Periodic Reporting for period 1 - CREATION (Mechanobiological optimization of regeneration in cell-enriched construct implants within degenerative Cartilages: a defect Repair method through restoring Energy AbsorpTION)
Berichtszeitraum: 2020-09-01 bis 2022-08-31
Knee Articular Cartilage (AC) is an irreplaceable soft tissue for healthy joint function. It is indispensable for absorbing and dissipating shocks to minimize peak loads in the underlying subchondral bone. Malalignment and joint instability are known to change cartilage loading, thereby contributing to cartilage degeneration and the development of non-traumatic osteoarthritis (OA). This condition is estimated to affect more than 40 million people across Europe and 1 in 10 of the population over 60 with an estimated socio-economic burden of 45 billion Euro. Worldwide, but also within Belgium, multi-disciplinary networks aim to seek a solution. OA is a multifactorial disease, with mechanical loading being one of the contributing factors to the initiation and progression of the disease.
Tissue engineering methods propose solutions to OA by implanting chondrocyte cell-enriched hydrogel/scaffold constructs within degenerative cartilage defects. By applying mechanical loads to stimulate the cells within the constructs, they initiate cartilage extracellular matrix (ECM) synthesis. The mechanical environment of the cell-seeded construct has a crucial role in defining the quality and quantity of the regenerated ECM. This will determine the mechanical performance of the cartilage tissue. Indeed, any repair method has to aim at restoring the unique cartilage mechanics, in particular, the energy absorption capacity.
This project aims at restoring energy absorption of degenerative cartilage by optimizing regeneration in cell-enriched construct implants. The goal was pursued by developing an in-silico framework for mechanobiological modelling of the regeneration and degeneration in the cartilage-implant compound during loading. The in silico models can then be used in optimization schemes to minimize differences between the energy absorption of construct implants and native human cartilage.
Tissue engineering methods propose solutions to OA by implanting chondrocyte cell-enriched hydrogel/scaffold constructs within degenerative cartilage defects. By applying mechanical loads to stimulate the cells within the constructs, they initiate cartilage extracellular matrix (ECM) synthesis. The mechanical environment of the cell-seeded construct has a crucial role in defining the quality and quantity of the regenerated ECM. This will determine the mechanical performance of the cartilage tissue. Indeed, any repair method has to aim at restoring the unique cartilage mechanics, in particular, the energy absorption capacity.
This project aims at restoring energy absorption of degenerative cartilage by optimizing regeneration in cell-enriched construct implants. The goal was pursued by developing an in-silico framework for mechanobiological modelling of the regeneration and degeneration in the cartilage-implant compound during loading. The in silico models can then be used in optimization schemes to minimize differences between the energy absorption of construct implants and native human cartilage.
The general objective of the CREATION project was to develop an in-silico adaptive FE model of regeneration-degeneration to optimize the mechanobiological environment of biological implants by restoring the cartilage’s energy absorption capacity. The general objective was followed by developing a novel integrated Cartilage Adaptive REorientation Degeneration (CARED) algorithm to predict the interaction between degenerative variations in main cartilage constituents (published in https://www.frontiersin.org/articles/10.3389/fbioe.2021.680257/full). CARED model was used to create ‘virtual knock-out’ cases to elucidate the effect of maladaptive changes on the main cartilage constituents during the degeneration process in OA. We used such an approach to study the main mechanisms of cartilage degeneration in different mechanical loadings associated with three different OA etiologies (a manuscript is under revision for publication in Osteoarthritis and Cartilage journal: Contribution of collagen degradation and proteoglycan depletion to cartilage degeneration in primary and secondary osteoarthritis: an in silico study). Validation experiments were performed by longitudinal loading of healthy and defected human cartilage explants within the bioreactor. The samples were used for histological measurements to determine the cartilage constituents (performed at the secondment lab. at the University of Eastern Finland) and gene expression behavior (performed at KU Leuven). The results are currently being analyzed to be compared with CARED model results. Moreover, an adaptive model for simulating the regeneration in cell-seeded constructs in degenerative cartilage was developed (presented at VPH 2022 conference in Porto: An in silico framework for virtual optimization of tissue engineering cartilage repair approaches).
Moreover, a mechanical characterization protocol to optimally identify the properties of hydrogel constructs and cartilage explants using simple unconfined compression experiments was developed. The protocol was developed based on an in silico parameter sensitivity analysis (published in: https://www.sciencedirect.com/science/article/pii/S1751616121004367). The developed protocol was also presented in a book chapter (Unconfined compression experimental protocol for cartilage explants and hydrogel constructs: from sample preparation to mechanical characterization. In: M. Stoddart, A. Armiento, E. Della Bella (editors) Cartilage Tissue Engineering, In-Press.). Moreover, the loading results of the longitudinal bioreactor experiments on healthy cartilage samples were used to determine the time-dependent changes in the absorbed energy by native cartilage explants.
Moreover, a mechanical characterization protocol to optimally identify the properties of hydrogel constructs and cartilage explants using simple unconfined compression experiments was developed. The protocol was developed based on an in silico parameter sensitivity analysis (published in: https://www.sciencedirect.com/science/article/pii/S1751616121004367). The developed protocol was also presented in a book chapter (Unconfined compression experimental protocol for cartilage explants and hydrogel constructs: from sample preparation to mechanical characterization. In: M. Stoddart, A. Armiento, E. Della Bella (editors) Cartilage Tissue Engineering, In-Press.). Moreover, the loading results of the longitudinal bioreactor experiments on healthy cartilage samples were used to determine the time-dependent changes in the absorbed energy by native cartilage explants.
Conducting this research the researcher took part in addressing OA, which is not only a European but a worldwide challenge and as a consequence, he took a step forward in the ‘Good Health and Well-Being’ goal of SDGs (Sustainable Development Goals). The supervision and leadership experience gained during the fellowship is essential in establishing an independent research group and supervising students. The researcher envisions leading a multidisciplinary group, with researchers with different backgrounds (e.g. mechanics, mathematics, biology, physics, and medicine). Therefore, working in a multidisciplinary environment within the hosting institution, the researcher learned about interdisciplinary teamwork and communication.
The key outcome of this project is the in silico framework for further understanding of OA disease progression and optimization of treatment approaches. The key stakeholders in general are the OA community, tissue engineering and biomedical engineering researchers. The stakeholders have been reached through publishing the results in top-ranked peer-reviewed scientific journals of the relevant communities including Osteoarthritis and Cartilage, Frontiers in Bioengineering and Biotechnology and Journal of Mechanical Behavior of Biomedical Materials in addition to the methodological book chapter that is in press in Cartilage Tissue Engineering book. Following Horizon 2020 guidelines, open access was ensured to all the publications by paying for the open access fee and by self-archiving the articles in the KUL OpenAIRE compliant repository ‘Lirias’. Furthermore, the results were presented in 11 relevant conferences on computational (bio)mechanics (WCCM, CMBBE, VPH), orthopaedics (EORS, OARSI and ORS) and biomechanics (ESB, ISB, WCB). This selection of conferences disseminated the project results to experts in mechanics, biology and modelling and clinicians. The researcher also acted as Marie Curie Ambassador, visiting research groups within and outside of the collaboration network with similar research interests, to give invited talks on the findings of the project. Research results were disseminated to the project partner through project meetings held at the University of Eastern Finland (Finland) before (online) and during the secondment. During the visit to Utrecht University (Netherlands), the results have been presented to the group of Prof. Jos Malda, a leading European group in the field of bio-printing for cartilage tissue engineering. The project updates were also shared through LinkedIn and Twitter by the researcher, supervisor and collaborators.
The key outcome of this project is the in silico framework for further understanding of OA disease progression and optimization of treatment approaches. The key stakeholders in general are the OA community, tissue engineering and biomedical engineering researchers. The stakeholders have been reached through publishing the results in top-ranked peer-reviewed scientific journals of the relevant communities including Osteoarthritis and Cartilage, Frontiers in Bioengineering and Biotechnology and Journal of Mechanical Behavior of Biomedical Materials in addition to the methodological book chapter that is in press in Cartilage Tissue Engineering book. Following Horizon 2020 guidelines, open access was ensured to all the publications by paying for the open access fee and by self-archiving the articles in the KUL OpenAIRE compliant repository ‘Lirias’. Furthermore, the results were presented in 11 relevant conferences on computational (bio)mechanics (WCCM, CMBBE, VPH), orthopaedics (EORS, OARSI and ORS) and biomechanics (ESB, ISB, WCB). This selection of conferences disseminated the project results to experts in mechanics, biology and modelling and clinicians. The researcher also acted as Marie Curie Ambassador, visiting research groups within and outside of the collaboration network with similar research interests, to give invited talks on the findings of the project. Research results were disseminated to the project partner through project meetings held at the University of Eastern Finland (Finland) before (online) and during the secondment. During the visit to Utrecht University (Netherlands), the results have been presented to the group of Prof. Jos Malda, a leading European group in the field of bio-printing for cartilage tissue engineering. The project updates were also shared through LinkedIn and Twitter by the researcher, supervisor and collaborators.