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MEFISTO - Meniscal functionalised scaffold to prevent knee Osteoarthritis onset after meniscectomy

Periodic Reporting for period 1 - MEFISTO (MEFISTO - Meniscal functionalised scaffold to prevent knee Osteoarthritis onset after meniscectomy)

Reporting period: 2019-04-01 to 2020-11-30

Meniscal injuries are one of the most common orthopaedic disorders with a constantly growing incidence due to active live styles across all age groups. For most of the 20th century, the preferred approach to treat injured meniscus was removal of the damaged tissue (meniscectomy), a practice that expanded with the advent of arthroscopy.
The meniscus-deficient knee has been associated with poor clinical outcomes due to impaired load-bearing and joint instability leading to deterioration of articular cartilage that with time progresses to osteoarthritis (OA). In recent decades, the understanding of meniscal function and management of meniscal injuries has evolved, and there is an increasing consensus amongst physicians to preserve the meniscus whenever possible.
Yet despite the known consequences, meniscectomy remains the most common treatment for meniscal lesions as it is a simple and fast procedure, and not all meniscal tears can be repaired. Thus, a huge rate of post-meniscectomy OA is expected in Europe in the coming years. Management of younger and active patients with meniscus loss is particularly challenging. They often suffer from disability and need early knee replacement that will place a huge economic burden on EU health systems in the future. Although meniscal repair and replacement has advanced tremendously, options are still limited. Meniscal allograft implantation is complicated by limited availability and local regulatory restrictions. Acellular scaffolds made from collagen and polyurethane are in clinical use for treatment of partial meniscus defects but are associated with controversial long-term clinical and radiological outcomes. Tissue engineering approaches are not yet available for clinical use. Thus, no adequate treatment option is currently available for these patients.
The MEFISTO project is taking on the challenge to develop innovative approaches using bioactive functionalised materials for meniscus tissue replacement as a strategy to prevent the onset of a post-meniscectomy OA epidemic in Europe. Our three-pronged approach is to develop two novel solutions for the treatment of meniscus loss, to provide a predictive treatment algorithm based on morphologic profiling of meniscectomized patients, and to analyse the socio-economic environment. The two treatment solutions follow different strategies: a vascularized bioactive biodegradable scaffold for the regeneration of the native meniscus targeting younger patients with early degenerative changes; and a bioactive, non-biodegradable meniscal prosthesis, designed as a mechanical unloading device and drug delivery system to modulate the inflammatory environment that targets patients with advanced OA.
During this first period of the MEFISTO project, progress has been made along different tasks. For the morphological profiling of meniscectomized patients to identify those who are at risk of early OA, clinical and imaging (MRI) data have been collected in the clinical centres. Meniscectomized patients were allocated into two groups: low risk (120 asymptomatic patients) and high-risk (120 symptomatic patients). Data collection is almost complete and a catalogue with 3D knee joint models from the imaging data is being built up. In this process, automated segmentation of MRI scans has been investigated, and an optimal MRI protocol has been identified for data collection of a control group. Statistical shape analysis on available 3D knee models has been performed as proof of concept. 3D visualizations of the most important modes of knee shape variations have been created. 3D models of medial and lateral menisci have been generated and are used as shape input for implant production.
Different prototypes of the biodegradable meniscal scaffold have been developed using 3D printing. Two kinds of bio-inks from different materials were synthesized and characterised: a hydrogel and a bio-ink based on collagen. Our experts in the development of collagen products for tissue regeneration in orthopaedics have established a cost-effective method to manufacture a suitable, 3D printable collagen bio-ink.
Our specialists in peptide technology for cell modulation and in drug-loaded nano/micro-particles are working on the functionalization of the bio-ink and non-biodegradable prosthesis. They have already identified and manufactured peptide complexes and drug-loaded micro-particles that have been used to functionalise the collagen bio-ink. The collagen bio-ink is 3D printable, and optimization with incorporation of microparticles and peptide complexes is ongoing. A cost-effective 3D bioprinting, post-processing and sterilization process has been established and scaffold prototypes with desired porosity and mechanical strength were produced.
The bio-active, non-biodegradable meniscal prosthesis with drug delivery capabilities is developed from a biocompatible medical grade polymer (polycarbonate-urethane or PCU). A special processing method is used to convert PCU pellets to powder for the 3D print technology SLS (selective laser sintering) by which the implants will be printed. Samples replicating the implant shape were successfully 3D printed and the printed material showed good mechanical and biocompatibility properties. 3D printed metal tooling for patient specific implants has been designed and the production method is being optimized. Processing techniques to create porosity inside the PCU bulk, as well as a coating strategy to functionalize the implant surface with drug-loaded microparticles have been developed.
Our biomedical experts have established and refined in vitro models for pre-clinical biocompatibility testing of implant materials and their inflammatory properties using monocytes/macrophages.
We also defined key performance indicators to assess the perceived project and a questionnaire for stakeholder analysis. Dissemination and communication of the project progress is ongoing through the MEFISTO website, social media channels and presentations at orthopaedic conferences and virtual meetings. The consortium continues to build and strengthen relationships with stakeholders.
The technological innovation lies in the development of novel biologically active functionalized nanobiomaterials that can interact with the surrounding articular tissues in a pre-determined fashion for different degrees of joint degeneration.
Currently, there are no reliable predictive factors for the progression of OA in the post meniscectomy knee. Most patients present to the surgeon when OA is already established, and it is too late for reconstructive procedures, thus leading to sacrifice of the joint. Therefore, the early identification and treatment of high-risk patients who are pre-disposed to OA after meniscectomy is vital. The impact is expected to be significant, as so many patients have undergone or will undergo meniscectomy. The interventions developed in MEFISTO will prevent these patients from receiving joint-sacrificing procedures whilst reducing the social burden, associated costs and high levels of morbidity resulting from OA.
A socio-economic analysis of the cost-effectiveness of existing meniscal substitutes in Europe and an evaluation of the impact of adopting MEFISTO into healthcare systems will explore and hopefully, demonstrate the benefits of the project for the EU healthcare system.
The MEFISTO concept