Abstract
The use of autologous cells derived from an articular cartilage biopsy to treat joint surface lesions was introduced in 1994 by Brittberg and Peterson. In a 2-step procedure, chondrocytes were harvested from a minor weight-bearing area of the knee joint during arthroscopy, expanded ex vivo and implanted during an arthrotomy 2–3 weeks later. However, throughout the in vitro expansion process, articular chondrocytes progressively lose their phenotypic traits and capacity to form stable cartilage tissue, thereby jeopardizing proper in vivo repair.
Data on dedifferentiation revealed that in vivo tissue formation of stable cartilage is governed by the interaction between environmental factors and inherent phenotypical characteristics. Characterized chondrocytes are an expanded population of cartilage cells that express a marker profile predictive for the formation of ectopic hyaline-like cartilage in vivo in a consistent and reproducible manner. A controlled and consistent manufacturing process was developed to maintain this phenotype stability. This involved optimisation of the biopsy procedures and mostly the culture process parameters. Characterized viable autologous cartilage cells expanded ex vivo expressing specific marker proteins were introduced in clinical practice in 2004.
A prospective randomized multicenter controlled trial compared characterized chondrocyte implantation (CCI) to microfracture in the treatment of symptomatic cartilage defects of the femoral condyles. The primary endpoint was successfully reached at 1 year, with CCI showing superior tissue regeneration. Clinical outcome at 12–18 months measured by the overall Knee injury and Osteoarthritis Outcome Score (KOOS) was comparable for both treatments. An extension at 3 and 5 years confirmed that a good clinical outcome was maintained over time for both treatments in the overall patient population. Strikingly, sub analysis of the long-term follow-up data revealed that early treatment by CCI resulted in statistically significant and most importantly clinically relevant better results when compared to microfracture, supporting a critical window of opportunity for genuine tissue regeneration. In addition, data from a large compassionate use program, whereby lesions were treated at diverse locations in the knee joint, corroborated the benefit of CCI found in the RCT. These data sets allow now to better define the treatment algorithms for symptomatic joint surface lesions of the knee in clinical practice.
JVL and MJ equally contributed to the manuscript
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References
Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy. 2002;18:730–4.
Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81:646–56.
Trattnig S, Domayer S, Welsch GW, Mosher T, Eckstein F. MR imaging of cartilage and its repair in the knee–a review. Eur Radiol. 2009;19:1582–94.
Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management of articular cartilage defects in the knee. J Bone Joint Surg Am. 2009;91:1778–90.
Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management of articular cartilage defects in the knee. Instr Course Lect. 2010;59:181–204.
Vanlauwe JJE, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP. Five year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am J Sports Med. 2011;39(12):2566–74.
Peterson L, Menche D, Grande D, et al. Chondrocyte transplantation - an experimental model in the rabbit. In: Transactions from the 30th Annual Orthopedic Research Society, Atlanta. 1984. Palantine: Orthopedic Research Society; 1984. p. 284.
Grande DA, Pitman MI, Peterson L, Menche D, Klein M. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte transplantation. J Orthop Res. 1989;7:208–18.
Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889–95.
Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982;30:215–24.
Giovannini S, Diaz-Romero J, Aigner T, Mainil-Varlet P, Nesic D. Population doublings and percentage of S100-positive cells as predictors of in vitro chondrogenicity of expanded human articular chondrocytes. J Cell Physiol. 2010;222:411–20.
Jones DG, Peterson L. Autologous chondrocyte implantation. J Bone Joint Surg Am. 2006;88:2502–20.
Dell’accio F, De Bari C, Luyten FP. Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. Arthritis Rheum. 2001;44:1608–19.
Vanlauwe J, Almqvist F, Bellemans J, Huskin JP, Verdonk R, Victor J. Repair of symptomatic cartilage lesions of the knee: the place of autologous chondrocyte implantation. Acta Orthop Belg. 2007;73:145–58.
Saris DB, Vanlauwe J, Victor J, Haspl M, Bohnsack M, Fortems Y, et al. Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am J Sports Med. 2008;36:235–46.
Saris DB, Vanlauwe J, Victor J, Almqvist KF, Verdonk R, Bellemans J, et al. Treatment of symptomatic cartilage defects of the knee: characterized chondrocyte implantation results in better clinical outcome at 36 months in a randomized trial compared to microfracture. Am J Sports Med. 2009;37 Suppl 1:10S–9.
European Medicines Agency, EMEA/724428/2009. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000878/WC500026031.pdf.
Vanlauwe J, Huylebroek J, Van der Bauwhede J. Clinical outcomes of characterized chondrocyte implantation. Cartilage. 2012;3(2):173–80.
Saris DB, Dhert WJ, Verbout AJ. Joint homeostasis. The discrepancy between old and fresh defects in cartilage repair. J Bone Joint Surg Br. 2003;85:1067–76.
Madry H, van Dijk CN, Mueller-Gerbl M. The basic science of the subchondral bone. Knee Surg Sports Traumatol Arthrosc. 2010;18:419–33.
Hoshiba T, Yamada T, Lu H, Kawazoe N, Chen G. Maintenance of cartilaginous gene expression on extracellular matrix derived from serially passaged chondrocytes during in vitro chondrocyte expansion. J Biomed Mater Res A. 2012;100:694–702.
Steinwachs M, Peterson L, Bobic V, Verdonk P, Niemeyer P. A consensus statement on surgical technique: cell-seeded collagen matrix-supported autologous chondrocyte transplantation (ACT-CS). Cartilage. 2012;3(1):5–12.
Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop Relat Res. 2001;(391 Suppl):S362–9.
Bedi A, Feeley BT, Williams III RJ. Management of articular cartilage defects of the knee. J Bone Joint Surg Am. 2010;92:994–1009.
Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy. 2003;19:477–84.
Gobbi A, Nunag P, Malinowski K. Treatment of full thickness chondral lesions of the knee with microfracture in a group of athletes. Knee Surg Sports Traumatol Arthrosc. 2005;13:213–21.
Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grontvedt T, Solheim E, et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am. 2004;86-A:455–64.
Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V, Ludvigsen TC, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007;89:2105–12.
Mainil-Varlet P, Van Damme B, Nesic D, Knutsen G, Kandel R, Roberts S. A new histology scoring system for the assessment of the quality of human cartilage repair: ICRS II. Am J Sports Med. 2010;38:880–90.
Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee Injury and Osteoarthritis Outcome Score (KOOS)–development of a self-administered outcome measure. J Orthop Sports Phys Ther. 1998;28:88–96.
Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes. 2003;1:64.
Minas T, Gomoll AH, Rosenberger R, Royce RO, Bryant T. Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques. Am J Sports Med. 2009;37:902–8.
Luyten FP, Denti M, Filardo G, Kon E, Engebretsen L. Definition and classification of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012;20:401–6.
Muckle DS. Open meniscectomy: enhanced recovery after synovial prostaglandin inhibition. J Bone Joint Surg Br. 1984;66:193–5.
Jiang CC, Liu YJ, Yip KM, Wu E. Physiological patellofemoral crepitus in knee joint disorders. Bull Hosp Jt Dis. 1993;53:22–6.
Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flanagan A. A prospective, randomised study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: Periosteum covered versus type I/III collagen covered. Knee. 2006;13:203–10.
Van Assche D, Van Caspel D, Vanlauwe J, Bellemans J, Saris DB, Luyten FP, et al. Physical activity levels after characterized chondrocyte implantation versus microfracture in the knee and the relationship to objective functional outcome with 2-year follow-up. Am J Sports Med. 2009;37 Suppl 1:42S–9.
Hanzlik S, Mahabir RC, Baynosa RC, Khiabani KT. Levels of evidence in research published in The Journal of Bone and Joint Surgery (American Volume) over the last thirty years. J Bone Joint Surg Am. 2009;91:425–8.
Harris JD, Siston RA, Pan X, Flanigan DC. Autologous chondrocyte implantation: a systematic review. J Bone Joint Surg Am. 2010;92:2220–33.
Basad E, Ishaque B, Bachmann G, Sturz H, Steinmeyer J. Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study. Knee Surg Sports Traumatol Arthrosc. 2010;18:519–27.
Van Wilder P. Advanced therapy medicinal products and exemptions to the regulation 1394/2007: How confident can we be? An exploratory analysis. Front Pharmacol. 2012;3:12.
Roobrouck VD, Clavel C, Jacobs SA, Ulloa-Montoya F, Crippa S, Sohni A, et al. Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells. 2011;29:871–82.
Roberts S, Hollander AP, Caterson B, Menage J, Richardson JB. Matrix turnover in human cartilage repair tissue in autologous chondrocyte implantation. Arthritis Rheum. 2001;44:2586–98.
Henderson I, Lavigne P, Valenzuela H, Oakes B. Autologous chondrocyte implantation: superior biologic properties of hyaline cartilage repairs. Clin Orthop Relat Res. 2007;455:253–61.
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Vanlauwe, J., Jelic, M., Limbourg, M.J., Luyten, F.P. (2014). Characterized Chondrocyte Implantation Challenges Current Paradigms for the Treatment of Symptomatic Joint Surface Lesions. In: Emans, P., Peterson, L. (eds) Developing Insights in Cartilage Repair. Springer, London. https://doi.org/10.1007/978-1-4471-5385-6_11
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