Periodic Reporting for period 2 - MAXIBONE (Personalised maxillofacial bone regeneration)
Período documentado: 2019-07-01 hasta 2020-12-31
Bone is the most frequently transplanted tissue with approximately 1 million procedures performed annually in Europe. There are a large number of edentulous patients with insufficient bone volume to place dental implants for prosthetic rehabilitation. Autologous bone transplantation is considered the gold standard for maxillofacial bone regeneration. However, patient’s bone stock is limited and complications are often associated with the donor site. We have previously demonstrated the feasibility and safety of an alternative to bone grafting by using culture expanded autologous bone marrow mesenchymal stem cells (MSCs) and biomaterials. However, there is a need to perform randomized late stage comparative clinical trial to demonstrate equivalent efficacy of stem cells and biomaterials as advanced therapy medicinal products in comparison to the current standard, autologous bone grafting. In view of the above, the objective of Maxibone are:
- To perform a comparative randomized clinical trial for bone augmentation of the maxillary and mandible of patients prior to dental implants to assess the safety and effectiveness of the cell therapy and biomaterials to regenerate bone in width and height in order to enable adequate implant placement
- To assess clinical efficacy of bone regeneration on 150 patients by using Cone Beam Computed Tomography and histology analysis of core biopsies.
- To perform a health economic evaluation of autologous culture expanded BM-MSCs on bone regeneration versus the standard of care, autologous bone grafting.
- To decrease the production costs of the cell therapy products by using automated bioreactors
- To develop patient specific 3D printed biomaterial scaffolds
- To perform a comparative randomized clinical trial for bone augmentation of the maxillary and mandible of patients prior to dental implants to assess the safety and effectiveness of the cell therapy and biomaterials to regenerate bone in width and height in order to enable adequate implant placement
- To assess clinical efficacy of bone regeneration on 150 patients by using Cone Beam Computed Tomography and histology analysis of core biopsies.
- To perform a health economic evaluation of autologous culture expanded BM-MSCs on bone regeneration versus the standard of care, autologous bone grafting.
- To decrease the production costs of the cell therapy products by using automated bioreactors
- To develop patient specific 3D printed biomaterial scaffolds
In the second reporting period of the project, the partners have submitted the clinical files and obtained approvals by the regulatory agencies and ethical committees of several European countries through a newly launched Voluntary Harmonization Procedure. Personal data protection was also a priority among the European multicentre clinical trials.
In October 2020, all clinical centres located in Bergen, Madrid, Barcelona, Spain, Créteil and Nantes have recruited and treated patients requiring a bone augmentation procedure after receiving their informed consent. As the clinical trial is randomised, one third of patients have received an autologous bone transplant (control group) and two thirds have received the Advanced Therapy Medicinal Product (ATMP) consisting of autologous culture expanded MSCs and synthetic calcium phosphate biomaterials (test group). To date, 20 patients have been successfully treated without adverse event and recruitment is continuing at a pace of 2 patients/month despite the hurdles of the COVID-19 outbreak.
Cell manufacturing partners (EFS, UULM) have continued to improve and to standardise the manufacturing process. They have tested automated bioreactors in order to decrease production costs. A standardised protocol has been exchanged between the manufacturing centres to screen for a predictive bone formation marker of the investigational medicinal product.
Despite the restrictions caused by the COVID-19 pandemia, the clinical centres could transport bone marrow to the manufacturing centres and the manufacturing centres could manufacture and ship (accompanied transports) 8 advanced medicinal products within a country (France), within the European Union (from France to Spain) and within Europe (from Germany to Norway).
The European project MAXIBONE has demonstrated the safety and efficacy of cultured autologous MSCs and biomaterials as an alternative to bone grafting. MAXIBONE has addressed limitations and advancements in cell-based therapies by optimising current methodologies and standard operating procedures in all stages of treatment from bone marrow harvest to MSCs culture, loading onto biomaterials and clinical applications.
In addition to starting the clinical trial, the partners have collaborated in R&D activities with the SME Mimetis Biomaterials to produce personalised biomaterial scaffolds by 3D printing from medical images. These 3D scaffolds together with human stem cells have been tested in ectopic and orthotopic sites of rodents to demonstrate osteoinduction. Bone regeneration with anatomy fitting 3D scaffolds and stem cells was also demonstrated in a large animal model of alveolar bone augmentation.
MAXIBONE has also contributed to a large dissemination of results through the research communities with publications, organisation of workshops and communications in major scientific conferences such as European Association of Osseointegration, Tissue Engineering and Regenerative Medicine Society, World Biomaterials Conference. These activities have contributed to disseminate the novel treatment methodologies in bone regeneration and these advancements accessible to researchers, clinicians, patients and healthcare industries.
The partners have gathered to the general assembly meeting in Madrid in February 2020 to present and discuss the latest results on the project.
In October 2020, all clinical centres located in Bergen, Madrid, Barcelona, Spain, Créteil and Nantes have recruited and treated patients requiring a bone augmentation procedure after receiving their informed consent. As the clinical trial is randomised, one third of patients have received an autologous bone transplant (control group) and two thirds have received the Advanced Therapy Medicinal Product (ATMP) consisting of autologous culture expanded MSCs and synthetic calcium phosphate biomaterials (test group). To date, 20 patients have been successfully treated without adverse event and recruitment is continuing at a pace of 2 patients/month despite the hurdles of the COVID-19 outbreak.
Cell manufacturing partners (EFS, UULM) have continued to improve and to standardise the manufacturing process. They have tested automated bioreactors in order to decrease production costs. A standardised protocol has been exchanged between the manufacturing centres to screen for a predictive bone formation marker of the investigational medicinal product.
Despite the restrictions caused by the COVID-19 pandemia, the clinical centres could transport bone marrow to the manufacturing centres and the manufacturing centres could manufacture and ship (accompanied transports) 8 advanced medicinal products within a country (France), within the European Union (from France to Spain) and within Europe (from Germany to Norway).
The European project MAXIBONE has demonstrated the safety and efficacy of cultured autologous MSCs and biomaterials as an alternative to bone grafting. MAXIBONE has addressed limitations and advancements in cell-based therapies by optimising current methodologies and standard operating procedures in all stages of treatment from bone marrow harvest to MSCs culture, loading onto biomaterials and clinical applications.
In addition to starting the clinical trial, the partners have collaborated in R&D activities with the SME Mimetis Biomaterials to produce personalised biomaterial scaffolds by 3D printing from medical images. These 3D scaffolds together with human stem cells have been tested in ectopic and orthotopic sites of rodents to demonstrate osteoinduction. Bone regeneration with anatomy fitting 3D scaffolds and stem cells was also demonstrated in a large animal model of alveolar bone augmentation.
MAXIBONE has also contributed to a large dissemination of results through the research communities with publications, organisation of workshops and communications in major scientific conferences such as European Association of Osseointegration, Tissue Engineering and Regenerative Medicine Society, World Biomaterials Conference. These activities have contributed to disseminate the novel treatment methodologies in bone regeneration and these advancements accessible to researchers, clinicians, patients and healthcare industries.
The partners have gathered to the general assembly meeting in Madrid in February 2020 to present and discuss the latest results on the project.
The promising clinical outcomes have an impact on the patients and on the society in general. Patients suffering from done defects are generally young and socially active individuals. However, their everyday life is impaired by edentulism condition and this disability has major impacts on patient’s psychology and generate high healthcare costs. The MAXIBONE clinical study will directly impact a large number of edentulous patients by developing new strategies for regenerative medicine allowing prosthetic rehabilitation without the associated morbidity of autologous bone transplantation.
The expertise and experience of the Blood Transfusion Institutes for production, quality controls and distribution of several ATMPs through Europe ensured safety and efficacy in addition to addressing economic issues. These institutes located in Germany and France have agreed to share their expertise and logistics to maximise the societal benefits by making these new treatment strategies widely and readily available to patients.
In the field of biomaterials, a new manufacturing process has been developed by a medical device company. This start-up company MIMETIS is able to 3D print custom scaffolds from medical images. In future, the biomaterials will be further personalised to fit the patient’s anatomy and ensure a precise bone reconstruction. The implication of Straumann, a leader in dental implants, reflects the interest of the European market in cell therapy for bone regeneration and will help to lever existing investments in fundamental research into regenerative medicine and more specifically in the maxillofacial area.
The project had also an impact on education and training in research by engaging a number of MSc, PhD and post-doctoral scientists who achieved good job opportunities.
MAXIBONE has therefore produced significant knowledge and expertise in bone tissue engineering from basic research to clinical translation. This project has demonstrated evidence based clinical research that further support the emerging field of regenerative and personalised medicine.
The expertise and experience of the Blood Transfusion Institutes for production, quality controls and distribution of several ATMPs through Europe ensured safety and efficacy in addition to addressing economic issues. These institutes located in Germany and France have agreed to share their expertise and logistics to maximise the societal benefits by making these new treatment strategies widely and readily available to patients.
In the field of biomaterials, a new manufacturing process has been developed by a medical device company. This start-up company MIMETIS is able to 3D print custom scaffolds from medical images. In future, the biomaterials will be further personalised to fit the patient’s anatomy and ensure a precise bone reconstruction. The implication of Straumann, a leader in dental implants, reflects the interest of the European market in cell therapy for bone regeneration and will help to lever existing investments in fundamental research into regenerative medicine and more specifically in the maxillofacial area.
The project had also an impact on education and training in research by engaging a number of MSc, PhD and post-doctoral scientists who achieved good job opportunities.
MAXIBONE has therefore produced significant knowledge and expertise in bone tissue engineering from basic research to clinical translation. This project has demonstrated evidence based clinical research that further support the emerging field of regenerative and personalised medicine.