title: High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis.
abstract: Murine models of osteoarthritis (OA) and post-traumatic OA have been widely used to study the development and progression of these diseases using genetically engineered mouse strains along with surgical or biochemical interventions. However, due to the small size and thickness of murine cartilage, the relationship between mechanical properties, molecular structure and cartilage composition has not been well studied. We adapted a recently developed AFM-based nano-rheology system to probe the dynamic nanomechanical properties of murine cartilage over a wide frequency range of 1 Hz to 10 kHz, and studied the role of glycosaminoglycan (GAG) on the dynamic modulus and poroelastic properties of murine femoral cartilage. We showed that poroelastic properties, highlighting fluid-solid interactions, are more sensitive indicators of loss of mechanical function compared to equilibrium properties in which fluid flow is negligible. These fluid-flow-dependent properties include the hydraulic permeability (an indicator of the resistance of matrix to fluid flow) and the high frequency modulus, obtained at high rates of loading relevant to jumping and impact injury in vivo. Utilizing a fibril-reinforced finite element model, we estimated the poroelastic properties of mouse cartilage over a wide range of loading rates for the first time, and show that the hydraulic permeability increased by a factor ~16 from knormal=7.80×10(-16)±1.3×10(-16) m(4)/N s to kGAG-depleted=1.26×10(-14)±6.73×10(-15) m(4)/N s after GAG depletion. The high-frequency modulus, which is related to fluid pressurization and the fibrillar network, decreased significantly after GAG depletion. In contrast, the equilibrium modulus, which is fluid-flow independent, did not show a statistically significant alteration following GAG depletion.
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Hadi T
authors.initials: HT
authors.lastname: Nia
authors.affiliation: University of Melbourne, Department of Paediatrics & Murdoch Children's Research Institute, Royal Childrens Hospital, Parkville, VIC, Australia.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Gauci
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Azadi
authors.affiliation: Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Han-Hwa
authors.initials: HH
authors.lastname: Hung
authors.affiliation: Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Eliot
authors.initials: E
authors.lastname: Frank
authors.affiliation: University of Melbourne, Department of Paediatrics & Murdoch Children's Research Institute, Royal Childrens Hospital, Parkville, VIC, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fosang
authors.affiliation: Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Ortiz
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States; Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, United States. Electronic address: alg@mit.edu.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Grodzinsky
mesh_terms: D053674:Aggrecans / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002356:Cartilage / Q000502:physiology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005269:Femur; D006025:Glycosaminoglycans / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D018625:Microscopy, Atomic Force; D010003:Osteoarthritis; D010539:Permeability; D012212:Rheology / Q000379:methods*
chemical_list: D053674:Aggrecans; D006025:Glycosaminoglycans
keywords: Aggrecan; Atomic force microscopy; Cartilage; Mouse model; Nanomechanics; Osteoarthritis