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3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite.

ABSTRACT: Bone is one of the most common sites of cancer metastasis, as its fertile microenvironment attracts tumor cells. The unique mechanical properties of bone extracellular matrix (ECM), mainly composed of hydroxyapatite (HA) affect a number of cellular responses in the tumor microenvironment (TME) such as proliferation, migration, viability, and morphology, as well as angiogenic activity, which is related to bone metastasis. In this study, we engineered a bone-mimetic microenvironment to investigate the interactions between the TME and HA using a microfluidic platform designed for culturing tumor cells in 3D bone-mimetic composite of HA and fibrin. We developed a bone metastasis TME model from colorectal cancer (SW620) and gastric cancer (MKN74) cells, which has very poor prognosis but rarely been investigated. The microfluidic platform enabled straightforward formation of 3D TME composed the hydrogel and multiple cell types. This facilitated monitoring of the effect of HA concentration and culture time on the TME. In 3D bone mimicking culture, we found that HA rich microenvironment affects cell viability, proliferation and cancer cell cytoplasmic volume in a manner dependent on the different metastatic cancer cell types and culture duration indicating the spatial heterogeneity (different origin of metastatic cancer) and temporal heterogeneity (growth time of cancer) of TME. We also found that both SW620 and MKN72 cells exhibited significantly reduced migration at higher HA concentration in our platform indicating inhibitory effect of HA in both cancer cells migration. Next, we quantitatively analyzed angiogenic sprouts induced by paracrine factors that secreted by TME and showed paracrine signals from tumor and stromal cell with a high HA concentration resulted in the formation of fewer sprouts. Finally we reconstituted vascularized TME allowing direct interaction between angiogenic sprouts and tumor-stroma microspheroids in a bone-mimicking microenvironment composing a tunable HA/fibrin composite. Our multifarious approach could be applied to drug screening and mechanistic studies of the metastasis, growth, and progression of bone tumors.

SUBMITTER: Ahn J

PROVIDER: S-EPMC6653063 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite.

Ahn Jungho J Lim Jungeun J Jusoh Norhana N Lee Jungseub J Park Tae-Eun TE Kim YongTae Y Kim Jangho J Jeon Noo Li NL

Frontiers in bioengineering and biotechnology 20190717

Bone is one of the most common sites of cancer metastasis, as its fertile microenvironment attracts tumor cells. The unique mechanical properties of bone extracellular matrix (ECM), mainly composed of hydroxyapatite (HA) affect a number of cellular responses in the tumor microenvironment (TME) such as proliferation, migration, viability, and morphology, as well as angiogenic activity, which is related to bone metastasis. In this study, we engineered a bone-mimetic microenvironment to investigate ...[more]

PMID: 31380359

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Project description:BackgroundImplant loosening is associated with inflammatory bone loss induced by ultra-high molecular weight polyethylene wear debris. We hypothesized that a hydroxyapatite-bisphosphonate composite improves periprosthetic bone quality and osseous integration of an intramedullary implant even in the presence of ultra-high molecular weight polyethylene particles in an experimental rat femur model.MethodsA preliminary in vitro study determined the optimal concentration of zoledronate (50 microM) that would maximally decrease osteoclasts without harming osteoblasts. Hydroxyapatite-coated intramedullary nails were implanted bilaterally in the femora of sixteen rats (the control group), and hydroxyapatite-zoledronate-coated nails were implanted bilaterally in the femora of sixteen rats (the experimental group). Ultra-high molecular weight polyethylene particles were introduced into the femoral canal before implantation. Eight rats from each group were killed at six weeks, and the remaining rats were killed at six months. Periprosthetic bone mass was analyzed by dual x-ray absorptiometry and microcomputed tomography. Osseous integration was examined by biomechanical testing of pullout strength.ResultsThe mean bone area (and standard deviation) in the periprosthetic bone region was significantly greater (p < 0.0001) in the hydroxyapatite-zoledronate group (2.388 +/- 0.960 mm2) than in the control group (0.933 +/- 0.571 mm2). This difference was larger in the six-week group than in the six-month group (p = 0.03). The average peak pullout force for the treated femora (241.0 +/- 95.1 N) was significantly greater (p < 0.0001) than that for the controls (55.6 +/- 49.0 N). This difference was similar in the six-week and six-month groups. The energy required for nail pullout was significantly greater (p < 0.0001) for the treated femora (521.6 +/- 293.8 N-mm) than for the controls (142.2 +/- 152.1 N-mm). This difference in energy to pullout was similar in the six-week and six-month groups. Regression analysis demonstrated a high correlation between periprosthetic bone mass and peak pullout force for both the six-week (r = 0.766, p = 0.0005) and six-month (r = 0.838, p < 0.0001) groups.ConclusionsSurface modification of implants with hydroxyapatite-zoledronate improves periprosthetic bone quality and osseous integration.Clinical relevanceHydroxyapatite-based site-specific delivery of bisphosphonates may be one way of reducing ultra-high molecular weight polyethylene wear particle-induced periprosthetic osteolysis and implant loosening.

Dataset Information

3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite.

Publications

3D Microfluidic Bone Tumor Microenvironment Comprised of Hydroxyapatite/Fibrin Composite.

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