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관절연골 손상의 치유과정에 관한 실험적 연구

관절연골 손상의 치유과정에 관한 실험적 연구
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(The) healing process of the articular cartilage injuries
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연세대학교 대학원
[영문] It was formerly believed that injured cartilage possessed no power of regeneration. In 1743 Hunter published an article, "The Structure and Disease of Articulating Cartilage" in which he said, "From Hippocrates to the present age it is universally allowed that ulcerated cartilage is a troublesome thing and that when once destroyed it is not repaired." Redfern, in 1851, described morphology and histology of wounds of the articular cartilage of joints in doss. He stated that the wound healed perfectly by the in growth of fibrous tissue, which he believed arose from the intercellular substance of the chondrocytes of the articular cartilage, and he initiated the concept that the cells of the articular cartilage play an active part in the healing of such a defect. After that many investigators have tried to determine whether injured articular cartilage is capable of regeneration or not. The reparative processes which occur fellowing injury to articular cartilage have been a controversial subject for many years. Certain investigators have reported having observed regeneration of articular cartilage, yet as to the extent of the healing, the nature of the heating tissue and the origin of the derived tissue, they are not in agreement. We can summarize five main views on the nature of the course of repair after injury of the articular cartilage. These views maintain: (1) that regeneration of damaged articular cartilage does not occur(Hunter, 1743 ; Leidy, 1849; Meachim, 1963; DePalma et at., 1966; Repo and Mitchell, 1971; Fuller and Ghadially, 1972); (2) that healing occurs as a result of proliferation of adjacent cartilage cells into hyaline cartilage (Calandruccio and Gilmer Jr., 1962); (3) that healing occurs as a connective tissue proliferation from adjacent perichondrium or fascia (Paget, 1853;Gies, 1882; Ciociola, 1921; Haebler, 1925; Maximow and Bloom, 1957); (4) that a cartilagenous defect is repaired by metaplasia of connective tissue arising from the subchondral bone into hyaline cartilage (Shands, 1931; DePalma et al., 1966): (5) that a cartilagenous defect is repaired by metaplasia of connective tissue arising from the subchondral bone into fibrocartilage or fibrous tissue (Campbell, 1969 ; Coventry et al., 1972). Articular cartilage from mature animals is totally avascular, aneural, and alymphatic and comprises a unique and extraordinary body tissue, whose structual, biochemical and metabolic characteristics have been virtually unexplored. On the nutrition of articular cartilage, Honner and Thompson (1971) concluded that in immature rabbits an isotope appeared to enter the cartilage from both the synovial fluid and the subchondral bone, while in the mature animals the isotope appeared to enter articular cartilage only from the synovial fluid. Tritiated thymidine is a radioactive nucleotide, with a very weak beta emanation, which lends itself well to the investigation of regenerating tissue. It is known that thymidine becomes fixed within the nucleus of a cell during the period of DNA synthesis. The need for new DNA and hence new thymidine only occurs when the chromosomes duplicate prior to mitotic division. Thus, thymidine uptake by a cell indicates an imminent division, and therefore, serves as a highly specific qualitative index of cellular reproduction. By autoradiographic analysis we intend to demonstrate which cells, if any, are involved in articular cartilage regeneration. Thus grain exposures of overlying photographic emulsion will be made from tritiated tissues by beta emanation, which remain well localized to the areas of emanation. From a clinical aspect, the healing of damaged cartilage has remained a very interesting subject in the prognosis of separated fractures and compressed fractures, in the fate of defects of articular cartilage and in chronic arthritis including rheumatoid arthritis. The purpose of the research is mainly to show: (1) whether the injured cartilage heals or not: (2) what tissue is related to the healing; (3) from where the tissue is derived; (4) how the healing process takes place after inaccurate reduction in osteochondral fracture. One hundred and twenty immature (500-700 gm.) and mature (about 2.0 kg.) albino rabbits (240 knee joints) were used in this experimental study. The animals were divided into 6 groups of immature and mature rabbits respectively, thus each group contained ten immature and ten mature rabbits. The animals were operated on in sterile conditions under nembutal anesthesia. (30 mg. per kg. of body weight). An anteromedial parapatellar incision was made over the knee joint and articular cartilage of the femoral condyle was exposed, with the patella dislocated laterally. Cartilage injuries and defects of various types according to groups were made and the wound closed. In group Ⅰ a defect was extended into subchondral bone with an osteotome and the fractured condyles allowed to heal for the observation period. In group Ⅱ a fracture fragment was reduced with approximately 1.0 mm. displacement with two Kirschner wires. In group Ⅲ a cartilage slice with a scalpel was made on the nonweight bearing surface of the patellar groove of the femoral condyle. In group Ⅳ a superficial cartilage slice, not reaching to the subchondral bone, was made on the weight bearing surface of the medial femoral condyle. In group Ⅴ a large superficial quadrangular cartilage defect measuring about 5X6XO.5mm, in size, not reaching to the subchondral bone, was made weight bearing surface of the medial femoral condyle. In group Ⅵ a deep 5 mm. core defect was made on the weight bearing surface of the medial femoral condyle reaching to the subchondral bone. The operated animals were sacrificed with an interval of 2 days, 5 days, and 1, 2, 3, 4, 6, 9, 12 and 20 weeks respectively after the creating of the articular cartilage injury. In each case 24 hoers prior to sacrifice 0.4m Ci per kg. of body weight of thymidinemethyl-H**3 (1.0 m Ci per 0.21 mg. in 1.0 ml. of sterile water with a specific activity of 2 curies per millimole) was injected by intravenous route. After sacrifice, the distal portions of the femora were resected and placed in 10% neutral formalin solution and fixed for a day. A(tar fixation they were decalcified and paraffin blocks made. Multiple sections of each specimen were cut at five mica and stained with hematoxylin and eosin for histological observation. For the autoradiography the multiple sections of each specimen, which were cut at five micra, were coated with Kodak NTB-3 nuclear emulsion and allowed to expose for periods of twenty five to twenty eight days. The autoradiographs were developed with Kodak D-19 developer and stained with hematoxylin and eosin. Autoradiographic technique was based on Messier and Leblond's dipping section method. The results observed in this study were mainly concentrated on the function of the joint, gross findings of the synovium, gross findings of the articular surface of cartilage, microscopic findings and autoradiographic findings. The function of the joints returned to normal ten days after operation, with subsidence of joint swelling and limping gait. The synovium showed continuous swelling and acute inflammatory change for a few weeks, and four weeks later numerous villi formations and pannus like projections were noticed and the chronic inflammatory change continued for 20 weeks. Gross findings of the articular cartilage revealed discoloration near the injured site in all groups regardless of maturity. Grossly there was healing in 6 weeks in group Ⅰ, in 12 weeks in group Ⅱ, in 6 weeks in group Ⅲ, in 9 weeks in group Ⅳ and in 20 weeks in group Ⅵ, but in group Ⅴ the defect site did not heal until 20 weeks later. Microscopic findings in the synovium showed swelling of the tissues and acute inflammatory reaction on the second day after operation. The swelling gradually subsided, but chronic inflammatory change remained. After 9 weeks there was noted round cell infiltration, fibrosis, thickening and villi formation in the tissue. In the deep injured group (1, 2 and 6), microscopic findings of the articular cartilage between 2 and 5 days showed appearance of fibroblasts and the defect site was filled by fibrin and articular cartilage near the defect revealed mild degenerative changes. In group Ⅰ it was noticed that the defect in the superficial layer of the cartilage filled with matrix from adjacent cartilage in the mature animal and the deep layer of the cartilage was filled with the fibrous tissue from the subchondral region after one week. After 9 to 12 weeks the defect was healed with hyaline cartilage and the joint surface retained its smoothness 12 weeks after in immature animals and 20 weeks in mature animals in the groups Ⅱ and Ⅵ. In the superficial injured group (3, 4 and 5), mild degenerative change was noticed near the defect between 2 and 5 days after surgery. This healed with hyaline cartliage in 4 to 6 weeks in group Ⅲ. However in group Ⅳ the defect site was filled with matrix flow from the adjacent cartilage and healed with hyaline cartilage in 9 to 12 weeks. In the large superficial cartilage defect group, the degenerative change near the defect continued until 20 weeks and it was observed no healing evidence. General1y the healing process was delayed in mature animals in all groups. The histologic and autoradiographic findings lead us to conclude that; 1) The synovium showed a nonspecific chronic inflammatory process. 2) There was a healing process of hyaline cartilage from metaplasia of subchondral granulation tissue after a complete linear defect in immature animals. In mature animals two types of delayed healing process were observed, one from the subchondral granulation tissue and the other from surface cartilage cells. 3) In inaccurate reduction after complete linear fracture into subchondral bone, the healing process was through metaplasia from subchondral granulation tissue in both immature and mature animals, but the smoothening of the joint surface was more delayed than in accurate reduction. 4) The healing process occured from the surface cartilage cells in scarified cartilages of the patellar groove. 5) In scarified cartilage of the medial femoral condyle, the healing process was similar to that observed in scarification of the patellar groove. 6) In large supericial cartilage detects no reparative process was observed and degenerative change continued after 20 weeks. 7) In deep 5mm. core deflects the reparative process was similar to that observed in complete linear defects with inaccurate reduction. 8) Autoradiographic study of complete defects into subchondral bone showed that the new cartilage was derived from subchondral granulation tissue, because labeled cells were more concentrated in the layer and in the subchondral granulation tissue than in the superficial layer of cartilage and that the new cartilage in the scarified animals was derived from the superficial cartilage cells.
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