Homo sapiens May Incorporate Daily Acute Cycles of "Conditioning-Deconditioning" to Maintain Musculoskeletal Integrity: Need to Integrate with Biological Clocks and Circadian Rhythm Mediators.

Human evolution required adaptation to the boundary conditions of Earth, including 1 g gravity. The bipedal mobility of Homo sapiens in that gravitational field causes ground reaction force (GRF) loading of their lower extremities, influencing the integrity of the tissues of those extremities. However, humans usually experience such loading during the day and then a period of relative unloading at night. Many studies have indicated that loading of tissues and cells of the musculoskeletal (MSK) system can inhibit their responses to biological mediators such as cytokines and growth factors. Such findings raise the possibility that humans use such cycles of acute conditioning and deconditioning of the cells and tissues of the MSK system to elaborate critical mediators and responsiveness in parallel with these cycles, particularly involving GRF loading. However, humans also experience circadian rhythms with the levels of a number of mediators influenced by day/night cycles, as well as various levels of biological clocks. Thus, if responsiveness to MSK-generated mediators also occurs during the unloaded part of the daily cycle, that response must be integrated with circadian variations as well. Furthermore, it is also possible that responsiveness to circadian rhythm mediators may be regulated by MSK tissue loading. This review will examine evidence for the above scenario and postulate how interactions could be both regulated and studied, and how extension of the acute cycles biased towards deconditioning could lead to loss of tissue integrity.

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

Perspective: Musculoskeletal (MSK) tissues such as articular cartilage, menisci, tendons, and ligaments are often injured throughout life as a consequence of accidents. Joints can also become compromised due to the presence of inflammatory diseases such as rheumatoid arthritis. Thus, there is a need to develop regenerative approaches to address such injuries to heterogeneous tissues and ones that occur in heterogeneous environments. Such injuries can compromise both the biomechanical integrity and functional capability of these tissues. Thus, there are several challenges to overcome in order to enhance success of efforts to repair and regenerate damaged MSK tissues. Challenges: 1. MSK tissues arise during development in very different biological and biomechanical environments. These early tissues serve as a template to address the biomechanical requirements evolving during growth and maturation towards skeletal maturity. Many of these tissues are heterogeneous and have transition points in their matrix. The heterogeneity of environments thus presents a challenge to replicate with regard to both the cells and the ECM. 2. Growth and maturation of musculoskeletal tissues occurs in the presence of anabolic mediators such as growth hormone and the IGF-1 family of proteins which decline with age and are low when there is a greater need for the repair and regeneration of injured or damaged tissues with advancing age. Thus, there is the challenge of re-creating an anabolic environment to enhance incorporation of implanted constructs. 3. The environments associated with injury or chronic degeneration of tissues are often catabolic or inflammatory. Thus, there is the challenge of creating a more favorable in vivo environment to facilitate the successful implantation of in vitro engineered constructs to regenerate damaged tissues. Conclusions: The goal of regenerating MSK tissues has to be to meet not only the biological requirements (components and structure) but also the heterogeneity of function (biomechanics) in vivo. Furthermore, for many of these tissues, the regenerative approach has to overcome the site of injury being influenced by catabolism/inflammation. Attempts to date using both endogenous cells, exogenous cells and scaffolds of various types have been limited in achieving long term outcomes, but progress is being made.

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

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.

Structural Consequences of a Partial Anterior Cruciate Ligament Injury on Remaining Joint Integrity: Evidence for Ligament and Bone Changes Over Time in an Ovine Model.

BACKGROUND: Severe injury to the knee joint often results in accelerated posttraumatic osteoarthritis (PTOA). In an ovine knee injury model, altered kinematics and degradation of the cartilage have been observed at 20 and 40 weeks after partial anterior cruciate ligament (ACL) transection (p-ACL Tx) surgery. However, changes to the integrity of the remaining intact intra-articular ligaments (posterolateral [PL] band and posterior cruciate ligament [PCL]) as well as the subchondral bone after anteromedial (AM) band Tx remain to be characterized. PURPOSE: (1) To investigate histological alterations to the remaining intact intra-articular ligaments, the synovium, and the infrapatellar fat pad (IPFP) and (2) to quantify subchondral bone changes at the contact surfaces of the proximal tibia at 20 and 40 weeks after AM band Tx. STUDY DESIGN: Descriptive laboratory study. METHODS: Mature female Suffolk cross sheep were allocated into 3 groups: nonoperative controls (n = 6), 20 weeks after partial ACL transection (p-ACL Tx; n = 5), and 40 weeks after p-ACL Tx (n = 6). Ligament, synovium, and IPFP sections were stained and graded. Tibial subchondral bone microarchitecture was assessed using high-resolution peripheral quantitative computed tomography. RESULTS: p-ACL Tx of the AM band led to significant change in histological scores of the PL band and the PCL at 20 weeks after p-ACL Tx (P = .031 and P = .033, respectively) and 40 weeks after p-ACL Tx (P = .011 and P = .029) as compared with nonoperative controls. Alterations in inflammatory cells and collagen fiber orientation contributed to the greatest extent of the combined histological score in the PL band and PCL. p-ACL Tx did not lead to chronic activation of the synovium or IPFP. Trabecular bone mineral density was strongly inversely correlated with combined gross morphological damage in the top and middle layers of the subchondral bone in the lateral tibial plateau for animals at 40 weeks after p-ACL Tx. CONCLUSION: p-ACL Tx influences the integrity (biology and structure) of remaining intact intra-articular ligaments and bone microarchitecture in a partial knee injury ovine model. CLINICAL RELEVANCE: p-ACL Tx leads to alterations in structural integrity of the remaining intact ligaments and degenerative changes in the trabecular bone mineral density, which may be detrimental to the injured athlete's knee joint in the long term.

Mapping Stresses on the Tibial Plateau Cartilage in an Ovine Model Using In-Vivo Gait Kinematics.

Understanding stresses within the knee joint is central to understanding knee function, and the etiology and progression of degenerative joint diseases such as post-traumatic osteoarthritis. In this study, in vivo gait kinematics of four ovine subjects were recorded using a highly accurate Instrumented Spatial Linkage (ISL) as each subject walked on a standard treadmill. The subjects were then sacrificed, and the right hind limbs removed. Ten purpose-built Fibre Bragg Grating (FBG) sensors were positioned within each stifle joint and used to measured contact stresses on the articulating surface of the tibial plateau as the recorded gait was replicated using a 6-degrees-of-freedom parallel robotic system. This study provides the first accurate, direct measurement of stress in a joint during in vivo gait replication. It was hypothesized that the results would indicate a direct link between gait kinematics and measured stress values. Contrary to this expectation no direct link was found between individualistic differences in kinematics and differences in stress magnitudes. This finding highlights the complex multifactorial nature of stress magnitudes and distribution patterns across articular joints. The results also indicate that stress magnitudes within the knee joint are highly position dependent with magnitudes varying substantially between points only a few mm apart.

Measuring the Internal Stress in Ovine Meniscus During Simulated In Vivo Gait Kinematics: A Novel Method Using Fibre Optic Technology.

Changes in stress transferred across articular joints have been described as a substantial factor in the initiation and progression of joint disease such as post-traumatic osteoarthritis and have thus been of interest to biomechanical researchers. However, to date, stress magnitudes within the menisci have not been successfully measured. In this study, a novel method for measuring stress within the menisci is presented. Small Fibre Bragg Grating (FBG) sensors were inserted inside menisci and used to measure mechanical stress during replicated gait cycles. In-vitro stress measurements within the menisci were preformed for healthy gait and gait following surgical damage to the joints. Together with our capability to reproduce in vivo motions accurately, the improvements in fibre optic technology have allowed for the first direct measurement of mechanical stress in menisci.

Methylprednisolone acetate mitigates IL1ß induced changes in matrix metalloproteinase gene expression in skeletally immature ovine explant knee tissues.

OBJECTIVE AND DESIGN: This study aimed at evaluating the effect of methylprednisolone (MPA) on messenger ribonucleic acid (mRNA) expression levels in immature ovine knee joint tissue explants following interleukin (IL)1ß induction and to assess responsiveness of the explants. MATERIAL OR SUBJECTS: Explants were harvested from the articular cartilage, synovium, and infrapatellar fat pad (IPFP) from immature female sheep. TREATMENT: Methylprednisolone. METHODS: The samples were allocated into six groups: (1) control, (2) MPA (10-3 M), (3) MPA (10-4 M), (4) IL1ß, (5) IL1ß + 10-3 M MPA, or (6) IL1ß + 10-4 M MPA. mRNA expression levels for molecules relevant to inflammation, cartilage degradation/anabolism, activation of innate immunity, and adipose tissue/hormones were quantified. Fold changes with MPA treatment were compared via the comparative CT method. RESULTS: Methylprednisolone treatment significantly suppressed MMPs consistently across the cartilage (MMP1, MMP3, and MMP13), synovium (MMP1 and MMP3), and IPFP (MMP13) (all p < 0.05). Other genes that were less consistently suppressed include endogenous IL1ß (cartilage) and IL6 (IPFP) (all p < 0.05), and others not affected either by IL-1 exposure or subsequent MPA include TGFß1, TLR4, and adipose-related molecules. CONCLUSIONS: Methylprednisolone significantly mitigated IL1ß induced mRNA expression for MMPs in the immature cartilage, synovium, and IPFP, but the extent of the responsiveness was tissue-, location-, and gene-specific.

Stress Measurements on the Articular Cartilage Surface Using Fiber Optic Technology and In-Vivo Gait Kinematics.

It has been hypothesized a change in stress on the cartilage of a joint is a significant factor in the initiation and progression of post-traumatic osteoarthritis. Without a reliable method for measuring stress, this hypothesis has largely gone untested. In this study, a novel, repeatable, and reliable method for measuring stress on the surface of articular cartilage in articular joints is presented. Small Fiber Bragg Grating (FBG) sensors capable of measuring normal stress between contact surfaces in diarthrodial joints were developed and validated. The small size of these sensors (diameter of 125-300 µm and sensing length of 1 mm) allows them to be inserted into the joint space without the removal of biomechanically relevant structures. In-vitro stresses on the surface of the cartilage for both healthy and surgically damaged joints were measured after implantation of the FBG sensors using in vivo generated gait kinematic data and a 6-degrees of freedom parallel robot. Along with our capability to reproduce in vivo motions accurately and the improvements in fiber optic technology, this study describes the first direct measurement of stress in a joint using in vivo gait kinematics.

Relative Surface Velocity of the Tibiofemoral Joint and Its Relation to the Development of Osteoarthritis After Joint Injury.

The relative velocity of the tibiofemoral surfaces during gait before and after partial-ACL and full MCL transection (p-ACL/MCL Tx) was examined in an ovine model (N = 5) and the relation between the variation in the relative sliding velocity component and gross morphological damage was investigated. We defined the in vivo kinematics of the tibiofemoral joints by using an instrumented spatial linkage and then determining the relative velocity components on the reconstructed femoral condyle surfaces. One major finding was that the magnitude of the relative velocity components was relatively high during the initial stance period of the gait and oscillated with a decaying envelope. Interestingly, for most subjects, the highest value of relative sliding velocity occurred during the stance phase, and not swing. The magnitude of the relative velocity components was increased in 3/5 subjects during stance after an injury. For the lateral compartment, there was a significant correlation (p value = 0.005) between the joint gross morphological damage and the increase in the maximum relative sliding velocity during stance. For the medial compartment, there was a trend (p value < 0.1) between the joint gross morphological score and the increase in the maximum relative sliding velocity during stance, 20 weeks after injury. In conclusion, a connection between an increase in the relative surface velocity and gross morphological damage might be due to an increase in the normal stress and the plowing friction between the surfaces.

Correlation of damage score in PTOA with changes in stress on cartilage in an ovine model.

Objective: There is a high risk of developing osteoarthritis (OA) following traumatic injury to the knee. Severe ligament injuries can disrupt the integrity of the multicomponent knee at both biological and biomechanical levels. We hypothesize changes in cartilages stresses could lead to tissue damage and development of OA. Design: The in-vivo gait kinematics of the stifle (knee) joint of four adult female ovine subjects were recorded prior to and at ten-and-twenty weeks following partial ACL-MCL transection. The subjects were sacrificed and the experimental joint from each subject was mounted on a parallel robotic system programmed with the kinematic findings. Ten custom-built Fibre Bragg Grating optic sensors were arranged to measure contact stresses on the surface of the tibial plateau articular cartilage. These sensors provide the first accurate stress measurements in a joint during gait replication using the previously recorded in-vivo kinematics. The relationship between the results obtained and observed focal damage was assessed. Results: The locations on the tibial plateaus that experienced the greatest change in contact stresses corresponded with the locations of focal damage development. No direct link was detected between individual animal differences in kinematics and variations in stress magnitudes or the development of focal cartilage damage. Conclusions: The findings highlight the importance of mechanical stress determinants in the integrated set point for the knee (with individual variation), and how injury-related stress changes correlate with development of PTOA.

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra-Articular Dexamethasone Treatment.

Anterior cruciate ligament reconstructive surgery can restore biomechanical stability, however, such surgery cannot reliably prevent the onset of post-traumatic osteoarthritis. The aim of this study was to elucidate the molecular response that occurs within the menisci following a surgical injury that allows bleeding into the joint space, and then to investigate the effect of dexamethasone (DEX) on this molecular response. Cell viability studies following acute controlled exposure to blood and blood plus DEX were also conducted. Forty-eight New Zealand white rabbits were randomly allocated into control, sham, surgical, and surgical + DEX groups (each group n = 6). Animals were sacrificed at 48 h and 9 weeks, and menisci were harvested. The messenger RNA (mRNA) expression levels for key inflammatory, and degradative proteins, as well as mRNA levels for autophagy pathway molecules were quantified, and statistically significant changes were described. Meniscal cell viability was calculated by incubating groups of medial and lateral menisci in autologous blood, or autologous blood plus DEX for 48 h (each group n = 4; total of eight medial and eight lateral menisci), and then conducting a histological live/dead assay. Results indicated a significant reduction in only medial meniscal cell viability when the tissue was exposed to blood in combination with DEX. A single administration of DEX following surgery significantly suppresses the elevated molecular expression for key inflammatory and degradative markers within menisci at 48 h and 9 weeks post-surgery. In vitro, autologous blood did not affect cell viability, but addition of DEX uniquely impacted the medial menisci. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2043-2052, 2019.

Three-dimensional in vivo kinematics and finite helical axis variables of the ovine stifle joint following partial anterior cruciate ligament transection.

Partial anterior cruciate ligament (p-ACL) rupture is a common injury, but the impact of a p-ACL injury on in vivo joint kinematics has yet to be determined in an animal model. The in vivo kinematics of the ovine stifle joint were assessed during 'normal' gait, and at 20 and 40 weeks after p-ACL transection (Tx). Gross morphological scoring of the knee was conducted. p-ACL Tx creates significant progressive post-traumatic osteoarthritis (PTOA)-like damage by 40 weeks. Statistically significant increases for flexion angles at hoof-strike (HS) and mid-stance (MST) were seen at 20 weeks post p-ACL Tx and the HS and hoof-off (HO) points at 40 weeks post p-ACL-Tx, therefore increased flexion angles occurred during stance phase. Statistically significant increases in posterior tibial shift at the mid-flexion (MF) and mid-extension (ME) points were seen during the swing phase of the gait cycle at 40 weeks post p-ACL Tx. Correlation analysis showed a strong and significant correlation between kinematic changes (instabilities) and gross morphological score in the inferior-superior direction at 40 weeks post p-ACL Tx at MST, HO, and MF. Further, there was a significant correlation between change in gross morphological combined score (ΔGCS) and the change in location of the helical axis in the anterior direction (ΔsAP) after p-ACL Tx for all points analyzed through the gait cycle. This study quantified in vivo joint kinematics before and after p-ACL Tx knee injury during gait, and demonstrated that a p-ACL knee injury leads to both PTOA-like damage and kinematic changes.

Alterations in Joint Angular Velocity Following Traumatic Knee Injury in Ovine Models.

Little effort has been directed towards the consequence of an injury on joint angular velocity. We hypothesized that the magnitude of knee joint angular velocity would be decreased after injury. Four injury groups were investigated in an ovine model: (1) anterior cruciate ligament (ACL) and medial collateral ligament (MCL) transection (ACL/MCL Tx) (n = 5), (2) lateral meniscectomy (Mx) (n = 5), (3) partial ACL transection (p-ACL Tx) (n = 5), and (4) partial-ACL and MCL transection (p-ACL/MCL Tx) (n = 5). The magnitude of the angular velocities decreased in the subjects of all groups at multiple points of the gait cycle. The maximum angular velocities during stance and the maximum extension angular velocities during swing were decreased in 15/20 and 17/20 subjects, respectively. There were strong correlations between morphological osteoarthritis scores and the reduction in the maximum extension angular velocities during swing 40 weeks post-p-ACL Tx and 20 weeks post-ACL/MCL Tx. There was no correlation between the decrease of the angular velocity and morphological osteoarthritis scores in the Mx group and the p-ACL/MCL Tx group. The reduction in angular velocity may be a helpful addition as a surrogate measure of OA risk after ACL injury, and could have clinical significance after further investigation in humans.

Alternative Approaches to the Assessment of the Systemic Circulation and Left Ventricular Performance: A Proof-of-Concept Study.

BACKGROUND: The purpose of this article is to examine the systemic circulation and left ventricular (LV) performance by alternative, nonconventional approaches: systemic vascular conductance (G SV ) and the head-capacity relation (ie, the relation between LV pressure and cardiac output), respectively; in so doing, we aspired to present a novel and improved interpretation of integrated cardiovascular function. METHODS: In 16 open-chest, anaesthetized pigs, we measured LV pressure (P LV ), central aortic pressure (P Ao ), and central venous pressure (P CV ) and aortic flow (Q Ao ). We calculated heart rate (HR), stroke volume, cardiac index (CI = cardiac output/body weight), mean PLV ( P ¯ LV ) , and the average arteriovenous pressure difference ( Δ P = P ¯ Ao - P ¯ CV ); G SV  = CI/( P ¯ Ao - P ¯ CV ). We studied the effects of changing loading conditions with the administration of phenylephrine (Δ P ¯ Ao ≥ +25 mm Hg), isoproterenol (ΔHR ∼+25%), sodium nitroprusside (Δ P ¯ Ao ≥ -25 mm Hg), and proximal aortic constriction (to maximize developed P LV and minimize Q Ao ). RESULTS: Sodium nitroprusside and isoproterenol increased G SV compared with phenylephrine and constriction. A maximum head-capacity curve was derived from pooled data using nonlinear regression on the maximum P ¯ LV values in Q Ao bins 12.5 mL/min/kg wide. The head-capacity relation and the plots of conductance were combined using CI as a common axis, which illustrated that CI is the output of the heart and the input of the circulation. CONCLUSIONS: Thus, at a given CI, G SV determines the driving pressure and, thereby, P Ao . We also demonstrated how decreases in G SV compensate for arterial hypotension by restoring the arteriovenous pressure difference and arterial pressure.

CONTEXTE: Le présent article examine l'efficacité de la circulation générale et la fonction ventriculaire gauche à l'aide de paramètres de rechange non conventionnels, soit la conductance vasculaire systémique (G VS ) pour l'une et la relation pression-volume (c.-à-d. la relation entre la pression ventriculaire gauche et le débit cardiaque) pour l'autre, dans le but de présenter une interprétation nouvelle et améliorée de la fonction cardiovasculaire intégrée. MÉTHODOLOGIE: Chez 16 porcs anesthésiés, nous avons mesuré à thorax ouvert la pression ventriculaire gauche (P VG ), la pression aortique centrale (P AC ), la pression veineuse centrale (P VC ) et le flux aortique (Q A ). Nous avons établi la fréquence cardiaque (FC), le volume d'éjection systolique, l'index cardiaque (IC; rapport entre le débit cardiaque et le poids corporel), la P VG moyenne ( P ¯ VG ) et la différence de pression artérioveineuse moyenne ( Δ P = P ¯ A C − P ¯ V C ); G VS  = IC/( P ¯ AC − P ¯ VC ). Nous avons aussi étudié les effets d'une modification des conditions de charge cardiaque provoquée par l'administration de phényléphrine (Δ P ¯ AC ≥ + 25 mmHg), d'isoprotérénol (ΔFC d'environ + 25 %) ou de nitroprussiate de sodium (Δ P ¯ AC ≥ − 25 mmHg) et par la constriction de l'aorte proximale (pour maximiser la P VG développée et réduire le plus possible le Q A ). RÉSULTATS: Le nitroprussiate de sodium et l'isoprotérénol ont augmenté la G VS comparativement à la phényléphrine et à la constriction. Une courbe de la relation pression-volume maximale a été dérivée à partir des données groupées, au moyen d'une régression non linéaire sur les valeurs maximales de la P ¯ VG réparties dans des classes de Q A de 12,5 ml/min/kg d'amplitude. La courbe de la relation pression-volume et le tracé de la conductance ont été superposés en utilisant l'IC comme axe commun, ce qui a permis de constater que l'IC correspond au débit cardiaque et au volume entrant dans la circulation. CONCLUSIONS: Pour un IC donné, la G VS détermine la pression motrice et donc, la P AC . Nous avons aussi démontré comment une diminution de la G VS compense l'hypotension artérielle en rétablissant la différence de pression artérioveineuse et la pression artérielle.

Are re-injured ligaments equivalent mechanically to injured ligaments: The role of re-injury severity?

The consequences of ligament re-injury have received limited attention. Although the mechanical properties of injured ligaments improve over time, these properties are never fully recaptured, rendering these injured ligaments susceptible to re-injury. Previous injury is a significant risk factor for recurrent injury, and this re-injury can result in longer absence from activity than the initial injury. A rabbit medial collateral ligament model was used to compare mechanically re-injured right medial collateral ligaments to injured left medial collateral ligaments. Two groups of different re-injury severity were investigated: 'minor' re-injury comparing transection re-injured right medial collateral ligaments to transection injured left medial collateral ligaments; 'major' re-injury comparing gap re-injured right medial collateral ligaments to transection injured left medial collateral ligaments. Initial injuries for both groups were right medial collateral ligament transections 1 week before re-injury. After 5-6 weeks of healing, mechanical testing was performed to determine (dimensionally) cross-sectional area; (structurally) medial collateral ligament laxity, failure load, and stiffness; and (materially) cyclic creep strain and failure stress. Because we wanted to evaluate whether the mechanical properties of re-injured ligaments were equivalent or, at least, no worse than injured ligaments, we used equivalence/noninferiority testing. This approach evaluates a research hypothesis of equivalence, rather than difference, and determines whether comparisons are 'statistically equivalent', 'noninferior', or 'potentially inferior'. Transection re-injured and gap re-injured ligaments were 'statistically equivalent' structurally to transection injured ligaments. Transection re-injured ligaments were 'noninferior' both materially and dimensionally to transection injured ligaments. Gap re-injured ligaments were 'potentially inferior' both materially and dimensionally to transection injured ligaments. Two differences between the re-injuries, which affect healing, may explain the mechanical outcomes: the presence or lack of healing products and the proximity of ligament ends at the time of re-injury. Our findings suggest that (in the short term) there is a severity of re-injury below which there is no additional disadvantage to the healing process, mechanical behaviour, and resulting potential for re-injury.

Correlation between translational and rotational kinematic abnormalities and osteoarthritis-like damage in two in vivo sheep injury models.

The relations between kinematic abnormalities and post traumatic osteoarthritis have not yet been clearly elucidated. This study was conducted to determine the finite helical axes parameters and the tibiofemoral translation vector in the knee joints of two surgically induced injury sheep models: anterior cruciate ligament and medial collateral ligament transection (ACL/MCL Tx) (n = 5) and lateral meniscectomy (n = 5). We hypothesized that morphological damage in the experimental joints would be correlated to alterations in these kinematic variables. There was no strong evidence that morphological damage to the joints 20 weeks post ACL/MCL transection or meniscectomy was correlated with alterations in the finite helical axes variables. Nevertheless, significant correlations were found between the morphological damage to the joints and the magnitude of the change in the translation vectors after ACL/MCL transection (significant correlations (p = 0.005) during stance and trends (p < 0.1) at all points analyzed during swing). It can be concluded that: (1) osteoarthritic-like morphological damage after ACL/MCL transection is more critically correlated to the absolute tibiofemoral translational change and (2) alterations in analyzed kinematic variables cannot solely define osteoarthritis risk after meniscal injuries. From a clinical perspective, our results suggest that the magnitude of the change in the translation vector, which is independent of the coordinate system and combines the effects of the three translational degrees of freedom, i.e. medial-lateral, anterior-posterior and inferior-superior, would be an osteoarthritis risk factor after ligament injury, and requires validation in humans.

Posttraumatic Osteoarthritis Development and Progression in an Ovine Model of Partial Anterior Cruciate Ligament Transection and Effect of Repeated Intra-articular Methylprednisolone Acetate Injections on Early Disease.

BACKGROUND: Partial anterior cruciate ligament (p-ACL) ruptures are a common injury of athletes. However, few preclinical models have investigated the natural history and treatment of p-ACL injuries. PURPOSE: To (1) demonstrate whether a controlled p-ACL injury model (anteromedial band transection) develops progressive gross morphological and histological posttraumatic osteoarthritis (PTOA)-like changes at 20 and 40 weeks after the injury and (2) investigate the efficacy of repeated (0, 5, 10, and 15 weeks) intra-articular injections of methylprednisolone acetate (MPA; 80 mg/mL) in the mitigation of potential PTOA-like changes after p-ACL transection. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-one 3- to 5-year-old female Suffolk-cross sheep were allocated to 4 groups: (1) nonoperative controls (n = 5), (2) 20 weeks after p-ACL transection (n = 5), (3) 40 weeks after p-ACL transection (n = 6), and (4) 20 weeks after p-ACL transection + MPA (n = 5). Gross morphological grading and histological analyses were conducted. mRNA expression levels for inflammatory, degradative, and structural molecules were assessed. RESULTS: p-ACL transection led to significantly more combined gross damage ( P = .008) and significant aggregate histological damage ( P = .009) at 40 weeks after p-ACL transection than the nonoperative controls, and damage was progressive over time. Macroscopically, MPA appeared to slightly mitigate gross damage at 20 weeks after p-ACL transection in some animals. However, microscopic analysis revealed that repeated MPA injections after p-ACL transection led to significant loss in proteoglycan content compared with the nonoperative controls and 20 weeks after p-ACL transection ( P = .008 and P = .008, respectively). CONCLUSION: p-ACL transection led to significant gross and histological damage by 40 weeks, which was progressive over time. Multiple repeated MPA injections were not appropriate to mitigate injury-related damage in a p-ACL transection ovine model as significant proteoglycan loss was observed in MPA-treated knees. CLINICAL RELEVANCE: A p-ACL injury leads to slow and progressive PTOA-like joint damage, and multiple repeated injections of glucocorticoids may be detrimental to the knee joint in the long term.

Fibril deformation under load of the rabbit Achilles tendon and medial collateral ligament femoral entheses.

Microscopic visualization under load of the region connecting ligaments/tendons to bone, the enthesis, has been performed previously; however, specific investigation of individual fibril deformation may add insight to such studies. Detailed visualization of fibril deformation would inform on the mechanical strategies employed by this tissue in connecting two mechanically disparate materials. Clinically, an improved understanding of enthesis mechanics may help guide future restorative efforts for torn or injured ligaments/tendons, where the enthesis is often a point of weakness. In this study, a custom ligament/tendon enthesis loading device was designed and built, a unique method of sample preparation was devised, and second harmonic and two-photon fluorescence microscopy were used to capture the fibril-level load response of the rabbit Achilles tendon and medial collateral ligament femoral entheses. A focus was given to investigation of the mechanical problem of fibril embedment. Resultant images indicate a rapid (occurring over approximately 60 µm) change in fibril orientation at the interface of ligament/tendon and calcified fibrocartilage early in the loading regime, before becoming relatively constant. Such a change in fibril angle helps confirm the materially graded region demonstrated by others, while, in this case, providing additional insight into fibril bending. We speculate that the scale of the mechanical problem (i.e., fibril diameters being on the order of 250 nm) allows fibrils to bend over the small (relative to the imaging field of view, but large relative to fibril diameter) distances observed; thus, potentially lessening required embedment lengths. Nevertheless, this behavior merits further investigation to be confirmed. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2506-2515, 2018.