Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation

Abstract

Mechanical cues are known to regulate tissue differentiation during skeletal healing. Quantitative characterization of this mechano-regulatory effect has great therapeutic potential. This study tested an existing theory that shear strain and interstitial fluid flow govern skeletal tissue differentiation by applying this theory to a scenario in which a bending motion applied to a healing transverse osteotomy results in cartilage, rather than bone, formation. A 3-D finite element mesh was created from micro-computed tomography images of a bending-stimulated callus and was used to estimate the mechanical conditions present in the callus during the mechanical stimulation. Predictions regarding the patterns of tissues-cartilage, fibrous tissue, and bone-that formed were made based on the distributions of fluid velocity and octahedral shear strain. These predictions were compared to histological sections obtained from a previous study. The mechano-regulation theory correctly predicted formation of large volumes of cartilage within the osteotomy gap and many, though not all patterns of tissue formation observed throughout the callus. The results support the concept that interstitial fluid velocity and tissue shear strain are key mechanical stimuli for the differentiation of skeletal tissues.

Mechano-regulation of mesenchymal stem cell differentiation and collagen organisation during skeletal tissue repair

“…The model predictions of tissue differentiation for the non-union of a fracture subject to cyclic bending loads can be compared to histological data from developing neoarthroses (Cullinane et al, 2002). The mechanoregulation algorithm predicted a mixture of cartilaginous and fibrous tissue, generally consistent with experimental findings and previous computational models (Cullinane et al, 2002(Cullinane et al, , 2003Hayward and Morgan, 2009). However we did not predict the bony arcade structures reported by Cullinane et al (2002).…”

“…These neoarthroses exhibited preferred fibre angles consistent with those seen in articular cartilage. Hayward and Morgan (2009) further demonstrated that the patterns of tissue differentiation observed experimentally could be predicted using the mechano-regulation theory of Prendergast et al (1997), providing further evidence to suggest that both strain and fluid flow are key regulators of tissue differentiation. What remains to be elucidated is the exact relationship between the mechanical environment and the molecular organisation of extracellular matrix at the repair site during skeletal tissue differentiation.…”

“…3). A plane strain finite element model was used to simulate ± 6 • bending for 24 days, the time period of loading investigated by Hayward and Morgan (2009). Fibre angles were measured in Cullinane et al (2003) where "The superficial zone was determined as the area immediately under the cartilage surface, the deep zone was the area immediately adjacent to the underlying bone, and the intermediate zone was exactly half way between the deep and superficial zones".…”

Interstitial fluid flow: simulation of mechanical environment of cells in the interosseous membrane

“…For example, Ng. et al [14] found that collagen aligned perpendicular to subtle flow, Vera et al [15] found that fluid flow would constitute a beneficial environment for endothelial cells' reproduction, Hayward et al [16] found that interstitial fluid velocity and tissue shear stress are key mechanical stimuli for the differentiation of skeletal tissues. Until recently, the distribution of capillaries in humans was assumed to be a uniform network which has no orientation and no specificity.…”

Tissue differentiation in an in vivo bioreactor: in silico investigations of scaffold stiffness

“…By characterising the skeletal tissues as biphasic materials, Prendergast et al [7] proposed that a biophysical stimulus (a combination of fluid flow and shear strain) regulated tissue formation. Although the mechanoregulation theories of Carter et al [5], Claes and Heigele [6], and Prendergast et al [7] have been able to capture the main aspects of tissue differentiation, the predictions by the theory of Prendergast et al [7] have been most successfully correlated with experimental results [8][9][10][11]. Another key factor that regulates tissue differentiation is the formation of blood vessels.…”