Articular cartilage injuries remain a clinical challenge and are associated with pain, disturbed function, and disability. About 2 million patients are diagnosed with articular cartilage defects every year in Europe and the USA.1 When not treated, such lesions predispose to osteoarthritis and might result in total replacement of the joint, with limits of implementation in younger individuals and massive costs for the health-care system.2 Cartilage repair treatments have the potential not only to relieve pain and improve the quality of life for younger patients but also to delay or eliminate the need for joint replacement. Current therapeutic options—eg, arthroscopic debridement, microfracture, autologous osteochondral grafting, and use of allografts or platelet-rich plasma—have major drawbacks, such as applicability to limited size defects, long and complex rehabilitation times, donor-site morbidity, or graft material availability.3 Even advanced therapies based on autologous articular chondrocyte implantation, although improving symptoms in short-term follow-up, cannot reproducibly and durably restore cartilage structure and function, and have yet to prove cost effective.4 Use of an autologous cell source with superior and less donor-dependent cartilage-forming capacity might enhance regenerative processes and lead to a predictable benefit for individual patients.
Chondrocytes from the nasal septum, compared with those from articular cartilage, show superior and more reproducible chondrogenic capacity, even across individuals of different ages.5, 6, 7 The chondrogenic properties of nasal chondrocytes are maintained after extensive culture expansion, so that a small biopsy specimen, obtained under minimally invasive conditions and with no relevant discomfort, is sufficient to generate biochemically and biomechanically mature grafts of clinically relevant dimensions.8 Indeed, engineered grafts based on autologous nasal chondrocytes have been used as an alternative to native cartilage for the reconstruction of the alar lobule of the nose after skin tumour resection, leading to complete structural, functional, and aesthetic recovery.9
Research in context
Evidence before this study
We searched MEDLINE for reports published in any language up to April, 2016, with the terms “nasal chondrocytes” and “articular cartilage repair“. We identified 16 publications, of which 14 were related to in-vitro experiments and two were reporting in-vivo tests in a rabbit or goat model. In the study with the goat model, implantation of nasal chondrocytes in human articular cartilage lesions was reported to be part of an ongoing clinical trial, which is now the subject of this report. Extending the second search term to “cartilage repair” beyond articulating joints identified one report of a completed clinical study, related to nasal lobule reconstruction after tumour resection.
Added value of this study
Our study shows the feasibility, safety, and preliminary evidence of clinical efficacy of engineered nasal cartilage grafts for post-traumatic articular cartilage injuries. Compared with conventional autologous articular chondrocyte implantation, the novelty of the described approach is related to use of cells derived from the nasal septum, which display superior and less donor-dependent chondrogenic capacity, and implantation of a developed cartilage tissue versus undifferentiated cells delivered as a suspension or through a scaffold (effectively, we tested a tissue therapy instead of a cellular therapy). The possibility to obtain a nasal cartilage biopsy specimen under minimally invasive conditions, by contrast with the need for arthroscopy for articular chondrocytes isolation, is an added benefit for the proposed treatment.
Implications of all the available evidence
Beyond self-assessed patients' satisfaction, we established temporal maturation of repair tissue, approaching the composition of native hyaline cartilage. This achievement could be related to the chondrogenic capacity of the delivered nasal chondrocytes or the presence of mature cartilaginous extracellular matrix around them, or both. Further randomised trials comparing our approach with conventional treatments are needed to provide definitive data for the efficacy of the grafts. Demonstration of a positive effect of this procedure on the reproducibility and durability of repair might produce a major shift in the treatment of challenging cartilage lesions, for which no current treatment is yet satisfactory.
The compatibility of grafts derived from nasal chondrocytes with implantation at an articular cartilage injury site is supported by findings of previous studies. For example, in one study, nasal chondrocytes responded to physical forces resembling joint loading in a similar manner to articular chondrocytes and upregulated molecules typically involved in joint lubrication.10 Moreover, nasal chondrocytes recovered after exposure to inflammatory factors typical of joint injuries11 and led to formation of hyaline tissue in rabbit articular cartilage defects.12 Furthermore, nasal chondrocytes could adopt the molecular identity of articular chondrocytes once implanted in a joint and contributed actively to repair of experimental goat cartilage defects.13
Our study aimed to assess the safety, feasibility, and potential efficacy of cartilage grafts engineered from autologous nasal chondrocytes for the treatment of post-traumatic cartilage injuries in the knee. The distinct innovation and potential advantage of our study relates not only to use of cells of superior and more reproducible chondrogenic capacity (nasal vs articular chondrocytes) but also—as a direct result of cellular quality—to implantation of tissues rich in hyaline-like extracellular matrix. This idea contrasts with typical use of suspensions of undifferentiated cells or of cell-seeded scaffolds not yet developed as mature cartilage tissues.