Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

A longitudinal study of the quantitative evaluation of patella cartilage after total knee replacement by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping at 3.0 T: preliminary results.

OBJECTIVE: To characterize the quantitative changes of patella cartilage over time after total knee arthroplasty (TKA) by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping at 3.0 T. METHOD: Twenty-six knees of 26 patients (23 women and three men, mean age, 75 years) with primary osteoarthritis and osteonecrosis of the knee underwent TKA with a zirconia ceramic implant in this prospective study. Twelve patients without patella resurfacing (NR group) and 14 patients with patella resurfacing (R group) had TKA with cemented fixation. The implant position was examined by radiograph, computed tomography (CT) and magnetic resonance imaging (MRI). The clinical scores were checked pre-operatively, 1 year post-operatively and at the final follow-up. Patella cartilage and its thickness were evaluated pre-operatively and 1 year after TKA by dGEMRIC and T2 mapping in the NR group only. Patella cartilage was divided into eight regions of interest: the deep and superficial layers of the outer lateral and medial half, and the inner lateral and medial half from the central ridge. RESULTS: The implant position was appropriate in all cases and clinical scores were not significantly different between the two groups. The post-operative dGEMRIC value of the outer medial half superficial zone in the NR group was significantly decreased compared with the pre-operation value (P<0.05), whereas T2 mapping was not significantly changed in all zones. The cartilage thickness of the outer zone was significantly thinner post-operatively (P<0.05). CONCLUSIONS: These findings indicate that osteoarthritic changes in the outer zone of patella cartilage occurred 1 year after TKA.

Atelocollagen-associated autologous chondrocyte implantation for the repair of chondral defects of the knee: a prospective multicenter clinical trial in Japan.

BACKGROUND: New tissue-engineering technology was developed to create a cartilage-like tissue in a three-dimensional culture using atelocollagen gel. The minimum 2-year followup outcome of transplanting autologous chondrocytes cultured in atelocollagen gel for the treatment of full-thickness defects of cartilage in knees was reported from the single institution. The present multicenter study was conducted to determine clinical and arthroscopic outcomes in patients who underwent atelocollagen-associated autologous chondrocyte implantation for the repair of chondral defects of the knees. METHODS: At six medical institutes in Japan, we prospectively evaluated the clinical and arthroscopic outcomes of transplanting autologous chondrocytes cultured in atelocollagen gel for the treatment of full-thickness defects of cartilage in 27 patients (27 knees) with cartilage lesions on a femoral condyle or on a patellar facet over 24 months. RESULTS: The Lysholm score significantly increased from 60.0 +/- 13.7 points to 89.8 +/- 9.5 points (P = 0.001). Concerning the ICRS grade for arthroscopic appearance, 6 knees (24%) were assessed as grade I (normal) and 17 knees (68%) as grade II (nearly normal). There were few adverse features, except for detachment of the graft in two cases. CONCLUSIONS: We concluded that transplanting chondrocytes in a newly formed matrix of atelocollagen gel can promote restoration of the articular cartilage of the knee.

A new method of nerve bridging with a collagen mesothelial tube.

The effectiveness of a collagen mesothelial tube for nerve bridging was investigated in an experimental model of repair of rat sciatic nerves. The right sciatic nerve was cut, the two stumps were reflected and a collagen mesothelial tube was placed in the gap. The rod was removed at 4 weeks after implantation. At this point, the "bridging" was performed with a 10-mm gap (Group M). Two control groups were similarly treated but one with a collagen tube (Group C) and the other with a silicone tube (Group S). Regeneration of the sciatic nerves was assessed using a sciatic function index, by measuring blood flow and by the number of regenerated axons at 4, 8 and 12 weeks after bridging. Group M showed significantly better results with respect to all three assessments. The collagen mesothelial tube used in our study appears to be a promising tool for bridging peripheral nerve defects.

Decrease in anterior knee laxity by electrical stimulation of normal and reconstructed anterior cruciate ligaments.

We have investigated the changes in anterior laxity of the knee in response to direct electrical stimulation of eight normal and 45 reconstructed anterior cruciate ligaments (ACLs). In the latter, the mean time from reconstruction was 26.7 months (24 to 32). The ACL was stimulated electrically using a bipolar electrode probe during arthroscopy. Anterior laxity was examined with the knee flexed at 20 degrees under a force of 134 N applied anteriorly to the tibia using the KT-2000 knee arthrometer before, during and after electrical stimulation. Anterior tibial translation in eight normal and 17 ACL-reconstructed knees was significantly decreased during stimulation, compared with that before stimulation. In 28 knees with reconstruction of the ACL, in 22 of which the grafts were found to have detectable somatosensory evoked potentials during stimulation, anterior tibial translation was not decreased. These findings suggest that the ACL-hamstring reflex arc in normal knees may contribute to the functional stability and that this may not be fully restored after some reconstructions of the ACL.

Reconstruction of the anterior cruciate ligament. Single- versus double-bundle multistranded hamstring tendons.

A total of 108 patients with unilateral instability of the knee, associated with rupture of the anterior cruciate ligament, was prospectively randomised for arthroscopic single- or double-bundle reconstruction of the ligament using hamstring tendons. The same post-operative rehabilitation protocol was used for all. The patients were followed up for a mean of 32 months (24 to 36). We measured the anterior laxity and joint position sense at different angles of flexion of the knee to determine whether both bundles in the double-bundle reconstruction contributed to the stability of the joint and proprioception. No significant difference was found between the two groups with regard to anterior laxity measured by the KT-2000 arthrometer with the knee at 20 degrees or 70 degrees flexion nor with regard to proprioception. A notchplasty was required less often in the double- compared with the single-bundle reconstruction. We did not find any advantage in a double-bundle as opposed to a single-bundle reconstruction in terms of stability or proprioception.

Repair of neglected Achilles tendon rupture using gastrocnemius fascial flaps.

BACKGROUND: Neglected Achilles tendon rupture is a rare disorder. In this article, we discuss the results of 10 patients with neglected Achilles tendon ruptures who were treated surgically. METHODS: Between 1980 and 1997, we treated 10 patients (6 men and 4 women) using gastrocnemius fascial flaps according to the method described by Lindholm. The mean age of the patients at the time of the operation was 51 years (range 38-57 years). They were followed-up for 26-192 months. RESULTS: There were significant differences between the American Orthopaedic Foot and Ankle Society (AOFAS) scale score before the operation (72.6+/-5.3) and the score at the most recent follow-up (98.1+/-2.5) (p<0.0001). On Cybex isokinetic strength testing, the peak torque deficiencies in plantar flexion ranged from 8% to 68% at the low setting and from 19% to 33% at the high setting preoperatively, and ranged from -9% to 17% at the low setting and from -13% to 23% at the high setting postoperatively. There were no re-ruptures. CONCLUSION: Our data indicate that the reconstructive technique using gastrocnemius fascial flaps can result in an excellent clinical and functional outcome.

Diagnosis of a tear of the tibiofibular syndesmosis. The role of arthroscopy of the ankle.

In 52 patients we compared the accuracy of standard anteroposterior (AP) radiography, mortise radiography and MRI with arthroscopy of the ankle for the diagnosis of a tear of the tibiofibular syndesmosis. In comparison with arthroscopy, the sensitivity, specificity and accuracy were 44.1%, 100% and 63.5% for standard AP radiography and 58.3%, 100% and 71.2% for mortise radiography. For MRI they were 100%, 93.1% and 96.2% for a tear of the anterior inferior tibiofibular ligament and 100%, 100% and 100% for a tear of the posterior inferior tibiofibular ligament. Standard AP and mortise radiography did not always provide a correct diagnosis. MRI was useful although there were two-false positive cases. We suggest that arthroscopy of the ankle is indispensable for the accurate diagnosis of a tear of the tibiofibular syndesmosis.

Induction of somatosensory evoked potentials by mechanical stimulation in reconstructed anterior cruciate ligaments.

We have determined whether somatosensory evoked potentials (SEPs) were detectable after direct mechanical stimulation of normal, injured and reconstructed anterior cruciate ligaments (ACLs) during arthroscopy. We investigated the position sense of the knee before and after reconstruction, and correlated the SEP with instability. Reproducible SEPs were detected in all 19 normal ACLs and in 36 of 38 ACLs reconstructed during a period of 13 months. Of the 45 injured ACLs, reproducible SEPs were detected in 26. The mean difference in anterior displacement in the SEP-positive group of the injured ACL group was significantly lower than that in the SEP-negative group. In the reconstructed group, the postoperative position sense was significantly better than the preoperative position sense. Our results indicate not only that sensory reinnervation occurs in the reconstructed ACL, but also that the response to mechanical loads can be restored, and is strongly related to improvement in position sense.

Arthroscopic assessment of human cartilage stiffness of the femoral condyles and the patella with a new tactile sensor.

We measured the stiffness of the cartilage of the human femoral condyles via an ultrasonic tactile sensor under arthroscopic control. The stiffness and the degeneration of articular cartilage were assessed in 105 knees in 74 patients (39 men, 35 women, age: 9-72 years) who underwent arthroscopic observation or surgery. Twenty-five knees suffered from traumatic cartilage injury, 14 from osteochondritis dissecans, 13 from osteoarthritis, 11 from meniscal injury and six from ligamentous injury, bipartita patellae (three knees), and symptomatic plica synovialis (two knees). The degeneration of cartilage was classified according to Outerbridge's grading system. The relationships between the stiffness and the grade of cartilage degeneration, and gender were analyzed. The stiffness of grade I (softening) and II (fissuring less than 0.5 inches in length) was significantly lower than that of intact cartilage. In contrast, the stiffness of grade IV (exposed subchondral bone) was significantly higher than that of any other group. The cartilage stiffness of the patella in women was significantly lower than that in men. The tactile sensor was useful for determining the intraoperative stiffness of healthy and diseased human cartilage in all grades.

Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee.

We investigated the clinical, arthroscopic and biomechanical outcome of transplanting autologous chondrocytes, cultured in atelocollagen gel, for the treatment of full-thickness defects of cartilage in 28 knees (26 patients) over a minimum period of 25 months. Transplantation eliminated locking of the knee and reduced pain and swelling in all patients. The mean Lysholm score improved significantly. Arthroscopic assessment indicated that 26 knees (93%) had a good or excellent outcome. There were few adverse features, except for marked hypertrophy of the graft in three knees, partial detachment of the periosteum in three and partial ossification of the graft in one. Biomechanical tests revealed that the transplants had acquired a hardness similar to that of the surrounding cartilage. We conclude that transplanting chondrocytes in a newly-formed matrix of atelocollagen gel can promote restoration of the articular cartilage of the knee.

Effects of low-intensity pulsed ultrasound on proliferation and chondroitin sulfate synthesis of cultured chondrocytes embedded in Atelocollagen gel.

The effects of low-intensity pulsed ultrasound (US) on the proliferation and chondroitin sulfate synthesis of cultured chondrocytes embedded in Atelocollagen gel in vitro were examined. Articular cartilage was harvested from the hip, knee, and shoulder joints of 10-week-old Japanese white rabbits. Chondrocytes isolated by collagenase digestion were embedded in type I collagen gel, Atelocollagen gel, and were cultured in Dulbecco's modified eagle's medium for 3 weeks. The US apparatus, SAFHS, was used to deliver an ultrasound signal with spatial and temporal average intensities of 30 mW/cm(2) (US group). The frequency was 1.5 MHz with a 200-microsecond tone burst repeated at 1.0 kHz. US treatments were administered for 20 min per day under culture dishes, with the medium replaced twice a week. Another group of cells was exposed to sham ultrasound as a control. Cell number, histological findings, synthesis of isomers of chondroitin sulfate, and stiffness of the chondrocyte-collagen gel composites were analyzed. US exposure promoted synthesis of chondroitin sulfate, especially chondroitin 6-sulfate, although it did not significantly enhance cell number and stiffness. In this three-dimensional culture model, these results suggest that US exposure may be clinically useful in improving the quality of chondrocyte-Atelocollagen implants for transplantation into articular cartilage defects.

Computed tomographic evaluation of the position of the leg for mortise radiographs.

We investigated the most advantageous internal rotation angle of the leg for mortise radiographs. One hundred and twenty-eight feet of 64 healthy volunteers with no histories of ankle or foot pathology (72 feet of 36 males, 56 feet of 28 females) were examined. The subjects had an average age of 29 years (range, 19 to 51 years), average height of 167 cm (range, 157 to 181 cm), and average foot length of 25 cm (range, 23 to 27 cm). We obtained a plain axial view at the level of the central patella and 5 mm proximal to the tibial plafond using computed tomography, and investigated the inclination angle of the distal tibiofibular joint to a horizontal plane, regarding it as a mortise angle. The mean mortise angle was 19.1 +/- 5.0 degrees. However, two peaks were observed at around 15 degrees and 20 degrees. This indicated that the mean mortise angle of the males was 21.2 +/- 4.6 degrees, and the mean mortise angle of the females was 16.4 +/- 4.1degrees, with a significant difference between the males and the females' mortise angle (P < 0.0001). There was no correlation between the mortise angle and the height (P = 0.899 in the males, and P = 0.871 in the females), nor between the mortise angle and the foot length (P = 0.359 in the males, and P = 0.512 in the females). Therefore, we concluded that the internal rotation angle of the leg for mortise radiography should be generally set up at about 20 degrees on males and 15 degrees on females.

Expression of cytokines after meniscal rasping to promote meniscal healing.

PURPOSE: We have developed a new surgical procedure of rasping a meniscal surface to repair a tear in the avascular zone. This procedure stimulates vascular induction to the tear, resulting in meniscal healing. The purpose of this study was to elucidate the mechanism of vascular induction and meniscal healing. TYPE OF STUDY: Randomized trial. METHODS: A full-thickness longitudinal tear of 5 mm in length was created in the avascular zone of the anterior segment of both medial menisci of rabbits. Meniscal rasping of about 0.5 mm in depth was then done on the femoral surface of the left meniscus from the parameniscal synovium to the inner portion including the longitudinal tear, and the right meniscus was left untreated as a control. After surgery, at 1, 7, 14, 28, 56, and 112 days, 4 rabbits were killed, both medial menisci were resected, and immunohistochemical staining with monoclonal antibodies was used to quantify expression of interleukin-1alpha (IL-1alpha), transforming growth factor-beta1 (TGF-beta1), platelet-derived growth factor (PDGF), and proliferating-cell nuclear antigen (PCNA) on the femoral surface of the menisci. A positive ratio of immunostaining was encountered. RESULTS: The positive ratio of IL-1alpha, TGF-beta1, PDGF, and PCNA on the rasped surface area reached its peak at 1, 7, 14, and 7 days, respectively, after surgery, and thereafter gradually declined. Although the time course of the positive ratio was different among these cytokines, the positive ratio on the rasped surface was significantly higher than that on the control surface at the early stage of the observation period. CONCLUSIONS: The cytokine network on the rasped meniscal surface appears to be the key to explaining the mechanism of vascular induction and meniscal healing by meniscal rasping.

AG-041R, a gastrin/CCK-B antagonist, stimulates chondrocyte proliferation and metabolism in vitro.

A newly synthesized compound, AG-041R, 3R-1-(2,2Diethoxyethyl)-3-((4methylphenyl) amino-carbonylmethyl)-3-((4methylphenyl)ureido-indoline-2-one), is a cholecyctokinin-B/gastrin receptor antagonist, but unexpectedly magnified cartilage formation in vivo. Indeed, AG-041R is a potentially effective reagent for the repair of articular cartilage defects. To clarify its effects on chondrocytes, we studied the proliferation, matrix formation, and gene expression of rabbit primary chondrocytes cultured in type I collagen gel composites with AG-041R. Both proliferation and glycosaminoglycan synthesis were stimulated with 1 microM AG-041R, but suppressed with 10 microM. The ratio of the amounts of two chondroitin sulfate isomers, chondroitin-6-sulfate to chondroitin-4-sulfate (an indicator of cartilage maturation), increased with 1 microM but decreased with 10 microM AG-041R. Gene expression analysis showed there was no change in the relative expression levels of chondrocyte markers, Type II collagen and Aggrecan, and osteoblast and adipocyte markers, Type I collagen and PPARgamma, respectively. These findings suggest that adequate concentrations of AG-041R stimulate proliferation of chondrocytes in the matrix, without changing their differentiated characteristics.

Current concepts in tissue engineering technique for repair of cartilage defect.

Hunter's observation in 1743 that cartilage "once destroyed, is not repaired," has not essentially changed for 250 years. At present, there is no well-established procedure for the repair of cartilage defect with articular cartilage, which has the same biochemical and biomechanical properties as the surrounding normal intact cartilage. In 1994, transplantation of human autologous chondrocytes in suspension, as reported by Brittberg et al., provided a potential procedure for articular cartilage repair. We have improved their procedure and developed a new technique which creates new cartilage-like tissue by cultivating autologous chondrocytes embedded in Atelocollagen gel for 3 weeks before transplantation. These improvements maintained the chondrocyte phenotype, evenly distributed chondrocytes throughout the osteochondral defects, and decreased the risk of leakage of grafted chondrocytes into the defects. Good clinical results suggest that this technique should be a promising procedure for repairing articular cartilage defect.

A case of superficial peroneal nerve injury during ankle arthroscopy.

We report a case of superficial peroneal nerve (SPN) injury caused by ankle arthroscopy. A 20-year-old woman underwent arthroscopy on her right ankle because of chronic ankle pain after a sprain. After arthroscopy, the patient complained of pain on the dorsum of her right foot and felt a radiating pain from the anterolateral portal to the dorsomedial aspect of her foot. Eight months after arthroscopy, we found that a neuroma had developed on the intermediate dorsal cutaneous nerve, and performed neurolysis of the SPN. Her symptoms gradually decreased after surgery, and had disappeared by 45 months. To avoid such an injury of the SPN, the safest placement of the anterolateral portal is necessary and is, according to our previous anatomic study, 2 mm lateral to the peroneus tertius tendon.

Intraosseous hypertension and venous congestion in osteonecrosis of the knee.

To determine whether an angiogenic factor affects the pathogenesis of the idiopathic osteonecrosis of the medial femoral condyle, intraosseous pressure and venogram in 11 knees with osteonecrosis were compared with intraosseous pressure and venogram in 11 knees with the medial type of osteoarthritis. Patients were matched by age, gender, obesity index, blood pressure, tibiofemoral angle, and clinical evaluation. The intraosseous pressure of the medial condyle of the knees with osteonecrosis (62.8 +/- 27.3 mm Hg) was significantly higher than that in the lateral condyle of the knees with osteonecrosis (25.4 +/- 18.9 mm Hg) and those of both condyles of the knees with osteoarthritis (medial, 31.6 +/- 17.4 mm Hg; lateral, 29.5 +/- 11.0 mm Hg). In contrast, there was no significant difference in the pressure between the medial and lateral condyles of the knees with osteoarthritis. Venography showed a marked disturbance of venous drainage in all patients with osteonecrosis. In addition, the average clearance time of the medium in the medial femoral condyle was significantly more prolonged in patients with osteonecrosis (17.7 +/- 6.1 minutes) than in patients with osteoarthritis (5.5 +/- 1.6 minutes). These data support the hypothesis that venous stasis within the medullar canal in the condyle increases intraosseous pressure and decreases arteriovenous pressure difference, leading to osteonecrosis.

Discrimination between several diterpenoid compounds in feeding by Gambusia affinis.

The alcyonacean soft coral Sinularia flexibilis Quoy and Gaimard produces a number of bioactive complementary (secondary) metabolites. The ability of three of these diterpenes - flexibilide, sinulariolide and dihydroflexibilide - to elicit differential discriminatory feeding behavior in Gambusia affinis was assessed in a feeding deterrence study. Terpene-impregnated fish flakes were offered to fish trained to feed on such food, and their responses (acceptance, rejection, avoidance, or no response) were assessed as indicative of feeding deterrence. Food treated with sinulariolide (a compound previously determined to be non-bioactive) was generally accepted at a 1% concentration. It was avoided and rejected, however, at a concentration of 10%, a concentration level generally restricted to polyp-rich branchlets. This indicated negative olfactory and palatability cues, respectively. Flexibilide-treated flakes were accepted to some extent by the fish at the 1% concentration, but strongly avoided at the 10% concentration, indicating effective feeding deterrence via olfaction. Dihydroflexibilide-impregnated flakes were strongly rejected even at low concentrations (1%) after tasting, indicating a negative palatibility cue. They were strongly avoided or rejected at higher concentrations (10%), indicating a negative olfactory cue as well. This response at higher concentrations indicates that sinulariolide and flexibilide become effective at concentrations between 1% and 10%. Such concentrations may be found in the polypary (polyp-bearing portion) of the soft coral colonies. Dihydroflexibilide elicited the strongest negative palatability response from these test fish. The feeding deterrence characteristics of the compounds determined here represent the potentials of individual compounds to elicit differential feeding responses in organisms like Gambusia which are capable of discriminating between different but closely related complementary (secondary) metabolites.

Proprioceptive improvement in knees with anterior cruciate ligament reconstruction.

The correlation between the prospective course of proprioceptive improvement and knee stability after anterior cruciate ligament reconstruction was investigated in 38 patients. Proprioception, on the basis of the patient's capacity to reposition the limb accurately, was evaluated at 3-month intervals for 24 months after hamstring graft anterior cruciate ligament surgery. Knee stability was evaluated concurrently with a KT-2000 knee arthrometer. Thirty patients experienced improvement in postoperative position sense in at least one of the examinations, although eight patients had no improvement at any time. Of the 30 patients who had improvement, 28 maintained improved position sense from 18 months to the final followup. Thirty patients maintained significantly better knee stability for a postoperative period of at least 24 months. These results indicated that a minimum of 18 months after anterior cruciate ligament reconstruction may be needed for complete restoration of the proprioceptive function in knees, although the mean position sense in all patients gradually improved from 9 months. Improvement in postoperative knee stability may have facilitated recovery of proprioception.