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Advanced Modelling Aided Design of Tissue Engineered Construct for Optimal Soft Tissue Repair

Periodic Reporting for period 1 - MADE-TEC (Advanced Modelling Aided Design of Tissue Engineered Construct for Optimal Soft Tissue Repair)

Reporting period: 2021-03-01 to 2023-02-28

Tissue engineering of articular cartilage in the lab is a promising approach for tissue repair of diarthrodial joints that are affected by osteoarthritis. However, the integrative properties of the engineered tissues are not well-understood, leading to a poor integration of these engineered constructs with the host natives tissues following implantation. Osteoarthritis is a joint disease that affects more than 40 million people in Europe. The overall mobility of the patients with osteoarthritis is severely limited due to pain and swelling of the affected joints, thereby predisposing the patients, especially of the elderly, to high risk of other morbidities such as cardiovascular disease, diabetes and obesity. Determination of an effective treatment strategy for osteoarthritis is crucial to meet the medical need of this patient group. In addition, the economic burden due to the medical treatments, down time and reduced working life of the affected patients can be reduced if a breakthrough is made in the area of tissue engineering. The over-arching goal of the current project was aimed at identifying the optimal distribution of material stiffness and cell density within the engineered constructs for enhanced functional integration of the engineered tissue constructs with host tissues post-implantation. Laboratory identification of the optimal material properties and cell distribution is extremely labour-, cost-, and time-consuming. Therefore, the current project proposed an in silico approach through the development of an advanced computational model capable of predicting the mechanical growth stimuli for cells residing in the biomaterials and the host tissue to which the engineered construct is implanted. The computational material model is able to provide insight into the mechanism of cell mechano-biology that is crucial for the understanding of cell responses to various forms of mechanical stimuli.

Conclusion of the actions
The progress of this fellowship was affected by the COVID-19 pandemic, especially during the year of 2021. Nevertheless, most goals initially set out for the proposal are achieved. In total, this fellowship leads to 9 peer-reviewed publications, 7 conference abstracts, and 4 manuscripts that are under preparation. The research output generated through this fellowship improves the current understanding of cartilage growth and degeneration, as well as the design of biomaterials used for tissue engineering.
A summary of the current progress for each research objective (RO) is described in the following:
RO-1: This research objective was achieved. A one-month research visit in November of 2021 to the laboratory of Prof. Jos Malda at the University Medical Center (UMC) Utrecht allowed the awardee to learn the state-of-the-art three-dimensional (3D) printing of fibrous mesh, and the use of photo-crosslinkable hydrogels for cell culture. Computation biomechanical models of articular cartilage and hydrogels with and without reinforcement by the fibrous mesh were successfully developed and validated using experimental data (doi:10.1016/j.actbio.2021.03.031). Multi-scale computational model accounting for length scale at the tissue and cell levels was also successfully developed (doi: 10.1007/s10439-021-02900-1) thereby allowing for accurate prediction of the deformation behaviour of the tissue and residing cells.

RO-2: This research objective was partially achieved. A 3-month research visit of UMC Utrecht from June to August of 2022 allowed the awardee to collect important experimental data related to the growth of cell-laden gelatin-based hydrogels and the associated changes of mechanical properties during different time points of the tissue growth. Computational biomechanical growth model was also constructed successfully based on the computational model available in the literature. However, the characterisation of the computation model was not completed due to a lack of time following the research visit (< 4 months before the end of the fellowship) and an early termination of the fellowship as the awardee started a faculty position at Carleton University in Canada on January 2023. Nevertheless, the awardee maintains a strong collaborative relationship with Profs. Korhonen and Malda, and will continue the unfinished work in Canada. Research updates regarding this project will be posted on the public website created on ResearchGate for this project.

RO-3: Due to the unforeseen pandemic, RO-3 initially drafted in the research proposal needed to be adjusted to follow a different, but relevant directions. Two new research goals were set to unravel the mechanism of cartilage degeneration through computational simulation. The first goal was aimed at investigating the mechanism that triggers the initial degradation of cartilage tissue at the onset of osteoarthritis. The second goal was aimed at investigating the mechanical effect of tissue crack, which is a risk factor of osteoarthritis, on cartilage tissues of different skeletal maturity. These two goals were successfully achieved and led to two publications in scientific peer-reviewed journals (doi: 10.1016/j.actbio.2022.09.002 and doi: 10.1002/jor.25243). Despite a change of direction, the research methods used in the new projects are aligned with those originally planned in the research proposal. Specifically, a numerical optimisation procedure was successfully developed to identify the material properties of the structural proteins in cartilage.

The research findings of this project were shared in three international conferences. In addition, the awardee was also invited to give research seminars on three occasions to discuss the findings of the project. The audience includes undergraduate and graduate students, as well as senior researchers and professors.
The state-of-the-art computational model for articular cartilage is a fibre-reinforced biphasic material model that takes into account the solid and fluid phases of the cartilage. Through the MSCA fellowship, a fibre-reinforced multi-phasic material model that extended the phasic consideration into the ionic phases was developed and tailored for healthy and diseased cartilages. The advances in the material model will allow future researcher to directly investigate the biomechanical and biochemical interactions occurring within biological tissues. The outcomes of the MSCA project inform the osteoarthritis research community the significance of collageneous structural disorganisation during early development of osteoarthritis, and provide new insights for the tissue engineering research community regarding the potential use of 3D printed fibrous mesh for additional mechanical stimulus through fluid pressurisation.

On the personal level, the research and transferrable skills acquired through the MSCA fellowship enriched the expertise of the awardee and made him a more complete researcher. The awardee is starting a research faculty position at the Carleton University in Canada on January 2023. The research collaborations developed during this fellowship with the researchers from the University of Eastern Finland and UMC Utrecht will continue in the future and strengthen the tie between European and Canadian universities, which is important to facilitate the collective efforts in tackling of the research problems that can have important impacts in the field of osteoarthritis and tissue engineering.
Summary figures for two of the projects performed during the MSCA fellowship