Periodic Reporting for period 2 - ScoliStorm (Adolescent Idiopathic Scoliosis: a Perfect Storm of Functional Anatomy, Biomechanics and Mechanobiology during Growth?)
Reporting period: 2023-04-01 to 2024-09-30
Adolescent idiopathic scoliosis (AIS) is a 3D deformity of the spine affecting previously healthy children, substantially reducing their quality of life and creating a life-long burden of disease. Although it has been indentified since the time of
Hippocrates (400 BC), we have not been able to rationally develop effective treatments and provide a cure for these children suffering from AIS because its cause and mechanism of disease are still unknown. ScoliStorm will create a paradigm shift in
AIS research by uncovering its complex perfect storm of anatomical, biomechanical and mechanobiological causes in the intervertebral disc and exploring this disease mechanism whereby predictive triggers are identified that can be used for
prevention and early treatment. We will study human subjects non-invasively through disease initiation and progression, creating for the first time a comprehensive dataset of healthy and scoliotic human spines that can be used for early detection
and treatment of juvenile spine conditions. We will create safe non-radiographic accurate imaging of the osseous spine, available in most hospitals, which can become the standard for diagnosis and monitoring of osseous injury and disease in
juveniles. We will develop high-throughput creation and use of subject specific in silico models, allowing simulation of organ and tissue function such that morphological imaging data can provide functional analysis of the patient for diagnosis and
treatment. Mechanisms affecting tissue adaptation will be mapped and show that normal processes by their coincidence can create an aberrant response and disease, providing an explanation applicable for other multifactorial diseases. Thus, a
unique dedicated and complete multidisciplinary process, combining 1) bioengineering analysis, exploiting imaging, in silico modeling, in vitro and ex vivo approaches
Hippocrates (400 BC), we have not been able to rationally develop effective treatments and provide a cure for these children suffering from AIS because its cause and mechanism of disease are still unknown. ScoliStorm will create a paradigm shift in
AIS research by uncovering its complex perfect storm of anatomical, biomechanical and mechanobiological causes in the intervertebral disc and exploring this disease mechanism whereby predictive triggers are identified that can be used for
prevention and early treatment. We will study human subjects non-invasively through disease initiation and progression, creating for the first time a comprehensive dataset of healthy and scoliotic human spines that can be used for early detection
and treatment of juvenile spine conditions. We will create safe non-radiographic accurate imaging of the osseous spine, available in most hospitals, which can become the standard for diagnosis and monitoring of osseous injury and disease in
juveniles. We will develop high-throughput creation and use of subject specific in silico models, allowing simulation of organ and tissue function such that morphological imaging data can provide functional analysis of the patient for diagnosis and
treatment. Mechanisms affecting tissue adaptation will be mapped and show that normal processes by their coincidence can create an aberrant response and disease, providing an explanation applicable for other multifactorial diseases. Thus, a
unique dedicated and complete multidisciplinary process, combining 1) bioengineering analysis, exploiting imaging, in silico modeling, in vitro and ex vivo approaches
Synthetic CT images of the thoracic-lumbar spine were validated using BoneMRI. This was then integrated into an adolescent idiopathic scoliosis specific MRI protocol of 8 sequences, making it possible to quickly and completely image all spinal structures, even with children of limited attention spans. These were used in clinical studies of sister/daughter subjects and 22q11.2DS patients (Earlybird 1 & 2). Currently, there are 31 sister/daughter and 11 microdeletions patient inclusions.
To correlate disc biomechanical properties to disc and growth plate maturity, we focused on establishing methodologies for assessment of structural, mechanical, and compositional properties of the disc and growth plate. While waiting for the collection of sufficient number and age range of human adolescent segments, we used bovine segments. Most interestingly, a 7T MRI 3D assessment of collagen fiber microarchitecture of the complete disc in an unaltered state, while quantifying water content noninvasively was achieved.
For eventual subject-specific biomechanical assessment of the spine, machine learning algorithms were developed for automatic segmentation of discs, vertebrae and facet joints. A new, faster, and more robust method for the automatic creation of subject-specific spine models was set up using an algorithm for mesh morphing. These methods are now being applied to build models specific to the subjects in the Earlybird studies.
As a first step towards a spinal biomechnical model, a generic spinal motion segment model with multiphasic discs was developed. After confirming model accuracy, a L4-L5 segment model was validated in all three rotational degrees-of-freedom against an experimental study. Then the model was adapted to subject-specific T11-12 segment models of a cohort of Earlybird subjects to assess effects of spinal instability with retroversion on ‘unlocking’ of the facet joints increasing rotationally instability and whether this could lead to higher strains in the annulus fibrosus in our cohort of subjects.
To identify growth plate morphogens (GPMs) responsible for negatively affecting IVD deformity during tissue remodelling, we narrowed our focus to seven cytokines most likely responsible for contributing to scoliosis. The ability of these morphogens to elicit a gene expression response in AF cells were explored. It was observed that three of the morphogens induced downstream pathway activation. An innovative 2.5D platform was developed such that AF cells could be cultured while preserving their native phenotype. Subsequently, a screening study to assess the impact of GPMs on AF cellular capacity for tissue remodeling was investigated. We are currently awaiting results from RNA sequencing. The most interesting results will be further verified at the protein level.
To correlate disc biomechanical properties to disc and growth plate maturity, we focused on establishing methodologies for assessment of structural, mechanical, and compositional properties of the disc and growth plate. While waiting for the collection of sufficient number and age range of human adolescent segments, we used bovine segments. Most interestingly, a 7T MRI 3D assessment of collagen fiber microarchitecture of the complete disc in an unaltered state, while quantifying water content noninvasively was achieved.
For eventual subject-specific biomechanical assessment of the spine, machine learning algorithms were developed for automatic segmentation of discs, vertebrae and facet joints. A new, faster, and more robust method for the automatic creation of subject-specific spine models was set up using an algorithm for mesh morphing. These methods are now being applied to build models specific to the subjects in the Earlybird studies.
As a first step towards a spinal biomechnical model, a generic spinal motion segment model with multiphasic discs was developed. After confirming model accuracy, a L4-L5 segment model was validated in all three rotational degrees-of-freedom against an experimental study. Then the model was adapted to subject-specific T11-12 segment models of a cohort of Earlybird subjects to assess effects of spinal instability with retroversion on ‘unlocking’ of the facet joints increasing rotationally instability and whether this could lead to higher strains in the annulus fibrosus in our cohort of subjects.
To identify growth plate morphogens (GPMs) responsible for negatively affecting IVD deformity during tissue remodelling, we narrowed our focus to seven cytokines most likely responsible for contributing to scoliosis. The ability of these morphogens to elicit a gene expression response in AF cells were explored. It was observed that three of the morphogens induced downstream pathway activation. An innovative 2.5D platform was developed such that AF cells could be cultured while preserving their native phenotype. Subsequently, a screening study to assess the impact of GPMs on AF cellular capacity for tissue remodeling was investigated. We are currently awaiting results from RNA sequencing. The most interesting results will be further verified at the protein level.
• The novel short AIS specific clinical MRI protocol is the first radiation-free spine imaging protocol, which allows to visualize all landmarks to detect patho-anatomical changes in the bone and soft-tissues in children. Unexpectedly, we were also able to shorten and simplify the protocol which could be used as a screening tool to assess risk for scoliosis, to screen for neural axis abnormalities, and to perform surgical planning and navigation in patients with more severe scoliosis. It can be potentially used in a broader clinical context, for example in patients with braces.
• The ability to use a single radiation-free MR sequence to automatically generate biomechanical models of the complete spine can be considered a breakthrough. Mesh morphing and automatic segmentation methods have existed for a while, but especially for the spine these have not been very efficient due to the complex structure of the spine. Our developed automatic machine learning segmentation and mesh morphing method has resulted in a robust method that always results in a working subject-specific biomechanical spine
• When developing the subject-specific FEM of the SMS, facet tropism (FT) was unexpectedly observed. FT is a difference in the orientation angle of facet joints (i.e. between the left and right sides) with respect to each other in the sagittal plane. When present, FT could lead to unequal biomechanical forces on the joints and on the disc, affecting the biomechanical response of the spine during rotation. Literature studies revealed the association between facet tropism and disc herniation or disc degeneration or disc protrusion or even osteoarthritis, but there are not relevant works which focus on the relationship with AIS. One of the goals of the next steps will be to explore this aspect for different spinal levels.
• The ability to use a single radiation-free MR sequence to automatically generate biomechanical models of the complete spine can be considered a breakthrough. Mesh morphing and automatic segmentation methods have existed for a while, but especially for the spine these have not been very efficient due to the complex structure of the spine. Our developed automatic machine learning segmentation and mesh morphing method has resulted in a robust method that always results in a working subject-specific biomechanical spine
• When developing the subject-specific FEM of the SMS, facet tropism (FT) was unexpectedly observed. FT is a difference in the orientation angle of facet joints (i.e. between the left and right sides) with respect to each other in the sagittal plane. When present, FT could lead to unequal biomechanical forces on the joints and on the disc, affecting the biomechanical response of the spine during rotation. Literature studies revealed the association between facet tropism and disc herniation or disc degeneration or disc protrusion or even osteoarthritis, but there are not relevant works which focus on the relationship with AIS. One of the goals of the next steps will be to explore this aspect for different spinal levels.