Treatment of Deep Cartilage Defects in the Knee with Autologous Chondrocyte Transplantation

University of Gothenburg, Goeteborg, Västra Götaland, Sweden
New England Journal of Medicine (Impact Factor: 55.87). 11/1994; 331(14):889-95. DOI: 10.1056/NEJM199410063311401
Source: PubMed


Full-thickness defects of articular cartilage in the knee have a poor capacity for repair. They may progress to osteoarthritis and require total knee replacement. We performed autologous chondrocyte transplantation in 23 people with deep cartilage defects in the knee.
The patients ranged in age from 14 to 48 years and had full-thickness cartilage defects that ranged in size from 1.6 to 6.5 cm2. Healthy chondrocytes obtained from an uninvolved area of the injured knee during arthroscopy were isolated and cultured in the laboratory for 14 to 21 days. The cultured chondrocytes were then injected into the area of the defect. The defect was covered with a sutured periosteal flap taken from the proximal medial tibia. Evaluation included clinical examination according to explicit criteria and arthroscopic examination with a biopsy of the transplantation site.
Patients were followed for 16 to 66 months (mean, 39). Initially, the transplants eliminated knee locking and reduced pain and swelling in all patients. After three months, arthroscopy showed that the transplants were level with the surrounding tissue and spongy when probed, with visible borders. A second arthroscopic examination showed that in many instances the transplants had the same macroscopic appearance as they had earlier but were firmer when probed and similar in appearance to the surrounding cartilage. Two years after transplantation, 14 of the 16 patients with femoral condylar transplants had good-to-excellent results. Two patients required a second operation because of severe central wear in the transplants, with locking and pain. A mean of 36 months after transplantation, the results were excellent or good in two of the seven patients with patellar transplants, fair in three, and poor in two; two patients required a second operation because of severe chondromalacia. Biopsies showed that 11 of the 15 femoral transplants and 1 of the 7 patellar transplants had the appearance of hyaline cartilage.
Cultured autologous chondrocytes can be used to repair deep cartilage defects in the femorotibial articular surface of the knee joint.

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Article: Treatment of Deep Cartilage Defects in the Knee with Autologous Chondrocyte Transplantation

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    • "Cellular and tissue-engineering therapies are considered the best options for the repair of many cartilage defects. In accordance with this, autologous and allogeneic chondrocytes are grafted into articular cartilage lesions with fair clinical outcomes (Brittberg et al., 1994; Jiang et al., 2011; Cucchiarini et al., 2014). Research is also under way to find compatible implants for facial, laryngeal and tracheal reconstruction, with some advances already being made in the clinical setting (Yanaga et al., 2009; Fabre et al., 2013). "
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    ABSTRACT: Advances in animal transgenesis may allow using xenogeneic chondrocytes in tissue-engineering applications for clinical cartilage repair. Porcine cartilage is rejected by humoral and cellular mechanisms that could be overcome by identifying key molecules triggering rejection and developing effective genetic-engineering strategies. Accordingly, high expression of α1,2-fucosyltransferase (HT) in xenogeneic cartilage protects from galactose α1,3-galactose (Gal)-mediated antibody responses. Now, we studied whether expression of a complement inhibitor provides further protection. First, porcine articular chondrocytes (PAC) were isolated from non-transgenic, single and double transgenic pigs expressing HT and moderate levels of human CD59 (hCD59) and their response to human serum was assessed. High recombinant expression of human complement regulatory molecules hCD59 and hDAF was also attained by retroviral transduction of PAC for further analyses. Complement activation on PAC after exposure to 20 % human serum for 24 hours mainly triggered the release of pro-inflammatory cytokines IL-6 and IL-8. Transgenic expression of HT and hCD59 did not suffice to fully counteract this effect. Nevertheless, the combination of blocking anti-Gal antibodies (or C5a) and high hCD59 levels conferred very high protection. On the contrary, high hDAF expression attained the most dramatic reduction in IL-6/IL-8 secretion by a single strategy, but the additional inhibition of anti-Gal antibodies or C5a did not provide further improvement. Notably, we demonstrate that both hCD59 and hDAF inhibit anaphylatoxin release in this setting. In conclusion, our study identifies genetic-engineering approaches to prevent humoral rejection of xenogeneic chondrocytes for use in cartilage repair.
    European cells & materials 11/2015; 30:258-270. · 4.89 Impact Factor
    • "In recent years, there has been increased interest in the use of cell-and tissue-engineering based therapies for the treatment of focal cartilage defects (Brittberg et al., 1994; Temenoff and Mikos, 2000). While significant progress has been made in this field, realising an efficacious therapeutic option for the treatment of OA remains elusive and is considered to be one of the greatest challenges in the field of orthopaedic medicine. "
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    ABSTRACT: Arthroplasty is currently the only surgical procedure available to restore joint function following articular cartilage and bone degeneration associated with diseases such as osteoarthritis (OA). A potential alternative to this procedure would be to tissue-engineer a biological implant and use it to replace the entire diseased joint. The objective of this study was therefore to tissue-engineer a scaled-up, anatomically shaped, osteochondral construct suitable for partial or total resurfacing of a diseased joint. To this end it was first demonstrated that a bone marrow derived mesenchymal stem cell seeded alginate hydrogel could support endochondral bone formation in vivo within the osseous component of an osteochondral construct, and furthermore, that a phenotypically stable layer of articular cartilage could be engineered over this bony tissue using a co-culture of chondrocytes and mesenchymal stem cells. Co-culture was found to enhance the in vitro development of the chondral phase of the engineered graft and to dramatically reduce its mineralisation in vivo. In the final part of the study, tissue-engineered grafts (~ 2 cm diameter) mimicking the geometry of medial femorotibial joint prostheses were generated using laser scanning and rapid prototyped moulds. After 8 weeks in vivo, a layer of cartilage remained on the surface of these scaled-up engineered implants, with evidence of mineralisation and bone development in the underlying osseous region of the graft. These findings open up the possibility of a tissueengineered treatment option for diseases such as OA.
    European cells & materials 09/2015; 30:163-186. · 4.89 Impact Factor
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    • "TE strategies for cartilage replacement, based on autologous chondrocytes and MSCs, have recently received significant attention (Amin et al. 2014; Getgood et al. 2009). However, any long-term cartilage repair strategy based on ACI must incorporate methods to prime autologous chondrocytes for cartilage-specific matrix production while suppressing the hypertrophic mineralization pathway, so as to prevent athrofibrosis, joint adhesion, cartilage injury and symptomatic hypertrophy post-ACI (Brittberg et al. 1994; Dreier 2010; Goldring and Goldring 2010; Niemeyer et al. 2008; Peterson et al. 2000). Although we recognize that this is a cell culturebased study, with the limitations implied thereby, our results motivate further investigation into the use of TRAP for the above purpose. "
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    ABSTRACT: Current approaches to treat osteoarthritis (OA) are insufficient. Autologous chondrocyte implantation (ACI) has been used for the past decade to treat patients with OA or focal cartilage defects. However, a number of complications have been reported post-ACI, including athrofibrosis and symptomatic hypertrophy. Thus, a long-term ACI strategy should ideally incorporate methods to 'prime' autologous chondrocytes to form a cartilage-specific matrix and suppress hypertrophic mineralization. The objective of this study is to examine the effects of tyrosine-rich amelogenin peptide (TRAP; an isoform of the developmental protein amelogenin) on human articular cartilage cell (HAC) chondrogenic differentiation and hypertrophic mineralization in vitro. Effects of chemically synthesized TRAP on HAC chondrogenic differentiation were determined by assessing: (1) sGAG production; (2) Alcian blue staining for proteoglycans; (3) collagen type II immunostaining; and (4) expression of the chondrogenic genes SOX9, ACAN and COL2A1. Hypertrophic mineralization was assayed by: (1) ALP expression; (2) Alizarin red staining for Ca(+2)-rich bone nodules; (3) OC immunostaining; and (4) expression of the osteogenic/hypertrophic genes Ihh and BSP. Chemically synthesized TRAP was found to suppress terminal osteogenic differentiation of HACs cultured in hypertrophic mineralization-like conditions, an effect mediated via down-regulation of the Ihh gene. Moreover, TRAP was found to augment chondrogenic differentiation of HACs via induction of SOX9 gene expression when cells were cultured in pro-chondrogenic media. The results obtained from this proof-of-concept study motivate further studies on the use of TRAP as part of a preconditioning regimen in autologous chondrocyte implantation procedures for OA patients and patients suffering from focal cartilage defects.
    Cell and Tissue Research 09/2015; DOI:10.1007/s00441-015-2292-7 · 3.57 Impact Factor
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