|
1
|
Xiao YB, Ravazzano L, Grano M, Colaianni G, Baldock C, Libonati F, Tarakanova A. Influence of Non-Cross-Linking AGEs on Mechanical Properties and Morphological Features of Tropocollagen Peptides: A Molecular Dynamics Study. ACS Biomater Sci Eng 2025. [PMID: 40343761 DOI: 10.1021/acsbiomaterials.5c00089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Collagen, a protein known for its long lifespan, is susceptible to accumulation of advanced glycation end products (AGEs) with age. These AGEs are considered markers that indicate the aging severity and influence the mechanics of tissues, leading to fragile bones and hardened skin. While many cross-linking AGEs have been widely studied for their ability to reduce the elasticity of biological tissues, contributing to skin hardening and fragile bones, through strong covalent bonds, non-cross-linking AGEs, or AGE adducts, are typically investigated as indicators of aging or as signaling factors in pathological conditions. However, recent experimental findings have revealed that the number of AGE adducts in aged bone is comparable to enzymatic cross-links, which are significantly more abundant than cross-linking AGEs. Based on these observations, we consider one of the most abundant AGE adducts - carboxymethyllysine (CML) - and employ molecular dynamics simulations to explore its direct impact on the mechanical and conformational properties of single tropocollagen molecules. Our models demonstrate that tropocollagen peptides, constructed based on sequences experimentally identified with sites of CML modifications in type I collagen derived from human cortical bone, exhibit heterogeneous behaviors under tensile testing. Still, most of these modified peptides display compromised structural stability, reduction in structural strength, and diminished energy dissipation ability when tension is applied. This study highlights the potential impact of non-cross-linking AGEs on collagen behavior at molecular scale and provides insights into the mechanisms underlying these modifications. Gaining a deeper understanding of the role of AGE adducts and their contribution to the aging process may pave the way for future solutions in antiaging research.
Collapse
Affiliation(s)
- Yu-Bai Xiao
- School of Mechanical, Aerospace, and Manufacturing Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| | - Linda Ravazzano
- Center for Nano Science and Technology@PoliMi, Istituto Italiano di Tecnologia, Via Rubattino 81, Milano 20134, Italy
| | - Maria Grano
- Department of Precision and Regenerative Medicine and Ionian Area - DiMePRe-J, University of Bari Aldo Moro, Bari 70124, Italy
| | - Graziana Colaianni
- Department of Precision and Regenerative Medicine and Ionian Area - DiMePRe-J, University of Bari Aldo Moro, Bari 70124, Italy
| | - Clair Baldock
- Manchester Cell-Matrix Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PT, U.K
| | - Flavia Libonati
- Center for Nano Science and Technology@PoliMi, Istituto Italiano di Tecnologia, Via Rubattino 81, Milano 20134, Italy
- Department of Mechanical, Energy, Management and Transportation Engineering (DIME), University of Genoa, Via all'Opera Pia 15/A, Genova 16145, Italy
| | - Anna Tarakanova
- School of Mechanical, Aerospace, and Manufacturing Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
- Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut 06269, United States
| |
Collapse
|
|
2
|
Burgess JK, Gosens R. Mechanotransduction and the extracellular matrix: Key drivers of lung pathologies and drug responsiveness. Biochem Pharmacol 2024; 228:116255. [PMID: 38705536 DOI: 10.1016/j.bcp.2024.116255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/19/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
The lung is a biomechanically active organ, with multiscale mechanical forces impacting the organ, tissue and cellular responses within this microenvironment. In chronic lung diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and others, the structure of the lung is drastically altered impeding gas exchange. These changes are, in part, reflected in alterations in the composition, amount and organization of the extracellular matrix within the different lung compartments. The transmission of mechanical forces within lung tissue are broadcast by this complex mix of extracellular matrix components, in particular the collagens, elastin and proteoglycans and the crosslinking of these components. At both a macro and a micro level, the mechanical properties of the microenvironment have a key regulatory role in ascertaining cellular responses and the function of the lung. Cells adhere to, and receive signals from, the extracellular matrix through a number of different surface receptors and complexes which are important for mechanotransduction. This review summarizes the multiscale mechanics in the lung and how the mechanical environment changes in lung disease and aging. We then examine the role of mechanotransduction in driving cell signaling events in lung diseases and finish with a future perspective of the need to consider how such forces may impact pharmacological responsiveness in lung diseases.
Collapse
Affiliation(s)
- Janette K Burgess
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
| | - Reinoud Gosens
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands
| |
Collapse
|
|
3
|
Mohammadkhah M, Klinge S. Review paper: The importance of consideration of collagen cross-links in computational models of collagen-based tissues. J Mech Behav Biomed Mater 2023; 148:106203. [PMID: 37879165 DOI: 10.1016/j.jmbbm.2023.106203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/25/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023]
Abstract
Collagen as the main protein in Extra Cellular Matrix (ECM) is the main load-bearing component of fibrous tissues. Nanostructure and architecture of collagen fibrils play an important role in mechanical behavior of these tissues. Extensive experimental and theoretical studies have so far been performed to capture these properties, but none of the current models realistically represent the complexity of network mechanics because still less is known about the collagen's inner structure and its effect on the mechanical properties of tissues. The goal of this review article is to emphasize the significance of cross-links in computational modeling of different collagen-based tissues, and to reveal the need for continuum models to consider cross-links properties to better reflect the mechanical behavior observed in experiments. In addition, this study outlines the limitations of current investigations and provides potential suggestions for the future work.
Collapse
Affiliation(s)
- Melika Mohammadkhah
- Technische Universität Berlin, Institute of Mechanics, Chair of Structural Mechanics and Analysis, Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin, Germany.
| | - Sandra Klinge
- Technische Universität Berlin, Institute of Mechanics, Chair of Structural Mechanics and Analysis, Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin, Germany
| |
Collapse
|
|
4
|
Leighton MP, Kreplak L, Rutenberg AD. Torsion and bistability of double-twist elastomers. SOFT MATTER 2023; 19:6376-6386. [PMID: 37577969 DOI: 10.1039/d3sm00554b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
We investigate the elastic properties of anisotropic elastomers with a double-twist director field, which is a model for collagen fibrils or blue phases. We observe a significant Poynting-like effect, coupling torsion (fibril twist) and extension. For freely-rotating boundary conditions, we identify a structural bistability at very small extensional strains which undergoes a saddle-node bifurcation at a critical strain - at approximately 1% strain for a parameterization appropriate for collagen fibrils. With clamped boundary conditions appropriate for many experimental setups, the bifurcation is not present. We expect significant helical shape effects when fixed torsion does not equal the equilibrium torsion of freely-rotating boundary conditions, due to residual torques.
Collapse
Affiliation(s)
- Matthew P Leighton
- Department of Physics, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
| | - Andrew D Rutenberg
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.
| |
Collapse
|
|
5
|
Yang F, Das D, Karunakaran K, Genin GM, Thomopoulos S, Chasiotis I. Nonlinear time-dependent mechanical behavior of mammalian collagen fibrils. Acta Biomater 2023; 163:63-77. [PMID: 35259515 PMCID: PMC9441475 DOI: 10.1016/j.actbio.2022.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 02/16/2022] [Accepted: 03/02/2022] [Indexed: 11/01/2022]
Abstract
The viscoelastic mechanical behavior of collagenous tissues has been studied extensively at the macroscale, yet a thorough quantitative understanding of the time-dependent mechanics of the basic building blocks of tissues, the collagen fibrils, is still missing. In order to address this knowledge gap, stress relaxation and creep tests at various stress (5-35 MPa) and strain (5-20%) levels were performed with individual collagen fibrils (average diameter of fully hydrated fibrils: 253 ± 21 nm) in phosphate buffered saline (PBS). The experimental results showed that the time-dependent mechanical behavior of fully hydrated individual collagen fibrils reconstituted from Type I calf skin collagen, is described by strain-dependent stress relaxation and stress-dependent creep functions in both the heel-toe and the linear regimes of deformation in monotonic stress-strain curves. The adaptive quasilinear viscoelastic (QLV) model, originally developed to capture the nonlinear viscoelastic response of collagenous tissues, provided a very good description of the nonlinear stress relaxation and creep behavior of the collagen fibrils. On the other hand, the nonlinear superposition (NSP) model fitted well the creep but not the stress relaxation data. The time constants and rates extracted from the adaptive QLV and the NSP models, respectively, pointed to a faster rate for stress relaxation than creep. This nonlinear viscoelastic behavior of individual collagen fibrils agrees with prior studies of macroscale collagenous tissues, thus demonstrating consistent time-dependent behavior across length scales and tissue hierarchies. STATEMENT OF SIGNIFICANCE: Pure stress relaxation and creep experiments were conducted for the first time with fully hydrated individual collagen fibrils. It is shown that collagen nanofibrils have a nonlinear time-dependent behavior which agrees with prior studies on macroscale collagenous tissues, thus demonstrating consistent time-dependent behavior across length scales and tissue hierarchies. This new insight into the non-linear viscoelastic behavior of the building blocks of mammalian collagenous tissues may serve as the foundation for improved macroscale tissue models that capture the mechanical behavior across length scales.
Collapse
Affiliation(s)
- Fan Yang
- Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Debashish Das
- Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Kathiresan Karunakaran
- Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Guy M Genin
- Mechanical Engineering and Materials Science, Washington University, St. Louis, MO 63130, USA
| | - Stavros Thomopoulos
- Orthopedic Surgery, Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Ioannis Chasiotis
- Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
| |
Collapse
|
|
6
|
Mariano CA, Sattari S, Ramirez GO, Eskandari M. Effects of tissue degradation by collagenase and elastase on the biaxial mechanics of porcine airways. Respir Res 2023; 24:105. [PMID: 37031200 PMCID: PMC10082978 DOI: 10.1186/s12931-023-02376-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/22/2023] [Indexed: 04/10/2023] Open
Abstract
BACKGROUND Common respiratory illnesses, such as emphysema and chronic obstructive pulmonary disease, are characterized by connective tissue damage and remodeling. Two major fibers govern the mechanics of airway tissue: elastin enables stretch and permits airway recoil, while collagen prevents overextension with stiffer properties. Collagenase and elastase degradation treatments are common avenues for contrasting the role of collagen and elastin in healthy and diseased states; while previous lung studies of collagen and elastin have analyzed parenchymal strips in animal and human specimens, none have focused on the airways to date. METHODS Specimens were extracted from the proximal and distal airways, namely the trachea, large bronchi, and small bronchi to facilitate evaluations of material heterogeneity, and subjected to biaxial planar loading in the circumferential and axial directions to assess airway anisotropy. Next, samples were subjected to collagenase and elastase enzymatic treatment and tensile tests were repeated. Airway tissue mechanical properties pre- and post-treatment were comprehensively characterized via measures of initial and ultimate moduli, strain transitions, maximum stress, hysteresis, energy loss, and viscoelasticity to gain insights regarding the specialized role of individual connective tissue fibers and network interactions. RESULTS Enzymatic treatment demonstrated an increase in airway tissue compliance throughout loading and resulted in at least a 50% decrease in maximum stress overall. Strain transition values led to significant anisotropic manifestation post-treatment, where circumferential tissues transitioned at higher strains compared to axial counterparts. Hysteresis values and energy loss decreased after enzymatic treatment, where hysteresis reduced by almost half of the untreated value. Anisotropic ratios exhibited axially led stiffness at low strains which transitioned to circumferentially led stiffness when subjected to higher strains. Viscoelastic stress relaxation was found to be greater in the circumferential direction for bronchial airway regions compared to axial counterparts. CONCLUSION Targeted fiber treatment resulted in mechanical alterations across the loading range and interactions between elastin and collagen connective tissue networks was observed. Providing novel mechanical characterization of elastase and collagenase treated airways aids our understanding of individual and interconnected fiber roles, ultimately helping to establish a foundation for constructing constitutive models to represent various states and progressions of pulmonary disease.
Collapse
Affiliation(s)
- Crystal A Mariano
- Department of Mechanical Engineering, University of California at Riverside, Riverside, CA, USA
| | - Samaneh Sattari
- Department of Mechanical Engineering, University of California at Riverside, Riverside, CA, USA
| | - Gustavo O Ramirez
- Department of Mechanical Engineering, University of California at Riverside, Riverside, CA, USA
| | - Mona Eskandari
- Department of Mechanical Engineering, University of California at Riverside, Riverside, CA, USA.
- BREATHE Center, School of Medicine, University of California at Riverside, Riverside, CA, USA.
- Department of Bioengineering, University of California at Riverside, Riverside, CA, USA.
| |
Collapse
|
|
7
|
Silva Barreto I, Pierantoni M, Hammerman M, Törnquist E, Le Cann S, Diaz A, Engqvist J, Liebi M, Eliasson P, Isaksson H. Nanoscale characterization of collagen structural responses to in situ loading in rat Achilles tendons. Matrix Biol 2023; 115:32-47. [PMID: 36435426 DOI: 10.1016/j.matbio.2022.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/29/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022]
Abstract
The specific viscoelastic mechanical properties of Achilles tendons are highly dependent on the structural characteristics of collagen at and between all hierarchical levels. Research has been conducted on the deformation mechanisms of positional tendons and single fibrils, but knowledge about the coupling between the whole tendon and nanoscale deformation mechanisms of more commonly injured energy-storing tendons, such as Achilles tendons, remains sparse. By exploiting the highly periodic arrangement of tendons at the nanoscale, in situ loading of rat Achilles tendons during small-angle X-ray scattering acquisition was used to investigate the collagen structural response during load to rupture, cyclic loading and stress relaxation. The fibril strain was substantially lower than the applied tissue strain. The fibrils strained linearly in the elastic region of the tissue, but also exhibited viscoelastic properties, such as an increased stretchability and recovery during cyclic loading and fibril strain relaxation during tissue stress relaxation. We demonstrate that the changes in the width of the collagen reflections could be attributed to strain heterogeneity and not changes in size of the coherently diffracting domains. Fibril strain heterogeneity increased with applied loads and after the toe region, fibrils also became increasingly disordered. Additionally, a thorough evaluation of radiation damage was performed. In conclusion, this study clearly displays the simultaneous structural response and adaption of the collagen fibrils to the applied tissue loads and provide novel information about the transition of loads between length scales in the Achilles tendon.
Collapse
Affiliation(s)
| | - Maria Pierantoni
- Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Malin Hammerman
- Department of Biomedical Engineering, Lund University, Lund, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Elin Törnquist
- Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Sophie Le Cann
- CNRS, Univ Paris Est Creteil, Univ Gustave Eiffel, UMR 8208, MSME, Créteil F-94010, France
| | - Ana Diaz
- Paul Scherrer Institut, Villigen PSI, Switzerland
| | - Jonas Engqvist
- Division of Solid Mechanics, Lund University, Lund, Sweden
| | - Marianne Liebi
- Paul Scherrer Institut, Villigen PSI, Switzerland; Department of Physics, Chalmers University, Gothenburg, Sweden; Center of X-ray Analytics, Empa, Swiss Federal Laboratories for Materials Science and Technology, St.Gallen, Switzerland
| | - Pernilla Eliasson
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Orthopaedics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hanna Isaksson
- Department of Biomedical Engineering, Lund University, Lund, Sweden.
| |
Collapse
|
|
8
|
Merry K, Napier C, Waugh CM, Scott A. Foundational Principles and Adaptation of the Healthy and Pathological Achilles Tendon in Response to Resistance Exercise: A Narrative Review and Clinical Implications. J Clin Med 2022; 11:4722. [PMID: 36012960 PMCID: PMC9410084 DOI: 10.3390/jcm11164722] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 12/03/2022] Open
Abstract
Therapeutic exercise is widely considered a first line fundamental treatment option for managing tendinopathies. As the Achilles tendon is critical for locomotion, chronic Achilles tendinopathy can have a substantial impact on an individual's ability to work and on their participation in physical activity or sport and overall quality of life. The recalcitrant nature of Achilles tendinopathy coupled with substantial variation in clinician-prescribed therapeutic exercises may contribute to suboptimal outcomes. Further, loading the Achilles tendon with sufficiently high loads to elicit positive tendon adaptation (and therefore promote symptom alleviation) is challenging, and few works have explored tissue loading optimization for individuals with tendinopathy. The mechanism of therapeutic benefit that exercise therapy exerts on Achilles tendinopathy is also a subject of ongoing debate. Resultingly, many factors that may contribute to an optimal therapeutic exercise protocol for Achilles tendinopathy are not well described. The aim of this narrative review is to explore the principles of tendon remodeling under resistance-based exercise in both healthy and pathologic tissues, and to review the biomechanical principles of Achilles tendon loading mechanics which may impact an optimized therapeutic exercise prescription for Achilles tendinopathy.
Collapse
Affiliation(s)
- Kohle Merry
- Department of Physical Therapy, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Centre for Hip Health and Mobility, Vancouver, BC V5Z 1M9, Canada
| | - Christopher Napier
- Department of Physical Therapy, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Centre for Hip Health and Mobility, Vancouver, BC V5Z 1M9, Canada
| | - Charlie M. Waugh
- Department of Physical Therapy, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Centre for Hip Health and Mobility, Vancouver, BC V5Z 1M9, Canada
| | - Alex Scott
- Department of Physical Therapy, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Centre for Hip Health and Mobility, Vancouver, BC V5Z 1M9, Canada
| |
Collapse
|
|
9
|
Effects of Extrusion and Irradiation on the Mechanical Properties of a Water–Collagen Solution. Polymers (Basel) 2022; 14:polym14030578. [PMID: 35160567 PMCID: PMC8840162 DOI: 10.3390/polym14030578] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/21/2022] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
This article describes 1D extension tests on bovine collagen samples (8% collagen in water). At such a high collagen concentration, the mechanical properties of semi-solid samples can be approximated by hyperelastic models (two-parametric HGO and Misof models were used), or simply by Hooke’s law and the modulus of elasticity E. The experiments confirm a significant increase in the E-modulus of the samples irradiated with high-energy electrons. The modulus E~9 kPa of non-irradiated samples increases monotonically up to E~250 kPa for samples absorbing an e-beam dose of ~3300 Gy. This amplification is attributed to the formation of cross-links by irradiation. However, E-modulus can be increased not only by irradiation but also by exposure to a high strain rate. For example, soft isotropic collagen extruded through a 200 mm long capillary increases the modulus of elasticity from 9 kPa to 30 kPa, and the increase is almost isotropic. This stiffening occurs when the corrugated collagen fibers are straightened and are aligned in the flow direction. It seems that the permanent structural changes caused by extrusion mitigate the effects of the ex post applied irradiation. Irradiation of extruded samples by 3300 Gy increases the modulus of E-elasticity only three times (from 30 kPa to approximately 90 kPa). Extruded and ex post irradiated samples show slight anisotropy (the stiffness in the longitudinal direction is on an average greater than the transverse stiffness).
Collapse
|
|
10
|
Vitrac O, Nguyen PM, Hayert M. In Silico Prediction of Food Properties: A Multiscale Perspective. FRONTIERS IN CHEMICAL ENGINEERING 2022. [DOI: 10.3389/fceng.2021.786879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Several open software packages have popularized modeling and simulation strategies at the food product scale. Food processing and key digestion steps can be described in 3D using the principles of continuum mechanics. However, compared to other branches of engineering, the necessary transport, mechanical, chemical, and thermodynamic properties have been insufficiently tabulated and documented. Natural variability, accented by food evolution during processing and deconstruction, requires considering composition and structure-dependent properties. This review presents practical approaches where the premises for modeling and simulation start at a so-called “microscopic” scale where constituents or phase properties are known. The concept of microscopic or ground scale is shown to be very flexible from atoms to cellular structures. Zooming in on spatial details tends to increase the overall cost of simulations and the integration over food regions or time scales. The independence of scales facilitates the reuse of calculations and makes multiscale modeling capable of meeting food manufacturing needs. On one hand, new image-modeling strategies without equations or meshes are emerging. On the other hand, complex notions such as compositional effects, multiphase organization, and non-equilibrium thermodynamics are naturally incorporated in models without linearization or simplifications. Multiscale method’s applicability to hierarchically predict food properties is discussed with comprehensive examples relevant to food science, engineering and packaging. Entropy-driven properties such as transport and sorption are emphasized to illustrate how microscopic details bring new degrees of freedom to explore food-specific concepts such as safety, bioavailability, shelf-life and food formulation. Routes for performing spatial and temporal homogenization with and without chemical details are developed. Creating a community sharing computational codes, force fields, and generic food structures is the next step and should be encouraged. This paper provides a framework for the transfer of results from other fields and the development of methods specific to the food domain.
Collapse
|
|
11
|
Muntz I, Fenu M, van Osch GJVM, Koenderink G. The role of cell-matrix interactions in connective tissue mechanics. Phys Biol 2021; 19. [PMID: 34902848 DOI: 10.1088/1478-3975/ac42b8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/13/2021] [Indexed: 11/12/2022]
Abstract
Living tissue is able to withstand large stresses in everyday life, yet it also actively adapts to dynamic loads. This remarkable mechanical behaviour emerges from the interplay between living cells and their non-living extracellular environment. Here we review recent insights into the biophysical mechanisms involved in the reciprocal interplay between cells and the extracellular matrix and how this interplay determines tissue mechanics, with a focus on connective tissues. We first describe the roles of the main macromolecular components of the extracellular matrix in regards to tissue mechanics. We then proceed to highlight the main routes via which cells sense and respond to their biochemical and mechanical extracellular environment. Next we introduce the three main routes via which cells can modify their extracellular environment: exertion of contractile forces, secretion and deposition of matrix components, and matrix degradation. Finally we discuss how recent insights in the mechanobiology of cell-matrix interactions are furthering our understanding of the pathophysiology of connective tissue diseases and cancer, and facilitating the design of novel strategies for tissue engineering.
Collapse
Affiliation(s)
- Iain Muntz
- Bionanoscience, TU Delft, Kavli Institute of Nanoscience Delft, Delft University of Technology, Van der Maasweg 9, Delft, Zuid-Holland, 2629 HC, NETHERLANDS
| | - Michele Fenu
- Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Zuid-Holland, 3000 CA, NETHERLANDS
| | - Gerjo J V M van Osch
- Orthopaedics; Otorhinolaryngology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Zuid-Holland, 3000 CA, NETHERLANDS
| | - Gijsje Koenderink
- Bionanoscience, TU Delft, Kavli Institute of Nanoscience Delft, Delft University of Technology, Van der Maasweg 9, Delft, Zuid-Holland, 2629 HZ, NETHERLANDS
| |
Collapse
|
|
12
|
Al Makhzoomi AK, Kirk TB, Allison GT. An AFM study of the nanostructural response of New Zealand white rabbit Achilles tendons to cyclic loading. Microsc Res Tech 2021; 85:728-737. [PMID: 34632676 DOI: 10.1002/jemt.23944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/14/2021] [Accepted: 09/09/2021] [Indexed: 01/21/2023]
Abstract
The nanostructural response of New Zealand white rabbit Achilles tendons to a fatigue damage model was assessed quantitatively and qualitatively using the endpoint of dose assessments of each tendon from our previous study. The change in mechanical properties was assessed concurrently with nanostructural change in the same non-viable intact tendon. Atomic force microscopy was used to study the elongation of D-periodicities, and the changes were compared both within the same fibril bundle and between fibril bundles. D-periodicities increased due to both increased strain and increasing numbers of fatigue cycles. Although no significant difference in D-periodicity lengthening was found between fibril bundles, the lengthening of D-periodicity correlated strongly with the overall tendon mechanical changes. The accurate quantification of fibril elongation in response to macroscopic applied strain assisted in assessing the complex structure-function relationship in Achilles tendons.
Collapse
Affiliation(s)
- Anas K Al Makhzoomi
- School of Allied Health, Faculty of Health Science, Curtin University, Perth, Western Australia, Australia
| | - Thomas B Kirk
- School of Science, Engineering and Technology, RMIT University Vietnam, Ho Chi Minh City, Vietnam
| | - Garry T Allison
- Associate Deputy Vice-Chancellor, Research Excellence, Curtin University, Perth, Western Australia, Australia
| |
Collapse
|
|
13
|
Leighton MP, Rutenberg AD, Kreplak L. D-band strain underestimates fibril strain for twisted collagen fibrils at low strains. J Mech Behav Biomed Mater 2021; 124:104854. [PMID: 34601435 DOI: 10.1016/j.jmbbm.2021.104854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/01/2021] [Accepted: 09/19/2021] [Indexed: 11/29/2022]
Abstract
Collagen fibrils are the main structural component of load-bearing tissues such as tendons, ligaments, skin, the cornea of the eye, and the heart. The D-band of collagen fibrils is an axial periodic density modulation that can be easily characterized by tissue-level X-ray scattering. During mechanical testing, D-band strain is often used as a proxy for fibril strain. However, this approach ignores the coupling between strain and molecular tilt. We examine the validity of this approximation using an elastomeric collagen fibril model that includes both the D-band and a molecular tilt field. In the low strain regime, we show that the D-band strain substantially underestimates fibril strain for strongly twisted collagen fibrils - such as fibrils from skin or corneal tissue.
Collapse
Affiliation(s)
- Matthew P Leighton
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, B3H 4R2, Nova Scotia, Canada; Department of Physics, Simon Fraser University, Burnaby, V5A 1S6, British Columbia, Canada
| | - Andrew D Rutenberg
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, B3H 4R2, Nova Scotia, Canada.
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, B3H 4R2, Nova Scotia, Canada
| |
Collapse
|
|
14
|
The Effect of Enzymatic Crosslink Degradation on the Mechanics of the Anterior Cruciate Ligament: A Hybrid Multi-Domain Model. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11188580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The anterior cruciate ligament’s (ACL) mechanics is an important factor governing the ligament’s integrity and, hence, the knee joint’s response. Despite many investigations in this area, the cause and effect of injuries remain unclear or unknown. This may be due to the complexity of the direct link between macro- and micro-scale damage mechanisms. In the first part of this investigation, a three-dimensional coarse-grained model of collagen fibril (type I) was developed using a bottom-up approach to investigate deformation mechanisms under tensile testing. The output of this molecular level was used later to calibrate the parameters of a hierarchical multi-scale fibril-reinforced hyper-elastoplastic model of the ACL. Our model enabled us to determine the mechanical behavior of the ACL as a function of the basic response of the collagen molecules. Modeled elastic response and damage distribution were in good agreement with the reported measurements and computational investigations. Our results suggest that degradation of crosslink content dictates the loss of the stiffness of the fibrils and, hence, damage to the ACL. Therefore, the proposed computational frame is a promising tool that will allow new insights into the biomechanics of the ACL.
Collapse
|
|
15
|
Casey DT, Bou Jawde S, Herrmann J, Mori V, Mahoney JM, Suki B, Bates JHT. Percolation of collagen stress in a random network model of the alveolar wall. Sci Rep 2021; 11:16654. [PMID: 34404841 PMCID: PMC8371101 DOI: 10.1038/s41598-021-95911-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 07/28/2021] [Indexed: 11/21/2022] Open
Abstract
Fibrotic diseases are characterized by progressive and often irreversible scarring of connective tissue in various organs, leading to substantial changes in tissue mechanics largely as a result of alterations in collagen structure. This is particularly important in the lung because its bulk modulus is so critical to the volume changes that take place during breathing. Nevertheless, it remains unclear how fibrotic abnormalities in the mechanical properties of pulmonary connective tissue can be linked to the stiffening of its individual collagen fibers. To address this question, we developed a network model of randomly oriented collagen and elastin fibers to represent pulmonary alveolar wall tissue. We show that the stress-strain behavior of this model arises via the interactions of collagen and elastin fiber networks and is critically dependent on the relative fiber stiffnesses of the individual collagen and elastin fibers themselves. We also show that the progression from linear to nonlinear stress-strain behavior of the model is associated with the percolation of stress across the collagen fiber network, but that the location of the percolation threshold is influenced by the waviness of collagen fibers.
Collapse
Affiliation(s)
- Dylan T Casey
- Depatment of Medicine, University of Vermont Larner College of Medicine, 149 Beaumont Ave, Burlington, VT, 05405, USA
- Complex Systems Center, University of Vermont, Burlington, VT, USA
| | - Samer Bou Jawde
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Jacob Herrmann
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Vitor Mori
- Depatment of Medicine, University of Vermont Larner College of Medicine, 149 Beaumont Ave, Burlington, VT, 05405, USA
| | - J Matthew Mahoney
- Department of Neurological Science, University of Vermont Larner College of Medicine, Burlington, VT, USA
- The Jackson Laboratory, Bar Harbor, ME, USA
| | - Béla Suki
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Jason H T Bates
- Depatment of Medicine, University of Vermont Larner College of Medicine, 149 Beaumont Ave, Burlington, VT, 05405, USA.
| |
Collapse
|
|
16
|
Obarska-Kosinska A, Rennekamp B, Ünal A, Gräter F. ColBuilder: A server to build collagen fibril models. Biophys J 2021; 120:3544-3549. [PMID: 34265261 DOI: 10.1016/j.bpj.2021.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/21/2021] [Accepted: 07/07/2021] [Indexed: 11/17/2022] Open
Abstract
Type I collagen is the main structural component of many tissues in the human body. It provides excellent mechanical properties to connective tissue and acts as a protein interaction hub. There is thus a wide interest in understanding the properties and diverse functions of type I collagen at the molecular level. A precondition is an atomistic collagen I structure as it occurs in native tissue. To this end, we built full-atom models of cross-linked collagen fibrils by integrating the low-resolution structure of collagen fibril available from x-ray fiber diffraction with high-resolution structures of short collagen-like peptides from x-ray crystallography and mass spectrometry data. We created a Web resource of collagen models for 20 different species with a large variety of cross-link types and localization within the fibril to facilitate structure-based analyses and simulations of type I collagen in health and disease. To easily enable simulations, we provide parameters of the modeled cross-links for an Amber force field. The repository of collagen models is available at https://colbuilder.h-its.org.
Collapse
Affiliation(s)
- Agnieszka Obarska-Kosinska
- Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Hamburg Unit c/o DESY, European Molecular Biology Laboratory, Hamburg, Germany
| | - Benedikt Rennekamp
- Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Max Planck School Matter-to-Life (MtL), Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany
| | - Aysecan Ünal
- Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Max Planck School Matter-to-Life (MtL), Heidelberg, Germany
| | - Frauke Gräter
- Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Max Planck School Matter-to-Life (MtL), Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany.
| |
Collapse
|
|
17
|
Liquid Crystal Elastomers for Biological Applications. NANOMATERIALS 2021; 11:nano11030813. [PMID: 33810173 PMCID: PMC8005174 DOI: 10.3390/nano11030813] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 11/16/2022]
Abstract
The term liquid crystal elastomer (LCE) describes a class of materials that combine the elastic entropy behaviour associated with conventional elastomers with the stimuli responsive properties of anisotropic liquid crystals. LCEs consequently exhibit attributes of both elastomers and liquid crystals, but additionally have unique properties not found in either. Recent developments in LCE synthesis, as well as the understanding of the behaviour of liquid crystal elastomers—namely their mechanical, optical and responsive properties—is of significant relevance to biology and biomedicine. LCEs are abundant in nature, highlighting the potential use of LCEs in biomimetics. Their exceptional tensile properties and biocompatibility have led to research exploring their applications in artificial tissue, biological sensors and cell scaffolds by exploiting their actuation and shock absorption properties. There has also been significant recent interest in using LCEs as a model for morphogenesis. This review provides an overview of some aspects of LCEs which are of relevance in different branches of biology and biomedicine, as well as discussing how recent LCE advances could impact future applications.
Collapse
|
|
18
|
Leighton MP, Kreplak L, Rutenberg AD. Non-equilibrium growth and twist of cross-linked collagen fibrils. SOFT MATTER 2021; 17:1415-1427. [PMID: 33325971 DOI: 10.1039/d0sm01830a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The lysyl oxidase (LOX) enzyme that catalyses cross-link formation during the assembly of collagen fibrils in vivo is too large to diffuse within assembled fibrils, and so is incompatible with a fully equilibrium mechanism for fibril formation. We propose that enzymatic cross-links are formed at the fibril surface during the growth of collagen fibrils; as a consequence no significant reorientation of previously cross-linked collagen molecules occurs inside collagen fibrils during fibril growth in vivo. By imposing local equilibrium only at the fibril surface, we develop a coarse-grained quantitative model of in vivo fibril structure that incorporates a double-twist orientation of collagen molecules and a periodic D-band density modulation along the fibril axis. Radial growth is controlled by the concentration of available collagen molecules outside the fibril. In contrast with earlier equilibrium models of fibril structure, we find that all fibrils can exhibit a core-shell structure that is controlled only by the fibril radius. At small radii a core is developed with a linear double-twist structure as a function of radius. Within the core the double-twist structure is largely independent of the D-band. Within the shell at larger radii, the structure approaches a constant twist configuration that is strongly coupled with the D-band. We suggest a stable radius control mechanism that corneal fibrils can exploit near the edge of the linear core regime; while larger tendon fibrils use a cruder version of growth control that does not select a preferred radius.
Collapse
Affiliation(s)
- Matthew P Leighton
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| | - Andrew D Rutenberg
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
| |
Collapse
|
|
19
|
Stammers M, Niewczas IS, Segonds-Pichon A, Clark J. Mechanical stretching changes crosslinking and glycation levels in the collagen of mouse tail tendon. J Biol Chem 2020; 295:10572-10580. [PMID: 32546479 PMCID: PMC7397108 DOI: 10.1074/jbc.ra119.012067] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 06/09/2020] [Indexed: 12/20/2022] Open
Abstract
Collagen I is a major tendon protein whose polypeptide chains are linked by covalent crosslinks. It is unknown how the crosslinking contributes to the mechanical properties of tendon or whether crosslinking changes in response to stretching or relaxation. Since their discovery, imine bonds within collagen have been recognized as being important in both crosslink formation and collagen structure. They are often described as acidic or thermally labile, but no evidence is available from direct measurements of crosslink levels whether these bonds contribute to the mechanical properties of collagen. Here, we used MS to analyze these imine bonds after reduction with sodium borohydride while under tension and found that their levels are altered in stretched tendon. We studied the changes in crosslink bonding in tail tendon from 11-week-old C57Bl/6 mice at 4% physical strain, at 10% strain, and at breaking point. The crosslinks hydroxy-lysino-norleucine (HLNL), dihydroxy-lysino-norleucine (DHLNL), and lysino-norleucine (LNL) in-creased or decreased depending on the specific crosslink and amount of mechanical strain. We also noted a decrease in glycated lysine residues in collagen, indicating that the imine formed between circulating glucose and lysine is also stress labile. We also carried out mechanical testing, including cyclic testing at 4% strain, stress relaxation tests, and stress-strain profiles taken at breaking point, both with and without sodium borohydride reduction. The results from both the MS studies and mechanical testing provide insights into the chemical changes during tendon stretching and directly link these chemical changes to functional collagen properties.
Collapse
|
|
20
|
Zapp C, Obarska-Kosinska A, Rennekamp B, Kurth M, Hudson DM, Mercadante D, Barayeu U, Dick TP, Denysenkov V, Prisner T, Bennati M, Daday C, Kappl R, Gräter F. Mechanoradicals in tensed tendon collagen as a source of oxidative stress. Nat Commun 2020; 11:2315. [PMID: 32385229 PMCID: PMC7210969 DOI: 10.1038/s41467-020-15567-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 03/10/2020] [Indexed: 12/31/2022] Open
Abstract
As established nearly a century ago, mechanoradicals originate from homolytic bond scission in polymers. The existence, nature and biological relevance of mechanoradicals in proteins, instead, are unknown. We here show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species, essential biological signaling molecules. Electron-paramagnetic resonance (EPR) spectroscopy of stretched rat tail tendon, atomistic molecular dynamics simulations and quantum-chemical calculations show that the radicals form by bond scission in the direct vicinity of crosslinks in collagen. Radicals migrate to adjacent clusters of aromatic residues and stabilize on oxidized tyrosyl radicals, giving rise to a distinct EPR spectrum consistent with a stable dihydroxyphenylalanine (DOPA) radical. The protein mechanoradicals, as a yet undiscovered source of oxidative stress, finally convert into hydrogen peroxide. Our study suggests collagen I to have evolved as a radical sponge against mechano-oxidative damage and proposes a mechanism for exercise-induced oxidative stress and redox-mediated pathophysiological processes. The existence, nature and biological relevance of mechanoradicals in proteins are unknown. Here authors show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species and suggest that collagen I evolved as a radical sponge against mechano-oxidative damage.
Collapse
Affiliation(s)
- Christopher Zapp
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.,Institute for Theoretical Physics, Heidelberg University, Philosophenweg 16, 69120, Heidelberg, Germany
| | - Agnieszka Obarska-Kosinska
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.,Hamburg Unit c/o DESY, European Molecular Biology Laboratory, Notkestrasse 85, 22607, Hamburg, Germany
| | - Benedikt Rennekamp
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.,Institute for Theoretical Physics, Heidelberg University, Philosophenweg 16, 69120, Heidelberg, Germany
| | - Markus Kurth
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany
| | - David M Hudson
- Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Davide Mercadante
- Biochemical Institute, University of Zuerich, Winterthurerstr. 190, 8057, Zuerich, Switzerland
| | - Uladzimir Barayeu
- Faculty of Biosciences, Heidelberg University, Im Neuenheimer Feld 234, 69120, Heidelberg, Germany.,Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Tobias P Dick
- Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Vasyl Denysenkov
- Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 7, 60438, Frankfurt am Main, Germany
| | - Thomas Prisner
- Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 7, 60438, Frankfurt am Main, Germany
| | - Marina Bennati
- Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Csaba Daday
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.,Interdisciplinary Center for Scientific Computing, Heidelberg University, INF 205, 69120, Heidelberg, Germany
| | - Reinhard Kappl
- Institute for Biophysics, Saarland University Medical Center, CIPMM Geb. 48, 66421, Homburg/Saar, Germany
| | - Frauke Gräter
- Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany. .,Interdisciplinary Center for Scientific Computing, Heidelberg University, INF 205, 69120, Heidelberg, Germany.
| |
Collapse
|
|
21
|
Vos BE, Martinez-Torres C, Burla F, Weisel JW, Koenderink GH. Revealing the molecular origins of fibrin's elastomeric properties by in situ X-ray scattering. Acta Biomater 2020; 104:39-52. [PMID: 31923718 DOI: 10.1016/j.actbio.2020.01.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/02/2020] [Accepted: 01/02/2020] [Indexed: 01/01/2023]
Abstract
Fibrin is an elastomeric protein forming highly extensible fiber networks that provide the scaffold of blood clots. Here we reveal the molecular mechanisms that explain the large extensibility of fibrin networks by performing in situ small angle X-ray scattering measurements while applying a shear deformation. We simultaneously measure shear-induced alignment of the fibers and changes in their axially ordered molecular packing structure. We show that fibrin networks exhibit distinct structural responses that set in consecutively as the shear strain is increased. They exhibit an entropic response at small strains (<5%), followed by progressive fiber alignment (>25% strain) and finally changes in the fiber packing structure at high strain (>100%). Stretching reduces the fiber packing order and slightly increases the axial periodicity, indicative of molecular unfolding. However, the axial periodicity changes only by 0.7%, much less than the 80% length increase of the fibers, suggesting that fiber elongation mainly stems from uncoiling of the natively disordered αC-peptide linkers that laterally bond the molecules. Upon removal of the load, the network structure returns to the original isotropic state, but the fiber structure becomes more ordered and adopts a smaller packing periodicity compared to the original state. We conclude that the hierarchical packing structure of fibrin fibers, with built-in disorder, makes the fibers extensible and allows for mechanical annealing. Our results provide a basis for interpreting the molecular basis of haemostatic and thrombotic disorders associated with clotting and provide inspiration to design resilient bio-mimicking materials. STATEMENT OF SIGNIFICANCE: Fibrin provides structural integrity to blood clots and is also widely used as a scaffold for tissue engineering. To fulfill their biological functions, fibrin networks have to be simultaneously compliant like skin and resilient against rupture. Here, we unravel the structural origin underlying this remarkable mechanical behaviour. To this end, we performed in situ measurements of fibrin structure across multiple length scales by combining X-ray scattering with shear rheology. Our findings show that fibrin sustains large strains by undergoing a sequence of structural changes on different scales with increasing strain levels. This demonstrates new mechanistic aspects of an important biomaterial's structure and its mechanical function, and serves as an example in the design of biomimicking materials.
Collapse
|
|
22
|
Rouède D, Schaub E, Bellanger JJ, Ezan F, Tiaho F. Wavy nature of collagen fibrils deduced from the dispersion of their second-order nonlinear optical anisotropy parameters ρ. OPTICS EXPRESS 2020; 28:4845-4858. [PMID: 32121716 DOI: 10.1364/oe.380089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/02/2020] [Indexed: 06/10/2023]
Abstract
From P-SHG experiments, second-order nonlinear optical anisotropy parameters ρ = χZZZ/χZXX of collagen tissues are calculated assuming the same model of supercoiled collagen fibril characterized by a variable angle θ. Dispersion of experimental ρ values is converted into distribution of θ values based on the wavy nature of collagen fibrils deduced from EM studies. For tendon, the results show that the dispersion of experimental ρ values is mainly due to Poisson photonic shot noise assuming a slight fibrillar undulation with θ = 2.2° ± 1.8°. However for skin and vessels, the dispersion of experimental ρ values is mainly due to a stronger fibrillar undulation with θ = 16.2° ± 1.3°. The results highlight that this undulation is reduced during the development of liver fibrosis therefore, contributing to the rigidity of the tissue.
Collapse
|
|
23
|
Revealing the assembly of filamentous proteins with scanning transmission electron microscopy. PLoS One 2019; 14:e0226277. [PMID: 31860683 PMCID: PMC6924676 DOI: 10.1371/journal.pone.0226277] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/22/2019] [Indexed: 11/19/2022] Open
Abstract
Filamentous proteins are responsible for the superior mechanical strength of our cells and tissues. The remarkable mechanical properties of protein filaments are tied to their complex molecular packing structure. However, since these filaments have widths of several to tens of nanometers, it has remained challenging to quantitatively probe their molecular mass density and three-dimensional packing order. Scanning transmission electron microscopy (STEM) is a powerful tool to perform simultaneous mass and morphology measurements on filamentous proteins at high resolution, but its applicability has been greatly limited by the lack of automated image processing methods. Here, we demonstrate a semi-automated tracking algorithm that is capable of analyzing the molecular packing density of intra- and extracellular protein filaments over a broad mass range from STEM images. We prove the wide applicability of the technique by analyzing the mass densities of two cytoskeletal proteins (actin and microtubules) and of the main protein in the extracellular matrix, collagen. The high-throughput and spatial resolution of our approach allow us to quantify the internal packing of these filaments and their polymorphism by correlating mass and morphology information. Moreover, we are able to identify periodic mass variations in collagen fibrils that reveal details of their axially ordered longitudinal self-assembly. STEM-based mass mapping coupled with our tracking algorithm is therefore a powerful technique in the characterization of a wide range of biological and synthetic filaments.
Collapse
|
|
24
|
The status and challenges of replicating the mechanical properties of connective tissues using additive manufacturing. J Mech Behav Biomed Mater 2019; 103:103544. [PMID: 32090944 DOI: 10.1016/j.jmbbm.2019.103544] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/29/2019] [Accepted: 11/16/2019] [Indexed: 01/23/2023]
Abstract
The ability to fabricate complex structures via precise and heterogeneous deposition of biomaterials makes additive manufacturing (AM) a leading technology in the creation of implants and tissue engineered scaffolds. Connective tissues (CTs) remain attractive targets for manufacturing due to their "simple" tissue compositions that, in theory, are replicable through choice of biomaterial(s) and implant microarchitecture. Nevertheless, characterisation of the mechanical and biological functions of 3D printed constructs with respect to their host tissues is often limited and remains a restriction towards their translation into clinical practice. This review aims to provide an update on the current status of AM to mimic the mechanical properties of CTs, with focus on arterial tissue, articular cartilage and bone, from the perspective of printing platforms, biomaterial properties, and topological design. Furthermore, the grand challenges associated with the AM of CT replacements and their subsequent regulatory requirements are discussed to aid further development of reliable and effective implants.
Collapse
|
|
25
|
Peacock CJ, Kreplak L. Nanomechanical mapping of single collagen fibrils under tension. NANOSCALE 2019; 11:14417-14425. [PMID: 31334733 DOI: 10.1039/c9nr02644d] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
At the most fundamental level, collagen fibrils are rope-like structures assembled from triple-helical collagen molecules. One key structural characteristic of the fibril is the 67 nm D-band pattern arising from the quarter-stagger packing of the molecules. Our current understanding of the structural changes induced by tensile loading of collagen fibrils comes mostly from atomistic molecular dynamics simulations and tissue level experiments. Tensile testing of individual fibrils is an upcoming field of investigation, and thus far structural analysis has always taken place after the fibrils have been ruptured or strained and subsequently dried. There is therefore a gap in understanding how the structure of collagen fibrils transforms under tension, and how this reorganization affects the functionality of collagen fibrils within tissues. In this study, atomic force microscopy based nanomechanical mapping is introduced to image hydrated collagen fibrils absorbed to an elastic substrate. Upon stretching the substrate between 5 and 30%, we observe a radial stiffening consistent with the fibrils being under tension. This is associated with an increase in D-band length. In addition the indentation modulus contrast associated with the D-band pattern increases linearly with D-band strain. These results provide direct confirmation of, and new information on the axially inhomogeneous structural response of collagen fibrils to applied tension as previously proposed on the basis of X-ray scattering experiments on stretched tissues. Furthermore our approach opens the road for studying the structural impacts of tension on cell-matrix interactions at the molecular level.
Collapse
Affiliation(s)
- Chris J Peacock
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, Canada.
| | | |
Collapse
|
|
26
|
Sorushanova A, Delgado LM, Wu Z, Shologu N, Kshirsagar A, Raghunath R, Mullen AM, Bayon Y, Pandit A, Raghunath M, Zeugolis DI. The Collagen Suprafamily: From Biosynthesis to Advanced Biomaterial Development. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1801651. [PMID: 30126066 DOI: 10.1002/adma.201801651] [Citation(s) in RCA: 602] [Impact Index Per Article: 100.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/03/2018] [Indexed: 05/20/2023]
Abstract
Collagen is the oldest and most abundant extracellular matrix protein that has found many applications in food, cosmetic, pharmaceutical, and biomedical industries. First, an overview of the family of collagens and their respective structures, conformation, and biosynthesis is provided. The advances and shortfalls of various collagen preparations (e.g., mammalian/marine extracted collagen, cell-produced collagens, recombinant collagens, and collagen-like peptides) and crosslinking technologies (e.g., chemical, physical, and biological) are then critically discussed. Subsequently, an array of structural, thermal, mechanical, biochemical, and biological assays is examined, which are developed to analyze and characterize collagenous structures. Lastly, a comprehensive review is provided on how advances in engineering, chemistry, and biology have enabled the development of bioactive, 3D structures (e.g., tissue grafts, biomaterials, cell-assembled tissue equivalents) that closely imitate native supramolecular assemblies and have the capacity to deliver in a localized and sustained manner viable cell populations and/or bioactive/therapeutic molecules. Clearly, collagens have a long history in both evolution and biotechnology and continue to offer both challenges and exciting opportunities in regenerative medicine as nature's biomaterial of choice.
Collapse
Affiliation(s)
- Anna Sorushanova
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Luis M Delgado
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Zhuning Wu
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Naledi Shologu
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Aniket Kshirsagar
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Rufus Raghunath
- Centre for Cell Biology and Tissue Engineering, Competence Centre Tissue Engineering for Drug Development (TEDD), Department Life Sciences and Facility Management, Institute for Chemistry and Biotechnology (ICBT), Zürich University of Applied Sciences, Wädenswil, Switzerland
| | | | - Yves Bayon
- Sofradim Production-A Medtronic Company, Trevoux, France
| | - Abhay Pandit
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| | - Michael Raghunath
- Centre for Cell Biology and Tissue Engineering, Competence Centre Tissue Engineering for Drug Development (TEDD), Department Life Sciences and Facility Management, Institute for Chemistry and Biotechnology (ICBT), Zürich University of Applied Sciences, Wädenswil, Switzerland
| | - Dimitrios I Zeugolis
- Regenerative, Modular and Developmental Engineering Laboratory (REMODEL), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, National University of Ireland Galway (NUI Galway), Galway, Ireland
| |
Collapse
|
|
27
|
Quigley AS, Bancelin S, Deska-Gauthier D, Légaré F, Veres SP, Kreplak L. Combining tensile testing and structural analysis at the single collagen fibril level. Sci Data 2018; 5:180229. [PMID: 30351303 PMCID: PMC6198748 DOI: 10.1038/sdata.2018.229] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 09/04/2018] [Indexed: 01/17/2023] Open
Abstract
Tensile testing to failure followed by imaging is a simple way of studying the structure-function relationship of connective tissues such as skin, tendon, and ligament. However, interpretation of these datasets is complex due to the hierarchical structures of the tissues spanning six or more orders of magnitude in length scale. Here we present a dataset obtained through the same scheme at the single collagen fibril level, the fundamental tensile element of load-bearing tissues. Tensile testing was performed on fibrils extracted from two types of bovine tendons, adsorbed on a glass surface and glued at both ends. An atomic force microscope (AFM) was used to pull fibrils to failure in bowstring geometry. The broken fibrils were then imaged by AFM for morphological characterization, by second harmonic generation microscopy to assess changes to molecular packing, and by fluorescence microscopy after incubation with a peptide probe that binds specifically to denatured collagen molecules. This dataset linking stress-strain curves to post-failure molecular changes is useful for researchers modelling or designing functional protein materials.
Collapse
Affiliation(s)
- Andrew S Quigley
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Canada
| | - Stéphane Bancelin
- Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunication, Varennes, Canada
| | | | - François Légaré
- Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunication, Varennes, Canada
| | - Samuel P Veres
- School of Biomedical Engineering, Dalhousie University, Halifax, Canada.,Division of Engineering, Saint Mary's University, Halifax, Canada
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Canada.,School of Biomedical Engineering, Dalhousie University, Halifax, Canada
| |
Collapse
|
|
28
|
Yapor JP, Neufeld BH, Tapia JB, Reynolds MM. Biodegradable crosslinked polyesters derived from thiomalic acid and S-nitrosothiol analogues for nitric oxide release. J Mater Chem B 2018; 6:4071-4081. [PMID: 31372219 PMCID: PMC6675467 DOI: 10.1039/c8tb00566d] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Crosslinked polyesters with Young's moduli similar to that of certain soft biological tissues were prepared via bulk polycondensation of thiomalic acid and 1,8-octanediol alone, and with citric or maleic acid. The copolymers were converted to nitric oxide (NO)-releasing S-nitrosothiol (RSNO) analogues by reaction with tert-butyl nitrite. Additional conjugation steps were avoided by inclusion of the thiolated monomer during the polycondensation to permit thiol conversion to RSNOs. NO release at physiological pH and temperature (pH 7.4, 37 °C) was determined by chemiluminescence-based NO detection. The average total NO content for poly(thiomalic-co-maleic acid-co-1,8-octanediol), poly(thiomalic-co-citric acid-co-1,8-octanediol), and poly(thiomalic acid-co-1,8-octanediol) was 130 ± 39 μmol g-1, 200 ± 35 μmol g-1, and 130 ± 11 μmol g-1, respectively. The antibacterial properties of the S-nitrosated analogues were confirmed against Escherichia coli and Staphylococcus aureus. The hydrolytic degradation products were analyzed by time-of-flight mass spectrometry after a 10-week study to investigate their composition. Tensile mechanical tests were performed on the non-nitrosated polymers as well as their S-nitrosated derivatives and suggested that the materials have appropriate Young's moduli and elongation values for biomedical applications.
Collapse
Affiliation(s)
- Janet P. Yapor
- Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
| | - Bella H. Neufeld
- Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
| | - Jesus B. Tapia
- Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
| | - Melissa M. Reynolds
- Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
- School of Biomedical Engineering, Colorado State University, Fort Collins, CO 80523, USA
| |
Collapse
|
|
29
|
Jansen KA, Licup AJ, Sharma A, Rens R, MacKintosh FC, Koenderink GH. The Role of Network Architecture in Collagen Mechanics. Biophys J 2018; 114:2665-2678. [PMID: 29874616 PMCID: PMC6129505 DOI: 10.1016/j.bpj.2018.04.043] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 04/18/2018] [Accepted: 04/23/2018] [Indexed: 01/13/2023] Open
Abstract
Collagen forms fibrous networks that reinforce tissues and provide an extracellular matrix for cells. These networks exhibit remarkable strain-stiffening properties that tailor the mechanical functions of tissues and regulate cell behavior. Recent models explain this nonlinear behavior as an intrinsic feature of disordered networks of stiff fibers. Here, we experimentally validate this theoretical framework by measuring the elastic properties of collagen networks over a wide range of self-assembly conditions. We show that the model allows us to quantitatively relate both the linear and nonlinear elastic behavior of collagen networks to their underlying architecture. Specifically, we identify the local coordination number (or connectivity) 〈z〉 as a key architectural parameter that governs the elastic response of collagen. The network elastic response reveals that 〈z〉 decreases from 3.5 to 3 as the polymerization temperature is raised from 26 to 37°C while being weakly dependent on concentration. We furthermore infer a Young's modulus of 1.1 MPa for the collagen fibrils from the linear modulus. Scanning electron microscopy confirms that 〈z〉 is between three and four but is unable to detect the subtle changes in 〈z〉 with polymerization conditions that rheology is sensitive to. Finally, we show that, consistent with the model, the initial stress-stiffening response of collagen networks is controlled by the negative normal stress that builds up under shear. Our work provides a predictive framework to facilitate future studies of the regulatory effect of extracellular matrix molecules on collagen mechanics. Moreover, our findings can aid mechanobiological studies of wound healing, fibrosis, and cancer metastasis, which require collagen matrices with tunable mechanical properties.
Collapse
Affiliation(s)
- Karin A Jansen
- Biological Soft Matter Group, AMOLF, Amsterdam, the Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Albert J Licup
- Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, the Netherlands
| | - Abhinav Sharma
- Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, the Netherlands; Leibniz Institute for Polymer Research, Dresden, Germany
| | - Robbie Rens
- Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, the Netherlands
| | - Fred C MacKintosh
- Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, the Netherlands; Departments of Chemical & Biomolecular Engineering, Chemistry, and Physics & Astronomy, Rice University, Houston, Texas; Center for Theoretical Biophysics, Rice University, Houston, Texas.
| | | |
Collapse
|
|
30
|
Asano S, Nakajima K, Kure K, Azuma K, Shimizu K, Murata H, Inoue T, Obata R, Asaoka R. Corneal biomechanical properties are associated with the activity and prognosis of Angioid Streaks. Sci Rep 2018; 8:8130. [PMID: 29802262 PMCID: PMC5970224 DOI: 10.1038/s41598-018-26430-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 05/08/2018] [Indexed: 11/26/2022] Open
Abstract
The aim of the current study is to investigate corneal biomechanical properties in detail using Ocular Response Analyzer (ORA) and Corvis ST (CST) tonometry and to analyze the association between corneal biomechanical properties and the frequency of intravitreal anti-vascular endothelial growth factor (VEGF) injections (FIV) in AS eyes with choroidal neovascularization (CNV). Twenty-eight eyes of 15 patients with AS were enrolled. Mean age of AS patients was 67.9 ± 9.8 years. ORA and CST measurements were carried out, in addition to comprehensive ophthalmic examinations. LogMAR visual acuity (VA) and ΔVA (the change of VA from baseline to the final visit) were calculated in each eye. Also, the relationships between FIV, and the variables of initial age at the observation period, axial length, and corneal biomechanical properties were investigated in eyes with AS using linear mixed model with model selection using AICc. In 28 AS eyes, 16 eyes underwent intravitreal anti-VEGF injections during follow-up period. Lower corneal hysteresis (CH), higher corneal resistant factor (CRF) and higher CST measured the DA ratio were associated with the increase of FIV in AS eyes (p = 0.01, p = 0.002, p = 0.027, respectively), suggesting the usefulness for monitoring of corneal biomechanical properties.
Collapse
Affiliation(s)
- Shotaro Asano
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kosuke Nakajima
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kana Kure
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Keiko Azuma
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kimiko Shimizu
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Hiroshi Murata
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Tatsuya Inoue
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Ryo Obata
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Ryo Asaoka
- Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| |
Collapse
|
|
31
|
Linka K, Hillgärtner M, Itskov M. Fatigue of soft fibrous tissues: Multi-scale mechanics and constitutive modeling. Acta Biomater 2018; 71:398-410. [PMID: 29550441 DOI: 10.1016/j.actbio.2018.03.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/21/2018] [Accepted: 03/05/2018] [Indexed: 10/17/2022]
Abstract
In recent experimental studies a possible damage mechanism of collagenous tissues mainly caused by fatigue was disclosed. In this contribution, a multi-scale constitutive model ranging from the tropocollagen (TC) molecule level up to bundles of collagen fibers is proposed and utilized to predict the elastic and inelastic long-term tissue response. Material failure of collagen fibrils is elucidated by a permanent opening of the triple helical collagen molecule conformation, triggered either by overstretching or reaction kinetics of non-covalent bonds. This kinetics is described within a probabilistic framework of adhesive detachments of molecular linkages providing collagen fiber integrity. Both intramolecular and interfibrillar linkages are considered. The final constitutive equations are validated against recent experimental data available in literature for both uniaxial tension to failure and the evolution of fatigue in subsequent loading cycles. All material parameters of the proposed model have a clear physical interpretation. STATEMENT OF SIGNIFICANCE Irreversible changes take place at different length scales of soft fibrous tissues under supra-physiological loading and alter their macroscopic mechanical properties. Understanding the evolution of those histologic pathologies under loading and incorporating them into a continuum mechanical framework appears to be crucial in order to predict long-term evolution of various diseases and to support the development of tissue engineering.
Collapse
|
|
32
|
Quigley AS, Bancelin S, Deska-Gauthier D, Légaré F, Kreplak L, Veres SP. In tendons, differing physiological requirements lead to functionally distinct nanostructures. Sci Rep 2018. [PMID: 29535366 PMCID: PMC5849720 DOI: 10.1038/s41598-018-22741-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The collagen-based tissues of animals are hierarchical structures: even tendon, the simplest collagenous tissue, has seven to eight levels of hierarchy. Tailoring tissue structure to match physiological function can occur at many different levels. We wanted to know if the control of tissue architecture to achieve function extends down to the nanoscale level of the individual, cable-like collagen fibrils. Using tendons from young adult bovine forelimbs, we performed stress-strain experiments on single collagen fibrils extracted from tendons with positional function, and tendons with energy storing function. Collagen fibrils from the two tendon types, which have known differences in intermolecular crosslinking, showed numerous differences in their responses to elongation. Unlike those from positional tendons, fibrils from energy storing tendons showed high strain stiffening and resistance to disruption in both molecular packing and conformation, helping to explain how these high stress tissues withstand millions of loading cycles with little reparative remodeling. Functional differences in load-bearing tissues are accompanied by important differences in nanoscale collagen fibril structure.
Collapse
Affiliation(s)
- Andrew S Quigley
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Canada
| | - Stéphane Bancelin
- Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunication, Varennes, Canada
| | | | - François Légaré
- Institut National de la Recherche Scientifique, Centre Énergie, Matériaux, Télécommunication, Varennes, Canada
| | - Laurent Kreplak
- Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Canada. .,School of Biomedical Engineering, Dalhousie University, Halifax, Canada.
| | - Samuel P Veres
- School of Biomedical Engineering, Dalhousie University, Halifax, Canada. .,Division of Engineering, Saint Mary's University, Halifax, Canada.
| |
Collapse
|
|
33
|
Karunaratne A, Li S, Bull AMJ. Nano-scale mechanisms explain the stiffening and strengthening of ligament tissue with increasing strain rate. Sci Rep 2018; 8:3707. [PMID: 29487334 PMCID: PMC5829138 DOI: 10.1038/s41598-018-21786-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 02/10/2018] [Indexed: 11/08/2022] Open
Abstract
Ligament failure is a major societal burden causing disability and pain. Failure is caused by trauma at high loading rates. At the macroscopic level increasing strain rates cause an increase in failure stress and modulus, but the mechanism for this strain rate dependency is not known. Here we investigate the nano scale mechanical property changes of human ligament using mechanical testing combined with synchrotron X-ray diffraction. With increasing strain rate, we observe a significant increase in fibril modulus and a reduction of fibril to tissue strain ratio, revealing that tissue-level stiffening is mainly due to the stiffening of collagen fibrils. Further, we show that the reduction in fibril deformation at higher strain rates is due to reduced molecular strain and fibrillar gaps, and is associated with rapid disruption of matrix-fibril bonding. This reduction in number of interfibrillar cross-links explains the changes in fibril strain; this is verified through computational modelling.
Collapse
Affiliation(s)
- Angelo Karunaratne
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
- Department of Mechanical Engineering, University of Moratuwa, Moratuwa, Sri Lanka
| | - Simin Li
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
- Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, UK
| | - Anthony M J Bull
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.
| |
Collapse
|
|
34
|
Pearson SJ, Engel AJ, Bashford GR. Changes in tendon spatial frequency parameters with loading. J Biomech 2017; 57:136-140. [PMID: 28410739 DOI: 10.1016/j.jbiomech.2017.03.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/20/2017] [Accepted: 03/24/2017] [Indexed: 10/19/2022]
Abstract
To examine and compare the loading related changes in micro-morphology of the patellar tendon. Fifteen healthy young males (age 19±3yrs, body mass 83±5kg) were utilised in a within subjects matched pairs design. B mode ultrasound images were taken in the sagittal plane of the patellar tendon at rest with the knee at 90° flexion. Repeat images were taken whilst the subjects were carrying out maximal voluntary isometric contractions. Spatial frequency parameters related to the tendon morphology were determined within regions of interest (ROI) from the B mode images at rest and during isometric contractions. A number of spatial parameters were observed to be significantly different between resting and contracted images (Peak spatial frequency radius (PSFR), axis ratio, spatial Q-factor, PSFR amplitude ratio, and the sum). These spatial frequency parameters were indicative of acute alterations in the tendon micro-morphology with loading. Acute loading modifies the micro-morphology of the tendon, as observed via spatial frequency analysis. Further research is warranted to explore its utility with regard to different loading induced micro-morphological alterations, as these could give valuable insight not only to aid strengthening of this tissue but also optimization of recovery from injury and treatment of conditions such as tendinopathies.
Collapse
Affiliation(s)
- Stephen J Pearson
- Centre of Health, Sport and Rehabilitation Sciences Research, University of Salford, Manchester M6 6PU, United Kingdom.
| | - Aaron J Engel
- Dept. of Biological Systems Engineering, University of Nebraska-Lincoln, USA
| | - Gregory R Bashford
- Dept. of Biological Systems Engineering, University of Nebraska-Lincoln, USA
| |
Collapse
|
|
35
|
Li Q, Bai Y, Jin T, Wang S, Cui W, Stanciulescu I, Yang R, Nie H, Wang L, Zhang X. Bioinspired Engineering of Poly(ethylene glycol) Hydrogels and Natural Protein Fibers for Layered Heart Valve Constructs. ACS APPLIED MATERIALS & INTERFACES 2017; 9:16524-16535. [PMID: 28448124 DOI: 10.1021/acsami.7b03281] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Layered constructs from poly(ethylene glycol) (PEG) hydrogels and chicken eggshell membranes (ESMs) are fabricated, which can be further cross-linked by glutaraldehyde (GA) to form GA-PEG-ESM composites. Our results indicate that ESMs composed of protein fibrous networks show elastic moduli ∼3.3-5.0 MPa and elongation percentages ∼47-56%, close to human heart valve leaflets. Finite element simulations reveal obvious stress concentration on a partial number of fibers in the GA-cross-linked ESM (GA-ESM) samples, which can be alleviated by efficient stress distribution among multiple layers of ESMs embedded in PEG hydrogels. Moreover, the polymeric networks of PEG hydrogels can prevent mineral deposition and enzyme degradation of protein fibers from incorporated ESMs. The fibrous structures of ESMs retain in the GA-PEG-ESM samples after subcutaneous implantation for 4 weeks, while those from ESM and GA-ESM samples show early degradation to certain extent, suggesting the prevention of enzymatic degradation of protein fibers by the polymeric network of PEG hydrogels in vivo. Thus, these GA-PEG-ESM layered constructs show heterogenic structures and mechanical properties comparable to heart valve leaflets, as well as improved functions to prevent progressive calcification and enzymatic degeneration, which are likely used for artificial heart valves.
Collapse
Affiliation(s)
- Qian Li
- Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences , Shenyang, Liaoning 110016, China
- Department of Chemistry, Northeastern University , Shenyang, Liaoning 110004, China
| | - Yun Bai
- Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences , Shenyang, Liaoning 110016, China
| | - Tao Jin
- Department of Civil and Environmental Engineering, Rice University , Houston, Texas 77005, United States
| | - Shuo Wang
- Institute of Bionanotechnology and Tissue Engineering, College of Life Sciences, Hunan University , Changsha, Hunan 410082, China
| | - Wei Cui
- Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences , Shenyang, Liaoning 110016, China
| | - Ilinca Stanciulescu
- Department of Civil and Environmental Engineering, Rice University , Houston, Texas 77005, United States
| | - Rui Yang
- Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences , Shenyang, Liaoning 110016, China
- School of Materials Science, University of Science and Technology of China , Hefei, Anhui 230026, China
| | - Hemin Nie
- Institute of Bionanotechnology and Tissue Engineering, College of Life Sciences, Hunan University , Changsha, Hunan 410082, China
| | - Linshan Wang
- Department of Chemistry, Northeastern University , Shenyang, Liaoning 110004, China
| | - Xing Zhang
- Shenyang National Laboratory for Materials Science, Institute of Metal Research, Chinese Academy of Sciences , Shenyang, Liaoning 110016, China
- School of Materials Science, University of Science and Technology of China , Hefei, Anhui 230026, China
| |
Collapse
|
|
36
|
Jin T, Stanciulescu I. Numerical investigation of the influence of pattern topology on the mechanical behavior of PEGDA hydrogels. Acta Biomater 2017; 49:247-259. [PMID: 27856282 DOI: 10.1016/j.actbio.2016.10.041] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 10/10/2016] [Accepted: 10/27/2016] [Indexed: 12/17/2022]
Abstract
Poly(ethylene glycol) diacrylate (PEGDA) hydrogels can be potentially used as scaffold material for tissue engineered heart valves (TEHVs) due to their good biocompatibility and biomechanical tunability. The photolithographic patterning technique is an effective approach to pattern PEGDA hydrogels to mimic the mechanical behavior of native biological tissues that are intrinsically anisotropic. The material properties of patterned PEGDA hydrogels largely depend on the pattern topology. In this paper, we adopt a newly proposed computational framework for fibrous biomaterials to numerically investigate the influence of pattern topology, including pattern ratio, orientation and waviness, on the mechanical behavior of patterned PEGDA hydrogels. The material parameters for the base hydrogel and the pattern stripes are directly calibrated from published experimental data. Several experimental observations reported in the literature are captured in the simulation, including the nonlinear relationship between pattern ratio and material linear modulus, and the decrease of material anisotropy when pattern ratio increases. We further numerically demonstrate that a three-region (toe-heel-linear) stress-strain relationship typically exhibited by biological tissues can be obtained by tuning the pattern waviness and the relative stiffness between the base hydrogel and pattern stripes. The numerical strategy and simulation results presented here can provide helpful guidance to optimize pattern design of PEGDA hydrogels toward the targeted material mechanical properties, therefore advance the development of TEHVs. STATEMENT OF SIGNIFICANCE Poly(ethylene glycol) diacrylate (PEGDA) hydrogels can be used as scaffold material for tissue engineered heart values (TEHVs) providing a promising alternative to generate suitable heart valve replacement method. The patterning of PEGDA hydrogels using photolithographic techniques creates materials that mimic the mechanical behavior of native heart valve tissues. However, targeted material properties are obtained via a trial-and-error process. Depending on experiments alone to explore the influence of pattern topology is expensive and time-consuming. We combine a newly proposed computational framework with published experimental data to numerically investigate the influence of pattern geometry on the mechanical behavior of patterned PEGDA hydrogels. The numerical strategy and simulation results presented here can provide guidance to optimize the design of PEGDA hydrogels with targeted material properties, therefore advance the development of TEHVs.
Collapse
Affiliation(s)
- Tao Jin
- Department of Civil and Environmental Engineering, Rice University, Houston, TX 77005, USA
| | - Ilinca Stanciulescu
- Department of Civil and Environmental Engineering, Rice University, Houston, TX 77005, USA.
| |
Collapse
|
|
37
|
Masic A, Schuetz R, Bertinetti L, Li C, Siegel S, Metzger H, Wagermaier W, Fratzl P. Multiscale Analysis of Mineralized Collagen Combining X-ray Scattering and Fluorescence with Raman Spectroscopy under Controlled Mechanical, Thermal, and Humidity Environments. ACS Biomater Sci Eng 2017; 3:2853-2859. [DOI: 10.1021/acsbiomaterials.6b00676] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Admir Masic
- Department
of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 02139 Cambridge, United States
| | - Roman Schuetz
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Luca Bertinetti
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Chenghao Li
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Stefan Siegel
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Hartmut Metzger
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Wolfgang Wagermaier
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Peter Fratzl
- Department
of Biomaterials, Max Planck Institute of Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| |
Collapse
|
|
38
|
Internal strain drives spontaneous periodic buckling in collagen and regulates remodeling. Proc Natl Acad Sci U S A 2016; 113:8436-41. [PMID: 27402741 DOI: 10.1073/pnas.1523228113] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Fibrillar collagen, an essential structural component of the extracellular matrix, is remarkably resistant to proteolysis, requiring specialized matrix metalloproteinases (MMPs) to initiate its remodeling. In the context of native fibrils, remodeling is poorly understood; MMPs have limited access to cleavage sites and are inhibited by tension on the fibril. Here, single-molecule recordings of fluorescently labeled MMPs reveal cleavage-vulnerable binding regions arrayed periodically at ∼1-µm intervals along collagen fibrils. Binding regions remain periodic even as they migrate on the fibril, indicating a collective process of thermally activated and self-healing defect formation. An internal strain relief model involving reversible structural rearrangements quantitatively reproduces the observed spatial patterning and fluctuations of defects and provides a mechanism for tension-dependent stabilization of fibrillar collagen. This work identifies internal-strain-driven defects that may have general and widespread regulatory functions in self-assembled biological filaments.
Collapse
|
|
39
|
Urie R, Quraishi S, Jaffe M, Rege K. Gold Nanorod-Collagen Nanocomposites as Photothermal Nanosolders for Laser Welding of Ruptured Porcine Intestines. ACS Biomater Sci Eng 2015; 1:805-815. [DOI: 10.1021/acsbiomaterials.5b00174] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Russell Urie
- Chemical
Engineering, Arizona State University, Tempe, Arizona 85287, United States
| | - Sana Quraishi
- Chemical
Engineering, Arizona State University, Tempe, Arizona 85287, United States
| | - Michael Jaffe
- College
of Veterinary Medicine, Midwestern University, Glendale, Arizona 85308, United States
| | - Kaushal Rege
- Chemical
Engineering, Arizona State University, Tempe, Arizona 85287, United States
| |
Collapse
|
|
40
|
Marino M. Molecular and intermolecular effects in collagen fibril mechanics: a multiscale analytical model compared with atomistic and experimental studies. Biomech Model Mechanobiol 2015. [PMID: 26220454 DOI: 10.1007/s10237-015-0707-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Both atomistic and experimental studies reveal the dependence of collagen fibril mechanics on biochemical and biophysical features such as, for instance, cross-link density, water content and protein sequence. In order to move toward a multiscale structural description of biological tissues, a novel analytical model for collagen fibril mechanics is herein presented. The model is based on a multiscale approach that incorporates and couples: thermal fluctuations in collagen molecules; the uncoiling of collagen triple helix; the stretching of molecular backbone; the straightening of the telopeptide in which covalent cross-links form; slip-pulse mechanisms due to the rupture of intermolecular weak bonds; molecular interstrand delamination due to the rupture of intramolecular weak bonds; the rupture of covalent bonds within molecular strands. The effectiveness of the proposed approach is verified by comparison with available atomistic results and experimental data, highlighting the importance of cross-link density in tuning collagen fibril mechanics. The typical three-region shape and hysteresis behavior of fibril constitutive response, as well as the transition from a yielding-like to a brittle-like behavior, are recovered with a special insight on the underlying nanoscale mechanisms. The model is based on parameters with a clear biophysical and biochemical meaning, resulting in a promising tool for analyzing the effect of pathological or pharmacological-induced histochemical alterations on the functional mechanical response of collagenous tissues.
Collapse
Affiliation(s)
- Michele Marino
- Institute of Continuum Mechanics, Leibniz Universität Hannover, Appelstraße 11, 30167, Hannover, Germany.
| |
Collapse
|
|
41
|
Masic A, Bertinetti L, Schuetz R, Chang SW, Metzger TH, Buehler MJ, Fratzl P. Osmotic pressure induced tensile forces in tendon collagen. Nat Commun 2015; 6:5942. [PMID: 25608644 PMCID: PMC4354200 DOI: 10.1038/ncomms6942] [Citation(s) in RCA: 141] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 11/21/2014] [Indexed: 11/12/2022] Open
Abstract
Water is an important component of collagen in tendons, but its role for the function of this load-carrying protein structure is poorly understood. Here we use a combination of multi-scale experimentation and computation to show that water is an integral part of the collagen molecule, which changes conformation upon water removal. The consequence is a shortening of the molecule that translates into tensile stresses in the range of several to almost 100 MPa, largely surpassing those of about 0.3 MPa generated by contractile muscles. Although a complete drying of collagen would be relevant for technical applications, such as the fabrication of leather or parchment, stresses comparable to muscle contraction already occur at small osmotic pressures common in biological environments. We suggest, therefore, that water-generated tensile stresses may play a role in living collagen-based materials such as tendon or bone.
Collapse
Affiliation(s)
- Admir Masic
- Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Luca Bertinetti
- Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Roman Schuetz
- Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Shu-Wei Chang
- Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, MIT, Cambridge, Massachusetts 02139, USA
| | - Till Hartmut Metzger
- Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| | - Markus J. Buehler
- Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, MIT, Cambridge, Massachusetts 02139, USA
| | - Peter Fratzl
- Department of Biomaterials, Max Planck Institute for Colloids and Interfaces, Research Campus Golm, 14424 Potsdam, Germany
| |
Collapse
|
|
42
|
Bonner TJ, Newell N, Karunaratne A, Pullen AD, Amis AA, M J Bull A, Masouros SD. Strain-rate sensitivity of the lateral collateral ligament of the knee. J Mech Behav Biomed Mater 2014; 41:261-70. [PMID: 25086777 DOI: 10.1016/j.jmbbm.2014.07.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/28/2014] [Accepted: 07/01/2014] [Indexed: 02/04/2023]
Abstract
The material properties of ligaments are not well characterized at rates of deformation that occur during high-speed injuries. The aim of this study was to measure the material properties of lateral collateral ligament of the porcine stifle joint in a uniaxial tension model through strain rates in the range from 0.01 to 100/s. Failure strain, tensile modulus and failure stress were calculated. Across the range of strain rates, tensile modulus increased from 288 to 905 MPa and failure stress increased from 39.9 to 77.3 MPa. The strain-rate sensitivity of the material properties decreased as deformation rates increased, and reached a limit at approximately 1/s, beyond which there was no further significant change. In addition, time resolved microfocus small angle X-ray scattering was used to measure the effective fibril modulus (stress/fibril strain) and fibril to tissue strain ratio. The nanoscale data suggest that the contribution of the collagen fibrils towards the observed tissue-level deformation of ligaments diminishes as the loading rate increases. These findings help to predict the patterns of limb injuries that occur at different speeds and improve computational models used to assess and develop mitigation technology.
Collapse
Affiliation(s)
- Timothy J Bonner
- The Academic Department of Military Surgery and Trauma, The Royal Centre for Defence Medicine, Birmingham B15 2SQ, UK; Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Nicolas Newell
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Angelo Karunaratne
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Andy D Pullen
- Department of Civil and Environmental Engineering, Imperial College London, London SW7 2AZ, UK
| | - Andrew A Amis
- Department of Mechanical Engineering, Imperial College London, London SW7 2AZ, UK; Department of Musculoskeletal Surgery, Imperial College London, London W6 8RF, UK
| | - Anthony M J Bull
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
| | - Spyros D Masouros
- Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
| |
Collapse
|
|
43
|
Massoud EIE. Healing of subcutaneous tendons: Influence of the mechanical environment at the suture line on the healing process. World J Orthop 2013; 4:229-240. [PMID: 24147258 PMCID: PMC3801242 DOI: 10.5312/wjo.v4.i4.229] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Tendon ruptures remain a significant musculoskeletal injury. Despite advances in surgical techniques and procedures, traditional repair techniques maintain a high incidence of rerupture or tendon elongation. Mechanical loading and biochemical signaling both control tissue healing. This has led some researchers to consider using a technique based on tension regulation at the suture line for obtaining good healing. However, it is unknown how they interact and to what extent mechanics control biochemistry. This review will open the way for understanding the interplay between mechanical loading and the process of tendon healing.
Collapse
|
|
44
|
Palko JR, Iwabe S, Pan X, Agarwal G, Komáromy AM, Liu J. Biomechanical properties and correlation with collagen solubility profile in the posterior sclera of canine eyes with an ADAMTS10 mutation. Invest Ophthalmol Vis Sci 2013; 54:2685-95. [PMID: 23518772 DOI: 10.1167/iovs.12-10621] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE We examined the biomechanical properties and correlation with the collagen solubility profile of the posterior sclera in a canine model of primary open-angle glaucoma caused by the G661R missense mutation in the ADAMTS10 gene. METHODS Scleral strips from ADAMTS10-mutant (affected) dogs and age-matched controls were collected. Viscoelastic properties (i.e., complex modulus and tan[δ]) were measured using dynamic mechanical analysis (DMA) with a 0.15% sinusoidal strain at different frequencies superimposed upon different preloads. A tensile ramp was performed following DMA. The collagen solubility profile was examined using a colorimetric hydroxyproline assay to determine the amount of soluble and insoluble collagen. The viscoelastic properties were compared between groups using linear mixed models for repeated measures at different preloads and frequencies. The correlation between the biomechanical properties and collagen content were evaluated using Pearson correlations. RESULTS Complex modulus and tan(δ) were significantly lower in the affected group (P < 0.001), and the differences were consistent at different preloads and frequencies. The B value from the tensile ramp test also was significantly lower in the affected group (P = 0.02). The insoluble collagen was significantly lower in the affected group (P < 0.05) and correlated positively with the complex modulus (R = 0.88, P < 0.005). CONCLUSIONS An inherently weaker and biochemically distinct posterior sclera was observed in dogs with the G661R missense mutation in ADAMTS10 before clinical indications of optic nerve damage. It remains to be shown whether and how the altered scleral biomechanics may affect the rate of glaucoma progression following intraocular pressure elevation.
Collapse
Affiliation(s)
- Joel R Palko
- Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA
| | | | | | | | | | | |
Collapse
|
|
45
|
Amruthwar SS, Puckett AD, Janorkar AV. Preparation and characterization of novel elastin-like polypeptide-collagen composites. J Biomed Mater Res A 2013; 101:2383-91. [DOI: 10.1002/jbm.a.34514] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 10/18/2012] [Accepted: 11/01/2012] [Indexed: 11/09/2022]
|
|
46
|
Rigozzi S, Müller R, Stemmer A, Snedeker J. Tendon glycosaminoglycan proteoglycan sidechains promote collagen fibril sliding—AFM observations at the nanoscale. J Biomech 2013; 46:813-8. [DOI: 10.1016/j.jbiomech.2012.11.017] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/02/2012] [Accepted: 11/03/2012] [Indexed: 10/27/2022]
|
|
47
|
Singhal A, Almer J, Dunand D. Variability in the nanoscale deformation of hydroxyapatite during compressive loading in bovine bone. Acta Biomater 2012; 8:2747-58. [PMID: 22465576 DOI: 10.1016/j.actbio.2012.03.036] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Revised: 03/10/2012] [Accepted: 03/21/2012] [Indexed: 11/27/2022]
Abstract
High-energy synchrotron X-ray diffraction is used to study in situ elastic strains in hydroxyapatite (HAP) for bovine femur cortical bone subjected to uniaxial compressive loading. Load-unload tests at room temperature (27°C) and body temperature (37°C) show that the load transfer to the stiff nanosized HAP platelets from the surrounding compliant protein matrix does not vary significantly (p<0.05) with temperature. This emphasizes that the stiffness of bone is controlled by the stiffness of the HAP phase, which remains unaffected by this change in temperature. Both the extent of hysteresis and the residual value of internal strains developed in HAP during load-unload cycling from 0 to -100 MPa increase significantly (p<0.05) with the number of loading cycles, indicative of strain energy dissipation and accumulation of permanent deformation. Monotonic loading tests, conducted at body temperature to determine the spatial variation of properties within the femur, illustrate that the HAP phase carries lower strain (and thus stresses) at the anterio-medial aspect of the femur than at the anterio-lateral aspect. This is correlated to higher HAP volume fractions in the former location (p<0.05). The Young's modulus of the bone is also found to correlate with the HAP volume fraction and porosity (p<0.05). Finally, samples with a primarily plexiform microstructure are found to be stiffer than those with a primarily Haversian microstructure (p<0.05).
Collapse
|
|
48
|
Veres SP, Lee JM. Designed to fail: a novel mode of collagen fibril disruption and its relevance to tissue toughness. Biophys J 2012; 102:2876-84. [PMID: 22735538 DOI: 10.1016/j.bpj.2012.05.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 04/13/2012] [Accepted: 05/07/2012] [Indexed: 11/16/2022] Open
Abstract
Collagen fibrils are nanostructured biological cables essential to the structural integrity of many of our tissues. Consequently, understanding the structural basis of their robust mechanical properties is of great interest. Here we present what to our knowledge is a novel mode of collagen fibril disruption that provides new insights into both the structure and mechanics of native collagen fibrils. Using enzyme probes for denatured collagen and scanning electron microscopy, we show that mechanically overloading collagen fibrils from bovine tail tendons causes them to undergo a sequential, two-stage, selective molecular failure process. Denatured collagen molecules-meaning molecules with a reduced degree of time-averaged helicity compared to those packed in undamaged fibrils-were first created within kinks that developed at discrete, repeating locations along the length of fibrils. There, collagen denaturation within the kinks was concentrated within certain subfibrils. Additional denatured molecules were then created along the surface of some disrupted fibrils. The heterogeneity of the disruption within fibrils suggests that either mechanical load is not carried equally by a fibril's subcomponents or that the subcomponents do not possess homogenous mechanical properties. Meanwhile, the creation of denatured collagen molecules, which necessarily involves the energy intensive breaking of intramolecular hydrogen bonds, provides a physical basis for the toughness of collagen fibrils.
Collapse
Affiliation(s)
- Samuel P Veres
- School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada.
| | | |
Collapse
|
|
49
|
Chandran PL, Paik DC, Holmes JW. Structural mechanism for alteration of collagen gel mechanics by glutaraldehyde crosslinking. Connect Tissue Res 2012; 53:285-97. [PMID: 22775003 PMCID: PMC3825191 DOI: 10.3109/03008207.2011.640760] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Soft collagenous tissues that are loaded in vivo undergo crosslinking during aging and wound healing. Bioprosthetic tissues implanted in vivo are also commonly crosslinked with glutaraldehyde (GA). While crosslinking changes the mechanical properties of the tissue, the nature of the mechanical changes and the underlying microstructural mechanism are poorly understood. In this study, a combined mechanical, biochemical and simulation approach was employed to identify the microstructural mechanism by which crosslinking alters mechanical properties. The model collagenous tissue used was an anisotropic cell-compacted collagen gel, and the model crosslinking agent was monomeric GA. The collagen gels were incrementally crosslinked by either increasing the GA concentration or increasing the crosslinking time. In biaxial loading experiments, increased crosslinking produced (1) decreased strain response to a small equibiaxial preload, with little change in response to subsequent loading and (2) decreased coupling between the fiber and cross-fiber direction. The mechanical trend was found to be better described by the lysine consumption data than by the shrinkage temperature. The biaxial loading of incrementally crosslinked collagen gels was simulated computationally with a previously published network model. Crosslinking was represented by increased fibril stiffness or by increased resistance to fibril rotation. Only the latter produced mechanical trends similar to that observed experimentally. Representing crosslinking as increased fibril stiffness did not reproduce the decreased coupling between the fiber and cross-fiber directions. The study concludes that the mechanical changes in crosslinked collagen gels are caused by the microstructural mechanism of increased resistance to fibril rotation.
Collapse
Affiliation(s)
| | - David C. Paik
- Department of Ophthalmology, Columbia University, NY
| | - Jeffrey W. Holmes
- Departments of Biomedical Engineering and Medicine, University of Virginia, Charlottesville, VA
| |
Collapse
|
|
50
|
Yang L, van der Werf KO, Dijkstra PJ, Feijen J, Bennink ML. Micromechanical analysis of native and cross-linked collagen type I fibrils supports the existence of microfibrils. J Mech Behav Biomed Mater 2011; 6:148-58. [PMID: 22301184 DOI: 10.1016/j.jmbbm.2011.11.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 11/10/2011] [Accepted: 11/16/2011] [Indexed: 01/28/2023]
Abstract
The mechanical properties of individual collagen fibrils of approximately 200 nm in diameter were determined using a slightly adapted AFM system. Single collagen fibrils immersed in PBS buffer were attached between an AFM cantilever and a glass surface to perform tensile tests at different strain rates and stress relaxation measurements. The stress-strain behavior of collagen fibrils immersed in PBS buffer comprises a toe region up to a stress of 5 MPa, followed by the heel and linear region at higher stresses. Hysteresis and strain-rate dependent stress-strain behavior of collagen fibrils were observed, which suggest that single collagen fibrils have viscoelastic properties. The stress relaxation process of individual collagen fibrils could be best fitted using a two-term Prony series. Furthermore, the influence of different cross-linking agents on the mechanical properties of single collagen fibrils was investigated. Based on these results, we propose that sliding of microfibrils with respect to each other plays a role in the viscoelastic behavior of collagen fibrils in addition to the sliding of collagen molecules with respect to each other. Our finding provides a better insight into the relationship between the structure and mechanical properties of collagen and the micro-mechanical behavior of tissues.
Collapse
Affiliation(s)
- L Yang
- Polymer Chemistry and Biomaterials, Faculty of Science & Technology and Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands
| | | | | | | | | |
Collapse
|