Orthopedic bioactive implants: Hydrogel enrichment of macroporous titanium for the delivery of mesenchymal stem cells and strontium

Lopa, Silvia; Mercuri, David; Colombini, Alessandra; Conti, G. De; Segatti, Francesco; Zagra, Luigi; Moretti, Matteo

doi:10.1002/jbm.a.34649

Cited by 28 publications

(18 citation statements)

References 50 publications

(62 reference statements)

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“…Based on literature data showing that cell populations with equivalent capacity to form bone metastasis also share equal expression of genes related to bone invasion and metastasis [ 13 ], we chose to use a single bone seeking clone [ 14 ], with equivalent bone metastatic potential as compared to other bone seeking clones [ 13 ]. BMSCs were harvested from 3 patients undergoing hip surgery, after informed consent, and were differentiated in osteogenic medium (OM), as described [ 15 ]. BOKL and BMSCs after direct co-culture with BMSCs or MRC-5 were retrieved by enzymatic digestion and separated by FACS sorting.…”

Section: Resultsmentioning

confidence: 99%

Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases

et al. 2014

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BackgroundBone metastases arise in nearly 70% of patients with advanced breast cancer, but the complex metastatic process has not been completely clarified yet. RANKL/RANK/OPG pathway modifications and the crosstalk between metastatic cells and bone have been indicated as potential drivers of the process. Interactions between tumor and bone cells have been studied in vivo and in vitro, but specific effects of the direct contact between human metastatic cells and human bone cells on RANKL/RANK/OPG pathway have not been investigated.FindingsWe directly co-cultured bone metastatic human breast cancer cells (BOKL) with osteo-differentiated human mesenchymal cells (BMSCs) from 3 different donors. BMSCs and BOKL were then enzymatically separated and FACS sorted. We found a significant increase in the RANKL/OPG ratio as compared to control, which was not observed in BOKL cultured in medium conditioned by BMSCs, neither in BOKL directly cultured with fibroblasts or medium conditioned by fibroblasts. Direct co-culture with osteo-differentiated BMSCs caused BOKL aggregation while proliferation was not affected by co-culture. To more specifically associate RANKL expression to osteogenic differentiation degree of BMSCs, we determined their osteogenic markers expression and matrix calcification relative to osteoblasts and fibroblasts.ConclusionsIn conclusion, our co-culture model allowed to demonstrate for the first time that direct contact but not paracrine interactions between human metastatic breast cancer cells and bone cells has a significant effect on RANKL/OPG expression in bone metastatic cells. Furthermore, only direct contact with the bone microenvironment induced BOKL clustering without however significantly influencing their proliferation and migration.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-238) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases

et al. 2014

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“…Bone marrow-derived human mesenchymal stem cells were obtained harvesting whole bone marrow aspirates from patients undergoing hip surgery and selected by plastic adherence according to an optimized protocol [49]. Cells of passage 7 or lower were cultured in osteogenic medium containing L-ascorbic acid, β-glycerophosphate, cholecalciferol and dexamethasone for at least 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone

Bersini¹,

Jeon²,

Dubini³

et al. 2014

Biomaterials

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452

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Cancer metastases arise following extravasation of circulating tumor cells with certain tumors exhibiting high organ specificity. Here, we developed a 3D microfluidic model to analyze the specificity of human breast cancer metastases to bone, recreating a vascularized bone-mimicking microenvironment with human osteo-differentiated bone marrow-derived mesenchymal stem cells and endothelial cells. The tri-culture system allowed us to study the transendothelial migration of highly metastatic breast cancer cells and to monitor their behavior within the bone-like matrix. Extravasation, quantified 24h after cancer cell injection, was significantly higher in the osteo-cell conditioned microenvironment compared to collagen gel-only matrices (77.5±3.7% vs. 37.6±7.3%), and the migration distance was also significantly greater (50.8±6.2µm vs. 31.8±5.0µm). Extravasated cells proliferated to form micrometastases of various sizes containing 4 to more than 60 cells by day 5. We demonstrated that the breast cancer cell receptor CXCR2 and the bone-secreted chemokine CXCL5 play a major role in the extravasation process, influencing extravasation rate and travelled distance. Our study provides a novel 3D in vitro quantitative data on extravasation and micrometastasis generation of breast cancer cells within a bone-mimicking microenvironment and demonstrates the potential value of microfluidic systems to better understand cancer biology and screen for new therapeutics.

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“…Primary GFP and RFP‐HUVECs were purchased from Angioproteomie (Boston, MA) and used at passage 6. MSCs were harvested from patients undergoing hip surgery after informed consent and isolated as described previously . Briefly, bone marrow aspirate was centrifuged for 10 min at 510 g and washed twice with PBS1X.…”

Section: Methodsmentioning

confidence: 99%

Rational Design of Prevascularized Large 3D Tissue Constructs Using Computational Simulations and Biofabrication of Geometrically Controlled Microvessels

Arrigoni

Bongio

Talò

et al. 2016

Adv Healthcare Materials

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A major challenge in the development of clinically relevant 3D tissue constructs is the formation of vascular networks for oxygenation, nutrient supply, and waste removal. To this end, this study implements a multimodal approach for the promotion of vessel-like structures formation in stiff fibrin hydrogels. Computational simulations have been performed to identify the easiest microchanneled configuration assuring normoxic conditions throughout thick cylindrical hydrogels (8 mm height, 6 mm ∅), showing that in our configuration a minimum of three microchannels (600 μm ∅), placed in a non-planar disposition, is required. Using small hydrogel bricks with oxygen distribution equal to the microchanneled configuration, this study demonstrates that among different culture conditions, co-culture of mesenchymal and endothelial cells supplemented with ANG-1 and VEGF leads to the most developed vascular network. Microchanneled hydrogels have been then cultured in the same conditions both statically and in a bioreactor for 7 d. Unexpectedly, the combination between shear forces and normoxic conditions is unable to promote microvascular networks formation in three-channeled hydrogels. Differently, application of either shear forces or normoxic conditions alone results in microvessels outgrowth. These results suggest that to induce angiogenesis in engineered constructs, complex interactions between several biochemical and biophysical parameters have to be modulated.

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Orthopedic bioactive implants: Hydrogel enrichment of macroporous titanium for the delivery of mesenchymal stem cells and strontium

Cited by 28 publications

References 50 publications

Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases

Direct but not indirect co-culture with osteogenically differentiated human bone marrow stromal cells increases RANKL/OPG ratio in human breast cancer cells generating bone metastases

A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone

Rational Design of Prevascularized Large 3D Tissue Constructs Using Computational Simulations and Biofabrication of Geometrically Controlled Microvessels

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