The synovial environment steers cartilage deterioration and regeneration.

Osteoarthritis (OA) was recently defined as an epidemic, and the lack of effective treatment is highly correlated to the limited knowledge regarding the underlying pathophysiology. Failure to regenerate upon trauma is thought to be one of the underlying causes for degenerative diseases, including OA. To investigate why lesions within an OA environment fail to heal, a heterogeneous cell population was isolated from the synovial fluid (SF) of OA patients. The cells' ability to undergo processes required for functional tissue regeneration was evaluated in the presence or absence of autologous SF. The obtained mechanistic findings were then used for the development of an immunomodulatory cell treatment, aimed to restore the pro-regenerative environment. Intra-articular injection in a clinical compassionate use study showed that the treatment restored the articular cartilage and joint homeostasis of OA patients. These findings confirm the role of pro-regenerative immune cells and their targeted influence on progenitor cells for degenerative joint disease therapies.

Significance of Brinkman and Stokes system conjuncture in human knee joint.

Stokes's equation in the fluid domain and Brinkman's equation in the porous media are combined in the current study which is designated by the Stokes-Brinkman coupling. The current paper gives a theoretical analysis of the Stokes-Brinkman coupling. It has been shown that such a model is a good match for the knee joint. A flow model has been investigated in order to get a better understanding of the convective diffusion of the viscous flow along the articular surfaces between the joints. The Beavers and Joseph slip conditions which are a specific boundary condition for the synovial fluid are used to solve the governing system of partial differential equations for the synovial fluid and the results are provided here. We develop formulas for the interfacial velocity for both flow through special slip condition and analyse the link between the slip parameters [Formula: see text] and [Formula: see text]. Thus, the damping force due to the porous medium naturally when we non-dimensionalize, some parameter which are controlling the structure like, [Formula: see text] and [Formula: see text]. Through the development of an analytical solution and numerical simulation (using the finite volume approach) it is hoped that the mechanisms of nutritional transport into the synovial joint will be better understood. According to the data the average concentration has a negative connection with both the axial distance and the duration spent in the experiment. Many graphs have been utilized to gain understanding into the problem's various characteristics including velocity and concentration, among others. Hyaluronate (HA) is considered to be present in porous cartilage surfaces and the viscosity of synovial fluid fluctuates in response to the amount of HA present.

Perforated flexible catheters improve joint fluid aspiration in shoulder cadavers.

A fluoroscopically controlled anterior approach in supine position is often used for arthrocentesis of the shoulder, but can lead to a high rate of dry aspirations. The aim of this study was to compare the aspiration performance of rigid needles and flexible catheters used with this approach. We hypothesized that a flexible catheter can significantly improve the amount of the obtained fluid. The glenohumeral joint of ten human cadaveric shoulder specimens were sequentially filled with 5, 10, 20 and 30 mL of contrast agent. For each volume the maximum aspirated amount of contrast agent with 4 different aspiration devices (20 gauge needle, 16 gauge needle, 16 gauge flexible catheter and 16 gauge perforated flexible catheter) were compared. All aspirations were done in supine cadaver position from anterior under fluoroscopic control. The aspirated amount of fluid was significantly higher using the 16 gauge perforated flexible catheter (p = 0.002-0.028) compared with all other devices when 5, 10 and 20 mL of contrast agent were in the joint. This perforated flexible catheter aspirated 80-96% of the available fluid while the standard 20 gauge needle aspirated 40-60%. Using a 16 gauge perforated flexible catheter in a supine anterior arthrocentesis technique results in aspiration of most of the fluid in human cadaveric shoulder specimens, while standard needles aspirate only about 50% of it. This can be clinically relevant when there is very little synovial fluid available and might reduce the number of insufficient aspirations.

Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis.

We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees.

Range-of-motion affects cartilage fluid load support: functional implications for prolonged inactivity.

OBJECTIVE: Joint movements sustain cartilage fluid load support (FLS) through a combination of contact migration and periodic bath exposure. Although there have been suggestions that small involuntary movements may disrupt load-induced exudation during prolonged inactivity, theoretical studies have shown otherwise. This work used well-controlled explant measurements to experimentally test an existing hypothesis that the range-of-motion must exceed the contact length to sustain non-zero FLS. METHOD: Smooth glass spheres (1.2-3.2 mm radius) were slid at 1.5 mm/s (Péclet number >100) against bovine osteochondral explants under varying normal loads (0.05-0.1 N) and migration lengths (0.05-7 mm) using a custom instrument. In situ deformation measurements were used to quantify FLS. RESULTS: Non-zero FLS was maintained at migration lengths as small as 0.05 mm or <10% the typical contact diameter. FLS peaked when track lengths exceeded 10 times the contact diameter. For migration lengths below this threshold, FLS decreased with increased contact stress. CONCLUSIONS: Migration lengths far smaller than the contact diameter can sustain non-zero FLS, which, from a clinical perspective, indicates that fidgeting and drifting can mitigate exudation and loss of FLS during prolonged sitting and standing. Nonetheless, FLS decreased monotonically with decreased migration length when migration lengths were less than 10 times the contact diameter. The results demonstrate: (1) potential biomechanical benefits from small movement (e.g., drifting and fidgeting); (2) the quantitative limits of those benefits; (3) and how loads, movement patterns, and mobility likely impact long term FLS.

Comparison of T2 Weighted, Fat-Suppressed T2 Weighted, and Three-Dimensional (3D) Fast Imaging Employing Steady-State Acquisition (FIESTA-C) Sequences in the Temporomandibular Joint (TMJ) Evaluation.

AIM: Osteonecrosis can affect the mandibular condyle, and bone marrow edema may be a precursor in osteonecrosis development in temporomandibular disorder (TMD) patients. Early detection of bone marrow changes is crucial for occurring osteonecrosis. The purpose of this study was to compare the diagnostic value of fast spin-echo T2 weighted (FSE-T2W), fat-suppressed T2W (FS-T2W), and three-dimensional (3D) fast imaging employing steady-state acquisition (FIESTA-C) MR sequences for early detection of bone marrow changes as well as TMJ soft tissue alterations. METHODS: A total of 60 joints with TMD were included in this study using a 1.5T MR machine (Signa HDxt, GE, Milwaukee, USA) using a dual surface TMJ coil. Qualitatively, the images were interpreted by two observers for disk configuration, disk position, joint fluid, and bone marrow changes. Quantitatively, signal intensity ratios (SIR) in the TMJ condyle, retrodiscal tissue, disk, and muscle were also measured using all tested sequences. Kappa coefficients were calculated to assess both intra- and interobserver agreements for each image set. The SIR of each sequence was compared using a one-way ANOVA Bonferroni-Dunn test. RESULTS: Overall intraobserver kappa coefficients ranged between 0.35 and 0.88 for joint fluid and between 0.22 and 0.82 for bone marrow changes diagnosis, suggesting high intraobserver agreement for FS-T2W and 3D FIESTA-C sequences than FSE T2W sequence (p < 0.05). 3D FIESTA-C showed higher agreement values for disk configuration and position detection than other sequences. CONCLUSIONS: 3D FIESTA-C sequences can be used and incorporated into routine MRI protocols for obtaining high-resolution TMJ MR images due to the short acquisition time and 3D nature of the sequence. Additional studies should be done for dynamic TMJ imaging with this sequence.

Accuracy of arthroscopic fluid pump systems in shoulder surgery: a comparison of 3 different pump systems.

BACKGROUND: Extra-articular fluid extravasation is a known complication during shoulder arthroscopy. The risk and amount of extravasation to a large degree is dependent on the fluid pressure delivered to the surgical site. Accurate measurement, knowledge, and control of the pressure delivered is thus important to surgeons, anesthetists, and the patient. The purpose of this study was to compare the pressure measurement accuracy of 3 arthroscopic fluid pumps, with 2 of them having 2 different settings. METHODS: Twenty-five patients (n = 5 per group) undergoing shoulder arthroscopy were selected. Three different arthroscopic fluid pumps (ConMed 24K, Stryker Crossflow, Arthrex Dual Wave) were tested in 5 different operational settings (Stryker, standard and dynamic mode; ConMed, with and without TIPS; Arthrex Dual Wave). In each operation, the set pump pressures and the subsequently delivered intra-articular surgical site fluid pressures were measured by a spinal needle connected to an anesthetic standard pressure transducer attached to the anesthetic machine. Independent measures of the surgical site pressures were obtained before multiple portals were created or extravasation had occurred. Measurements were taken at the beginning of surgery. RESULTS: Measurements of the mean intra-articular pressure were found to not be significantly different from the set pressure for the ConMed 24K with TIPS (0.98 ± 0.02-fold) and Stryker Crossflow in standard mode (0.98 ± 0.02-fold). However, actual pressure was significantly greater than the set pressure for the ConMed 24K without TIPS (by 1.30 ± 0.13-fold), Stryker Crossflow in dynamic mode (by 1.82 ± 0.08-fold), and Arthrex Dual Wave (by 2.19 ± 0.06-fold). CONCLUSION: Independently measured intra-articular pressure can be more than double the set pressure for some arthroscopic pumps. Measuring intra-articular pressure can thus aid in adjusting the set pressure. This could minimize the risk of intraoperative complications.

K+ and Ca2+ Channels Regulate Ca2+ Signaling in Chondrocytes: An Illustrated Review.

An improved understanding of fundamental physiological principles and progressive pathophysiological processes in human articular joints (e.g., shoulders, knees, elbows) requires detailed investigations of two principal cell types: synovial fibroblasts and chondrocytes. Our studies, done in the past 8-10 years, have used electrophysiological, Ca2+ imaging, single molecule monitoring, immunocytochemical, and molecular methods to investigate regulation of the resting membrane potential (ER) and intracellular Ca2+ levels in human chondrocytes maintained in 2-D culture. Insights from these published papers are as follows: (1) Chondrocyte preparations express a number of different ion channels that can regulate their ER. (2) Understanding the basis for ER requires knowledge of a) the presence or absence of ligand (ATP/histamine) stimulation and b) the extraordinary ionic composition and ionic strength of synovial fluid. (3) In our chondrocyte preparations, at least two types of Ca2+-activated K+ channels are expressed and can significantly hyperpolarize ER. (4) Accounting for changes in ER can provide insights into the functional roles of the ligand-dependent Ca2+ influx through store-operated Ca2+ channels. Some of the findings are illustrated in this review. Our summary diagram suggests that, in chondrocytes, the K+ and Ca2+ channels are linked in a positive feedback loop that can augment Ca2+ influx and therefore regulate lubricant and cytokine secretion and gene transcription.

Intra-articular infiltration of adipose-derived stromal vascular fraction cells slows the clinical progression of moderate-severe knee osteoarthritis: hypothesis on the regulatory role of intra-articular adipose tissue.

BACKGROUND: The infiltration of the stromal vascular fraction (SVF) of autologous adipose tissue to treat osteoarthritis has been used for several years demonstrating its safety and noticeable efficacy. This article presents clinical data from patients afftected by moderate and severe knee osteoarthritis demonstrating safety and clinical efficacy of the treatment when this autologous cell product is injected in the knee joint and patients evaluated post-operatively after 1 year. However, what do we know about the mechanism that underlies this clinical improvement? This article proposes, for the first time in our opinion, a hypothesis of the mode of action that involves structural and molecular interactions between SVF and infrapatellar fat pad (IFP). As consequence, there would be a re-education of intra-articular adipose tissue, which we consider a key player for the clinical effect observed in the mid and long term mainly due to immuno-regulatory mechanisms. METHODS: This is a retrospective and not controlled study that evaluated 50 patients (100 joints) ranging from 50 to 89 years old, separated by age cohorts. Clinical efficacy was assessed using the Lequesne, WOMAC, and VAS scales, by ultrasound control and quantification of the biochemical profiles of synovial fluid. RESULTS: There were no serious adverse effects. All the indexes studied showed a significant clinical improvement after 1-year follow-up for all ages and OA degree groups. This finding was correlated with the ultrasound observations and biochemical data, which show a marked decrease in catabolic and pro-inflammatory molecules (MMP-2, IL-1B, IL-6, and IL-8) and significant increase for anabolic and anti-inflammatory molecules (IGF-1 and IL-10). CONCLUSIONS: We conclude that intra-articular SVF infiltration for knee OA treatment is safe and effective during 1 year. We propose that applied SVF cells cause a cascade of molecular and structural events that, through complex interactions between IFP and SVF, re-educating the intra-articular fatty tissue towards a homeostatic, protective, and anti-inflammatory function, which will ultimately promote the restructuring and regeneration of damaged tissues.

Analysis of a mathematical model of rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disease characterized by inflammation in the synovial fluid within the synovial joint connecting two contiguous bony surfaces. The inflammation diffuses into the cartilage adjacent to each of the bony surfaces, resulting in their gradual destruction. The interface between the cartilage and the synovial fluid is an evolving free boundary. In this paper we consider a two-phase free boundary problem based on a simplified model of rheumatoid arthritis. We prove global existence and uniqueness of a solution, and derive properties of the free boundary. In particular it is proved that the free boundary increases in time, and the cartilage shrinks to zero as [Formula: see text], even under treatment by a drug. It is also shown in the reduced one-phased problem, with cartilage alone, that a larger prescribed inflammation function leads to a faster destruction of the cartilage.

Osteoarthritic Milieu Affects Adipose-Derived Mesenchymal Stromal Cells.

The objective of this study was to define the effects of osteoarthritic (OA) milieu on good manufactured practice-adipose-derived mesenchymal stromal cells (GMP-ASC) that are commonly utilized in cell therapies. Two different OA milieu: OA synovial fluid (SF) and OA-conditioned medium (CM) from synoviocytes were used to treat GMP-ASC both in normoxia or hypoxia. GMP-ASC were tested for cell migration, proliferation, cytokine receptors expression (CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR5, IL6R), and cytokines (CXCL8/IL8, CXCL10/IP10, CXCL12/SDF-1, CCL2/MCP1, CCL3/MIP1α, CCL4/MIP1ß, CCL5/RANTES, IL6) release. Healthy SF was used as controls. We demonstrated that GMP-ASC show an increase in proliferation, migration, and modulation of CXCR1, CXCR3, CCR1, and CCR5 receptors in hypoxic condition. Moreover, GMP-ASC migration increased 15-fold when treated either with OA-SF or OA-CM compared with healthy SF both in normoxia and hypoxia. GMP-ASC treated in both OA milieu showed an increase in CXCR3, CCR3, and IL6R and a decrease in CCR1 and CCR2 receptors. In OA-SF, we detected higher amount of CXCL10/IP10 than in OA-CM, while CCL2/MCP1 and CCL4/MIP1ß were higher in OA-CM compared with OA-SF. CXCL10/IP10 was the only chemokine of the OA milieu, which was down-modulated after treatment with GMP-ASC. In conclusion, we demonstrated specific effects of OA milieu on both GMP-ASC proliferation, migration, and cytokine receptor expression that were strictly dependent on the inflammatory and hypoxic environment. The use of characterized OA milieu is crucial to define the therapeutic effect of GMP-ASC and indicates that CXCL10/IP10-CXCR3 axis is partially involved in the GMP-ASC effect on synovial macrophages. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:336-347, 2020.

Meniscus Form and Function.

The menisci are 2 fibrocartilaginous crescents anchored via bony and ligamentous attachments to surrounding structures. Their biochemical composition and multilayered structure make them ideal for converting compressive forces to tensile forces in addition to improving joint congruity and providing shock absorption to weight bearing. The medial meniscus maintains more attachments at both the horns and the midbody than the lateral meniscus, making it more susceptible to injury. Understanding of the gross anatomy, vascular anatomy, biochemical composition, and microstructure is key to understanding causes of meniscal pathology as well as treatment options for restoring its primary functions.

The time course and mechanisms of change in biomarkers of joint metabolism in response to acute exercise and chronic training in physiologic and pathological conditions.

PURPOSE: The benefits of exercise across the lifespan and for a wide spectrum of health and diseases are well known. However, there remains less clarity as to the effects of both acute and chronic exercise on joint health. Serum biomarkers of joint metabolism are sensitive to change and have the potential to differentiate between normal and adverse adaptations to acute and chronic load. Therefore, the primary objective of this review is to evaluate how serum biomarkers can inform our understanding of how exercise affects joint metabolism. METHODS: A comprehensive literature search was completed to identify joint biomarkers previously used to investigate acute and chronic exercise training. RESULTS: Identified biomarkers included those related to joint cartilage, bone, synovium, synovial fluid, and inflammation. However, current research has largely focused on the response of serum cartilage oligomeric matrix protein (COMP) to acute loading in healthy young individuals. Studies demonstrate how acute loading transiently increases serum COMP (i.e., cartilage metabolism), which is mostly dependent on the duration of exercise. This response does not appear to be associated with any lasting deleterious changes, cartilage degradation, or osteoarthritis. CONCLUSION: Several promising biomarkers for assessing joint metabolism exist and may in future enhance our understanding of the physiological response to acute and chronic exercise. Defining 'normal' and 'abnormal' biomarker responses to exercise and methodological standardisation would greatly improve the potential of research in this area to understand mechanisms and inform practice.

Computational Simulation of Synovial Fluid Kinematics of the Scapholunate Joint.

Background: The interaction between wrist kinematics and synovial fluid pressure has yet to be studied. To our knowledge, this is the first study to determine the effect of scapholunate joint kinematics on synovial fluid pressure change using finite volume method. Methods: The carpal bones of a cadaveric hand were obtained from Computed Tomography (CT) scans. CT images of the carpal bones were segmented and reconstructed into 3D model. The 3D synovial fluid model between the scaphoid and lunate was constructed and then used for computational simulations. The kinematics data of scapholunate joint obtained from radioulnar deviation of the wrist was investigated. Results: It was found that the pressure in synovial fluid varied from -1.68 to 2.64 Pa with maximum pressure located at the scaphoid-fluid interface during the radial deviation. For ulnar deviation, the pressure increased gradually from the scaphoid-fluid interface towards the lunate-fluid interface (-1.37 to 0.37 Pa). Conclusions: This new computational model provides a basis for the study of pathomechanics of ligament injury with the inclusion of synovial fluid.

Quantitative characterization of viscoelastic properties of synovial fluid from forelimb joints of orthopedically normal Thoroughbreds and warmblood horses.

OBJECTIVE: To determine whether differences existed in the viscoelastic properties of synovial fluid samples from the metacarpophalangeal, intercarpal, and distal interphalangeal joints of orthopedically normal athletic horses. ANIMALS: 45 warmblood horses and 30 Thoroughbreds (age range, 4 to 16 years). PROCEDURES: Synovial fluid samples were aseptically obtained via arthrocentesis from 1 metacarpophalangeal, intercarpal, and distal interphalangeal joint of each horse, and nucleated cell counts were performed. A commercial ELISA was used to measure sample hyaluronic acid concentrations, and full rheological characterization of samples was performed to measure the elastic or storage modulus G' and viscous or loss modulus G" at 37.5°C (representing the body temperature of horses). Findings were compared among joints and between breed groups by means of ANOVA. RESULTS: Significant differences in synovial fluid G' and G" values were identified between Thoroughbreds and warmblood horses for the metacarpophalangeal joint, between the metacarpophalangeal and intercarpal joints of Thoroughbreds, and between the metacarpophalangeal and distal interphalangeal joints and intercarpal and distal interphalangeal joints of warmblood horses. No significant differences were identified between breed groups or among joints in synovial fluid hyaluronic concentrations or nucleated cell counts. CONCLUSIONS AND CLINICAL RELEVANCE: Viscoelastic properties of the forelimb joints of orthopedically normal Thoroughbreds and warmblood horses differed within and between these 2 groups, mainly as a function of the evaluated joint. To the authors' knowledge, this was the first study of its kind, and additional research is warranted to better understand the viscoelastic properties of synovial fluid in horses to optimize their locomotive function.

Cartilage Oligomeric Matrix Protein Levels in Type 2 Diabetes Associated with Primary Knee Osteoarthritis Patients.

AIMS: (1) To evaluate the association between type 2 diabetes mellitus (T2D) and primary knee osteoarthritis (KOA); and (2) to compare synovial fluid (SF) cartilage oligomeric matrix protein (COMP) concentrations and glycemic control parameters in patients with T2D, with and without primary KOA. METHODS: A total of 231 individuals were included in this study. Primary KOA was confirmed according to the criteria established by the American College of Rheumatology. The presence of T2D was determined by medical history. In addition, fasting plasma glucose and glycated hemoglobin were analyzed to confirm diabetic and nondiabetic status. RESULTS: Our results showed an association between T2D and primary KOA after covariate adjustments (OR = 3.755, p = 0.000024, 95% CI: 2.033-6.934). In addition, SF COMP levels were significantly higher in T2D groups with and without primary KOA (p = 0.00035; p = 0.001 respectively) when compared to nonT2D controls. CONCLUSION: This study suggests a strong association between T2D and primary KOA; in addition, the presence of T2D may have an influence in SF COMP levels in subjects with and without primary KOA. The glycemic control parameters and duration of diabetes may be useful as an indirect indicator of SF COMP levels to prevent the effects of chronic exposure to hyperglycemia and subsequent damage to the articular cartilage.

Effect of hyaluronic acid on phospholipid model membranes.

The role of hyaluronic acid (HA) in supporting low friction and low abrasion during movement in synovial joints is still not fully understood. In this study, we set out to investigate the interaction between HA and representative lipid model membranes, bilayers as well as monolayers, in detail using a variety of calorimetric, spectroscopic, scattering and microscopic techniques, to explore their role in lubrication of articular cartridge. We also cover a wide range of pressures to mimic pressures occurring upon joint movement, aiming at elucidating a possible mechanism for the low friction forces in synovial joints. Effects of HA on lipid bilayer membranes, encompassing significant adsorption at the membrane, penetration of the hydrophobic regions of the HA between lipid head groups, or changes of the temperature- and pressure dependent phase behavior of the membrane or mechanical properties could not be observed. High molecular weight HA at physiological NaCl concentrations might rather operate independently, via an entropy-driven excluded volume effect, to control the hydrodynamics of the synovial fluid. Minor effects are observed only at domain boundaries using lipid monolayers. As lubrication of natural joints is a synergistic effect, other components of the synovial fluid, such as proteoglycans, might play a more active role.

Mathematical principles and methods of biological surface lubrication with phospholipids bilayers.

This paper presents a mini-review of investigations performed by the authors in the field of hydrodynamic theory of lubrication of biological systems and synthetic processing of results to indicate the influence of biologically live material properties on biological liquid viscosity variations. The goal of the presented study was to demonstrate a new principle of a general mathematical theory applied to the mechanism of hydrodynamic lubrication of human joint cartilage surfaces with phospholipids bilayer and to indicate analytical solutions of hydrodynamic pressure, temperature and bio-fluid velocity components. Moreover, 3D variations of dynamic synovial fluid viscosity are assessed, particularly its variations across the entire film thickness. A new 3D analytical and numerical model has been elaborated on the basis of tribology methods, based on the assumptions of an ultra-thin boundary layer of non-Newtonian fluid. The analysed elements also included phospholipid concentrations, power hydrogen ion and collagen fiber concentrations in synovial, biological fluids, as well as electrostatic field, cartilage or biological surface wettability. The obtained results of our analysis demonstrate relationships which occur among hydrodynamic pressure, human joint load carrying capacity and phospholipid bilayer in the cartilage superficial layer. According to the best knowledge of the Authors, the obtained results may find applications in a broad scope of spatiotemporal models in biology and health science.

Microscale frictional strains determine chondrocyte fate in loaded cartilage.

Mounting evidence suggests that altered lubricant levels within synovial fluid have acute biological consequences on chondrocyte homeostasis. While these responses have been connected to increased friction, the mechanisms behind this response remain unknown. Here, we combine a frictional bioreactor with confocal elastography and image-based cellular assays to establish the link between cartilage friction, microscale shear strain, and acute, adverse cellular responses. Our incorporation of cell-scale strain measurements reveals that elevated friction generates high shear strains localized near the tissue surface, and that these elevated strains are closely associated with mitochondrial dysfunction, apoptosis, and cell death. Collectively, our data establish two pathways by which chondrocytes negatively respond to friction: an immediate necrotic response and a longer term pathway involving mitochondrial dysfunction and apoptosis. Specifically, in the surface region, where shear strains can exceed 0.07, cells are predisposed to acute death; however, below this surface region, cells exhibit a pathway consistent with apoptosis in a manner predicted by local shear strains. These data reveal a mechanism through which cellular damage in cartilage arises from compromised lubrication and show that in addition to boundary lubricants, there are opportunities upstream of apoptosis to preserve chondrocyte health in arthritis therapy.