Elsevier

The Lancet

Volume 388, Issue 10055, 22–28 October 2016, Pages 1985-1994
The Lancet

Articles
Nasal chondrocyte-based engineered autologous cartilage tissue for repair of articular cartilage defects: an observational first-in-human trial

https://doi.org/10.1016/S0140-6736(16)31658-0Get rights and content

Summary

Background

Articular cartilage injuries have poor repair capacity, leading to progressive joint damage, and cannot be restored predictably by either conventional treatments or advanced therapies based on implantation of articular chondrocytes. Compared with articular chondrocytes, chondrocytes derived from the nasal septum have superior and more reproducible capacity to generate hyaline-like cartilage tissues, with the plasticity to adapt to a joint environment. We aimed to assess whether engineered autologous nasal chondrocyte-based cartilage grafts allow safe and functional restoration of knee cartilage defects.

Methods

In a first-in-human trial, ten patients with symptomatic, post-traumatic, full-thickness cartilage lesions (2–6 cm2) on the femoral condyle or trochlea were treated at University Hospital Basel in Switzerland. Chondrocytes isolated from a 6 mm nasal septum biopsy specimen were expanded and cultured onto collagen membranes to engineer cartilage grafts (30 × 40 × 2 mm). The engineered tissues were implanted into the femoral defects via mini-arthrotomy and assessed up to 24 months after surgery. Primary outcomes were feasibility and safety of the procedure. Secondary outcomes included self-assessed clinical scores and MRI-based estimation of morphological and compositional quality of the repair tissue. This study is registered with ClinicalTrials.gov, number NCT01605201. The study is ongoing, with an approved extension to 25 patients.

Findings

For every patient, it was feasible to manufacture cartilaginous grafts with nasal chondrocytes embedded in an extracellular matrix rich in glycosaminoglycan and type II collagen. Engineered tissues were stable through handling with forceps and could be secured in the injured joints. No adverse reactions were recorded and self-assessed clinical scores for pain, knee function, and quality of life were improved significantly from before surgery to 24 months after surgery. Radiological assessments indicated variable degrees of defect filling and development of repair tissue approaching the composition of native cartilage.

Interpretation

Hyaline-like cartilage tissues, engineered from autologous nasal chondrocytes, can be used clinically for repair of articular cartilage defects in the knee. Future studies are warranted to assess efficacy in large controlled trials and to investigate an extension of indications to early degenerative states or to other joints.

Funding

Deutsche Arthrose-Hilfe.

Introduction

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.

Section snippets

Study design and patients

We did an observational first-in-human study at University Hospital Basel in Switzerland. We enrolled patients aged 18–55 years old with post-traumatic full-thickness cartilage lesions (2–6 cm2, International Cartilage Repair Society [ICRS] grade III or IV) on the femoral condyle or trochlea. Further inclusion and exclusion criteria are listed in the appendix (p 3).

We designed this study in accordance with the Declaration of Helsinki and it was approved by the ethics committee of Basel (EKBB

Results

Between Aug 29, 2012, and April 28, 2016, ten patients were enrolled into the study (two women and eight men). Patients' baseline characteristics are shown in table 1. Nine patients reached 24 months of follow-up. One individual was excluded because of independent sport injuries, which needed additional surgery at various sites, including the same location of the repair tissue. Two patients received treatment for two separate defects, using two fragments of the same engineered graft.

An adequate

Discussion

We have shown that use of cartilage tissue engineered from autologous nasal chondrocytes for clinical repair of traumatic knee cartilage defects is feasible and safe. In our small cohort of patients for this phase 1 study, despite the variable degree of defect filling, self-assessment scores and MRI quantitative analyses established a satisfactory clinical outcome and a gradually improving quality of repair tissue over time.

Cellular therapies for treatment of traumatic cartilage defects are

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