Untreated Joints Research Articles

Transplantation of Chemically Processed Decellularized Meniscal Allografts.

Objective The aim of this study was to evaluate the chondroprotective effect of chemically decellularized meniscal allografts transplanted into the knee joints of adult merino sheep. Methods Lateral sheep meniscal allografts were chemically processed by a multistep method to yield acellular, sterile grafts. The grafts were transplanted into the knee joints of sheep that were treated by lateral meniscectomy. Joints treated by meniscectomy only and untreated joints served as controls. The joints were analyzed morphologically 6 and 26 weeks after surgery by the macroscopical and histological OARSI (Osteoarthritis Research Society International) score. Additionally, the meniscal grafts were biomechanically tested by cyclic indentation. Results Lateral meniscectomy was associated with significant degenerative changes of the articular cartilage of the lateral joint compartment. Transplanted lateral meniscal allografts retained their integrity during the observation period without inducing significant synovitis or foreign body reactions. Cellular repopulation of the grafts was only present on the surface and the periphery of the lateral meniscus, but was still completely lacking in the center of the grafts at week 26. Transplantation of processed meniscal allografts could not prevent degenerative changes of the articular cartilage in the lateral joint compartment. Compared with healthy menisci, the processed grafts were characterized by a significantly reduced dynamic modulus, which did not improve during the observation period of 26 weeks in vivo. Conclusion Chemically decellularized meniscal allografts proved their biocompatibility and durability without inducing immunogenic reactions. However, insufficient recellularization and inferior stiffness of the grafts hampered chondroprotective effects on the articular cartilage.

Evaluation of Chitosan-Glycerol Phosphate in Experimental Osteochondral Joint Defects in Horses

The aim of the present study was to investigate the long-term effects of chitosan-glycerol phosphate (chitosan- GP) gel with the articular environment following implantation into experimental osteochondral defects in horses. The animals were submitted to experimental arthroscopy of both tibiotarsal joints for creation of osteochondral defects on the medial aspect of the lateral trochlear ridge. One hindlimb was randomly selected for treatment with chitosan-GP gel, while the contralateral hindlimb served as untreated control. Horses were followed at different time points over 24 months, by clinical, radiographic, ultrasonographic, and synovial fluid analysis. Enlargement of all operated joints occurred in both hindlimbs during the first 30 days. No radiographic signs of osteoarthritis appeared, in treated or untreated joints. Ultrasonography revealed similar defect filling tissue, and synovial fluid with similar characteristics in either treated or untreated control joints, with osteochondral defect areas progressively decreasing. Synovial fluid analysis have shown no differences in the total protein, prostaglandin E2, chondroitin sulfate, and hyaluronic acid concentrations, and white blood cell count, when comparing treated to untreated control joints. In conclusion, Chitosan-GP is biocompatible with the equine articular environment, and did not cause relevant clinical effects, inflammatory response or toxic effects in the horse joints.

Surface Modification by Nanoimprint Lithography for Improvement of the Joint Strength of Composites

To improve the strength of adhesively bonded composite joints, surface modification of composites by nanoimprint lithography (NIL) is investigated. Since microstructures can be fabricated during the curing of composites, this technique reduces the time required and costs involved in conventional surface preparation such as chemical etching or sand blasting. Since structural adhesives are susceptible to peeling, a pyramidal microstructure is chosen for the surface modification pattern. Such a pattern divides the stress at the interface into peel and shear components; thus, the apparent joint strength is greater than that of an untreated joint with a flat surface. We fabricated the pyramidal microstructure on carbon fiber reinforced plastic and determined the adhesive strength both analytically and experimentally. In the analysis, interfacial stresses were calculated using the finite element method and the interfacial fracture was defined using the peel and shear mixed-mode criterion based on the average stress criterion. In the experiment, tensile butt joint tests were performed for NIL and untreated joints and the apparent strengths were measured. The NIL joint was found to be 52% stronger than the untreated joint according to the finite element method calculation and 67% stronger according to the tensile tests.

Pharmacokinetic studies of meloxicam following oral and transdermal administration in Beagle dogs

The potential for topical delivery of meloxicam was investigated by examining its pharmacokinetic profiles in plasma and synovial fluid following oral and transdermal administration in Beagle dogs. The experiment was a two-period, crossover design using 6 Beagle dogs. Meloxicam tablets were administered orally at a dose of 0.31 mg/kg, and meloxicam gel was administered transdermally at a dose of 1.25 mg/kg. Drug concentrations in plasma and synovial fluid were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The pharmacokinetic parameters were calculated using the Topfit 2.0 program. The pharmacokinetic results showed that AUC(0-t) (23.9+/-8.26 microg.h.mL(-1)) in plasma after oral administration was significantly higher than after transdermal delivery (1.00+/-0.43 microg.h.mL(-1)). In contrast, the ratio of the average concentration in synovial fluid to that in plasma following transdermal administration was higher than that for an oral delivery. The synovial fluid concentration in the treated leg was much higher than that in the untreated leg, whereas the synovial fluid concentration in the untreated leg was similar to the plasma concentration. The high concentration ratio of synovial fluid to plasma indicates direct penetration of meloxicam following topical administration to the target tissue. This finding is further supported by the differences observed in meloxicam concentrations in synovial fluid in the treated and untreated joints at the same time point. Our results suggest that transdermal delivery of meloxicam is a promising method for decreasing its adverse systemic effects.Acta Pharmacologica Sinica (2009) 30: 1060-1064; doi: 10.1038/aps.2009.73; published online 8 June 2009.

Effect of surface-applied treatments on the above-ground performance of simulated timber joinery

Summary We examined the effect of surface-applied treatments on the above-ground decay resistance of the tenon of mortice-and-tenon timber joints designed to simulate joinery that is exposed to the weather. Joints made from untreated radiata pine, Douglas-fir, brush box, spotted gum and copper-chrome-arsenic (CCA) treated radiata pine were exposed to the weather for 9 y on above-ground racks at five sites throughout eastern Australia. Results indicate (1) a poorly maintained external paint film generally accelerated decay, (2) a brush coat of water-repellent preservative inside the joints often extended serviceability (in some cases by a factor of up to seven times that of untreated joints) and (3) the level of protection provided by a coat of primer applied inside the joint varied and in most cases was not as effective as the water-repellent preservative treatment.

Exosomes Derived from IL-10-Treated Dendritic Cells Can Suppress Inflammation and Collagen-Induced Arthritis

We have demonstrated previously that local, adenoviral-mediated gene transfer of viral IL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. This contralateral effect is mediated in part by APCs able to traffic from the treated joint to lymph nodes as well as to untreated joints. Moreover, injection of dendritic cells (DC) genetically modified to express IL-4 or Fas ligand was able to reverse established murine arthritis. To examine the ability of exosomes derived from immunosuppressive DCs to reduce inflammation and autoimmunity, murine models of delayed-type hypersensitivity and collagen-induced arthritis were used. In this study, we demonstrate that periarticular administration of exosomes purified from either bone marrow-derived DCs transduced ex vivo with an adenovirus expressing viral IL-10 or bone marrow-derived DCs treated with recombinant murine IL-10 were able to suppress delayed-type hypersensitivity responses within injected and untreated contralateral joints. In addition, the systemic injection of IL-10-treated DC-derived exosomes was able suppress the onset of murine collagen-induced arthritis as well as reduce severity of established arthritis. Taken together, these data suggest that immature DCs are able to secrete exosomes that are involved in the suppression of inflammatory and autoimmune responses. Thus DC-derived exosomes may represent a novel, cell-free therapy for the treatment of autoimmune diseases.

The effects of surface steam treatment on bacterial reduction and storage of beef primals and retail cuts

Beef primals and retail joints were rapidly heated and cooled using steam condensation and evaporation heat transfer processes. Treatments of beef primals to 100 or 120 °C showed no significant differences. After 3 weeks of vacuum-packed storage at 0 °C, mean total viable count (TVC) and enterobacteriaceae counts for treated primals were approximately 1 log 10 cfu cm −2 lower than for un-treated primals. Levels were similar after 6 weeks of vacuum-packed storage. The effects of a second treatment on retail joints cut from treated and un-treated primals that had been stored in vacuum packs for 3 weeks showed TVC and enterobacteriaceae counts for treated joints were approximately 1 log 10 cfu cm −2 lower than for un-treated joints after 4 and 8 days of over-wrapped storage. The results suggest the steam decontamination treatment used can remove small but significant ( p < 0.05) numbers of bacteria from the beef surface.

The effect of surface pretreatment and moisture on the fatigue performance of adhesively-bonded aluminium

Adhesively-bonded aluminium single lap shear joints were tested to failure under fatigue loading to ascertain the effects of surface pretreatment and moisture in both durability and fracture path. The aluminium substrate used was AA5754 with and without a silicon-based pretreatment. The adhesive used was a commercially available DGEBA-based epoxy resin cured by a modified dicyandiamide.Fatigue tests were performed at 20Hz using an R-ratio of 0.1. To monitor the effects of moisture, tests were performed in a chamber that generated 96% relative humidity (r.h.). SN curves were generated and several microscopic and surface analysis techniques were employed to characterise the failure mode of the joints. The techniques included simple visual observation, SEM, TEM and high magnification video recordings.The fatigue performance of pretreated and untreated joints were similar when tested in air, but the performance of the untreated joints was greatly reduced when tested in 96% r.h. The differences in fatigue performance between untreated and pretreated joints in 96% r.h. are thought to be due to differences in failure mode of the joints arising from the improved interfacial bonding between the pretreatment and the adhesive. Pretreated joints failed predominantly cohesively through the adhesive, while untreated joints failed mainly interfacially at the adhesive/aluminium interface. High magnification video recordings have also shown that the adhesive fillet is a significant factor in determining the life of a single lap joint.

The effect of laser treatment on the mechanical and electrical properties of busbar joints

A high proportion of the faults in electrical substations are due to the overheating of busbar joints. Surface contamination due to atmospheric corrosion is a main cause. Laser surface treatments have previously been applied by the authors to improve the surface hardness and corrosion resistance of aluminium alloys. Similarly, a chromium protective coating can be produced on copper by laser-alloying. This should allow more reliable bolt-together busbar joints to be made up on site with less attention to surface cleanliness. In this study, experimental investigations were made into the mechanical and electrical properties of laser-treated copper busbar joints under various conditions of applied torque and current flow. It was found that the maximum hardness of the laser-alloyed layer could reach HV95, which is almost 50% higher than that of the original sample. There were insignificant differences between the temperature distribution associated with the laser-alloyed and the untreated samples. The corrosion resistance of the laser-alloyed sample is slightly better than that of the original sample in the salt spray corrosion test. The electric conductivity of the uncorroded laser-alloyed joints was only slightly lower than that of the uncorroded untreated joints.

The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen.

We have demonstrated previously that local, adenoviral-mediated gene transfer of vIL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. These therapeutic effects observed in distant untreated joints following local intra-articular gene delivery have been termed the 'contralateral effect'. To begin to understand the underlying immunologic mechanism that confers this effect, a dual-antigen model of antigen-induced arthritis (AIA) in rabbit knee joints was utilized. Rabbits were immunized against two antigens, ovalbumin and keyhole limpet hemocyanin, and AIA generated by intra-articular injection of each antigen into contralateral knees. Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix degradation, while preserving near normal levels of cartilage matrix synthesis within treated joints. However, no antiarthritic effect was conferred in the contralateral control joints that received only a marker gene, in contrast to the results seen in a single-antigen AIA model. These results suggest that the distant antiarthritic effects associated with local gene delivery to joints are antigen-specific, and not due to vIL-10-induced generalized immunosuppression of the animal.

The use of intra-articular Na-hyaluronate as a potential chondroprotective device in experimentally induced acute articular cartilage injury and repair in rabbits

Objective: This study examined if viscosupplementation from intra-articular administration of a commercially available form of hyaluronan (HA) could promote the restoration of proteoglycan (PG) depletion induced by chymopapain and then if the repair could be maintained once HA treatment was discontinued. Methods: Animals received cartilage injury with intra-articular chymopapain (2.0 mg) followed by weekly treatment with intra-articular HA. HA treated animals were compared to injured animals with no treatment, contralateral untreated joints and joints from normal controls. The effect of intra-articular HA alone on articular cartilage was also examined. Results: Serum keratan sulfate levels confirmed degradation of the cartilage PGs in the chymopapain-injected knees. Intra-articular chymopapain resulted in marked loss of PGs. There were no significant differences among the control groups (untreated control, HA/800 treatment only). HA treatment did not affect the loss of PGs caused by chymopapain after 42 days. However, in animals receiving chymopapain injury followed by weekly HA treatment for 42 days and then 42 days of free cage activity without HA, cartilage PG contents were significantly increased. Intra-articular HA alone had no effect on the articular cartilage. Conclusion: The results in the present study suggest a potential protective effect of HA on chymopapain-induced acute articular cartilage injury in rabbits that, in time, permits damaged cartilage to resynthesize matrix PGs after the HA treatment is discontinued.

Ex Vivo Gene Delivery of IL-1Ra and Soluble TNF Receptor Confers a Distal Synergistic Therapeutic Effect in Antigen-Induced Arthritis

Intra-articular expression of antagonists of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in arthritic rabbit knee and mouse ankle joints by direct adenoviral-mediated intraarticular delivery results in amelioration of disease pathology in both the treated and contralateral untreated joints. Previous experiments suggest that direct adenoviral infection of resident antigen-presenting cells (APCs) and subsequent traveling of these cells to other sites of inflammation and lymph nodes might be responsible for this "contralateral effect." To determine whether genetic modification of APCs is required for the contralateral effect, we have used an ex vivo approach utilizing genetically modified fibroblasts to express IL-1 receptor antagonist protein (IL-1Ra) and soluble TNF-alpha receptor (sTNFR) locally in arthritic joints. Retroviral vectors carrying IL-1Ra, sTNFR-Ig, or both genes together were used to stably infect autologous rabbit fibroblasts that were then injected intra-articularly into arthritic rabbit knee joints. The intra-articular delivery of either IL-1Ra- or sTNFR-Ig-expressing fibroblasts was antiinflammatory and chondro-protective in both the injected and noninjected contralateral joints. In addition, we demonstrate that the co-delivery of both antagonists in combination results in a synergistic effect in disease amelioration in both the treated and nontreated joints. These ex vivo results suggest that trafficking of vector-modified inflammatory cells is not the main mechanism responsible for the observed distal spread of the therapeutic effect. Moreover, the results demonstrate that local, ex vivo gene therapy for arthritis could be effective in blocking pathologies within untreated, distant arthritic joints.

Viral IL-10 gene transfer inhibits DTH responses to soluble antigens: evidence for involvement of genetically modified dendritic cells and macrophages.

Expression of the viral interleukin-10 (vIL-10) gene within one joint of an animal with polyarticular, inflammatory arthritis suppresses disease in both treated and untreated joints (the "contralateral effect"). We used a mouse delayed-type hypersensitivity (DTH) model to investigate this phenomenon. Adenoviral delivery of the vIL-10 gene suppressed DTH reactions in injected and contralateral paws. T lymphocytes recovered from immunized mice injected with the adenoviral vector (ad-vIL-10) were unable to transfer the DTH response, but were not inhibitory. Peritoneal exudate cells recovered from mice injected intraperitoneally with ad-vIL-10 inhibited DTH reactions in recipient mice, but only when the donor mice had been sensitized to the antigen used to incite the DTH response. Dendritic cells (DCs) recovered from the draining lymph nodes of mice injected with ad-vIL-10 behaved similarly. Bone-marrow-derived DCs cultured ex vivo with ad-vIL-10 or recombinant mouse IL-10 also suppressed DTH reactions by adoptive transfer when pulsed with the inciting antigen. Collectively, these data suggest a mechanism for the contralateral effect in which genetically modified macrophages and DCs present antigen in the context of high, local concentrations of vIL-10, thereby generating unresponsive T lymphocytes. These findings suggest new ways in which to treat immune-driven diseases by gene and cell therapy.

Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4.

Dendritic cells (DC) are APCs that are able to stimulate or inhibit immune responses, depending on levels of expression of MHC class I and II costimulatory molecules and cytokines. Our previous studies have suggested that the observed contralateral effect, where injection of a vector carrying certain immunomodulatory genes into one joint resulted in inhibition of arthritis in untreated joints, is mediated by in vivo modification of DC. Therefore, we have examined the ability of genetically modified DC to suppress established murine collagen-induced arthritis (CIA) after i.v. delivery. IL-4 has been shown to partially reduce the severity of CIA after repeated injection of recombinant protein or by injection of an adenoviral vector expressing IL-4. Here we demonstrate that i.v. injection of immature DC, infected with an adenoviral vector expressing IL-4, into mice with established CIA resulted in almost complete suppression of disease, with no recurrence for up to 4 wk posttreatment. Injection i.v. of fluorescently labeled DC demonstrated that the cells rapidly migrated to the liver and spleen after 6 h and to the lymph nodes by 24 h. In culture, spleen cells from DC/IL-4-treated mice produced less IFN-gamma after stimulation by collagen than did control groups. In addition, DC/IL-4 administration decreased the level of specific Abs against type II collagen, in particular the IgG2 Th1 isotype 14 days posttreatment. These results demonstrate the ability to treat effectively established murine arthritis by systemic administration of DC expressing IL-4.

Amino-p-benzoquinone Adducts and Polymers as Adhesion Promoters for Steel

Phenolic and quinonoid compounds are widely studied in biological sciences because of their ability to chelate heavy metals like iron and copper and recently have found new applications in synthetic macromolecules. Amino-p-benzoquinone polymers, poly[(2,5-hexamethylenediamino)-1,4-benzoquinone] and poly{[2,5-(2,2′-bistrifluoromethyl)-4,4′-biphenylenediamino]1,4-benzoquinone} were synthesized and evaluated as adhesion promoters for steel/epoxy joints. An improvement in the torsional shear strength of these joints was observed when these polymers were used as adhesion promoters. The durability of the adhesive bond was also improved after boiling water treatment, relative to untreated and silane-treated joints. The improvement in adhesion could be attributed to the formation of a chelate between the polyaminoquinone (PAQ) and the iron surface and a chemical reaction between the PAQ and the epoxy resin. A low molecular weight model compound, bis[2,5-(4-methylanilido)]-1,4-benzoquinone, was also used to study coupling between the epoxy adhesive and the steel surface. Electron spin resonance (ESR), atomic absorption spectroscopy and infrared spectroscopy were used to document the epoxy-coupling agent reaction and the chelate formation.

Static and Dynamic Behavior of Concrete Lift Joint Interfaces

Displacement controlled shear tests on concrete lift joint specimens with different surface preparations are conducted to compare dynamic sliding joint behavior with the static behavior. Experimental results indicate that the coefficient of friction decreases with the increase in normal load, under both static and dynamic shear. The shear strength is dependent on surface preparation. Monolithic specimens and water-blasted joints show higher shear strengths than untreated joints and plane independent joint surfaces. No strength degradation is noticeable under dynamic sliding shear tests since hysteresis loops are very stable. No dependency of shear strength on frequency content of the imposed shear displacements is observed. An empirical lift joint constitutive model is developed as a function of a basic friction coefficient and a roughness friction coefficient that is dependent upon the type of surface preparation. The proposed lift joint constitutive model is used to study the seismic sliding response of...

NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint.

The transcription factor NF-kappaB is a pivotal regulator of inflammatory responses. While the activation of NF-kappaB in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-kappaB in animal models of RA. We demonstrate that in vitro, NF-kappaB controlled expression of numerous inflammatory molecules in synoviocytes and protected cells against tumor necrosis factor alpha (TNFalpha) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-kappaB was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-kappaB by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IkappaBalpha profoundly enhanced apoptosis in the synovium of rats with SCW- and pristane-induced arthritis. This indicated that the activation of NF-kappaB protected the cells in the synovium against apoptosis and thus provided the potential link between inflammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-kappaB. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-kappaB.

Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus and topical routes of administration in dogs.

The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus i.v. and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Peak MTX concentrations in SF occurred at 38 +/- 5 min following bolus i.v. dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 +/- 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 +/- 1.2 hr) and SF (12.7 +/- 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 +/- 0.21 hr) was longer than that in plasma (2.56 +/- 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at approximately 4 hr, lasting for approximately 20 hr. The bioavailability of MTX from the gel was 11.8 +/- 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.

Interfacial chemistry and adhesion: The role of surface analysis in the design of strong stable interfaces for improved adhesion and durability

AbstractDurability is a key issue in widening the application of adhesive bonding technology. This paper describes a fundamental study of the adhesion loss in epoxy‐steel bonds exposed to water, and the development of steel pretreatments, which significantly enhance durability. XPS studies have revealed two weak links in epoxy/steel bonds, both of which must be improved for optimum performance. They are displacement of the adhesive from the steel and breakdown of the oxide on the metal surface. The former has been addressed by applying monomolecular layers of an aminosilane adhesion promoter to the steel surface. Oxide instability has been remedies by use of a novel and simple treatment that modifies the oxide chemistry to a depth of 2–5 nm. Combining these, results in a joint that loses no strength after 2000 h of water immersion at 50°C, whereas untreated joints lose 68% of their strength after only 400 h. The study shows how careful identification of failure modes, combined with appropriate modification of the substrate surface, can be used to design strong stable interfaces. These modification, which affect only a few molecular layers, have a large impact on both bond strength and durability.

Intraarticular Sodium Hyaluronate Injections in the Pond-Nuki Experimental Model of Osteoarthritis in Dogs

The effect of the intraarticular sodium hyaluronate (HA) injection on the osteoarthritic knee joint has been evaluated in dogs using an experimental model of osteoarthritis induced by sectioning the anterior cruciate ligament. Seven weeks after surgery, the damage, graded according to Mankin's scale, was significantly reduced in knee joints treated with HA from the second week postsurgery compared to untreated joints. When intraarticular HA therapy was initiated after the seventh week, osteoarthritis progression was still reduced compared to controls. Both morphology and morphometry showed a beneficial effect of HA on the cartilage response to the damage, as well as a clearcut inhibitory effect on the development of the fibroblastlike cell layer on the articular cartilage in untreated joints. The beneficial effects on the cartilage integrity and response to osteoarthritic damage might be related to a primary effect of HA on the cartilage surface. However, these effects do not exclude the possibility that, in addition, HA might act on the synovial membrane by limiting the synovial reaction.