Periodic Reporting for period 3 - MULT2D (Multiscale Mechanics of Bone Fragility in Type-2 Diabetes)
Periodo di rendicontazione: 2022-02-01 al 2023-07-31
Dr Ted Vaughan’s group is conducting a European Research Council project (MULT2D) to examine how bone fragility occurs in long-term Type-2 diabetes. People with Type-2 diabetes are at higher risk of skeletal bone fractures, however the precise reason for this remains unknown. Interestingly, the elevated bone fragility in T2 diabetes is not accompanied by a reduction in bone mass, which is commonly seen in other bone diseases such as osteoporosis. This presents distinct clinical challenges in terms of both assessment and treatment of T2 diabetic bone disease, as traditional screening methods, such as DEXA scanning, are unable to provide quantitative measures of fracture probability. The MULT2D project seeks to better understand the physical mechanisms that are responsible for diabetic bone fragility using a combination of experimental and computational mechanics approaches. MULT2D is evaluating the behaviour of human T2 diabetic bone tissue through mechanical testing to help establish quantitative relationships between fracture behaviour and properties of the bone tissue itself. MULT2D is also developing computational models that will help provide predictions for fracture in this cohort, which will enable a strategy for clinical fracture risk assessment to be developed. Protecting against fracture in this patient population is vital as fracture healing itself is associated with increased complications compared to healthy individuals.
In WP1, a preclinical animal model is being conducted to investigate bone fragility in T2 Diabetes. This animal study is currently underway, with several animal groups currently housed in the Biomedical Research Unit at the host institution. To date, preliminary experiments have been carried out and detailed protocols and test rigs for the planned work in Tasks 1.1 1.2 and 1.3 have been established. Preliminary results have been presented as podium presentations by two team members at the BioEngineering in Ireland (BINI) Conference 2020, which took place in January 2020.
In WP2, a computational framework for bone fragility is being developed. In Task 2.1 Molecular Dynamics models describing the behaviour of both Collagen and Non-Collagenous proteins have been developed. Based on this work, the project has uncovered a novel finding on the role of Osteocalcin in bone fracture events and have a journal manuscript under revision in Nature Scientific Reports. A further manuscript is in preparation. Findings have also been presented in a podium presentation at the BINI 2020 conference. Task 2.2 has developed a preliminary coarse-grain framework for Mineralised Collagen, which will be used to explore the role of enzymatic and non-enzymatic crosslinking on mechanical behaviour. Task 2.3 has developed a finite element model for lamellar bone using a representative volume element approach, with detailed parameter studies carried out to explore behaviour in the elastic regime Task 2.4 is not scheduled to start yet.
In WP3, ethical approval was obtained in Year 1 from the local Research Ethics Committee that enabled human tissue to be obtained from patients undergoing total hip replacements at of the Galway Regional Hospitals to be obtained. Due to COVID-19, collection of tissue from local hospitals has been paused since March 2020. Despite this, work across all Tasks in WP3 has continued as planned using suitable animal tissue as an alternative. It is expected that tissue collection from the hospital will commence in the coming months. Task 3.1: preliminary work on the indentation-based response of human T2 diabetic tissue has been carried out. In Task 3.2 the compressive biomechanical response of trabecular bone from T2 diabetic patients has been evaluated and detailed micro-CT imaging of the tissue has commenced. Already, a proof-of-concept study has been published in the Journal of Bone and Mineral Research Plus. Findings have also been presented in a podium presentation at the BINI 2020 conference. Task 3.3 is not scheduled to start yet, however a PhD student has been recruited to work on this beginning in M19.
In WP2, a computational framework for bone fragility is being developed. In Task 2.1 Molecular Dynamics models describing the behaviour of both Collagen and Non-Collagenous proteins have been developed. Based on this work, the project has uncovered a novel finding on the role of Osteocalcin in bone fracture events and have a journal manuscript under revision in Nature Scientific Reports. A further manuscript is in preparation. Findings have also been presented in a podium presentation at the BINI 2020 conference. Task 2.2 has developed a preliminary coarse-grain framework for Mineralised Collagen, which will be used to explore the role of enzymatic and non-enzymatic crosslinking on mechanical behaviour. Task 2.3 has developed a finite element model for lamellar bone using a representative volume element approach, with detailed parameter studies carried out to explore behaviour in the elastic regime Task 2.4 is not scheduled to start yet.
In WP3, ethical approval was obtained in Year 1 from the local Research Ethics Committee that enabled human tissue to be obtained from patients undergoing total hip replacements at of the Galway Regional Hospitals to be obtained. Due to COVID-19, collection of tissue from local hospitals has been paused since March 2020. Despite this, work across all Tasks in WP3 has continued as planned using suitable animal tissue as an alternative. It is expected that tissue collection from the hospital will commence in the coming months. Task 3.1: preliminary work on the indentation-based response of human T2 diabetic tissue has been carried out. In Task 3.2 the compressive biomechanical response of trabecular bone from T2 diabetic patients has been evaluated and detailed micro-CT imaging of the tissue has commenced. Already, a proof-of-concept study has been published in the Journal of Bone and Mineral Research Plus. Findings have also been presented in a podium presentation at the BINI 2020 conference. Task 3.3 is not scheduled to start yet, however a PhD student has been recruited to work on this beginning in M19.
Summary: In the first 30 months of this project we have delivered significant advances in the field, which is evident from the generation of three journal papers in leading journals in the field (e.g. Nature Scientific Reports and the Journal of Bone and Mineral Research Plus) with a further two manuscripts currently under review in the Biophysical Journal and the Journal of Mechanical Behaviour of Biomedical Materials. This research has led to 17 conference presentations at leading national and international meetings including the Bioengineering in Ireland (BINI) conference, European Orthopaedic Research Society (ORS), the European Society for Biomechanics (ESB), the International Conference of Computational Plasticity and the International Symposium on Computer Methods in Biomechanics and Biomedical Engineering.
Our key findings beyond the state-of-the-art are as follows:
-In WP1, a relationship has been established between bone composition and bone fragility at whole-bone and tissue-levels. However, it appears that there is little correlation between the yield and ultimate stress of the tissue with AGE content, but instead acid phosphate content had a significantly negative correlation. These results suggest that the primary contributor to impaired biomechanical properties in long-term T2 diabetes is an altered bone remodelling/turnover process. This has never been shown quantitatively before.
-In WP2, or work in molecular dynamics have provided to systematically investigate how structural alterations to matrix proteins, which underlie the pathogenesis of diabetes, affect mesoscale tissue behaviour. Based on this work, the project has uncovered novel findings on the structural roles of both osteocalcin and osteopontin in bone fracture events. This has revealed that both proteins have excellent capacity for energy dissipation, with the structure of osteocalcin potentially altered during T2 diabetes, which could lead to impaired behaviour.
-In WP3, it was found, for the first time, that trabecular bone mineralisation is significantly more heterogeneous in T2 diabetes compared to non-diabetic controls. The observed alterations in mineral heterogeneity may play an important tissue-level role in bone fragility associated with osteoporotic and diabetic bone. Like WP1, we found using an in vitro model for diabetes that increased AGE content in bone tissue did not lead to impaired mechanical properties, suggesting that other mechanisms must be responsible for bone fragility in Type-2 diabetes.
Our key findings beyond the state-of-the-art are as follows:
-In WP1, a relationship has been established between bone composition and bone fragility at whole-bone and tissue-levels. However, it appears that there is little correlation between the yield and ultimate stress of the tissue with AGE content, but instead acid phosphate content had a significantly negative correlation. These results suggest that the primary contributor to impaired biomechanical properties in long-term T2 diabetes is an altered bone remodelling/turnover process. This has never been shown quantitatively before.
-In WP2, or work in molecular dynamics have provided to systematically investigate how structural alterations to matrix proteins, which underlie the pathogenesis of diabetes, affect mesoscale tissue behaviour. Based on this work, the project has uncovered novel findings on the structural roles of both osteocalcin and osteopontin in bone fracture events. This has revealed that both proteins have excellent capacity for energy dissipation, with the structure of osteocalcin potentially altered during T2 diabetes, which could lead to impaired behaviour.
-In WP3, it was found, for the first time, that trabecular bone mineralisation is significantly more heterogeneous in T2 diabetes compared to non-diabetic controls. The observed alterations in mineral heterogeneity may play an important tissue-level role in bone fragility associated with osteoporotic and diabetic bone. Like WP1, we found using an in vitro model for diabetes that increased AGE content in bone tissue did not lead to impaired mechanical properties, suggesting that other mechanisms must be responsible for bone fragility in Type-2 diabetes.