Non-invasive electroarthrography measures cartilage in live horses and correlates to direct measurements of cartilage streaming potentials in weight bearing regions of equine metacarpophalangeal joints.

OBJECTIVE: To perform non-invasive Electroarthrography (EAG) on live horses and establish relationships between EAG and direct measurements of cartilage streaming potentials in weight bearing areas of the equine metacarpophalangeal joint. DESIGN: EAG was performed bilaterally on the metacarpophalangeal joints of live horses (n = 3). Separate experiments used metacarpophalangeal joint explants (n = 11) to measure EAG obtained during simulated loading followed by direct measurements of cartilage streaming potentials on joint surfaces using the Arthro-BST probe. Joints were assigned to relatively normal (n = 5) and mildly degraded (n = 6) groups based on histological scoring of Safranin-O/Fast Green stained sections. RESULTS: EAG, involving application of electrodes to skin surrounding the joint and repeated weight shifting, was well-tolerated in live horses. One pair of distal forelimbs were available for analogous ex vivo EAG testing and measurements were strongly correlated to in vivo EAG measurements obtained on the same joints (r = 0.804, p = 0.016, n = 8). Both indirect (EAG) and direct (Arthro-BST) measurements of cartilage streaming potentials distinguished between normal and mildly degraded cartilage with statistically significant differences at 5 of 6 and 4 of 6 electrodes during simulated standing and walking, respectively. Strong and moderate correlations for weight bearing regions on the dorsal phalanx and central metacarpus were detected during both standing and walking. At the metacarpus/sesamoid interface a moderate correlation occurred during walking. CONCLUSION: Non-invasive EAG was used successfully in a clinical scenario and correlated to direct measurements of streaming potentials in weight bearing cartilage. These data support the potential of EAG to contribute to the diagnosis and treatment of degenerative joint diseases.

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis.

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

Chitosan-platelet-rich plasma implants improve rotator cuff repair in a large animal model: Pilot study.

Freeze-dried formulations of chitosan can be solubilized in platelet-rich plasma (PRP) to form injectable implants that are used as an adjunct treatment during surgical repair of the rotator cuff. The purpose of the current study was to assess chitosan-PRP implant residency, test safety, and assess efficacy over standard-of-care controls in a sheep model of rotator cuff repair. The infraspinatus tendon was transected unilaterally and immediately repaired with suture anchors in 22 skeletally mature ewes. In treatment groups, formulations containing chitosan, trehalose, and calcium chloride were solubilized with autologous leukocyte-rich PRP and injected at the tendon-bone interface and on top of the repaired site (1 mL or 2 mL doses). Implant residency was assessed histologically at 1 day. Outcome measures included MRI assessment at baseline, 6 weeks, and 12 weeks, histopathology and clinical pathology. Chitosan-PRP implants were resident at the injection site at 1 day and induced recruitment of polymorphonuclear cells. The tendon gap, which corresponds to the length of abnormally hyperintense tissue attached to the humeral head, was decreased by treatment with the 2 mL dose when compared to controls at 12 weeks on MRI images. Some histological features were improved by the 2 mL dose treatment compared to controls at 12 weeks. There was no treatment-specific effect on all standard safety outcome measures, which suggests high safety. This study provides preliminary evidence on the safety and efficacy of chitosan-PRP implants in a large animal model that could potentially be translated to a clinical setting.

Chitosan-Platelet-Rich Plasma Implants Improve Rotator Cuff Repair in a Large Animal Model: Pivotal Study.

The purpose of this study was to assess the safety and efficacy of chitosan-platelet-rich plasma (PRP) hybrid implants used as an adjunct to surgical rotator cuff repair in a pivotal Good Laboratory Practice (GLP)-compliant study. The infraspinatus tendon was transected in 48 skeletally mature ewes and repaired with a transosseous-equivalent (TOE) technique. In the two treatment groups, a chitosan-PRP solution was injected at the footprint between the tendon and the bone and on top of the repaired site (2 mL or 3 mL doses, n = 12 per group). To further assess chitosan safety, a chitosan-water solution was injected at the same sites (3 mL, n = 12). Outcome measures included Magnetic Resonance Imaging (MRI) assessment and clinical pathology at 3 months and 6 months and histopathology at 6 months. The tendon gap was decreased at 3 months on MRI images and certain histopathological features were improved at 6 months by chitosan-PRP treatment compared to controls. The group treated with chitosan-water was not different from controls. Chitosan-PRP treatment induced no negative effects in the sheep, which suggests high safety. This study provides further evidence on the safety and efficacy of chitosan-PRP for rotator cuff repair augmentation, which could eventually be used in a clinical setting.

Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Comparative Evaluation of Two Glass Polyalkenoate Cements: An In Vivo Pilot Study Using a Sheep Model.

Poly(methyl methacrylate) (PMMA) is used to manage bone loss in revision total knee arthroplasty (rTKA). However, the application of PMMA has been associated with complications such as volumetric shrinkage, necrosis, wear debris, and loosening. Glass polyalkenoate cements (GPCs) have potential bone cementation applications. Unlike PMMA, GPC does not undergo volumetric shrinkage, adheres chemically to bone, and does not undergo an exothermic setting reaction. In this study, two different compositions of GPCs (GPCA and GPCB), based on the patented glass system SiO2-CaO-SrO-P2O5-Ta2O5, were investigated. Working and setting times, pH, ion release, compressive strength, and cytotoxicity of each composition were assessed, and based on the results of these tests, three sets of samples from GPCA were implanted into the distal femur and proximal tibia of three sheep (alongside PMMA as control). Clinical CT scans and micro-CT images obtained at 0, 6, and 12 weeks revealed the varied radiological responses of sheep bone to GPCA. One GPCA sample (implanted in the sheep for 12 weeks) was characterized with no bone resorption. Furthermore, a continuous bone-cement interface was observed in the CT images of this sample. The other implanted GPCA showed a thin radiolucent border at six weeks, indicating some bone resorption occurred. The third sample showed extensive bone resorption at both six and 12 weeks. Possible speculative factors that might be involved in the varied response can be: excessive Zn2+ ion release, low pH, mixing variability, and difficulty in inserting the samples into different parts of the sheep bone.

In vivo analysis of a proprietary glass-based adhesive for sternal fixation and stabilization using rabbit and sheep models.

Wire cerclage remains the standard method of care for sternal fixation, following median sternotomy, despite being beset with complications. An emerging treatment option has been to augment the wires with an adhesive. A patented ionomeric glass (mole fraction: SiO2:0.48, ZnO:0.36, CaO:0.12, SrO:0.04) has been used to formulate GPC+, a glass polyalkenoate cement (GPC), by mixing it with poly(acrylic) acid (PAA) and de-ionized water. In a human cadaver study, this material, when applied with wire cerclage, was able to significantly reduce sternal instability. However, the material has yet to be tested in pertinent animal models. Here, after a series of physical and mechanical tests to confirm suitability of the experimental material for implantation, three samples of GPC+ were implanted in either the tibia or femur of three different rabbits, alongside sham defects, for two different time modalities. A further seven samples of GPC+ and one poly(methyl methacrylate) control (PMMA) were implanted in either the tibia or femur of two different sheep. The sheep containing the PMMA was sacrificed at 8 weeks and the other at 16 weeks, to evaluate time dependent biological response. Upon sacrifice, microCT images were acquired and histology slides prepared for analysis. All three GPC+ samples implanted in the rabbit model, for the two time modalities, were characterized by minimal bone resorption along with a mild inflammatory response. Five of the seven GPC+ materials implanted in the sheep model (all three implanted for 8 weeks and two of those implanted for 16 weeks) were associated with mild to moderate immune response, comparable to that observed with PMMA, as well as mild bone resorption. The remaining two GPC + materials (implanted in the sheep model for 16 weeks) exhibited no bone resorption or inflammatory response and appeared to stimulate increased bone density at the implant site. These results suggest that GPC + can be a viable bone adhesive for use in hard tissue applications such as sternal fixation and stabilization. Experiments performed to synthesize & test Sr-doped glass adhesive for sternal fixation. (1) Sr-doped ionomeric glass fired, ground down and mixed with aqueous polyacrylic acid to produce the adhesive. (2) Adhesive characterized and tested by a suite of laboratory-based tests to ensure suitability for implantation. (3) Adhesive implanted into a rabbit model (distal femur, 12 weeks post implantation) where micro-CT images confirmed an excellent bone/cement interface, no evidence of bone resorption and some bone remodelling. (4) Adhesive subsequently implanted into a sheep model; at 16-weeks, a continuous bone-adhesive interface is seen suggesting no bone resorption. There was an increase in the peri-implant radiodensity, suggesting enhanced mineral content of the bone surrounding the GPC+ implant.

Experimentally induced spine osteoarthritis in rats leads to neurogenic inflammation within neurosegmentally linked myotomes.

Naturally occurring spine osteoarthritis is clinically associated with the manifestation of chronic inflammatory muscle (myofascial) disease. The purpose of this study was to investigate the causal association between experimentally induced spine osteoarthritis and neurogenic inflammatory responses within neurosegmentally linked myotomes. Wistar Kyoto rats were randomly assigned to spine facet compression surgery (L4-L6) or sham surgery. Animals exposed to facet compression surgery demonstrated radiographic signs of facet-osteoarthritis (L4-L6 spinal levels) and sensory changes (allodynia, thermal hyperalgesia) at 7, 14 and 21 days post-intervention, consistent with the induction of central sensitization; no radiologic or sensory changes were observed after sham surgery. Increased levels of proinflammatory biomarkers including substance P (SP), calcitonin gene related peptide (CGRP), protease-activated receptor-2 (PAR2) and calcium/calmodulin dependent protein kinase II (CaMKII) were observed post-surgery within neurosegmentally-linked rectus femoris (L2-L5) muscle when compared to the non-segmentally linked biceps brachii (C4-C7) muscle; no differences were observed between muscles in the sham surgery group. These findings offer novel insight into the potential role of spine osteoarthritis and neurogenic inflammatory mechanisms in the pathophysiology of chronic inflammatory muscle (myofascial) disease.

Anionic Contrast-Enhanced MicroCT Imaging Correlates with Biochemical and Histological Evaluations of Osteoarthritic Articular Cartilage.

This study addressed difficulties in evaluating osteoarthritis (OA) progression in species with thin cartilage. Feasibility of using short, nonequilibrium contrast-enhanced micro-computed tomography (CE-µCT) to evaluate the physical and biochemical properties of cartilage was investigated. A preliminary in vitro study using CE-µCT study was performed using bovine osteochondral blocks with intact, mildly damaged (fibrillated), or severely damaged (delaminated) cartilage. Delamination of the superficial zone resulted in elevated apparent density compared with intact cartilage after 10 minutes of anionic contrast exposure (P < 0.01). OA was induced by unilateral meniscal destabilization in n = 20 sheep divided into: early phase OA (n = 9) and late phase OA (n = 11), while n = 4 remained as naive controls. In vivo anionic nonequilibrium contrast CT of the operated stifle was conducted in the early phase sheep 13 weeks postoperatively using clinical resolution CT. Cartilage visibility in the contrasted leg was significantly improved compared with the noncontrasted contralateral stifle (P < 0.05). Animals were sacrificed at 3 months (early phase) or 12 months (late phase) for additional ex vivo CE-µCT, and correlative tests with biochemical and histological measures. Concentration of sulfated glycosaminoglycan (sGAG) significantly varied between control, early, and late phase OA (P < 0.005) and showed a negative (r = -0.56) relationship with apparent density in the medial tibial plateau (R2 = 0.28, P < 0.001). Histologically, parameters in proteoglycan and cartilage surface structure correlated with increasing attenuation. While previous studies have shown that CE-CT increases the apparent density of proteoglycan-depleted cartilage, we concluded that superficial zone disruption also contributes to this phenomenon.

Non-invasive Electroarthrography Measures Load-Induced Cartilage Streaming Potentials via Electrodes Placed on Skin Surrounding an Articular Joint.

OBJECTIVE: We aimed to demonstrate that electroarthrography (EAG) measures streaming potentials originating in the cartilage extracellular matrix during load bearing through electrodes adhered to skin surrounding an articular joint. DESIGN: Equine metacarpophalangeal joints were subjected to simulated physiological loads while (1) replacing synovial fluid with immersion buffers of different electrolyte concentrations and (2) directly degrading cartilage with trypsin. RESULTS: An inverse relationship between ionic strength and EAG coefficient was detected. Compared to native synovial fluid, EAG coefficients increased (P < 0.05) for 5 of 6 electrodes immersed in 0.1X phosphate-buffered saline (PBS) (0.014 M NaCl), decreased (P < 0.05) for 4 of 6 electrodes in 1X PBS (0.14 M NaCl), and decreased (P < 0.05) for all 6 electrodes in 10X PBS (1.4 M NaCl). This relationship corresponds to similar studies where streaming potentials were directly measured on cartilage. EAG coefficients, obtained after trypsin degradation, were reduced (P < 0.05) in 6 of 8, and 7 of 8 electrodes, during simulated standing and walking, respectively. Trypsin degradation was confirmed by direct cartilage assessments. Streaming potentials, measured by directly contacting cartilage, indicated lower cartilage stiffness (P < 10-5). Unconfined compression data revealed reduced Em, representing proteoglycan matrix stiffness (P = 0.005), no change in Ef, representing collagen network stiffness (P = 0.15), and no change in permeability (P = 0.24). Trypsin depleted proteoglycan as observed by both dimethylmethylene blue assay (P = 0.0005) and safranin-O stained histological sections. CONCLUSION: These data show that non-invasive EAG detects streaming potentials produced by cartilage during joint compression and has potential to become a diagnostic tool capable of detecting early cartilage degeneration.

Culturing Articular Cartilage Explants in the Presence of Autologous Adipose Tissue Modifies Their Inflammatory Response to Lipopolysaccharide.

The purpose of the current study was to explore the effect of autologous adipose tissue on cartilage responses to lipopolysaccharide (LPS). We hypothesized that LPS elicits an inflammatory response in cartilage, and that response is augmented in the presence of adipose tissue. Furthermore, we hypothesized that this augmented inflammatory response is due, at least in part, to increased exposure of cartilage to adipose tissue-derived c3a. Porcine cartilage explants from market-weight pigs were cultured in the presence or absence of autologous adipose tissue for 96 hours, the final 48 hours of which they were stimulated with LPS (0 or 10 µg/mL). Adipose tissue explants were also cultured alone, in the presence or absence of LPS. Media from all cartilage treatments was assayed for c3a/c3a des Arg, PGE2, GAG, and NO, and the viability of cartilage tissue was determined by differential fluorescent staining. Media from adipose tissue explants was assayed for c3a/c3a des Arg and PGE2. LPS produced a significant increase in PGE2, GAG, and NO production when cartilage was cultured in the absence of adipose tissue. Coculture of adipose tissue prevented a significant increase in PGE2 in cartilage explants. There was no effect of adipose tissue on LPS-induced GAG or NO, but the presence of adipose tissue significantly reduced cell viability in LPS-stimulated cartilage explants. Adipose tissue explants from lean animals reduced inflammatory responses of cartilage to LPS via a c3a/c3a des Arg-independent mechanism and were associated with a significant decline in cell viability. Thus, contrary to our hypothesis, adipose tissue from lean animals does not augment the inflammatory response of cartilage to stimulation by LPS. The mechanism of modulatory effects of adipose tissue on LPS-induced increase in PGE2 and decline in chondrocyte viability requires further research but appears to have occurred via a mechanism that is independent of adipocentric c3a/c3a des Arg.

Intra-articular xenogeneic mesenchymal stem cell-based therapy increases CD4+CD25+ cells in synovial fluid.

Osteoarthritis (OA) is a chronic joint disease afflicting a substantial portion of the world's population with no currently available cure. Mesenchymal stem cell (MSC)-based therapies have been observed to have a mild beneficial effect in OA but the mechanism behind their action remains unclear. This study aimed to identify the lymphocytic response to a xenogeneic human umbilical cord-derived MSC-based cell therapy. A unilateral medial meniscal release model was employed in an ovine model of post-traumatic OA, with the contralateral limb employed as the control. A dose of 1.0 × 107 MSCs was administered to a subset of the OA group as well as to a normal sham-operated group. Synovial fluid was aspirated periodically for 13 weeks for flow cytometry analysis. At the termination of the study the stifle joints were collected and analyzed for potential pathologic changes. Cell therapy induced a transient influx of CD4+ leukocytes; there was a similar significant increase in the proportion of CD4+CD25+ and CD4+CD25hi leukocytes in response to cell therapy, the latter being a subset that may be composed of regulatory T cells. There was no significant effect of the cell therapy treatment on the proportion of synovial fluid-derived CD8+ cells or BAQ44A+ B cells. iNOS expression of intimal lining macrophages was evident but reduced in the cell therapy OA group suggesting macrophage phenotype transformation. There were no inflammatory or histological changes that could be attributed to the cell therapy. Cell therapy induced chemotaxis of CD4+ cells to the joint but these cells were not associated with pathological changes, despite their expression of activation markers (CD25+).

Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy.

OBJECTIVE: The objective of this study was to describe in life methods by which osteoarthritis can be staged in order to time therapeutic interventions that are relevant to osteoarthritis (OA) clinical trials. METHODS: Twenty-two sheep underwent arthroscopic meniscal destabilization to induce OA. Serial computed tomography (CT) imaging and arthroscopy were used to monitor osteoarthritis progression at 3-month intervals over 9 months. Eleven sheep received 1 intra-articular injection of hyaluronate 3 months after OA induction and another group of 11 received saline. A linear mixed model was used to define the trajectory of shape change in the medial joint compartment. Ordinal logistic regression was used to investigate the association between morphological changes and sclerosis. RESULTS: Three months after meniscal destabilization there were early bipolar chondral lesions in the medial compartment of the knee, as well as osteophytes and bone remodeling. Superficial fissures and cartilage cracks progressed to discrete areas of cartilage thinning and fibrillation on the medial tibial plateau by 6 months that became cartilage erosions by nine months. A linear mixed effect model demonstrated significant change in medial compartment length and width with over time (P < 0.05) for both groups. A significant association between severity of sclerosis and medial compartment morphology was also observed. CONCLUSIONS: The induction of osteoarthritic lesions with meniscal release model can be followed using noninvasive and minimally invasive procedures allowing for real-time decisions about redosing therapies, or other changes such as extending trial timelines without sacrificing animals to conduct assessments.

Increased Substance P Immunoreactivity in Ipsilateral Knee Cartilage of Rats Exposed to Lumbar Spine Injury.

OBJECTIVE: The present study aimed to investigate whether experimentally induced lumbar facet-joint OA lead to degenerative changes and enhanced SP expression within the ipsilateral neurosegmentally linked tibiofemoral cartilage. METHODS: Adult male Sprague-Dawley rats were assigned to left side L5-L6 facet mechanical compression injury (surgery) (n = 6), L5-L6 facet exposure with no compression (sham) (n = 5), or naïve (no surgery) (n = 4) groups. The morphology of the tibiofemoral articular cartilage was assessed using a modified Mankin scoring system. Immunohistochemistry was used to examine the density of chondrocytes stained positive for SP (cells/cm2) in the ipsilateral tibiofemoral cartilage at 28 days postintervention. RESULTS: Tibiofemoral cartilage in the surgery group showed consistent loss of superficial zone chondrocytes, mild roughening of the articular surface and occasional chondrocyte clusters as well as a greater density of SP mainly in the superficial cartilage zone compared with sham and naïve groups, although they also had a basic SP-expression. CONCLUSION: Our results support the hypothesis that neurogenic mechanisms may mediate the spread of SP to neurosegmentally linked heterologous joints affecting the distal cartilage homeostasis. These findings contribute additional insight into the potential role of neurogenic inflammation with implications in the pathophysiology of chronic inflammatory joint disease and OA.

Poly(ester amide) particles for controlled delivery of celecoxib.

Many potential pharmacological treatments for osteoarthritis can result in undesirable side effects due to the systemic administration of drugs, making the direct delivery of drugs to joints an attractive alternative. Poly(ester amide)s (PEAs) have been shown to exhibit promising properties for the development of particle-based intra-articular delivery vehicles. However, a limited range of PEA structures has been investigated. In this study, we prepared and characterized the properties of two different PEA particles composed of l-phenylalanine, sebacic acid, and either 1,4-butanediol or 1,8-octanediol (PBSe and POSe, respectively). The anti-inflammatory drug celecoxib (CXB) was encapsulated into the particles. Despite minor structural differences, PBSe and POSe exhibited different thermal and mechanical properties, and encapsulation of CXB influenced these properties. PBSe-CXB particles provided a slower release of drug in vitro relative to POSe-CXB. Toxicity studies showed that particles without drug exhibited low toxicity to ATDC5 and C2C12 cells, while the PBSe-CXB particles exhibited concentration-dependent toxicity. Host response to the particles was evaluated in an ovine model. No adverse effects were observed following intra-articular injection and it was observed that the particles diffused into the surrounding tissues. This work shows the importance of structural tuning in PEA delivery vehicles and demonstrates their potential for further development. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1235-1243, 2019.

Beyond Cartilage Repair: The Role of the Osteochondral Unit in Joint Health and Disease.

IMPACT STATEMENT: In this comprehensive review, we are providing a holistic overview of osteochondral tissue development, disease, pain localization, as well as structural evaluation and current repair strategies. This review is intended to serve as a broad introduction to this multidisciplinary research area. It is a thorough examination of the biological aspects of the osteochondral unit from a tissue engineering perspective, highlighting the importance of the subchondral bone in chondral and osteochondral lesion repair and pain relief.

Association between naturally occurring spine osteoarthritis in geriatric rats and neurogenic inflammation within neurosegmentally linked skeletal muscle.

OBJECTIVE: This study aimed to investigate the association between naturally occurring spinal osteoarthritis (OA) (L3-L5), the expression of substance P (SP) centrally (L4-L5) and the presence of neurogenic inflammation within the neurosegmentally linked quadriceps (L2-L5) in elderly rats versus young controls. DESIGN: Eight aged (27 ±â€¯3.2 months) and six young (4 ±â€¯0.0 months) male Wistar Kyoto rats were euthanized and submitted to micro-computerized tomography for determination of spine OA. SP expression (% area) at the dorsal horn of the spinal cord as well as the relative expression of SP and protease-activated receptor 2 (PAR2) to alpha-tubulin within quadriceps muscle were determined by immunohistochemistry and Western Blot. RESULTS: Spine osteoarthritis was confirmed in all aged rats but no young controls. Aged rats expressed significant increase of SP protein expression within the dorsal horn (MD = 0.086; 95% CI [0.026 to 0.145]; p = 0.0094) and quadriceps (MD = 1.209; 95% CI [0.239 to 2.179]; p = 0.0191) and PAR2 (MD = 0.797; 95% CI [0.160 to 1.435]; p = 0.0187) compared to young controls. CONCLUSION: These observations provide novel insight into the potential role of neurogenic inflammation in the pathophysiology of myofascial pain syndrome in the naturally occurring spinal OA in elderly population.

Thermoresponsive and Covalently Cross-Linkable Hydrogels for Intra-Articular Drug Delivery.

The local delivery of drugs to joints is a recognized strategy in the treatment of osteoarthritis. Hydrogels, particularly those that can be injected as liquids but undergo gelation in the joint, are promising platforms for intra-articular drug delivery. However, their properties must be carefully designed and tuned to achieve sustained drug release, which has been a challenge with previous hydrogels. We describe here the use of a combination of noncovalent thermal gelation and covalent cross-linking with poly(caprolactone-co-lactide)(PCLA)-poly(ethylene glycol)(PEG)-PCLA triblock copolymers to achieve hydrogels with sustained drug release in joints. The hybrid cross-linking approach afforded higher viscoelastic and compression moduli compared to noncovalent cross-linking alone and enabled celecoxib as well as other drugs to be loaded without substantially compromising the mechanical properties. Celecoxib release in vitro was much slower for the hybrid cross-linked hydrogel, with only 20% released over 22 days, compared to 90% released over 22 days for a noncovalently cross-linked hydrogel. Furthermore, the burst release of celecoxib was reduced in vivo in horse joints compared to noncovalent systems, and the drug was detected in synovial fluid for a period of two months. Overall, this new hydrogel system shows significant promise as a platform for further development in intra-articular delivery.

Peripheral fixation of meniscal allograft does not reduce coronal extrusion under physiological load.

PURPOSE: Meniscal graft extrusion is a concern following meniscal allograft transplantation (MAT). MAT surgical techniques continue to evolve in an effort to reduce extrusion; however, improvements remain difficult to measure in vivo. A novel MRI-compatible in vitro loading device capable of applying physiologically relevant loads has been developed, allowing for the measurement of extrusion under a variety of controllable conditions. The objective of this study was to compare maximal medial MAT extrusion (1) with and (2) without an additional peripheral third point of fixation on the tibial plateau. METHODS: Twelve human cadaveric knees underwent medial MAT, utilizing soft tissue anterior and posterior root fixation via transosseous suture, with a third transosseous suture tied over a button providing peripheral fixation on the tibial plateau. The joint was positioned at 5 degrees of flexion and loaded to 1 × body weight (647.7 ± 159.0 N) during MR image acquisition, with and without peripheral fixation. The joint was then positioned at 30 degrees of flexion and the process was repeated. Maximal coronal extrusion was measured. RESULTS: An increase in maximal coronal meniscal extrusion was noted between the unloaded and loaded states. At 30 degrees of flexion, with the addition of a peripheral fixation point, a statistically significant difference in absolute extrusion (p = 0.02) and relative percent extrusion (p = 0.04) between the unloaded and loaded state was found. The addition of a peripheral fixation suture resulted in an overall mean percent difference of - 2.49% (SD 14.1; 95% CI - 11.95, 6.97; n.s.) in extrusion at 5 degrees of flexion and a mean percent difference of - 0.95% (SD 7.3; 95% CI - 5.62, 3.71; n.s.) in extrusion at 30 degrees of flexion. These differences were not statistically significant. CONCLUSION: These results suggest that the addition of a peripheral anchor in medial MAT does not reduce the amount of maximal coronal extrusion and, therefore, may not confer any clinical benefit. Surgical techniques utilized to reduce MAT extrusion need further investigation to understand if the added technical difficulty and potential expense is warranted.