Mechanoregulation analysis of bone formation in tissue engineered constructs requires a volumetric method using time-lapsed micro-computed tomography

Griesbach, Julia K.; Schulte, Friederike A.; Schädli, Gian Nutal; Rubert, Marina; Müller, Ralph

doi:10.1016/j.actbio.2024.03.008

Cited by 2 publications

(4 citation statements)

References 63 publications

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“…Segmented greyscale images of day 49 and 56 were converted to Young's Modulus using the conversion function published by Zhang et al and voids within the scaffolds were assigned a Young's modulus of 3kPa to account for not mineralized connecting structures (39,40). Due to the uneven and soft top of the scaffolds, which varied between samples, we implemented a top pad with a Young's Modulus of 5GPa with multiple thicknesses adapted to the scaffold geometry (Fig.…”

Section: Micro-finite Element Analysismentioning

confidence: 99%

“…Due to the uneven and soft top of the scaffolds, which varied between samples, we implemented a top pad with a Young's Modulus of 5GPa with multiple thicknesses adapted to the scaffold geometry (Fig. 4A), enabling more realistic boundary conditions and force flow (40,60). Padding thickness was adjusted so that it ranged from minimal contact with the scaffold to a contact area of 70% of the maximum cross sectional area of each sample, increasing one voxel in thickness at a time.…”

Section: Micro-finite Element Analysismentioning

confidence: 99%

“…For this, registered, segmented and binarized images of day 49 and 56 were superimposed, and tissue present in both images was labelled quiescent and tissue only present on day 56, but not on day 49 was labelled formation. To associate effective strain from micro-FE analysis with tissue formation, we applied a previously developed method, which uses a volumetric projection of surface effective strain into the formation volumes (40). Mean effective strain of formation volumes was calculated and compared to mean effective strain on the quiescent surface.…”

Section: Mechanoregulation Analysismentioning

confidence: 99%

“…Mean effective strain of formation volumes was calculated and compared to mean effective strain on the quiescent surface. Additionally, conditional probability curves for tissue formation were calculated as described elsewhere (40,63). AUC for tissue formation was computed based on formation associated effective strain and effective strain on the scaffold surface, resulting in a value between 0.5 and 1, indicating the level of mechanoregulation present in tissue formation (64,65).…”

Section: Mechanoregulation Analysismentioning

confidence: 99%

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3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta

Griesbach,

de Leeuw,

Minacci

et al. 2024

Preprint

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Osteogenesis imperfecta (OI) is a heterogeneous group of rare genetic diseases characterized by increased bone fragility and deformities. The pathomechanisms of OI are poorly understood, hindering the development of disease-specific therapy. Addressing the limited understanding of OI and the lack of targeted treatments remains a challenge, given its varied symptoms and large clinical spectrum. Animal models have greatly advanced the understanding of the disease; however, the heterogeneity and subtype-specific symptoms are difficult to translate to humans. In vitro models offer a promising tool for translational medicine, as they have the potential to yield patient-specific insights in a controlled environment using patient derived-cells. We used mechanically loaded 3D-bioprinted patient-specific organotypic bone models and time-lapsed micro-computed tomography to demonstrate dysregulation of mineralization in FKBP10-related OI compared to healthy controls. In contrast to healthy controls, tissue mineral density and stiffness were decoupled, such that hypermineralization observed in OI samples did not lead to increased stiffness. Additionally, we were able to replicate experimental stiffness using sample specific micro-finite element analysis. This allowed us to show mineral formation in regions of high local strain, suggesting mechanoregulation in FKBP10-related OI organotypic bone models is comparable to healthy controls. Regional analysis of mineralization showed increased heterogeneous mineralization, microarchitectural inhomogeneities and scaffold microporosity of OI samples compared to healthy controls. Our results suggest that the observed dysregulation of mineralization is the main driver for the altered mineral-mechanics properties observed in FKBP10-related organotypic bone models.

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Section: Micro-finite Element Analysismentioning

confidence: 99%

Section: Micro-finite Element Analysismentioning

confidence: 99%

Section: Mechanoregulation Analysismentioning

confidence: 99%

Section: Mechanoregulation Analysismentioning

confidence: 99%

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3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta

Griesbach,

de Leeuw,

Minacci

et al. 2024

Preprint

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Combined physical and pharmaceutical anabolic osteoporosis therapies synergistically increase bone response and local mechanoregulation

Schulte,

Griesbach,

Weigt

et al. 2024

Preprint

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Bone loss in postmenopausal osteoporosis is caused by a remodeling imbalance towards increased bone resorption. Existing osteoporosis therapies are systemic and designed to recover bone mass, using the same molecular pathways that also allow bone to adapt to changing mechanical demands. Supraphysiological mechanical loading induces use a process on the tissue level called mechanoregulation, ensuring that bone is formed where needed and resorbed where unneeded. Little focus has been on combination therapy of physical and pharmaceutical therapy. Here, we report the effects of combining physical therapy in the form of mechanical loading with pharmaceutical treatment, i.e. bisphosphonates (BIS), parathyroid hormone (PTH), or sclerostin antibodies (SclAB) in ovariectomized C57Bl/6J mice. Mechanical loading synergistically potentiated trabecular bone mass under PTH or SclAB therapy but only marginally increased trabecular bone mass under BIS treatment. Bone remodeling was targeted to underlying micro-mechanical stimuli through mechanoregulation in all pharmaceutical treatments, but to different extents. BIS treatment showed higher untargeted remodeling compared to anabolic treatments, both alone and in combination with mechanical loading. Mechanical loading potentiated the mechanoregulatory response of SclAB treatment (synergistically) and PTH treatment (additively), indicating that in anabolic treatments, mechanical loading potentiates treatment efficacy by inducing more targeted bone formation and resorption. These findings suggest that incorporating physical therapy into anabolic pharmaceutical treatment regimens holds promise for enhancing therapeutic outcomes in osteoporosis management.

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Mechanoregulation analysis of bone formation in tissue engineered constructs requires a volumetric method using time-lapsed micro-computed tomography

Cited by 2 publications

References 63 publications

3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta

3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta

Combined physical and pharmaceutical anabolic osteoporosis therapies synergistically increase bone response and local mechanoregulation

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