Vagotomy accelerates the onset of symptoms during early disease progression and worsens joint-level pathogenesis in a male rat model of chronic knee osteoarthritis.

Objective: Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may offer insights into OA's influences beyond the articular joint. We hypothesized that low vagal tone would accelerate onset of OA-related gait changes and worsen joint damage in a rat knee OA model. Methods: Knee OA was induced in male Sprague Dawley rats by transecting the medial collateral ligament and medial meniscus. Then, left cervical vagus nerve transection (VGX, n â€‹= â€‹9) or sham VGX (non-VGX, n â€‹= â€‹6) was performed. Gait and tactile sensitivity were assessed at baseline and across 12 weeks, with histology and systemic inflammation evaluated at endpoint. Results: At week 4, VGX animals showed limping gait characteristics through shifted stance times from their OA to non-OA limb (p â€‹= â€‹0.055; stance time imbalance â€‹= â€‹1.6 â€‹± â€‹1.6%) and shifted foot strike locations (p â€‹< â€‹0.001; spatial symmetry â€‹= â€‹48.4 â€‹± â€‹0.835%), while non-VGX animals walked with a balanced and symmetric gait. Also at week 4, while VGX animals had a mechanical sensitivity (50% withdrawal threshold) of 13.97 â€‹± â€‹7.70 compared to the non-VGX animal sensitivity of 29.74 â€‹± â€‹9.43, this difference was not statistically significant. Histologically, VGX animals showed thinner tibial cartilage and greater subchondral bone area than non-VGX animals (p â€‹= â€‹0.076; VGX: 0.80 â€‹± â€‹0.036 â€‹mm2; non-VGX: 0.736 â€‹± â€‹0.066 â€‹mm2). No group differences in systemic inflammation were observed at endpoint. Conclusions: VGX resulted in quicker onset of OA-related symptoms but remained unchanged at later timepoints. VGX also had thinner cartilage and abnormal bone remodeling than non-VGX. Overall, low vagal tone had mild effects on OA symptoms and joint remodeling, and not at the level seen in common OA comorbidities.

Mild exercise expedites joint clearance and slows joint degradation in a joint instability model of osteoarthritis in male rats.

OBJECTIVE: Exercise remains a hallmark treatment for post-traumatic osteoarthritis (PTOA) and may maintain joint homeostasis in part by clearing inflammatory cytokines, cells, and particles. It remains largely unknown whether exercise-induced joint clearance can provide therapeutic relief of PTOA. In this study, we hypothesized that exercise could slow the progression of preclinical PTOA in part by enhancing knee joint clearance. DESIGN: Surgical medial meniscal transection was used to induce PTOA in 3-month-old male Lewis rats. A sham surgery was used as a control. Mild treadmill walking was introduced 3 weeks post-surgery and maintained to 6 weeks post-surgery. Gait and isometric muscle torque were measured at the study endpoint. Near-infrared imaging tracked how exercise altered lymphatic and venous knee joint clearance during discrete time points of PTOA progression. RESULTS: Exercise mitigated joint degradation associated with PTOA by preserving glycosaminoglycan content and reducing osteophyte volume (effect size (95% Confidence Interval (CI)); 1.74 (0.71-2.26)). PTOA increased hind step widths (0.57 (0.18-0.95) cm), but exercise corrected this gait dysfunction (0.54 (0.16-0.93) cm), potentially indicating pain relief. Venous, but not lymphatic, clearance was quicker 1-, 3-, and 6-weeks post-surgery compared to baseline. The mild treadmill walking protocol expedited lymphatic clearance rate in moderate PTOA (3.39 (0.20-6.59) hrs), suggesting exercise may play a critical role in restoring joint homeostasis. CONCLUSIONS: We conclude that mild exercise has the potential to slow disease progression in part by expediting joint clearance in moderate PTOA.

Intra-articular delivery of an indoleamine 2,3-dioxygenase galectin-3 fusion protein for osteoarthritis treatment in male Lewis rats.

OBJECTIVE: Osteoarthritis (OA) is driven by low-grade inflammation, and controlling local inflammation may offer symptomatic relief. Here, we developed an indoleamine 2,3-dioxygenase and galectin-3 fusion protein (IDO-Gal3), where IDO increases the production of local anti-inflammatory metabolites and Gal3 binds carbohydrates to extend IDO's joint residence time. In this study, we evaluated IDO-Gal3's ability to alter OA-associated inflammation and pain-related behaviors in a rat model of established knee OA. METHODS: Joint residence was first evaluated with an analog Gal3 fusion protein (NanoLuc™ and Gal3, NL-Gal3) that produces luminescence from furimazine. OA was induced in male Lewis rats via a medial collateral ligament and medial meniscus transection (MCLT + MMT). At 8 weeks, NL or NL-Gal3 were injected intra-articularly (n = 8 per group), and bioluminescence was tracked for 4 weeks. Next, IDO-Gal3s's ability to modulate OA pain and inflammation was assessed. Again, OA was induced via MCLT + MMT in male Lewis rats, with IDO-Gal3 or saline injected into OA-affected knees at 8 weeks post-surgery (n = 7 per group). Gait and tactile sensitivity were then assessed weekly. At 12 weeks, intra-articular levels of IL6, CCL2, and CTXII were assessed. RESULTS: The Gal3 fusion increased joint residence in OA and contralateral knees (p < 0.0001). In OA-affected animals, both saline and IDO-Gal3 improved tactile sensitivity (p = 0.008), but IDO-Gal3 also increased walking velocities (p ≤ 0.033) and improved vertical ground reaction forces (p ≤ 0.04). Finally, IDO-Gal3 decreased intra-articular IL6 levels within the OA-affected joint (p = 0.0025). CONCLUSION: Intra-articular IDO-Gal3 delivery provided long-term modulation of joint inflammation and pain-related behaviors in rats with established OA.

High frequency alternating current neurostimulation decreases nocifensive behavior in a disc herniation model of lumbar radiculopathy.

BACKGROUND: The purpose of this study was to evaluate if kilohertz frequency alternating current (KHFAC) stimulation of peripheral nerve could serve as a treatment for lumbar radiculopathy. Prior work shows that KHFAC stimulation can treat sciatica resulting from chronic sciatic nerve constriction. Here, we evaluate if KHFAC stimulation is also beneficial in a more physiologic model of low back pain which mimics nucleus pulposus (NP) impingement of a lumbar dorsal root ganglion (DRG). METHODS: To mimic a lumbar radiculopathy, autologous tail NP was harvested and placed upon the right L5 nerve root and DRG. During the same surgery, a cuff electrode was implanted around the sciatic nerve with wires routed to a headcap for delivery of KHFAC stimulation. Male Lewis rats (3 mo., n = 18) were separated into 3 groups: NP injury + KHFAC stimulation (n = 7), NP injury + sham cuff (n = 6), and sham injury + sham cuff (n = 5). Prior to surgery and for 2 weeks following surgery, animal tactile sensitivity, gait, and static weight bearing were evaluated. RESULTS: KHFAC stimulation of the sciatic nerve decreased behavioral evidence of pain and disability. Without KHFAC stimulation, injured animals had heightened tactile sensitivity compared to baseline (p < 0.05), with tactile allodynia reversed during KHFAC stimulation (p < 0.01). Midfoot flexion during locomotion was decreased after injury but improved with KHFAC stimulation (p < 0.05). Animals also placed more weight on their injured limb when KHFAC stimulation was applied (p < 0.05). Electrophysiology measurements at end point showed decreased, but not blocked, compound nerve action potentials with KHFAC stimulation (p < 0.05). CONCLUSIONS: KHFAC stimulation decreases hypersensitivity but does not cause additional gait compensations. This supports the idea that KHFAC stimulation applied to a peripheral nerve may be able to treat chronic pain resulting from sciatic nerve root inflammation.

Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase.

The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory conditions.

Effects of Repeat Test Exposure on Gait Parameters in Naïve Lewis Rats.

Rodent gait analysis has emerged as a powerful, quantitative behavioral assay to characterize the pain and disability associated with movement-related disorders. In other behavioral assays, the importance of acclimation and the effect of repeated testing have been evaluated. However, for rodent gait analysis, the effects of repeated gait testing and other environmental factors have not been thoroughly characterized. In this study, fifty-two naïve male Lewis rats ages 8 to 42 weeks completed gait testing at semi-random intervals for 31 weeks. Gait videos and force plate data were collected and processed using a custom MATLAB suite to calculate velocity, stride length, step width, percentage stance time (duty factor), and peak vertical force data. Exposure was quantified as the number of gait testing sessions. Linear mixed effects models were used to evaluate the effects of velocity, exposure, age, and weight on animal gait patterns. Relative to age and weight, repeated exposure was the dominant parameter affecting gait variables with significant effects on walking velocity, stride length, fore and hind limb step width, fore limb duty factor, and peak vertical force. From exposure 1 to 7, average velocity increased by approximately 15 cm/s. Together, these data indicate arena exposure had large effects on gait parameters and should be considered in acclimation protocols, experimental design, and subsequent data analysis of rodent gait data.

Intra-Articular Delivery of an Indoleamine 2,3-Dioxygenase Galectin-3 Fusion Protein for Osteoarthritis Treatment in Male Lewis Rats.

Objective : Controlling joint inflammation can improve osteoarthritis (OA) symptoms; however, current treatments often fail to provide long-term effects. We have developed an indoleamine 2,3-dioxygenase and galectin-3 fusion protein (IDO-Gal3). IDO converts tryptophan to kynurenines, directing the local environment toward an anti-inflammatory state; Gal3 binds carbohydrates and extends IDO's joint residence time. In this study, we evaluated IDO-Gal3's ability to alter OA-associated inflammation and pain-related behaviors in a rat model of established knee OA. Methods : Joint residence was first evaluated with an analog Gal3 fusion protein (NanoLuc™ and Gal3, NL-Gal3) that produces luminescence from furimazine. OA was induced in male Lewis rats via a medial collateral ligament and medial meniscus transection (MCLT+MMT). At 8 weeks, NL or NL-Gal3 were injected intra-articularly (n=8 per group), and bioluminescence was tracked for 4 weeks. Next, IDO-Gal3's ability to modulate OA pain and inflammation was assessed. Again, OA was induced via MCLT+MMT in male Lewis rats, with IDO-Gal3 or saline injected into OA-affected knees at 8 weeks post-surgery (n=7 per group). Gait and tactile sensitivity were then assessed weekly. At 12 weeks, intra-articular levels of IL6, CCL2, and CTXII were assessed. Results : The Gal3 fusion increased joint residence in OA and contralateral knees (p<0.0001). In OA-affected animals, IDO-Gal3 improved tactile sensitivity (p=0.002), increased walking velocities (p≤0.033), and improved vertical ground reaction forces (p≤0.04). Finally, IDO-Gal3 decreased intra-articular IL6 levels within the OA-affected joint (p=0.0025). Conclusion : Intra-articular IDO-Gal3 delivery provided long-term modulation of joint inflammation and pain-related behaviors in rats with established OA.

Wheel Running Exacerbates Joint Damage after Meniscal Injury in Mice, but Does Not Alter Gait or Physical Activity Levels.

PURPOSE: Exercise and physical activity are recommended to reduce pain and improve joint function in patients with knee osteoarthritis (OA). However, exercise has dose effects, with excessive exercise accelerating OA development and sedentary behaviors also promoting OA development. Prior work evaluating exercise in preclinical models has typically used prescribed exercise regimens; however, in-cage voluntary wheel running creates opportunities to evaluate how OA progression affects self-selected physical activity levels. This study aimed to evaluate how voluntary wheel running after a surgically induced meniscal injury affects gait characteristics and joint remodeling in C57Bl/6 mice. We hypothesize that injured mice will reduce physical activity levels as OA develops after meniscal injury and will engage in wheel running to a lesser extent than the uninjured animals. METHODS: Seventy-two C57Bl/6 mice were divided into experimental groups based on sex, lifestyle (physically active vs sedentary), and surgery (meniscal injury or sham control). Voluntary wheel running data were continuously collected throughout the study, and gait data were collected at 3, 7, 11, and 15 wk after surgery. At end point, joints were processed for histology to assess cartilage damage. RESULTS: After meniscal injury, physically active mice showed more severe joint damage relative to sedentary mice. Nevertheless, injured mice engaged in voluntary wheel running at the same rates and distances as mice with sham surgery. In addition, physically active mice and sedentary mice both developed a limp as meniscal injury progressed, yet exercise did not further exacerbate gait changes in the physically active mice, despite worsened joint damage. CONCLUSIONS: Taken together, these data indicate a discordance between structural joint damage and joint function. Although wheel running after meniscal injury did worsen OA-related joint damage, physical activity did not necessarily inhibit or worsen OA-related joint dysfunction or pain in mice.

The response of money market funds to the COVID-19 pandemic.

The Covid-19 Pandemic has increased the attention paid to money market funds. Using Covid-19 cases and a measure of lockdowns, shutdowns, etc., we analyze if money market fund investors and managers responded to the intensity of the pandemic. We ask whether or not the Federal Reserve implementation of the Money Market Mutual Fund Liquidity Facility (MMLF) had an effect on market participant behavior. We find that institutional prime investors responded significantly to the MMLF. Fund managers responded to the intensity of the pandemic but largely ignored the reduction in uncertainty created by the implementation of the MMLF.

Application of magnetic particle imaging to evaluate nanoparticle fate in rodent joints.

Nanoparticles are a promising approach for improving intra-articular drug delivery and tissue targeting. However, techniques to non-invasively track and quantify their concentration in vivo are limited, resulting in an inadequate understanding of their retention, clearance, and biodistribution in the joint. Currently, fluorescence imaging is often used to track nanoparticle fate in animal models; however, this approach has limitations that impede long-term quantitative assessment of nanoparticles over time. The goal of this work was to evaluate an emerging imaging modality, magnetic particle imaging (MPI), for intra-articular tracking of nanoparticles. MPI provides 3D visualization and depth-independent quantification of superparamagnetic iron oxide nanoparticle (SPION) tracers. Here, we developed and characterized a polymer-based magnetic nanoparticle system incorporated with SPION tracers and cartilage targeting properties. MPI was then used to longitudinally assess nanoparticle fate after intra-articular injection. Magnetic nanoparticles were injected into the joints of healthy mice, and evaluated for nanoparticle retention, biodistribution, and clearance over 6 weeks using MPI. In parallel, the fate of fluorescently tagged nanoparticles was tracked using in vivo fluorescence imaging. The study was concluded at day 42, and MPI and fluorescence imaging demonstrated different profiles in nanoparticle retention and clearance from the joint. MPI signal was persistent over the study duration, suggesting NP retention of at least 42 days, much longer than the 14 days observed based on fluorescence signal. These data suggest that the type of tracer - SPIONs or fluorophores - and modality of imaging can affect interpretation of nanoparticle fate in the joint. Given that understanding particle fate over time is paramount for attaining insights about therapeutic profiles in vivo, our data suggest MPI may yield a quantitative and robust method to non-invasively track nanoparticles following intra-articular injection on an extended timeline.

African Spiny Mice (Acomys) Exhibit Mild Osteoarthritis Following Meniscal Injury.

OBJECTIVE: Hyaline cartilage has limited innate healing abilities and hyaline cartilage loss is a hallmark of osteoarthritis (OA). Animal models can provide important insights into cartilage regeneration potential. One such animal model, the African spiny mouse (Acomys), is capable of regenerating skin, skeletal muscle, and elastic cartilage. This study aims to evaluate whether these regenerative abilities protect Acomys with meniscal injury from OA-related joint damage and behaviors indicative of joint pain and dysfunction. DESIGN: Acomys received destabilization of the medial meniscus (DMM) surgery (n = 11) or a skin incision (n = 10). Gait testing occurred at 4, 6, 8, 10, and 12 weeks after surgery. At endpoint, joints were processed for histology to assess cartilage damage. RESULTS: Following joint injury, Acomys with DMM surgery altered their walking patterns by increasing the percent stance time on the contralateral limb relative to the operated limb, thereby reducing the amount of time the injured limb must bear weight on its own throughout the gait cycle. Histological grading indicated evidence of OA-related joint damage in Acomys with DMM surgery; these changes were primarily driven by loss of structural integrity in the hyaline cartilage. CONCLUSIONS: Acomys developed gait compensations, and the hyaline cartilage in Acomys is not fully protected from OA-related joint damage following meniscal injury, although this damage was less severe than that historically found in C57BL/6 mice with an identical injury. Thus, Acomys do not appear to be completely protected from OA-related changes, despite the ability to regenerate other wounded tissues.

Hypertension contributes to exacerbated osteoarthritis pathophysiology in rats in a sex-dependent manner.

BACKGROUND: Hypertension is a common comorbidity of osteoarthritis (OA) with known autonomic dysregulation; thus, the autonomic nervous system may provide a shared underlying mechanism. The objective of this study was to examine the role of the autonomic nervous system in a preclinical model of OA and hypertension. METHODS: Experiments were conducted in spontaneously hypertensive rats and a normotensive control strain, including male and female rats. OA was surgically induced via medial meniscus transection with skin incision used as a sham control (n = 7-8/strain/sex/surgery). Tactile sensitivity, anxiety-related behavior, and serum corticosterone were measured at baseline then bi-weekly across 8 weeks. At weeks 9-10, cardiovascular responses to a chemical vagal nerve agonist were determined to indirectly evaluate vagus nerve function. The joint structure was assessed via grading of histological sections. RESULTS: In males, OA resulted in thinner cartilage in both hypertensive (OA vs. non-OA p < 0.001) and normotensive (OA vs. non-OA p < 0.001). Only females with comorbid hypertension and OA displayed thinner cartilage (p = 0.013). Male hypertensive OA animals had increased calcified subchondral bone compared to normotensive OA animals (p = 0.043) while female hypertensive OA animals had increased calcified subchondral bone compared to hypertensive sham animals (p < 0.001). All MCLT+MMT groups developed low-grade synovitis; interestingly, hypertensive OA females had higher synovitis scores than normotensive OA females (p = 0.046). Additionally, hypertension led to larger drops in blood pressure with vagal activation in both OA (hypertensive vs. normotensive p = 0.018) and sham (hypertensive vs. normotensive p < 0.001) male animals. In females, this trend held true only in OA animals (normotensive vs. hypertensive p = 0.005). CONCLUSION: These data provide preliminary evidence that hypertension influences OA progression and encourages further study into the autonomic nervous system as a possible mechanism.

Recommendations for the analysis of rodent gait data to evaluate osteoarthritis treatments.

Behavioral assays of animal pain and disability can increase the clinical relevance of a preclinical study. However, pain and symptoms are difficult to measure in preclinical models. Because animals often alter their movement patterns to reduce or avoid joint pain, gait analysis can be an important tool for quantifying OA-related symptoms in rodents. Technologies to measure rodent gait continue to advance and have been the focus of prior reviews. Regardless of the techniques used, the analysis of rodent gait data can be complex due to multiple confounding variables. The goal of this review is to discuss recent advances in the understanding of OA-related gait changes and provide recommendations on the analysis of gait data. Recent studies suggest OA-affected animals reduce vertical loading through their injured limb while walking, indicating dynamic ground reaction forces are important data to collect when possible. Moreover, gait data analysis depends on accurately measuring and accounting for the confounding effects of velocity and other covariates (such as animal size) when interpreting shifts in various gait parameters. Herein, we discuss different statistical techniques to account for covariates and interpret gait shifts. In particular, this review will discuss residualization and linear mixed effects models, including how both techniques can account for inter- and intra-animal variability and the effects of velocity. Furthermore, this review discusses future considerations for using rodent gait analysis, while highlighting the intricacies of gait analysis as a tool to measure joint function and behavioral outcomes.

Neuromodulation as a Potential Disease-Modifying Therapy for Osteoarthritis.

PURPOSE OF REVIEW: The following review discusses the therapeutic potential of targeting the autonomic nervous system (ANS) for osteoarthritis (OA) treatment and encourages the field to consider the candidacy of bioelectronic medicine as a novel OA treatment strategy. RECENT FINDINGS: The study of OA pathogenesis has focused on changes occurring at the joint level. As such, treatments for OA have been aimed at the local joint environment, intending to resolve local inflammation and decrease pain. However, OA pathogenesis has shown to be more than joint wear and tear. Specifically, OA-related peripheral and central sensitization can prompt neuroplastic changes in the nervous system beyond the articular joint. These neuroplastic changes may alter physiologic systems, like the neuroimmune axis. In this way, OA and related comorbidities may share roots in the form of altered neuroimmune communication and autonomic dysfunction. ANS modulation may be able to modify OA pathogenesis or reduce the impact of OA comorbidities. Moreover, blocking chronic nociceptive drive from the joint may help to prevent maladaptive nervous system plasticity in OA.

Apoptosis-Decellularized Peripheral Nerve Scaffold Allows Regeneration across Nerve Gap.

Peripheral nerve injury results in loss of motor and sensory function distal to the nerve injury and is often permanent in nerve gaps longer than 5 cm. Autologous nerve grafts (nerve autografts) utilize patients' own nerve tissue from another part of their body to repair the defect and are the gold standard in care. However, there is a limited autologous tissue supply, size mismatch between donor nerve and injured nerve, and morbidity at the site of nerve donation. Decellularized cadaveric nerve tissue alleviates some of these limitations and has demonstrated success clinically. We previously developed an alternative apoptosis-assisted decellularization process for nerve tissue. This new process may result in an ideal scaffold for peripheral nerve regeneration by gently removing cells and antigens while preserving delicate topographical cues. In addition, the apoptosis-assisted process requires less active processing time and is inexpensive. This study examines the utility of apoptosis-decellularized peripheral nerve scaffolds compared to detergent-decellularized peripheral nerve scaffolds and isograft controls in a rat nerve gap model. Results indicate that, at 8 weeks post-injury, apoptosis-decellularized peripheral nerve scaffolds perform similarly to detergent-decellularized and isograft controls in both functional (muscle weight recovery, gait analysis) and histological measures (neurofilament staining, macrophage infiltration). These new apoptosis-decellularized scaffolds hold great promise to provide a less expensive scaffold for nerve injury repair, with the potential to improve nerve regeneration and functional outcomes compared to current detergent-decellularized scaffolds.

Autonomic Nervous System Dysregulation and Osteoarthritis Pain: Mechanisms, Measurement, and Future Outlook.

PURPOSE OF REVIEW: The autonomic nervous system is an important regulator of stress responses and exhibits functional changes in chronic pain states. This review discusses potential overlap among autonomic dysregulation, osteoarthritis (OA) progression, and chronic pain. From this foundation, we then discuss preclinical to clinical research opportunities to close gaps in our knowledge of autonomic dysregulation and OA. Finally, we consider the potential to generate new therapies for OA pain via modulation of the autonomic nervous system. RECENT FINDINGS: Recent reviews provide a framework for the autonomic nervous system in OA progression; however, research is still limited on the topic. In other chronic pain states, functional overlaps between the central autonomic network and pain processing centers in the brain suggest relationships between concomitant dysregulation of the two systems. Non-pharmacological therapeutics, such as vagus nerve stimulation, mindfulness-based meditation, and exercise, have shown promise in alleviating painful symptoms of joint diseases, and these interventions may be partially mediated through the autonomic nervous system. The autonomic nervous system appears to be dysregulated in OA progression, and further research on rebalancing autonomic function may lead to novel therapeutic strategies for treating OA pain.

Age alters gait compensations following meniscal injury in male rats.

With age, susceptibility to osteoarthritis (OA) and OA-related pain and disability increases. Like in OA patients, gait patterns in rodent OA models shift to protect the injured limb during loading. However, unlike in OA patients, it is unknown how age affects gait changes in rodent OA models. In this study, gait compensations following meniscal injury in 3-, 6-, and 9-month-old rats were evaluated to examine age-effects of OA-related joint dysfunction. Rats 3, 6, and 9 months received medial collateral ligament transection plus medial meniscus transection (MCLT + MMT) surgery (n = 8/age group) or a skin incision (n = 8/age group). Postsurgery, rats underwent gait testing at 2, 4, 6, and 8 weeks. Postmortem, joints were processed for histology to assess cartilage damage. MCLT + MMT rats walked with reduced vertical loading in their injured limbs immediately after injury and throughout OA progression. Compared to sham-operated limbs, 6- and 9-month MCLT + MMT animals reduced loading in their injured limbs while 3-month MCLT + MMT animals did not. MCLT + MMT rats also increased stance time on the injured limb compared to the contralateral limb. Additionally, for the MCLT + MMT animals, 6- and 9-month animals had significantly worse cartilage damage compared to 3-month animals. These data indicated age at injury onset affects how animals load the OA-affected joint, with older animals developing gait compensations that more markedly reduce weight on the injured limb during walking.

A Novel Device for the Quantification of Synovial Fluid Viscosity Via Magnetic Deflection.

Changes in synovial fluid viscosity may be used to detect joint disease; however, methods to evaluate these changes at the point-of-care are currently rudimentary. Previously, we demonstrated that magnetic particle translation through static synovial fluid could serve as a surrogate marker of synovial fluid mechanics. In this work, we examine the magnetic deflection of a stream of particles flowing through a stream of synovial fluid and relate this deflection to changes in fluid mechanics. First, a flow device was designed, where a stream of magnetic particles flows along with synovial fluid. As the particle stream approaches and passes a fixed permanent magnet, the particle stream deflects. Conceptually, as the synovial fluid viscosity decreases, the deflection of the particle stream should increase due to a decreased drag force opposing the force magnetization. To assess this concept, particle deflection was first measured in Newtonian glycerol solutions of known varying viscosity under different flow conditions. Next, the device was used to test bovine synovial fluid viscosity, which had been progressively degraded using ultrasonication. A strong correlation was observed between the deflection of the magnetic particles and the viscosity of the glycerol solutions (R2 = 0.987) and the amount of ultrasonic degradation of synovial fluid (R2 = 0.7045). In the future, the principle of particle deflection may be used to design point-of-care quantification of synovial fluid mechanics, as the assessment does not require particles to be separated from the fluid for quantification and could be conducted under simple flow conditions.

Chronic Pain is Associated With Reduced Sympathetic Nervous System Reactivity During Simple and Complex Walking Tasks: Potential Cerebral Mechanisms.

BACKGROUND: Autonomic dysregulation may lead to blunted sympathetic reactivity in chronic pain states. Autonomic responses are controlled by the central autonomic network (CAN). Little research has examined sympathetic reactivity and associations with brain CAN structures in the presence of chronic pain; thus, the present study aims to investigate how chronic pain influences sympathetic reactivity and associations with CAN brain region volumes. METHODS: Sympathetic reactivity was measured as change in skin conductance level (ΔSCL) between a resting reference period and walking periods for typical and complex walking tasks (obstacle and dual-task). Participants included 31 people with (n = 19) and without (n = 12) chronic musculoskeletal pain. Structural 3 T MRI was used to determine gray matter volume associations with ΔSCL in regions of the CAN (i.e., brainstem, amygdala, insula, and anterior cingulate cortex). RESULTS: ΔSCL varied across walking tasks (main effect p = 0.036), with lower ΔSCL in chronic pain participants compared to controls across trials 2 and 3 under the obstacle walking condition. ΔSCL during typical walking was associated with multiple CAN gray matter volumes, including brainstem, bilateral insula, amygdala, and right caudal anterior cingulate cortex (p's < 0.05). The difference in ΔSCL from typical-to-obstacle walking were associated with volumes of the midbrain segment of the brainstem and anterior segment of the circular sulcus of the insula (p's < 0.05), with no other significant associations. The difference in ΔSCL from typical-to-dual task walking was associated with the bilateral caudal anterior cingulate cortex, and left rostral cingulate cortex (p's < 0.05). CONCLUSIONS: Sympathetic reactivity is blunted during typical and complex walking tasks in persons with chronic pain. Additionally, blunted sympathetic reactivity is associated with CAN brain structure, with direction of association dependent on brain region. These results support the idea that chronic pain may negatively impact typical autonomic responses needed for walking performance via its potential impact on the brain.

Fast nanoparticle rotational and translational diffusion in synovial fluid and hyaluronic acid solutions.

Nanoparticles are under investigation as diagnostic and therapeutic agents for joint diseases, such as osteoarthritis. However, there is incomplete understanding of nanoparticle diffusion in synovial fluid, the fluid inside the joint, which consists of a mixture of the polyelectrolyte hyaluronic acid, proteins, and other components. Here, we show that rotational and translational diffusion of polymer-coated nanoparticles in quiescent synovial fluid and in hyaluronic acid solutions is well described by the Stokes-Einstein relationship, albeit with an effective medium viscosity that is much smaller than the macroscopic low shear viscosity of the fluid. This effective medium viscosity is well described by an equation for the viscosity of dilute polymer chains, where the additional viscous dissipation arises because of the presence of the polymer segments. These results shed light on the diffusive behavior of polymer-coated inorganic nanoparticles in complex and crowded biological environments, such as in the joint.