Periodic Reporting for period 2 - JOINTPROMISE (PRECISION MANUFACTURING OF MICROENGINEERED COMPLEX JOINT IMPLANTS)
Période du rapport: 2021-07-01 au 2022-12-31
There is convincing evidence, that deep osteochondral defects of the joint surface leads to a high rate of osteoarthritis (OA) over time. The disease process in OA, the most prevalent arthritic disease affecting 25% of the adult population, involves the entire joint affecting both the articular cartilage and the underlying bone. Hence, it is crucial to consider the entire osteochondral unit as a target for repair. Tissue engineered implants could provide a solution for the regeneration and prevent the development of OA.
This project aims to address this unmet clinical need by developing complex joint implants that will possess the spatially inbuilt biologic information for regenerating these challenging defects. Breakthroughs in organoid technologies have allowed the development of cartilaginous microtissue structures that can predictively execute regenerative programs upon implantation. These microtissues can be used as building blocks for bottom-up 3D bioprinting of living joint implants. In order to be able to produce scaled-up implants containing at the same time a highly precise structure, integration of bioprinting technologies is needed. Moreover, in order to cover rising clinical demand will need to integrate automated systems, bioprinting and bioreactor technologies. In order to demonstrate implant feasibility and efficacy, large osteochondral defect repair will be studied in a large animal model relevant to the patient. Taken together we strive to develop an automated, GMP-grade platform producing large, patterned and vascularized joint implants, addressing a major socioeconomic challenge of the European ageing society.
This project aims to address this unmet clinical need by developing complex joint implants that will possess the spatially inbuilt biologic information for regenerating these challenging defects. Breakthroughs in organoid technologies have allowed the development of cartilaginous microtissue structures that can predictively execute regenerative programs upon implantation. These microtissues can be used as building blocks for bottom-up 3D bioprinting of living joint implants. In order to be able to produce scaled-up implants containing at the same time a highly precise structure, integration of bioprinting technologies is needed. Moreover, in order to cover rising clinical demand will need to integrate automated systems, bioprinting and bioreactor technologies. In order to demonstrate implant feasibility and efficacy, large osteochondral defect repair will be studied in a large animal model relevant to the patient. Taken together we strive to develop an automated, GMP-grade platform producing large, patterned and vascularized joint implants, addressing a major socioeconomic challenge of the European ageing society.
The project started January 1st, 2020, for a 60 + 6 months duration. The project timeline has been adjusted with a 6 months extension due to Covid-19 pandemic and its impact in recruiting, mobility and the supply chain of materials.
During the first reporting period, technical work progressed according to the plan:
• Activities focused on problem definition, investigation of candidate methods and technologies, protocols for quality characterization, requirements for automation software for the robotics platform, establishment of data processing and communication platform and the preparation of clinic procedures for data collection.
• During the remaining part of the first reporting period, indication of proof of concepts for each specific technology to the microtissue material and its characterization was included.
Specific Technical objectives
1.A novel bioreactor design was decided by the consortium and manufactured by Stem Cell Technologies. It was tested at KU Leuven and preliminary results were encouraging. The bioreactor is necessary to produce sufficient micro-tissues for the large animal experiments and to select the bio-printing technology for macro-tissue assembly. Poietis developed a cartridge for the continuous provision of microtissue suspension during bioprinting. Proof of concept of successful microtissue bioprinting was provided and extrusion bioprinting specific hydrogels were used. Essential hardware components for the automated system were defined. A report on the system requirements, process maps and descriptions were specified in the detailed User Requirement Specification (URS).
2. Definitions for microtissue properties as a response to process conditions and the development of the chondrogenic phenotype were carried out. The QC technologies used in this proposal are both automated brightfield as well as nanoprobes and fluorescence imaging. Integrated omics was discussed and protocols for exometabolomics analysis were developed. Maastricht University developed a novel nanoprobe design that will report the expression of secreted proteins and manufactured ultrasmall nanoparticles, and started assays to evaluate their diffusion in cartilaginous microtissues.
3. Testing the manufactured implants in two clinically relevant demonstrators will be carried out in the second half of the project since the implants destined for defect regeneration will be manufactured.
During the first reporting period, technical work progressed according to the plan:
• Activities focused on problem definition, investigation of candidate methods and technologies, protocols for quality characterization, requirements for automation software for the robotics platform, establishment of data processing and communication platform and the preparation of clinic procedures for data collection.
• During the remaining part of the first reporting period, indication of proof of concepts for each specific technology to the microtissue material and its characterization was included.
Specific Technical objectives
1.A novel bioreactor design was decided by the consortium and manufactured by Stem Cell Technologies. It was tested at KU Leuven and preliminary results were encouraging. The bioreactor is necessary to produce sufficient micro-tissues for the large animal experiments and to select the bio-printing technology for macro-tissue assembly. Poietis developed a cartridge for the continuous provision of microtissue suspension during bioprinting. Proof of concept of successful microtissue bioprinting was provided and extrusion bioprinting specific hydrogels were used. Essential hardware components for the automated system were defined. A report on the system requirements, process maps and descriptions were specified in the detailed User Requirement Specification (URS).
2. Definitions for microtissue properties as a response to process conditions and the development of the chondrogenic phenotype were carried out. The QC technologies used in this proposal are both automated brightfield as well as nanoprobes and fluorescence imaging. Integrated omics was discussed and protocols for exometabolomics analysis were developed. Maastricht University developed a novel nanoprobe design that will report the expression of secreted proteins and manufactured ultrasmall nanoparticles, and started assays to evaluate their diffusion in cartilaginous microtissues.
3. Testing the manufactured implants in two clinically relevant demonstrators will be carried out in the second half of the project since the implants destined for defect regeneration will be manufactured.
The progress during its first half focused on technologies for the automated scalable expansion of cartilaginous microtissues. A novel bioreactor was tested specifically for microtissue production and its integration to the automated platform. Results indicated that cartilaginous microtissues cultured in it exhibited similar properties to those cultured in AggreWell albeit faster. This novel bioreactor will support the production of sufficient microtissues to use in the large animal experiments, as well as to characterize and select the bio-printing technology for macro-tissue assembly.
A novel laser based process increased the capacity and throughput of the printing process by targeting specific cartilaginous microtissues. In addition, successful microtissue bioprinting was provided which is the first proof that this technology can be used for 3D cell aggregates/microtissues/organoids. For extrusion bioprinting, novel bioinks/hydrogels were used while the fusion of the microtissue was explored in addition to their capacity to host endothelial cells.
Essential hardware components and the corresponding material for the automated system were defined. Currently, the automated platform is in construction and integration with the bioprinter are underway. A novel cartridge for the continuous provision of microtissues suspensions during bioprinting has been enabled. Robotic-based experiments for cartilaginous microtissue differentiation were done with a liquid handler.
Future experiments and activities will focus on the integration of the single processes in a streamlined integrated process. The automated platform will be finalized and installed in order to produce and test microtissue-based osteochondral implants for assessment in the large animal models. Feasibility of the platform to produce the necessary amount and quality of microtissues will be the first priority. Subsequently, the functionality of the osteochondral implant will be evaluated in large animal models. The quality control panel, as developed in the first half will enable the characterization of the identity and regenerative capacity of the product. We expect that the microtissue-based product will result in healing and regeneration of deep osteochondral defects of the knee joint which is currently a challenge in the field.
Here are some key socio-economic impact and wider societal implications of Jointpromise to consider:
Improved Quality of Life: By providing effective cartilage implants, this project can improve quality of life for individuals suffering from OA. Patients will experience reduced pain, improved joint function, and increased mobility, allowing them to engage in daily activities and enjoy a more active lifestyle.
Economic Benefits: By offering large-scale cartilage implants, the project can reduce the need for expensive and recurrent treatments such as pain medications, physical therapy, and joint replacement surgeries.
Accessibility and Equity: This project can contribute to improving accessibility and equity in healthcare. OA affects individuals from all socio-economic backgrounds. By focusing on large-scale production, the project can aim for affordability and availability, ensuring that more patients can benefit from this innovative treatment.
A novel laser based process increased the capacity and throughput of the printing process by targeting specific cartilaginous microtissues. In addition, successful microtissue bioprinting was provided which is the first proof that this technology can be used for 3D cell aggregates/microtissues/organoids. For extrusion bioprinting, novel bioinks/hydrogels were used while the fusion of the microtissue was explored in addition to their capacity to host endothelial cells.
Essential hardware components and the corresponding material for the automated system were defined. Currently, the automated platform is in construction and integration with the bioprinter are underway. A novel cartridge for the continuous provision of microtissues suspensions during bioprinting has been enabled. Robotic-based experiments for cartilaginous microtissue differentiation were done with a liquid handler.
Future experiments and activities will focus on the integration of the single processes in a streamlined integrated process. The automated platform will be finalized and installed in order to produce and test microtissue-based osteochondral implants for assessment in the large animal models. Feasibility of the platform to produce the necessary amount and quality of microtissues will be the first priority. Subsequently, the functionality of the osteochondral implant will be evaluated in large animal models. The quality control panel, as developed in the first half will enable the characterization of the identity and regenerative capacity of the product. We expect that the microtissue-based product will result in healing and regeneration of deep osteochondral defects of the knee joint which is currently a challenge in the field.
Here are some key socio-economic impact and wider societal implications of Jointpromise to consider:
Improved Quality of Life: By providing effective cartilage implants, this project can improve quality of life for individuals suffering from OA. Patients will experience reduced pain, improved joint function, and increased mobility, allowing them to engage in daily activities and enjoy a more active lifestyle.
Economic Benefits: By offering large-scale cartilage implants, the project can reduce the need for expensive and recurrent treatments such as pain medications, physical therapy, and joint replacement surgeries.
Accessibility and Equity: This project can contribute to improving accessibility and equity in healthcare. OA affects individuals from all socio-economic backgrounds. By focusing on large-scale production, the project can aim for affordability and availability, ensuring that more patients can benefit from this innovative treatment.