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BIOengineered grafts for Cartilage Healing In Patients (BIO-CHIP)

Periodic Reporting for period 3 - BIO-CHIP (BIOengineered grafts for Cartilage Healing In Patients (BIO-CHIP))

Reporting period: 2018-11-01 to 2019-10-31

Articular cartilage injuries in the knee cause pain, lead to poor joint function and disability. Although 2 million defects are diagnosed each year in Europe and the USA, their treatment is still a challenge for orthopedic surgeons. Spontaneous healing of cartilage lesions is poor and if left untreated they may predispose to osteoarthritis and ultimately replacement of the total joint.
Cartilage repair procedures have the potential to relieve pain and improve the quality of life in younger patients and may delay or eliminate the need for joint replacement in the elderly. However, current treatments still have major drawbacks and the quality of the resulting repair tissue is often poor in comparison to native cartilage. The implantation of autologous articular chondrocytes (AC, cells harvested from a small biopsy of the patient’s own knee cartilage) at the damaged site to induce cartilage regeneration has represented a major breakthrough in the field. However, probably due to the variable quality of the cells used, even these treatments cannot yet offer predictable, reproducible and durable restoration of cartilage structure and function.
The BIO-CHIP project introduces two innovations with the potential to improve the clinical outcome of cartilage repair:
• use of a different source of cells: cells are not harvested from the knee joint (AC), but are taken from the nasal septum (Nasal Chondrocytes, NC). In addition to reduced donor-site morbidity, NC have been shown to have a higher and more reproducible capacity to regenerate cartilage tissue than AC. Moreover, they can adapt to the joint environment, including exposure to mechanical forces associated with weight bearing, and can withstand inflammation associated with trauma and surgery;
• engineering of a mature cartilage tissue: the NC-based implant can be developed to various degrees of functional maturation depending on the culture time. In particular, thanks to the use of NC, grafts can reach biochemical and mechanical maturation approaching that of native cartilage, in contrast to typical tissues engineered using AC. A more mature tissue could offer higher functionality upon implantation and superior long-term performance, though this hypothesis has never been clinically tested.
The project capitalizes on a previous phase I clinical study, which successfully demonstrated the safety and feasibility of implanting an engineered nasal cartilage graft to treat articular cartilage injuries.
The BIO-CHIP project targets two main objectives:
• conduct a multicenter (Croatia, Germany, Italy and Switzerland), prospective, phase II clinical study to treat 108 patients to determine the effect of maturation (degree of functionality) of NC-based cartilage grafts on the clinical outcome;
• explore in a large animal model the possibility to extend the clinical indications of the engineered grafts from acute, traumatic cartilage injuries to currently untreatable, degenerative cases (pre-osteoarthritic lesions).
The clinical study “Nose to Knee II”, carried out in 5 centers, is now approved by all ethical committees and national authorities.
Permission to manufacture the cell-based grafts in Germany and Switzerland has been obtained from the national authorities ensuring that the quality of the ATMPs meets agreed standards. So far, grafts satisfying the defined specifications have successfully been manufactured for all but one patient and shipped to the respective clinical sites. New quality control assays to assess cell viability, identity, purity and potency are being developed and validated. These tests need to be performed in short times due to the short shelf life of the ATMPs, provide quantitative information and be non-destructive to avoid compromising the implant.
So far, no serious adverse reactions were detected for any of the treated patients. Two patients had to be excluded intraoperatively from the study due to more severe lesions than originally anticipated or comorbidities and one was excluded due to a failed graft manufacturing. The collected data are regularly monitored in a harmonized manner to ensure correct and complete documentation and respect for patients' rights as per international guidelines.
106 patients have been recruited with 89 patients treated by October 2019. 39 patients have completed the 12 months follow-up and 12 patients have completed the 24 months follow-up. Even though no conclusions can be drawn yet due to the limited number of patients, all patients seemed to benefit from the treatment as indicated by an increase of the clinical scores from the self-assessed validated questionnaires Knee injury and Osteoarthritic Outcome Scores (KOOS) of more than 10 points. Moreover, also the assessment of the Magnetic Resonance Imaging (MRIs) 12 and 24 months postoperative indicated that all grafts were in place and integration with the adjacent cartilage is ongoing.
Alongside the clinical and manufacturing issues, the future market potential of the products has been considered through an analysis of current and future clinical indications, treatments and their respective costs. Given the currently high production costs, automation of the production process using a bioreactor is crucial for future commercialization. Two strategies for future commercialization have been identified. In Switzerland a scientific advice meeting with authorities has indicated, that application for marketing authorization could be possible for defects larger than 4cm2. For the European market, the application for hospital exemption (local authorization for this state) has been evaluated for Germany and Croatia.
To extend the range of clinical indications to currently untreatable diseases such as osteoarthritis, a large animal study is in progress to evaluate the suitability of the engineered cartilage grafts in kissing lesions facing each other on both sides of the knee joint, which are considered as (pre)osteoarthritic. Two different time points (6 weeks and 6 months after implantation) were chosen. Results show good retention and integration of the implanted grafts as well as an improved quality of the repair tissue from 6 weeks to 6 months. Inflammatory responses detected after 6 weeks post implantation decreased over time and although the remodeling process was still ongoing after 6 months, promising results can be expected in the long term. The results of this study demonstrate that the treatment with a nasal cartilage graft is suitable for this condition and phase I trial could be performed in patients with pre-osteoarthritic lesions based on these preclinical data.
A number of scientific presentations and articles in the popular press have targeted both the medical community and the public. A website (http://biochip-h2020.eu/) describes the project and several national and international trial databases (clinicaltrials.gov NCT02673905) offer relevant information to potential patients and the public community.
The development of a successful therapy for cartilage lesions would have strong implications for patients suffering from cartilage damages, including (i) a positive effect on the quality of life through a reduction in pain and increased mobility, (ii) a potential delay in the onset of degenerative cartilage diseases and of the associated need for joint replacement. In turn, this clinical outcome would have relevant consequences in the global reduction of healthcare costs.
Fig.2 Steps in the tissue engineering of nasal cartilage grafts in BIO-CHIP.
Fig. 1 Use of nasal chondrocytes for the treatment of cartilage lesions.