The instrumented sheep knee to elucidate insights into osteoarthritis development and progression: A sensitive and reproducible platform for integrated research efforts

Abstract

Background: Osteoarthritis of the knee is a very common condition that has been difficult to treat. The majority of cases are considered idiopathic. Much research effort remains focused on biology rather than the biomechanics of such joints. Some new methods were developed and validated to better appreciate the subtleties of the biomechanical integrity of joints, and how changes in biomechanics can contribute to osteoarthritis. Methods: Over the past 15 years our lab has enhanced the sensitivity of the assessment of knee biomechanics of an instrumented, trained large animal model (sheep) of osteoarthritis and integrated the findings with biological and histological assessments. These new methods include gait analysis before and after injury followed by robotic validation post-sacrifice, and more recently using Fibre Bragg Grating sensors to detect alterations in cartilage stresses. Results: A review of the findings obtained with this model are presented. The findings indicate that sheep, like humans, exhibit individual characteristics. They also indicate that joint kinetics, rather than kinematics may better define the alterations induced by injury. With the addition of Fibre Bragg Grating sensors, it has been possible to measure with good accuracy, alterations to cartilage stresses following a controlled knee injury. Interpretation: Using this model as Proof of Concept, this sheep system can now be viewed as a sensitive platform to address many questions related to risk for development of idiopathic osteoarthritis of the human knee, the efficacy of potential interventions to correct biomechanical disruptions, and how joint biomechanics and biology are integrated during aging.

Osteoarthritis as an Umbrella Term for Different Subsets of Humans Undergoing Joint Degeneration: The Need to Address the Differences to Develop Effective Conservative Treatments and Prevention Strategies

“…While post-traumatic osteoarthritis constitutes ~12% of human knee OA patients [ 11 , 28 ], the vast majority of preclinical research is performed with PTOA models and most is performed with small animal models such as mice [ 29 , 30 ] which yield scientifically interesting results (mainly biological) but based on the low rate of progress, little clinical relevance. Some research has been performed with larger preclinical models such as sheep [ 31 ] or pigs or others [ 32 , 33 ], which has provided some more interesting mechanical outputs but again has primarily used post-traumatic OA approaches. In spite of this limitation, the use of large animal models has reinforced the fact that patient heterogeneity is a critical issue that needs to be faced, particularly in the design of clinical trials.…”

Perspective: Challenges Presented for Regeneration of Heterogeneous Musculoskeletal Tissues that Normally Develop in Unique Biomechanical Environments

“…Finally, while not a challenge per se, choosing an appropriate preclinical model is also of critical importance going forward to optimize tissue engineering approaches for regeneration of connective tissues of the MSK system, particularly those of joints such as the knee where the engineered construct would function in a complex mechanical and biological environment. This would be facilitated by having a preclinical model where biology (histology and molecular biology) and biomechanics can be assessed, as well as imaging for longitudinal studies (Hart et al, 2021). Thus, models such as pigs (Ando et al, 2007;Shimomura et al, 2010;Sieker et al, 2016) or sheep (Hart et al, 2021;Brzezinski et al, 2017) should be considered rather than smaller models that are more constrained regarding assessment potential.…”

“…This would be facilitated by having a preclinical model where biology (histology and molecular biology) and biomechanics can be assessed, as well as imaging for longitudinal studies (Hart et al, 2021). Thus, models such as pigs (Ando et al, 2007;Shimomura et al, 2010;Sieker et al, 2016) or sheep (Hart et al, 2021;Brzezinski et al, 2017) should be considered rather than smaller models that are more constrained regarding assessment potential.…”

Simulated Tibiofemoral Joint Reaction Forces for Three Previously Studied Gait Modifications in Healthy Controls

“…With the advancement in computing power computational models are becoming a common approach to directly estimate JRFs in the knee during gait [41][42][43][44][45][46][47][48]. While it is impractical to measure JRFs in-vivo [49], computational models are capable of estimating internal forces during functional movements (i.e. walking, running, crouch gait) [45,46,[50][51][52][53][54].…”