Growth-factor-induced healing of partial-thickness defects in adult articular cartilage.

OBJECTIVE: We have previously shown (Hunziker and Rosenberg, J Bone Joint Surg 1996;78A:721-33) that synovial cells can be induced to migrate into partial-thickness articular cartilage defects, therein to proliferate and subsequently to deposit a scar-like tissue. We now wished to ascertain whether these synovial cells could be stimulated to transform into chondrocytes, and thus to lay down cartilage tissue, by the timely introduction of a differentiation factor. DESIGN: Partial-thickness defects were created in the knee-joint cartilage of adult miniature pigs. These were then filled with a fibrin matrix containing a free chemotactic/mitogenic factor and a liposome-encapsulated chondrogenic differentiation one. Tissue was analyzed (immuno)histochemically at 2, 6 and 12 months. RESULTS: Defects became filled with cartilage-like tissue which registered positive for all major cartilage-matrix components; it remained compositionally stable throughout the entire follow-up period. CONCLUSION: Although still requiring considerable refinement, our one-step, growth-factor-based treatment strategy has the basic potential to promote intrinsic healing of partial-thickness articular cartilage defects, thus obviating the need for transplanting cells or tissue.

Treatment of canine intervertebral disc displacement with chondroitinase ABC.

STUDY DESIGN: This study demonstrated the therapeutic value of chemonucleolysis with chondroitinase ABC to canine intervertebral disc displacement. OBJECTIVES: To determine the efficacy of Chondroitinase ABC in the management of canine intervertebral disc displacement. SUMMARY OF BACKGROUND DATA: No previous study has assessed the chemonucleolysis with chondroitinase ABC in the displaced discs. The changes of intervertebral disc syndrome were evaluated in this study. METHODS: Fifty-nine dogs with symptoms and signs of intervertebral disc displacement were treated with Chondroitinase ABC by a single intradisc injection. The changes in symptoms and signs of disc herniation in the dogs were followed from 7 days to 3 years after treatment. RESULTS: Forty-eight dogs were evaluated for the efficacy of the chemonucleolytic treatment with chondroitinase ABC. At 1 week after injection, 45 of 48 dogs showed some improvement in symptoms and signs. No adverse reactions were observed. There was no recurrence of symptoms in nine dogs who were observed from 14 months to 3 years after injection. CONCLUSION: Chemonucleolytic treatment with chondroitinase ABC is an effective and safe method for the management of canine intervertebral disc displacement.

Update on chemonucleolysis.

A review of the world medical literature on chemonucleolysis with an emphasis on recent studies, meta-analyses, and the history of the procedure in North America from a regulatory, social, and medicolegal perspective was performed to determine the current status of chemonucleolysis in the management of disc displacement. The world literature supports the use of chymopapain for chemonucleolysis as a safe and effective alternative to surgical disc excision. The efficacy of chymopapain has been shown by prospective, randomized, placebo-controlled, double-blind trials with a minimum 10-year follow-up period. The safety of chymopapain injection compared with surgery has been demonstrated in meta-analyses and in extensive post-marketing surveillance in the United States and Europe. Clinical studies with collagenase and laboratory studies with chondroitinase ABC have shown that chemonucleolysis can be performed with enzymes other than chymopapain. Clinical trials have been performed with collagenase for chemonucleolysis, but all of the results have not been published. Preclinical research with chondroitinase ABC has demonstrated its usefulness for chemonucleolysis in the animal model, but human trials have not begun.

Chondroitinase ABC (pharmaceutical grade) for chemonucleolysis. Functional and structural evaluation after local application on intraspinal nerve structures and blood vessels.

STUDY DESIGN: The effects on nerve tissue and blood vessels of locally applied chondroitinase ABC were studied in two experimental models using chymopapain and the vehicle of chondroitinase ABC for controls. OBJECTIVES: To assess the effects of chondroitinase ABC on blood vessels and nerve tissue after local application. SUMMARY OF BACKGROUND DATA: Chondroitinase ABC has been suggested for chemonucleolysis because it has a high specificity for nucleus pulposus matrix, which could mean a high efficiency in dissolving disc tissue combined with a low risk of side effects on other tissues. METHODS: Chondroitinase ABC or controls were injected intrathecally in the pig, and nerve conduction velocity and histologic changes were assessed after 7 days. The same substances were injected into the hamster cheek pouch and studied for 60 minutes for microvascular effects. The vehicle for the enzyme was used as a negative control and chymopapain in a therapeutic concentration served as a positive control. RESULTS: In all series there was a slight intrathecal fibrotic reaction that was most pronounced after chymopapain injection. The effects on nerve conduction velocity and nerve morphology were similar between chondroitinase ABC and its vehicle. Chymopapain induced a significant reduction in nerve conduction velocity and pronounced histologic changes. In the cheek pouch, chymopapain induced a stand-still of blood flow at the injection site, and microhemorrhage and macromolecular leakage from the vessels at the border of the injection site. Only a slightly reduced blood flow was occasionally found after injection of chondroitinase ABC and controls. CONCLUSIONS: In agreement with the current literature, these observations indicate that chondroitinase ABC is safe regarding adverse effects on nerve tissue and blood vessels. The slight reduction in conduction velocity after intrathecal injection of chondroitinase ABC or its vehicle is most likely the result of surgical injury while releasing the nerve roots from the intrathecal fibrous adhesions. Such adhesions may be related to the laminectomy per se, and probably have no pathophysiologic significance.

Experimental chemonucleolysis with chondroitinase ABC in monkeys.

STUDY DESIGN: Experimental chemonucleolysis with chondroitinase ABC as compared with chymopapain was investigated in monkeys. The effects of these two enzymes were analyzed morphologically and biochemically. OBJECTIVES: The results of the present study facilitate the clinical application of chondroitinase ABC. SUMMARY OF BACKGROUND DATA: Many experimental studies on chemonucleolysis with chondroitinase ABC have been reported mostly in rabbits. Further examination in animals that are more similar to humans is necessary for its clinical application. METHODS: Ten mature rhesus monkeys were used. Lumbar intervertebral discs from six monkeys were injected with either chondroitinase ABC, chymopapain, or physiologic saline. The animals were killed not more than 6 weeks after injection, and their discs were examined morphologically and biochemically. The remaining four monkeys were used for a longer follow-up study to determine the changes in chondroitinase ABC-injected discs. RESULTS: Degenerative changes of discs were more severe with the injection of chymopapain, although the content of hyaluronic acid, chondroitin sulfate, and dermatan sulfate decreased more with the injection of chondroitinase ABC. In a longer follow-up study, chondroitinase ABC-injected discs recovered somewhat morphologically and biochemically. CONCLUSIONS: The results confirm that selective degradation is achieved with chondroitinase ABC in vivo in monkeys and that chondroitinase ABC is less toxic to discs than chymopapain is. From these considerations, chondroitinase ABC is believed to have a high potential for clinical application.

Effects of chondroitinase ABC on degenerative intervertebral discs.

The effects of chondroitinase ABC on surgically induced degenerative rabbit intervertebral discs were determined during a 12-week period by magnetic resonance imaging, radiography, and histologic examination. Rabbit intervertebral discs were surgically extruded, inducing disc degeneration 12 weeks before injection of chondroitinase ABC. Magnetic resonance imaging showed a hypointense area in the center of the surgically induced disc degeneration. After injection of chondroitinase ABC, the hypointense area became more intense, but reversed somewhat by the end of the 12-week period. Additional evidence of the effects of chondroitinase ABC on a surgically induced degenerative disc model was shown by radiographic evidence of shrinkage of the disc after injection. Histologic examination revealed a fibrous degenerative disc induced by surgical extrusion. However, the staining properties of the matrix of the nucleus pulposus was similar to that of normal discs before chondroitinase ABC injection, but diminished after the injection, with slight recovery at 12 weeks. The results suggest that chondroitinase ABC induces chemonucleolysis in the degenerated disc. Also, chondroitinase ABC does not destroy the degenerative disc matrix ability to regenerate after 12 weeks.

Nucleolysis of the rabbit intervertebral disc using chondroitinase ABC.

The nucleolytic action of chondroitinase ABC was studied by the use of rabbit lumbar intervertebral discs. The injection of one unit of enzyme results in necrosis of the nucleus pulposus. Radiologic, histologic, and biochemical changes were evident in discs studied 2 days after injection, and consistent nucleolysis was seen in those studied after 6 days. These results show that chondroitinase ABC deserves further evaluation as a possible chemonucleolytic enzyme.

Effects of chondroitinase ABC on intrathecal and peripheral nerve tissue. An in vivo experimental study on rabbits.

The enzyme chondroitinase ABC has recently been suggested for use in chemonucleolysis. The effects of 200 U ml of chondroitinase ABC were studied on intrathecal and peripheral nerve tissue in rabbits. After the intrathecal (subarachnoid) application of 0.2 ml of either the diluent in the control group (N = 2) or chondroitinase in the study group (N = 4), no neurologic deficit was detected. Compared with the control group, no morphologic changes at the light microscopic level were induced in the spinal cord by chondroitinase. No neurophysiologic differences were detected between tibial nerves after exposure to 1 ml of the diluent (control, N = 8) or chondroitinase (the other leg) for 4 weeks, nor did the study group, compared with the control group, show any morphologic changes in the tibial nerves. Because the concentration of chondroitinase ABC tested was approximately 40 times higher than might be used clinically for chemonucleolysis, the present study indicates a wide margin of safety for unwanted side effects on nerve tissue.

Experimental chemonucleolysis with chondroitinase ABC.

Chemonucleolysis has recently become an established treatment for intervertebral disc protrusion. However, the exact mechanism of chemonucleolysis is still unknown. If mechanisms of chemonucleolysis include diminution of intradiscal pressure followed by subsequent regeneration of the nucleus pulposus, then a more selective enzyme for glycosaminoglycan, chondroitinase ABC, might be used for chemonucleolysis instead of chymopapain. Thus experimental chemonucleolysis with chondroitinase ABC compared with chymopapain was investigated. In rabbits, chondroitinase ABC is as effective for chemonucleolysis as chymopapain, but the chemonucleolysis process with chondroitinase ABC was milder than with chymopapain. At an early chemonucleolysis phase, chondroitinase ABC action was chiefly limited to digestion of the matrix, and a large number of cells in the nucleus pulposus remained. During long-term observations of chemonucleolysis with chondroitinase ABC, nuclear structure was restored to a nearly normal state. Although limited, this study indicates that chondroitinase ABC might be more suitable than chymopapain for chemonucleolysis.