenerative Disease of the Mitral Valve. International Journal of Cardiology, 167, 1603-1609.

[60]   Xu, J., Rodriguez, D., Petitclerc, E., Kim, J.J., Hangai, M., Yuen, S.M., Davis, G.E. and Brooks, P.C. (2001) Proteolytic Exposure of a Cryptic Site within Collagen Type IV Is Required for Angiogenesis and tumor Growth in Vivo. The Journal of Cell Biology, 154, 1069-1079.

[61]   MMP1 Matrix Metallopeptidase 1 [Homo Sapiens (Human)], Gene ID: 4312, updated on 25-Nov-2018, Full Report, NCBI.

[62]   MMP2 Matrix Metallopeptidase 2 [Homo Sapiens (Human)], Gene ID: 4313, updated on 2-Dec-2018, Full Report, NCBI.

[63]   MMP3 Matrix Metallopeptidase 2 [Homo Sapiens (Human)], Gene ID: 4314, updated on 22-Nov-2018, Full Report, NCBI.

[64]   MMP8 Matrix Metallopeptidase 8 [Homo Sapiens (Human)], Gene ID: 4317, updated on 22-Nov-2018, Full Report, NCBI.

[65]   MMP9 Matrix Metallopeptidase 9 [Homo Sapiens (Human)], Gene ID: 4318, updated on 2-Dec-2018, Full Report, NCBI.

[66]   MMP10 Matrix Metallopeptidase 10 [Homo Sapiens (Human)], Gene ID: 4319, updated on 22-Nov-2018, Full Report, NCBI.

[67]   MMP13 Matrix Metallopeptidase 13 [Homo Sapiens (Human)], Gene ID: 4322, updated on 24-Nov-2018, Full Report, NCBI.

[68]   MMP14 Matrix Metallopeptidase 14 [Homo Sapiens (Human)], Gene ID: 4323, updated on 24-Nov-2018, Full Report, NCBI.

[69]   Itoh, Y. (2015) Membrane-Type Matrix Metalloproteinases: Their Functions and Regulations. Matrix Biology, 44-46, 207-223.

[70]   MMP15 Matrix Metallopeptidase 15 [Homo Sapiens (Human)], Gene ID: 4324, updated on 22-Nov-2018, Full Report, NCBI.

[71]   Ramachandran, G.N. and Kartha, G. (1955) Structure of Collagen. Nature, 176, 593-595.

[72]   Orgel, J.P., Irving, T.C., Miller, A. and Wess, T.J. (2006) Microfibrillar Structure of Type I Collagen in Situ. Proceedings of the National Academy of Sciences of the United States of America, 103, 9001-9005.

[73]   Overall, C.M. (2002) Molecular Determinants of Metalloproteinase Substrate Specificity: Matrix Metalloproteinase Substrate Binding Domains, Modules, and Exosites. Molecular Biotechnology, 22, 51-86.

[74]   Rosenblum, G., Van den Steen, P.E., Cohen, S.R., Bitler, A., Brand, D.D., Opdenakker, G. and Sagi, I. (2010) Direct Visualization of Protease Action on Collagen Triple Helical Structure. PLoS ONE, 5, e11043.

[75]   Ohuchi, E., Imai, K., Fujii, Y., Sato, H., Seiki, M. and Okada, Y. (1997) Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules. The Journal of Biological Chemistry, 272, 2446-2451.

[76]   Li, J., Brick, P., O’Hare, M.C., Skarzynski, T., Lloyd, L.F., Curry, V.A., Clark, I.M., Bigg, H.F., Hazleman, B.L., Cawston, T.E. and Blow, D.M. (1995) Structure of Full-Length Porcine Synovial Collagenase Reveals a C-Terminal Domain Containing a Calcium-Linked, Four-Bladed β-Propeller. Structure, 3, 541-549.

[77]   Murphy, G. and Nagase, H. (2011) Localizing Matrix Metalloproteinase Activities in the Pericellular Environment. The FEBS Journal, 278, 2-15.

[78]   Manka, S.W., Carafoli, F., Visse, R., Bihan, D., Raynal, N., Farndale, R.W., Murphy, G., Enghild, J.J., Hohenester, E. and Nagase, H. (2012) Structural Insights into Triple-Helical Collagen Cleavage by Matrix Metalloproteinase 1. Proceedings of the National Academy of Sciences of the United States of America, 109, 12461-12466.

[79]   Welgus, H.G., Stricklin, G.P., Eisen, A.Z., Bauer, E.A., Cooney, R.V. and Jeffrey, J.J. (1979) A Specific Inhibitor of Vertebrate Collagenase Produced by Human Skin Fibroblasts. The Journal of Biological Chemistry, 254, 1938-1943.

[80]   Vater, C.A., Mainardi, C.L. and Harris, E.D. (1979) Inhibitor of Human Collagenase from Cultures of Human Tendon. Journal of Biological Chemistry, 254, 3045-3053.

[81]   TIMP1 TIMP Metallopeptidase Inhibitor 1 [Homo Sapiens (Human)], Gene ID: 7076, updated on 7-Dec-2018, Full Report, NCBI.

[82]   Taraboletti, G., Morbidelli, L., Donnini, S., Parenti, A., Granger, H.J., Giavazzi, R. and Ziche, M. (2000) The Heparin Binding 25 kDa Fragment of Thrombospondin-1 Promotes Angiogenesis and Modulates Gelatinase and TIMP2 Production in Endothelial Cells. The FASEB Journal, 14, 1674-1676.

[83]   TIMP2 TIMP Metallopeptidase Inhibitor 2 [Homo Sapiens (Human)], Gene ID: 7077, updated on 7-Dec-2018, Full Report, NCBI.

[84]   Arris, C.E., Bevitt, D.J., Mohamed, J., Li, Z., Langton, K.P., Barker, M.D., Clarke, M.P. and McKie, N. (2003) Expression of Mutant and Wild-Type TIMP3 in Primary Gingival Fibroblasts from Sorsby’s Fundus Dystrophy Patients. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1638, 20-28.

[85]   Thomas Fréour, T., Jarry, A., Bach-Ngohou, K., Dejoie, T., Bou-Hanna, C., Denis, M.G., Mosnier, J.F., Laboisse, C.L. and Masson, D. (2009) TACE Inhibition Amplifies TNF-α-Mediated Colonic Epithelial Barrier Disruption. International Journal of Molecular Medicine, 23, 41-48.

[86]   Qi, J.H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Andrew Baker, A. and Anand-Apte, B. (2003) A Novel Function for Tissue Inhibitor of Metalloproteinases-3 (TIMP3): Inhibition of Angiogenesis by Blockage of VEGF Binding to VEGF Receptor-2. Nature Medicine, 9, 407-415.

[87]   TIMP3 TIMP Metallopeptidase Inhibitor 3 [Homo Sapiens (Human)], Gene ID: 7078, updated on 8-Dec-2018, Full Report, NCBI.

[88]   Casagrande, V., Mauriello, A., Bischetti, S., Mavilio, M., Federici, M. and Menghin, R. (2017) Hepatocyte Specific TIMP3 Expression Prevents Diet Dependent Fatty Liver Disease and Hepatocellular Carcinoma. Scientific Reports, 7, Article No. 6747.

[89]   TIMP4 TIMP Metallopeptidase Inhibitor 4 [Homo Sapiens (Human)], Gene ID: 7079, updated on 7-Dec-2018, Summary, NCBI.

[90]   Lizarraga, F., Espinosa, M., Ceballos-Cancino, G., Vazquez-Santillan, K., Bahena-Ocampo, I., Schwarz-Cruzy Celis, A., Vega-Gordillo, M., Garcia Lopez, P., Maldonado, V. and Melendez-Zajgla, J. (2016) Tissue Inhibitor of Metalloproteinases-4 (TIMP-4) Regulates Stemness in Cervical Cancer Cells. Molecular Carcinogenesis, 55, 1952-1961.

[91]   Lizarraga, F., Ceballos-Cancino, G., Espinosa, M., Vazquez-Santillan, K., Maldonado, V. and Melendez-Zajgla, J. (2015) Tissue Inhibitor of Metalloproteinase-4 Triggers Apoptosis in Cervical Cancer Cells. PLoS ONE, 10, e0135929.

[92]   Haerian, B.S., Sha’ari, H.M., Fong, C.Y., Tan, H.J., Wong, S.W., Ong, L.C., Raymond, A.A., Tan, C.T. and Mohamed, Z. (2015) Contribution of TIMP4 rs3755724 Polymorphism to Susceptibility to Focal Epilepsy in Malaysian Chinese. Journal of Neuroimmunology, 278, 137-143.

[93]   Groft, L.L., Muzik, H., Rewcastle, N.B., Johnston, R.N., Knauper, V., Lafleur, M.A., Forsyth, P.A. and Edwards, D.R. (2001) Differential Expression and Localization of TIMP-1 and TIMP-4 in Human Gliomas. British Journal of Cancer, 85, 55-63.

[94]   Kannus, P. and Józsa, L. (1991) Histopathological Changes Preceding Spontaneous Rupture of a Tendon. A Controlled Study of 891 Patients. The Journal of Bone and Joint Surgery, 73, 1507-1525.

[95]   Veres, S.P. and Lee, J.M. (2012) Designed to Fail: A Novel Mode of Collagen Fibril Disruption and Its Relevance to Tissue Toughness. Biophysical Journal, 102, 2876-2884.

[96]   Veres, S.P., Harrison, J.M. and Lee, J.M. (2014) Mechanically Overloading Collagen Fibrils Uncoils Collagen Molecules, Placing Them in a Stable, Denatured State. Matrix Biology, 33, 54-59.

[97]   Baldwin, S.J., Kreplak, L. and Lee, J.M. (2016) Characterization via Atomic Force Microscopy of Discrete Plasticity in Collagen Fibrils from Mechanically Overloaded Tendons: Nano-Scale Structural Changes Mimic Rope Failure. Journal of the Mechanical Behavior of Biomedical Materials, 60, 356-366.

[98]   Medalia, O. and Geiger, B. (2010) Frontiers of Microscopy-Based Research into Cell-Matrix Adhesions. Current Opinion in Cell Biology, 22, 659-668.

[99]   Knight, D.P. and Vollrath, F. (2002) Biological Liquid Crystal Elastomers. Philosophical Transactions of the Royal Society B, 357, 155-163.

[100]   Hulmes, D.J.S. (2002) Building Collagen Molecules, Fibrils, and Suprafibrillar Structures. Journal of Structural Biology, 137, 2-10.

[101]   Hamley, I.W. (2010) Liquid Crystal Phase Formation by Biopolymers. Soft Matter, 6, 1863-1871.

[102]   Diamant, J., Keller, A., Baer, E., Litt, M. and Arridge, R.G. (1972) Collagen; Ultrastructure and Its Relation to Mechanical Properties as a Function of Ageing. Proceedings of the Royal Society B: Biological Sciences, 180, 293-315.

[103]   Jarvinen, T.A., Jarvinen, T.L., Kannus, P., Józsa, L. and Jarvinen, M. (2004) Collagen Fibres of the Spontaneously Ruptured Human Tendons Display Decreased Thickness and Crimp Angle. Journal of Orthopaedic Research, 22, 1303-1309.

[104]   Bass, E.C., Wistrom, E.V., Diederich, C.J., Nau, W.H., Pellegrino, R., Ruberti, J. and Lotz, J.C. (2004) Heat Induced Changes in Porcine Annulus Fibrosus Biomechanics. Journal of Biomechanics, 37, 233-240.

[105]   Nabeshima, Y., Grood, E.S., Sakurai, A. and Herman, J.H. (1996) Uniaxial Tension Inhibits Tendon Collagen Degradation by Collagenase in Vitro. Journal of Orthopaedic Research, 14, 123-130.

[106]   Ruberti, J.W. and Hallab, N.J. (2005) Strain-Controlled Enzymatic Cleavage of Collagen in Loaded Matrix. Biochemical and Biophysical Research Communications, 336, 483-489.

[107]   Wyatt, K.E., Bourne, J.W. and Torzilli, P.A. (2009) Deformation-Dependent Enzyme Mechanokinetic Cleavage of Type I Collagen. Journal of Biomechanical Engineering, 131, Article ID: 051004.

[108]   Bhole, A.P., Flynn, B.P., Liles, M., Saeidi, N., Dimarzio, C.A. and Ruberti, J.W. (2009) Mechanical Strain Enhances Survivability of Collagen Micronetworks in the Presence of Collagenase: Implications for Load-Bearing Matrix Growth and Stability. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 367, 3339-3362.

[109]   Flynn, B.P., Bhole, A.P., Saeidi, N., Liles, M., DiMarzio, C.A. and Ruberti, J.W. (2010) Mechanical Strain Stabilizes Reconstituted Collagen Fibrils against Enzymatic Degradation by Mammalian Collagenase Matrix Metalloproteinase 8 (MMP-8). PLoS ONE, 5, e12337.

[110]   Wu, H., Byrne, M.H., Stacey, A., Goldring, M.B., Birkhead, J.R., Jaenisch, R. and Krane, S.M. (1990) Generation of Collagenase-Resistant Collagen by Site-Directed Mutagenesis of Murine Pro Alpha 1(I) Collagen Gene. Proceedings of the National Academy of Sciences of the United States of America, 87, 5888-5892.

[111]   Flynn, B.P., Tilburey, G.E. and Ruberti, J.W. (2013) Highly Sensitive Single-Fibril Erosion Assay Demonstrates Mechanochemical Switch in Native Collagen Fibrils. Biomechanics and Modeling in Mechanobiology, 12, 291-300.

[112]   Welgus, H.G., Jeffrey, J.J., Stricklin, G.P., Roswit, W.T. and Eisen, A.Z. (1980) Characteristics of the Action of Human Skin Fibroblast Collagenase on Fibrillar Collagen. The Journal of Biological Chemistry, 255, 6808-6813.

[113]   Toledano, M., Aguilera, F.S., Yamauti, M., Ruiz-Requena, M.E. and Osorio, R. (2013) In Vitro Load-Induced Dentin Collagen-Stabilization against MMPs Degradation. Journal of the Mechanical Behavior of Biomedical Materials, 27, 10-18.

[114]   Tonge, T.K., Ruberti, J.W. and Nguyen, T.D. (2015) Micromechanical Modeling Study of Mechanical Inhibition of Enzymatic Degradation of Collagen Tissues. Biophysical Journal, 109, 2689-2700.

[115]   Chithra, P., Sajithlal, G.B. and Chandrakasan, G. (1998) Influence of Aloe vera on Collagen Characteristics in Healing Dermal Wounds in Rats. Molecular and Cellular Biochemistry, 181, 71-76.

[116]   Heinemeier, K.M., Schjerling, P., Heinemeier, J., Magnusson, S.P. and Kjaer, M. (2013) Lack of Tissue Renewal in Human Adult Achille Tendon Is Revealed by Nuclear Bomb 14C. The FASEB Journal, 27, 2074-2079.

[117]   Leikina, E., Mertts, M.V., Kuznetsova, N. and Leikin, S. (2002) Type I Collagen Is Thermally Unstable at Body Temperature. Proceedings of the National Academy of Sciences of the United States of America, 99, 1314-1318.

[118]   Bruckner, P. and Eikenberry, E.F. (1984) Procollagen Is More Stable in Cellulo than in Vitro. European Journal of Biochemistry, 140, 397-399.

[119]   Steinmann, B., Bruckner, P. and Superti-Furga, A. (1991) Cyclosporin A Slows Collagen Triple-Helix Formation in Vivo: Indirect Evidence for a Physiologic Role of Peptidyl-Prolyl Cis-Trans-Isomerase. The Journal of Biological Chemistry, 266, 1299-1303.

[120]   Kadler, K.E., Hojima, Y. and Prockop, D.J. (1988) Assembly of Type I Collagen Fibrils de Novo. Between 37 and 41 Degrees C the Process Is Limited by Micro-Unfolding of Monomers. Journal of Biological Chemistry, 263, 10517-10523.

[121]   Bell, M.L. and Engvall, E. (1982) The Specific Detection of Collagenous Proteins after Electrophoresis Using Enzyme-Conjugated Collagen-Binding Fibronectin Fragments. Analytical Biochemistry, 123, 329-335.

[122]   Bachinger, H.P., Bruckner, P., Timpl, R., Prockop, D.J. and Engel, J. (1980) Folding Mechanism of the Triple Helix in Type-III Collagen and Type-III pN-Collagen: Role of Disulfide Bridges and Peptide Bond Isomerization. The FEBS Journal, 106, 619-632.

[123]   Bruckner, P. and Prockop, D.J. (1981) Proteolytic Enzymes as Probes for the Triple-Helical Conformation of Procollagen. Analytical Biochemistry, 110, 360-368.

[124]   Davis, J.M. and Bachinger, H.P. (1993) Hysteresis in the Triple Helix-Coil Transition of Type III. The Journal of Biological Chemistry, 268, 25965-25972.

[125]   Nerenberg, P.S. and Stultz, C.M. (2008) Differential Unfolding of α1 and α2 Chains in Type I Collagen and Collagenolysis. Journal of Molecular Biology, 382, 246-256.

[126]   Miles, C.A., Sims, T.J., Camacho, N.P. and Bailey, A.J. (2002) The Role of α2 Chain in the Stabilization of the Collagen Type I Heterotrimer: A Study of the Type I Homotrimer in oim Mouse Tissues. Journal of Molecular Biology, 321, 797-805.

[127]   Han, S., Makareeva, E., Kuznetsova, N.V., DeRidder, A.M., Sutter, M.B., Losert, W., Phillips, C.L., Visse, R., Nagase, H. and Leikin, S. (2010) Molecular Mechanism of Type I Collagen Homotrimer Resistance to Mammalian Collagenases. The Journal of Biological Chemistry, 285, 22276-22281.

[128]   Makareeva, E., Han, S., Vera, J.C., Sackett, D.L., Holmbeck, K., Phillips, C.L., Visse, R., Nagase, H. and Leikin, S. (2010) Carcinomas Contain a Matrix Metalloproteinase-Resistant Isoform of Type I Collagen Exerting Selective Support to Invasion. Cancer Research, 70, 4366-4374.

[129]   Huang, K.A., Yi, B.R. and Choi, K.C. (2011) Molecular Mechanisms and in Vivo Mouse Models of Skin Aging Associated with Dermal Alterations. Laboratory Animal Research, 27, 1-8.

[130]   Hakala, M., Risteli, L., Manelius, J., Nieminen, P. and Risteli, J. (1993) Increased Type I Collagen Degradation Correlates with Disease Severity in Rheumatoid Arthritis. Annals of the Rheumatic Diseases, 52, 866-869.

[131]   González, A., López, B., Querejeta, R. and Diez, J. (2002) Regulation of Myocardial Fibrillar Collagen by Angiotensin II. A Role in Hypertensive Heart Disease? Journal of Molecular and Cellular Cardiology, 34, 1585-1593.

[132]   Lombardi, R., Betocchi, S., Losi, M.A., Tocchetti, C.G., Aversa, M., Miranda, M., Alessandro, G.D., Cacace, A., Ciampi, Q. and Chiariello, M. (2003) Collagen Turnover in Hypertrophic Cardiomyopathy. Circulation, 108, 1455-1460.

[133]   Misof, K., Landis, W.J., Klaushofer, K. and Fratzl, P. (1997) Collagen from the Osteogenesis Imperfecta Mouse Model (oim) Shows Reduced Resistance against Tensile Stress. Journal of Clinical Investigation, 100, 40-45.

[134]   McBride, D.J., Choe, V., Shapiro, J.R. and Brodsky, B. (1997) Altered Collagen Structure in Mouse Tail Tendon Lacking the α2(I) Chain. Journal of Molecular Biology, 270, 275-284.

[135]   Phillips, C.L., Pfeiffer, B.J., Luger, A.M. and Franklin, C.L. (2002) Novel Collagen Glomerulopathy in a Homotrimeric Type I Collagen Mouse (oim). Kidney International, 62, 383-391.

[136]   Gay, S., Vijanto, J., Raekallio, J. and Penttinen, R. (1978) Collagen Types in Early Phases of Wound Healing in Children. Acta Chirurgica Scandinavica, 144, 205-211.

[137]   Wooley, P.H., Luthra, H.S., Stuart, J.M. and David, C.S. (1981) Type II Collagen-Induced Arthritis in Mice. I. Major Histocompatibility Complex (I Region) Linkage and Antibody Correlates. The Journal of Experimental Medicine, 154, 688-700.

[138]   Maroudas, A., Palla, G. and Gilav, E. (1992) Racemization of Aspartic Acid in Human Articular Cartilage. Connective Tissue Research, 28, 161-169.

[139]   Maffulli, N., Khan, K.M. and Puddu, G. (1998) Overuse Tendon Conditions: Time to Change a Confusing Terminology. Arthroscopy, 14, 840-843.

[140]   Xu, Y. and Murrell, G.A. (2008) The Basic Science of Tendinopathy. Clinical Orthopaedics and Related Research, 466, 1528-1538.

[141]   Khan, K., Cook, J., Kannus, P., Maffulli, N. and Bonar, S. (2002) Time to Abandon the “Tendinitis” Myth: Painful, Overuse Tendon Conditions Have a Non-Inflammatory Pathology. BMJ, 324, 626-627.

[142]   Riley, G. (2005) Chronic Tendon Pathology: Molecular Basis and Therapeutic Implications. Expert Reviews in Molecular Medicine, 7, 1-25.

[143]   Sharma, P. and Maffulli, N. (2005) Tendon Injury and Tendinopathy: Healing and Repair. The Journal of Bone and Joint Surgery, 87, 187-202.

[144]   Ralphs, J.R. (2002) Cell Biology of Tendons. European Cells & Materials Journal, 4, 39-40.

[145]   Wall, M.E., Otey, C., Qi, J. and Banes, A.J. (2006) Connexin 43 Is Localized with Actin in Tenocytes. Cell Motility, 64, 121-130.

[146]   Maeda, E., Pian, H. and Ohashi, T. (2017) Temporal Regulation of Gap Junctional Communication between Tenocytes Subjected to Static Tensile Strain with Physiological and Nonphysiological Amplitudes. Biochemical and Biophysical Research Communications, 482, 1170-1175.

[147]   Wenstrup, R.J., Florer, J.B., Brunskill, E.W., Bell, S.M., Chervoneva, I. and Birk, D.E. (2004) Type V Collagen Controls the Initiation of Collagen Fibril Assembly. The Journal of Biological Chemistry, 279, 53331-53337.

[148]   da Silva, M.L., Caplan, A.I. and Nardi, N.B. (2008). In Search of the in Vivo Identity of Mesenchymal Stem Cells. Stem Cells, 26, 2287-2299.

[149]   Kalamajski, S. and Oldberg, A. (2010) The Role of Small Leucine-Rich Proteoglycans in Collagen Fibrillogenesis. Matrix Biology, 29, 248-253.

[150]   Perryman, S.V. and Sylvester, K.G. (2006) Repair and Regeneration: Opportunities for Carcinogenesis from Tissue Stem Cells. Journal of Cellular and Molecular Medicine, 10, 292-308.

[151]   Smith, A.A., Li, J., Liu, B., Hunter, D., Pyles, M., Gilletle, M., Dhamdhere, G.R., Abo, A., Oro, A., Helms, J.A. (2016) Activating Hair Follicle Stem Cells via R-spondin2 to Stimulate Hair Growth, J. Investigative Dermatology, 136(8):1549-1558.

[152]   Donnelly, E., Ascenzi, M.G. and Farnum, C. (2010) Primary Cilia Are Highly Oriented with Respect to Collagen Direction and Long Axis of Extensor Tendon. Journal of Orthopaedic Research, 28, 77-82.

[153]   Matthews, T.J.W., Hand, G.C., Rees, J.L., Athanasou, N.A. and Carr, A.J. (2006) Pathology of the Torn Rotator Cuff Tendon, Reduction in Potential for Repair as Tear Size Increases. The Bone and Joint Journal, 88, 489-495.

[154]   Archambault, J., Tsuzaki, M., Herzog, W. and Banes, A.J. (2006) Stretch and Interleukin-1β Induce Matrix Metalloproteinases in Rabbit Tendon Cells in Vitro. Journal of Orthopaedic Research, 20, 36-39.

[155]   Tsuzaki, M., Guyton, G., Garrett, W., Archambault, J.M., Herzog, W., Almekinders, L., Bynum, D., Yang, X. and Banes, A.J. (2003) IL-1β Induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1β and IL-6 in Human Tendon Cells. Journal of Orthopaedic Research, 21, 256-264.

[156]   Millar, N.L., Wei, A.Q., Molloy, T.J., Bonar, F. and Murrell, G.A. (2009) Cytokines and Apoptosis in Supraspinatus Tendinopathy. The Bone & Joint Journal, 91B, 417-424.

[157]   Schoenenberger, A.D., Foolen, J., Moor, P., Silvan, U., Jess, G. and Snedeker, J.G. (2018) Substrate Fiber Alignment Mediates Tendon Cell Response to Inflammatory Signalling. Acta Biomaterialia, 71, 306-317.

[158]   Phelan, K. and May, K.M. (2015) Basic Techniques in Mammalian Cell Tissue Culture. Current Protocols in Cell Biology, 66, 1.1.1-1.1.22.

[159]   Zajac, E., Schweighofer, B., Kupriyanova, T.A., Juncker-Jensen, A., Minder, P., Quigley, J.P. and Deryugina, E.I. (2013) Angiogenic Capacity of M1- and M2-Polarized Macrophages Is Determined by the Levels of TIMP-1 Complexed with Their Secreted proMMP-9. Blood, 122, 4054-4067.

[160]   Zhang, B., Luo, Q., Sun, J., Xu, B., Ju, Y., Yang, L. and Song, G. (2015) MGF Enhances Tenocyte Invasion through MMP-2 Activity via the FAK-ERK1/2 Pathway. Wound Repair and Regeneration, 23, 394-402.

[161]   Grant, T.M., Thompson, M.S., Urban, J. and Yu, J. (2013) Elastic Fibres Are Broadly Distributed in Tendon and Highly Localized around Tenocytes. Journal of Anatomy, 222, 573-579.

[162]   Kannus, P. (2000) Structure of the Tendon Connective Tissue. Scandinavian Journal of Medicine & Science in Sports, 10, 312-320.

[163]   Thorpe, C.T., Peffers, M.J., Simpson, D., Halliwell, E., Screen, H.R.C. and Clegg, P.D. (2016) Anatomical Heterogeneity of Tendon: Fascicular and Interfascicular Tendon Compartments Have Distinct Proteomic Composition. Scientific Reports, 6, Article No. 20455.

[164]   THBS4 Thrombospondin 4 [Homo Sapiens (Human)], Gene ID: 7060, updated on 7-Dec-2018, Full Report, NCBI.

[165]   UniProtKB-P49747 (COMP_HUMAN) 2018.

[166]   UniProtKB Q06828 (FMOD_HUMAN) 2018.

[167]   DCN Decorin [Homo Sapiens (Human)] Gene ID: 1634, updated on 7-Dec-2018, Full Report, NCBI.

[168]   Svensson, R.B., Smith, S.T., Moyer, P.J. and Magnusson, S.P. (2018) Effects of Maturation and Advanced Glycation on Tensile Mechanics of Collagen Fibrils from Rat Tail and Achilles Tendons. Acta Biomaterialia, 70, 270-280.

[169]   de Mos, M., van der Windt, A.E., Jahr, H., van Schie, H.T.M., Weinans, H., Verhaar, J.A.N. and van Osch, G.J.V.M. (2008) Can Plateletrich Plasma Enhance Tendon Repair? A Cell Culture Study. The American Journal of Sports Medicine, 36, 1171-1178.

[170]   Giusti, I., Sandra D’Ascenzo, S.D., Mancò, A., Stefano, G.D., Francesco, M.D., Rughetti, A., Mas, A.D., Properzi, G., Calvisi, V. and Dolo, V. (2014) Platelet Concentration in Platelet-Rich Plasma Affects Tenocyte Behavior in Vitro. BioMed Research International, 2014, Article ID: 630870.

[171]   Lamkanfi, M. and Dixit, V.M. (2009) IL-33 Raises Alarm. Immunity, 31, 5-7.

[172]   Bartel, D.P. (2009) MicroRNAs: Target Recognition and Regulatory Functions. Cell, 136, 215-233.

[173]   Millar, N.L., Gilchrist, D.S., Akbar, M., Reilly, J.H., Kerr, S.C., Campbell, A.L., Murrell, G.A.C., Liew, F.Y., Kurowska-Stolarska, M. and Mclnnes, L.B. (2015) MicroRNA29a Regulates IL-33-Mediated Tissue Remodelling in Tendon Disease. Nature Communications, 6, Article No. 6774.

[174]   Millar, N.L., Murrell, G.A.C. and McInnes, I.B. (2017) Inflammatory Mechanisms in Tendinopathy—Towards Translation. Nature Reviews, 13, 110-112.

[175]   Gee, M.D., Lynn, B. and Cotsell, B. (1997) The Relationship between Cutaneous C Fiber Type and Antidromic Vasodilatation in the Rabbit and the Rat. Journal of Physiology, 503, 31-44.

[176]   Lui, S.L., Chan, L.Y., Zhang, X.H., Zhu, W., Chan, T.M., Fung, P.C.W. and Lai, K.N. (2001) Effect of Mycophenolate Mofetil on Nitric Oxide Production and Inducible Nitric Oxide Synthase Gene Expression during Renal Ischaemia-Reperfusion Injury. Nephrology Dialysis Transplantation, 16, 1577-1582.

[177]   Schaffer, M.R., Tantry, U., Gross, S.S., Wasserkrug, H.L. and Barbul, A. (1996) Nitric Oxide Regulates Wound Healing. Journal of Surgical Research, 63, 237-240.

[178]   Xia, W., Szomor, Z., Wang, Y. and Murrell, G.A.C. (2006) Nitric Oxide Enhances Collagen Synthesis in Cultured Human Tendon Cells. Journal of Orthopaedic Research, 24, 159-172.

[179]   Lin, J.H., Wang, M.X., Wei, A., Zhu, W., Diwan, A.D. and Murrell, G.A.C. (2001) Temporal Expression of Nitric Oxide Synthase Isoforms in Healing Achilles Tendon. Journal of Orthopaedic Research, 19, 136-142.

[180]   Murrell, G.A.C. (2007) Using Nitric Oxide to Treat Tendinopathy. British Journal of Sports Medicine, 41, 227-231.

[181]   Bokhari, A.R. and Murrell, G.A. (2012) The Role of Nitric Oxide in Tendon Healing. Journal of Shoulder and Elbow Surgery, 21, 238-244.

[182]   Menon, A., Pettinari, L., Martinelli, C., Colombo, G., Portinaro, N., Dalle-Donne, I., Agostino, M.C. and Gagliano, N. (2013) New Insights in Extracellular Matrix Remodeling and Collagen Turnover Related Pathways in Cultured Human Tenocytes after Ciprofloxacin Administration. Muscles, Ligaments and Tendons Journal, 3, 122-131.

[183]   Brilla, C.G., Matsubara, L.S. and Weber, K.T. (1993) Antifibrotic Effects of Spironolactone in Preventing Myocardial Fibrosis in Systemic Arterial Hypertension. The American Journal of Cardiology, 71, A12-A16.

[184]   Horn, M.A., Graham, H.K., Richards, M.A., Clarke, J.D., Greensmith, D.J., Briston, S.J., Hall, M.C.S., Dibb, K.M. and Trafford, A.W. (2012) Age-Related Divergent Remodeling of the Cardiac Extracellular Matrix in Heart Failure: Collagen Accumulation in the Young and Loss in the Aged. Journal of Molecular and Cellular Cardiology, 53, 82-90.

[185]   Stickens, D., Behonick, D.J., Ortega, N., Heyer, B., Hartenstein, B., Yu, Y., Fosang, A.J., Schorpp-Kistner, M., Angel, P. and Werb, Z. (2004) Altered Endochondral Bone Development in Matrix Metalloproteinase 13-Deficient Mice. Development, 131, 5883-5895.

[186]   Bataller, R. and Brenner, D.A. (2005) Liver Fibrosis. Journal of Clinical Investigation, 115, 209-218.

[187]   Riley, G.P., Harrall, R.L., Watson, P.G., Cawston, T.E. and Hazleman, B.L. (1995) Collagenase (MMP-1) and TIMP-1 in Destructive Corneal Disease Associated with Rheumatoid Arthritis. Eye, 9, 703-718.

[188]   Barnes, M.J. and Farndale, R.W. (1999) Collagens and Atherosclerosis. Experimental Gerontology, 34, 513-525.

[189]   Akiyama, K., Shikata, K., Sugimoto, H., Matsuda, M., Shikata, Y., Fujimoto, N., Obata, K., Matsui, H. and Makino, H. (1997) Changes in Serum Concentrations of Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases and Type IV Collagen in Patients with Various Types of Glomerulonephritis. Research Communications in Molecular Pathology and Pharmacology, 95, 115-128.

[190]   Van Haaften, W.T., Mortensen, J.H., Karsdal, M.A., Bay-Jensen, A.C., Dijkstra, G. and Olinga, P. (2017) Misbalance in Type III Collagen Formation/Degradation as a Novel Serological Biomarker for Penetrating (Montreal B3) Crohn’s Disease. Alimentary Pharmacology & Therapeutics, 46, 26-39.

[191]   Gautieri, A., Uzel, S., Vesentini, S., Redaelli, A. and Buehler, M.J. (2009) Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils. Biophysical Journal, 97, 857-865.

[192]   Chang, S.W., Shefelbine, S.J. and Buehler, M.L. (2012) Structural and Mechanical Differences between Collagen Homo- and Heterotrimers: Relevance for the Molecular Origin of Brittle Bone Disease. Biophysical Journal, 102, 640-648.

[193]   Lee, J.S., Park, I.S., Park, K.B., Kang, D.H., Lee, C.H. and Hwang, S.H. (2008) Familial Intracranial Aneurysms. Journal of Korean Neurosurgical Society, 44, 136-140.

[194]   Steinmann, B., Royce, P.M. and Superti-Furga, A. (1993) Chapter 9. The Ehlers-Danlos Syndrome. In: Royce, P.M. and Steinmann, B., Eds., Connective Tissue and Its Heritable Disorders, Wiley, New York, 431-523.

[195]   Maw, G.J., Mackenzie, I.L. and Taylor, N.A.S. (1995) Redistribution of Body Fluids during Postural Manipulations. Acta Physiologica Scandinavica, 155, 157-163.

[196]   Husmann, M., Barton, M., Amann-Vesti, B. and Franzock, U.K. (2006) Postural Effects on Interstitial Fluid Pressure in Humans. Journal of Vascular Research, 43, 321-326.

[197]   Fung, P.C.W. and Kong, R.K.C. (2018) Relationship among the Meridians, Sinew Channels and Integrative Five Fluid Circulation System. Traditional Chinese Medicine, 7, 74-92.

[198]   Lund, T., Wiig, H., Reed, R.K. and Aukland, K. (1987) A “New” Mechanism for Oedema Generation: Strongly Negative Interstitial Fluid Pressure Causes Rapid Fluid Flow into Thermally Injured Skin. Acta Physiologica Scandinavica, 129, 433-435.

[199]   Wiig, H., Rubin, K. and Reed, R.K. (2003) New and Active Role of the Interstitium in Control of Interstitial Fluid Pressure: Potential Therapeutic Consequences. Acta Anaesthesiologica Scandinavica, 47, 111-121.

[200]   Lidén, A. (2006) Integrin αVβ3-Directed Contraction by Connective Tissue Cells Role in Control of Interstitial Fluid Pressure and Modulation by Bacterial Proteins. Ph.D. Thesis, Faculty of Medicine, Uppsala University, Uppsala.

[201]   Svendsen, O.S., Barczyk, M.M., Popova, S.N., Lidén, A., Gullberg, D. and Wiig, H. (2009) The α11β1 Integrin Has a Mechanistic Role in Control of Interstitial Fluid Pressure and Edema Formation in Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1864-1870.

[202]   Finkelstein, A.V., Badretdin, A.J., Galzitskaya, O.V., Ivankov, D.N., Bogatyreva, N.S. and Garbuzynskiy, S.O. (2017) There and Back Again: Two Views on the Protein Folding Puzzle. Physics of Life Reviews, 21, 56-71.

[203]   Englandera, S.W. and Maynea, L. (2017) The Case for Defined Protein Folding Pathways. Proceedings of the National Academy of Sciences of the United States of America, 114, 8253-8258.

[204]   Svensson, R.B., Herchenhan, A., Starborg, T., Larsen, M., Kadler, K.E., Qvortrup, K. and Magnusson, S.P. (2017) Evidence of Structurally Continuous Collagen Fibrils in Tendons. Acta Biomaterialia, 50, 293-301.

[205]   Raspanti, M., Congiu, T. and Guizzardi, S. (2002) Structural Aspects of the Extracellular Matrix of the Tendon: An Atomic Force and Scanning Electron Microscopy Study. Archives of Histology and Cytology, 65, 37-43.

[206]   Kanzaki. Y., Terasaki, F., Okabe, M., Fujita, S., Katashima, T., Otsuka, K. and Ishizaka, N. (2010) Three-Dimensional Architecture of Cardiomyocytes and Connective Tissue in Human Heart Revealed by Scanning Electron Microscopy. Circulation, 122, 1973-1974.

[207]   Fung, P.C.W. and Kong, R.K.C. (2018) New Insights on Stimulating the Lung Meridian Based on Modern Neurophysiology. Chinese Medicine, Scientific Research, 9, 75-117.