Unravelling the Role of Mechanical Stimuli in Regulating Cell Fate During Osteochondral Defect Repair

Abstract

In a previous study, we developed a computational mechanobiological model to explore the role of substrate stiffness and local oxygen availability in regulating cell fate during spontaneous osteochondral defect repair. While this model successfully simulated many aspects of the regenerative process, it was unable to predict the spatial pattern of bone formation observed during the latter stages of the repair process. The objective of this study was, therefore, to investigate the role of tissue strain in regulating the spatial and temporal patterns of stem cell differentiation during spontaneous osteochondral defect repair.Motivated by the findings of a number of prior in vitro studies, our computational mechanobiological model was updated to include rules based on the hypothesis that chondrocyte hypertrophy and endochondral ossification were inhibited in regions of high strain. The model also considered the hypothesis that excessively high magnitudes of local strain result in the formation of mechanically inferior fibrocartilage. These rules were first developed by attempting to simulate stem cell differentiation within an in vitro bioreactor system which was capable of controlling the levels of oxygen and mechanical cues within MSC-laden hydrogels. The updated model was able to predict the experimentally observed behaviour whereby the groups which were subjected to dynamic compression presented a reduction in chondrocyte hypertrophy and calcific deposition. Following this, the updated model was then used to simulate the pattern of tissue formation which had been experimentally observed during spontaneous osteochondral defect repair. As well as correctly predicting the spatial pattern of bone formation, the updated model also provided insights into the role that the mechanical environment plays on the spontaneous repair process; namely, that oxygen regulates endochondral ossification during the early phases of repair, while, during the latter stages, mechanics plays a key role in directing this process.

The Functional Response of Mesenchymal Stem Cells to Electron‐Beam Patterned Elastomeric Surfaces Presenting Micrometer to Nanoscale Heterogeneous Rigidity

“…[47] We suggest that this localized contractile unit is a prime candidate for this role and our results set the size scale for this unit. Direct mechanical cues have been shown to play a significant role in regulating Osteochondral differentiation [48] and it was interesting to note that substrates possessing heterogeneous rigidity with spot rigidities > 50 MPa were able to increase focal adhesion co-localization and initiate the activation of differential functional pathways in hMSCs following only 12h of culture relative to cells cultured in oseospecific or chondrospecific induction media. In this study, it was noted that heterogeneous rigidity induced significant activation of defined pathways involved in the processes of chondrogenic, osteogenic and angiogenic function relative to cells cultured in osteochondrogenic conditions on homogenous substrates.…”

Mechanical Stress Inhibits Early Stages of Endogenous Cell Migration: A Pilot Study in an Ex Vivo Osteochondral Model

“…The interface layer (S2) showed the highest cell invasion in unloaded control constructs in comparison to the adjacent layers, suggesting a new potential pattern of migration in the osteochondral unit where either cells present in the subchondral bone or in the calcified cartilage highly participate in defect restoration [ 49 , 50 , 51 ]. Previous models of cell recruitment in osteochondral defects mainly studied the migration of chondrocytes and subchondral bone derived cells, whereby the latter may include osteoblasts, osteoclasts, MSCs or even hematopoietic stem cells [ 52 , 53 ]. It is generally accepted that stem cells have the highest migration and proliferation rate, osteoblasts are assigned an intermediate rate, while chondrocytes undergo little migration or proliferation [ 53 ].…”

Regeneration of Osteochondral Defects Using Developmentally Inspired Cartilaginous Templates

“…A previously developed computational model was used to predict BMSC differentiation and tissue development in the empty and treated defect (47,(54)(55)(56). This model utilised an iterative procedure which is outlined in greater detail in a previous study (56).…”

“…undergo spatially defined differentiation in vivo in response to the unique environmental conditions within an OC defect, resulting in the development of a repair tissue consisting of hyaline articular cartilage overlying a layer of bone formed via endochondral ossification. A computational mechanobiological model was then employed to elucidate the environmental and mechanicalconditions in vivo to provide further insight into the factors regulating the repair tissue phenotype(47,48).…”