Autologous chondrocyte transplantation: a phase 1 study protocol to validate the safety and feasibility of a new advanced cell therapy product for articular cartilage repair in Brazil

Alessandro Rozim Zorzi, Eliane Antonioli, Moises Cohen, Camila Cohen Kaleka, Andrea Tiemi Kondo, José Mauro Kutner, Mario Ferretti


Background: Membrane-assisted autologous chondrocyte transplantation is considered the gold standard surgical technique to treat greater than two millimetres diameter cartilage lesions in the knee in patients after conservative treatment failure. However, this technique is only available in developed countries of North America, Europe and Japan. According to Brazilian law, it is considered an advanced cell therapy product. There is currently no product of this type enabled for clinical use in Brazil. Following the request of the Brazilian regulatory agency (ANVISA), this phase 1 study was developed. The objective is to access feasibility and safety of a new membrane-assisted autologous chondrocyte product.

Methods: Three participants with a larger than two millimetres articular cartilage lesion in the distal femur or the patella, which did not improve their symptoms with conservative treatment, will be submitted to an arthroscopically assisted cartilage biopsy. After isolation and expansion in a good manufacturing practices facility, chondrocyte seeded collagen membranes will be surgically inserted in the lesion and fixed with fibrin glue. The follow-up period will last 1 year. Primary outcome will be incidence and severity of complications according to NCI-CTCAE version 4.0. Secondary outcomes will be Western-Ontario McMaster Universities Osteoarthritis Index scale, International Knee Documentation Committee subjective scale and magnetic resonance observation of cartilage repair tissue magnetic resonance scale.

Conclusions: This study, together with previous preclinical results and international experience, will allow patients in Latin America to have access to this advanced cell therapy.

Trial Registration: Brazilian registry of clinical trials RBR-6fgy76 ( Ethical approval: CAAE: 73911617.2.0000.0071.


Cartilage, Pain, Knee, Regenerative medicine, Cell therapy, Chondrocytes

Full Text:



Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy: J Arthroscopic Related Surgery. 2002;18(7):730-4.

Widuchowski W, Widuchowski J, Trzaska T. Articular cartilage defects: Study of 25,124 knee arthroscopies. Knee. 2007;14(3):177-82.

Curl WW, Krome J, Gordon S, Rushing J, Smith BP, Poehling GG. Cartilage Injuries: A Review of 31,516 Knee Arthroscopies. Arthroscopy: J Arthroscopic Related Surg. 1997;13(4):456-60.

Widuchowski W, Widuchowski J, Faltus R, Lukasik P, Kwiatkowski G, Szyluk K, et al. Long-term clinical and radiological assessment of untreated severe cartilage damage in the knee: a natural history study. Scandinavian J Medicine Science Sports. 2011;21(1):106-10.

Widuchowski W, Widuchowski J, Koczy B, Szyluk K. Untreated Asymptomatic Deep Cartilage Lesions Associated With Anterior Cruciate Ligament Injury: Results at 10- and 15-Year Follow-Up. Am J Sports Med. 2009;37(4):688-92.

Figueroa D, Calvo R, Vaisman A, Carrasco MA, Moraga C, Delgado I. Knee Chondral Lesions: Incidence and Correlation Between Arthroscopic and Magnetic Resonance Findings. Arthroscopy: J Arthroscopic Related Surg. 2007;23(3):312-5.

Nicolini AP, Carvalho RT, Dragone B, Lenza M, Cohen M, Ferretti M. Updates in biological therapies for knee injuries: full thickness cartilage defect. Curr Rev Musculoskelet Med. 2014;7(3):256-62.

Gomoll AH, Farr J, Gillogly SD, Kercher J, Minas T. Surgical management of articular cartilage defects of the knee. J Bone Joint Surg Am. 2010;92:2470-90.

Steadman JR, Rodkey WG, Singleton SB. Microfracture technique forfull-thickness chondral defects: Technique and clinical results. Operative techniques in 1997.

Solheim E, Hegna J, Inderhaug E, Oyen J, Harlem T, Strand T. Results at 10-14 years after microfracture treatment of articular cartilage defects in the knee. Knee Surg Sports Traumatol Arthrosc. Springer Berlin Heidelberg; 2014: 1-7.

Montgomery SR, Foster BD, Ngo SS, Terrell RD, Wang JC, Petrigliano FA, et al. Trends in the surgical treatment of articular cartilage defects of the knee in the United States. Knee Surg Sports Traumatol Arthrosc. Springer Berlin Heidelberg; 2014;22(9):2070-5.

Gomoll AH, Minas T. The quality of healing: articular cartilage. Wound Repair Regen. 2014;22 Suppl 1(S1):30-8.

Gomoll AH, Madry H, Knutsen G, van Dijk N, Seil R, Brittberg M, et al. The subchondral bone in articular cartilage repair: current problems in the surgical management. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):434-47.

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(5):902-8.

Lane JG, Healey RM, Chen AC, Sah RL, Amiel D. Can Osteochondral Grafting Be Augmented With Microfracture in an Extended-Size Lesion of Articular Cartilage? Am J Sports Med. 2010;38(7):1316-23.

Camp CL, Stuart MJ, Krych AJ. Current concepts of articular cartilage restoration techniques in the knee. Sports Health. Sage Publications; 2014;6(3):265-73.

Chesterman PJ, Smith AU. Homotransplantation of articular cartilage and isolated chondrocytes. JBJS. 1968;50(1):184-197.

Peterson L, Menche D, Grande D. Chondrocyte transplantation. An experimental model in the rabbit. In: Transactions from the 30th annual Orthopedic Research Society, Atlanta: 1984.

Grande DA, Pitman MI, Peterson L, Menche, D. and Klein, M. (1989), 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(14):889-95.

Rosenberger RE, Gomoll AH, Bryant T, Minas T. Repair of large chondral defects of the knee with autologous chondrocyte implantation in patients 45 years or older. Am Orthop Society Sports Med. 2008;36(12):2336-44.

Oussedik S, Tsitskaris K, Parker D. Treatment of Articular Cartilage Lesions of the Knee by Microfracture or Autologous Chondrocyte Implantation: A Systematic Review. Arthroscopy. 2013;(S1):S3-S10.

Jacobi M, Villa V, Magnussen RA, Neyret P. MACI - a new era? Sports Medicine, Arthroscopy, Rehabilitation, Therapy & Technology. BioMed Central Ltd; 2011;3(1):10.

Harris JD, Hussey K, Wilson H, Pilz K, Gupta AK, Gomoll A, et al. Biological knee reconstruction for combined malalignment, meniscal deficiency, and articular cartilage disease. Arthroscopy. 2015;31(2):275-82.

Zheng M-H, Willers C, Kirilak L, Yates P, Xu J, Wood D, et al. Matrix-Induced Autologous Chondrocyte Implantation (MACI ®): Biological and Histological Assessment. Tissue Engineering. 2007;13(4):737-46.

Bartlett W. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: A Prospective, Randomised Study. Br Editorial Society Bone Joint Surg. 2005;87(5):640-5.

Saris D, Price A, Widuchowski W, Bertrand-Marchand M, Caron J, Drogset JO, et al. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Two-Year Follow-up of a Prospective Randomized Trial. Am Orthop Society Sports Med. 2014;42(6):1384-94.

Herbort M, Zelle S, Rosenbaum D, Osada N, Raschke M, Petersen W, et al. Arthroscopic Fixation of Matrix-Associated Autologous Chondrocyte Implantation: Importance of Fixation Pin Angle on Joint Compression Forces. YJARS. Elsevier Inc; 2011;27(6):809-16.

Ebert JR, Robertson WB, Woodhouse J, Fallon M, Zheng MH, Ackland T, et al. Clinical and Magnetic Resonance Imaging-Based Outcomes to 5 Years After Matrix-Induced Autologous Chondrocyte Implantation to Address Articular Cartilage Defects in the Knee. Am J Sports Med. 2011;39(4):753-63.

Marlovits S, Aldrian S, Wondrasch B, Zak L, Albrecht C, Welsch G, et al. Clinical and Radiological Outcomes 5 Years After Matrix-Induced Autologous Chondrocyte Implantation in Patients With Symptomatic, Traumatic Chondral Defects. Am J Sports Med. 2012;40(10):2273-80.

Gomoll AH, Probst C, Farr J, Cole BJ, Minas T. Use of a Type I/III Bilayer Collagen Membrane Decreases Reoperation Rates for Symptomatic Hypertrophy After Autologous Chondrocyte Implantation. Am J Sports Med. 2009;37(1):20-3.

Saris D, Price A, Widuchowski W, Bertrand-Marchand M, Caron J, Drogset JO, et al. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Two-Year Follow-up of a Prospective Randomized Trial. Am J Sports Med. Am Orthop Society Sports Med. 2014;42(6):1384-94.

Cohen M, Nery C, Peccin MS, Ressio CR. Autologous chondrocyte implantation to treat femoral condyle and talar lesions. Einstein. 2008;6(1):37-41.

Lombello C, Reis GM, Cohen M. Study on human chondrocyte culture viability for autologous transplantation in clinical application. Einstein. 2003;1:84-8.

Antonioli E, Piccinato CA, Nader HB, Cohen M, Goldberg AC, Ferretti M. Modulation of Hyaluronan Synthesis by the Interaction between Mesenchymal Stem Cells and Osteoarthritic Chondrocytes. Stem Cells International. Hindawi Publishing Corporation; 2015;2015(2):640218-11.

Antonioli E, Lobo AO, Ferretti M, Cohen M, Marciano FR, Corat EJ, et al. An evaluation of chondrocyte morphology and gene expression on superhydrophilic vertically-aligned multi-walled carbon nanotube films. Mater Sci Eng C Mater Biol Appl. 2013;33(2):641-7.

Pintan GF, de Oliveira AS, Lenza M, Antonioli E, Ferretti M. Update on biological therapies for knee injuries: osteoarthritis. Curr Rev Musculoskelet Med. Springer US; 2014;7(3):263-9.

da Cunha Cavalcanti FMM, Doca D, Cohen M, Ferretti M. Updating on diagnosis and treatment of chondral lesion of the knee. Revista Brasileira de Ortopedia. 2012;47(1):12-20.

Zorzi A, Amstalden E, Plepis A, Martins V, Ferretti M, Antonioli E, et al. Effect of human adipose tissue mesenchymal stem cells on the regeneration of ovine articular cartilage. Int J Mol Sci. 2015;16(11):26813-31.

National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). 2010: 1-80.

Fernandes MI. Tradução e validação do questionário de qualidade de vida específico para osteoartrose WOMAC (Western Ontário McMaster Universities) para a língua portuguesa. [dissertação]. São Paulo: Universidade Federal de São Paulo, Escola Paulista de Medicina; 2003.

Metsavaht L, Leporace G, Riberto M, de Mello Sposito MM, Batista LA. Translation and Cross-Cultural Adaptation of the Brazilian Version of the International Knee Documentation Committee Subjective Knee Form: Validity and Reproducibility. Am J Sports Med. 2010;38(9):1894-9.

Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S. Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical outcome after 2 years. European J Radiol. 2006;57(1):16-23.

Martín AR, Patel JM, Zlotnik HM, Carey JL, Mauck RL. Emerging therapies for cartilage regeneration in current excluded “red knee” populations. NPJ Regen Med. 2019;4:12.