Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

Zhou, Qi; Lyu, Shengyu; Bertrand, Anthony A.; Hu, Allison C.; Chan, Candace H.; Ren, Xiaoyan; Dewey, Maynard M.; Tiffany, Aleczandria S.; Harley, Brendan A.C.; Lee, Justine C.

doi:10.1101/2020.03.09.982231

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Our findings are consistent with this observation, suggesting increased OPG secretion by hMSCs in MC-HB composites may be due to increased release of Calcium and Phosphate ions during degradation (vs. MC scaffolds or MC-Fluffy composites). This indicates that inclusion of Hyperelastic Bone 3D-prints could not only regenerate bone through increased stiffness, which has been linked with greater mechanotransduction-induced bone formation in mineralized collagen scaffolds [88], but also provide additional inorganic ions to safely elevate OPG levels without the need of gene therapy or growth factors [56]. The timing of increased OPG production during significant Hyperelastic Bone degradation further suggests that the Hyperelastic Bone reinforcement structure may play an active role in promoting an osteogenic response in addition to passive mechanical reinforcement.…”

Section: Discussionmentioning

confidence: 95%

Inclusion of a 3D-printed Hyperelastic bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

Dewey

Nosatov

Subedi

et al. 2020

Preprint

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Regenerating craniomaxillofacial bone defects is a challenging endeavor due to the large quantity of missing bone tissue and irregular shape of the defect. Mineralized collagen scaffolds have been shown to promote bone formation in vivo and mineral formation in vitro. Here we describe inclusion of a 3D-printed polymer or ceramic-based mesh into a mineralized collagen scaffold to improve mechanical and biological activity. We examine flexible mineralized collagen reinforced with 3D-printed Fluffy-PLG (ultraporous polylactide-co-glycolide co-polymer) or Hyperelastic Bone (90wt% calcium phosphate in PLG). We show degradation byproducts and acidic release from the resulting printed structures have limited negative impact on the viability of mesenchymal stem cells. Inclusion of Hyperelastic Bone mesh to form a reinforced collagen composite significantly improves mechanical performance (elastic modulus, push-out strength). Composites formed from the mineralized collagen scaffold and either Hyperelastic Bone or Fluffy-PLG reinforcement both supported human bone-marrow derived mesenchymal stem cell osteogenesis and new bone formation. While collagen composites reinforced with Fluffy-PLG showed the greatest new mineral formation, Hyperelastic Bone reinforced composites elicited significantly increased secretion of soluble osteoprotegerin, a soluble glycoprotein and endogenous inhibitor of osteoclast activity. Future work will focus on further adapting the polymer mesh architecture to confer improved shape-fitting capacity as well as to investigate the role of polymer reinforcement on MSC-osteoclast interactions as a means to increase regenerative potential.

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Section: Discussionmentioning

confidence: 95%

Inclusion of a 3D-printed Hyperelastic bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

Dewey

Nosatov

Subedi

et al. 2020

Preprint

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“…Collagen’s hierarchical structure provides many unique opportunities for tuning macroscopic mechanical properties. , Parameters such as fiber dimensions, polymerization condition, and fibrillar cross-link density can be manipulated prior to polymerization, yielding hydrogels with variable but static mechanical properties. ,, Considering these physical attributes are essential for many cell–scaffold interactions and mechanotransduction. ,− the field is limited to varying the properties of static gels and extrapolating between conditions to predict how cells would respond to in vivo. Although this approach has uncovered several relationships between substrate mechanics and cell fate decisions, it fails to capture real time changes that occur during development and disease. ,,, …”

Section: Discussionmentioning

confidence: 99%

An Optogenetic Platform to Dynamically Control the Stiffness of Collagen Hydrogels

Hopkins

Valois

Stull

et al. 2020

ACS Biomater. Sci. Eng.

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The extracellular matrix (ECM) is comprised of a meshwork of biomacromolecules whose composition, architecture, and macroscopic properties, such as mechanics, instruct cell fate decisions during development and disease progression. Current methods implemented in mechanotransduction studies either fail to capture real-time mechanical dynamics or utilize synthetic polymers that lack the fibrillar nature of their natural counterparts. Here we present an optogenetic-inspired tool to construct light-responsive ECM mimetic hydrogels comprised exclusively of natural ECM proteins. Optogenetic tools offer seconds temporal resolution and submicron spatial resolution, permitting researchers to probe cell signaling dynamics with unprecedented precision. Here we demonstrated our approach of using SNAP-tag and its thiol targeted substrate, benzylguanine-maleimide, to covalently attach blue-light responsive proteins to collagen hydrogels. The resulting material (OptoGel) -in addition to encompassing the native biological activity of collagen-stiffens upon exposure to blue light and softens in the dark. Optogels have immediate use in dissecting the cellular response to acute mechanical inputs and may also have applications in next-generation bio-interfacing prosthetics.

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“…This was shown by higher YAP/TAZ expression in cells grown on optimum matrix stiffness, which was E = 50 kPa for OS cells (Jabbari et al, 2015). Moreover, increased YAP/TAZ‐mediated differentiation was accompanied with upregulated Wnt/β‐catenin signalling in stiffer, mineralized bone regenerative scaffolds (Zhou et al, 2021).…”

Section: Physical Microenvironmentmentioning

confidence: 99%

Osteosarcoma mechanobiology and therapeutic targets

Shoaib

Fan

Irudayaraj

2021

British J Pharmacology

100

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Osteosarcoma is one of the most common primary tumours of the bone, with a 5-year survival rate of less than 20% after the development of metastases. Osteosarcoma is highly predisposed in Paget's disease of the bone, and both have common characteristic skeletal features due to rapid bone remodelling. Osteosarcoma prognosis is location dependent, which further emphasizes the likely contribution of the bone microenvironment in its pathogenesis. Mechanobiology describes the processes involved when mechanical cues from the changing physical microenvironment of the bone are transduced to biological pathways through mechanosensitive cellular components. Mechanobiology-driven therapies have been used to curb tumour progression by direct alteration of the physical microenvironment or inhibition of metastasis-associated mechanosensitive proteins. This review emphasizes the contribution of mechanobiology to the progression of osteosarcoma and sheds light on current mechanobiology-based therapies and potential new targets for improving disease management. Additionally, the many different 3D models currently used to study osteosarcoma mechanobiology are summarized.

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Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

Abstract: One Sentence Summary: Increasing stiffness of nanoparticulate mineralized collagen scaffolds induces osteogenic differentiation via activation of YAP/TAZ and b-catenin.

Cited by 8 publications

References 34 publications

Inclusion of a 3D-printed Hyperelastic bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

Inclusion of a 3D-printed Hyperelastic bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

An Optogenetic Platform to Dynamically Control the Stiffness of Collagen Hydrogels

Osteosarcoma mechanobiology and therapeutic targets

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