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Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis.

ABSTRACT: Breast cancer frequently metastasizes to bone, where it leads to secondary tumor growth, osteolytic bone degradation, and poor clinical prognosis. Hydroxyapatite Ca(10)(PO(4))(6)(OH)(2) (HA), a mineral closely related to the inorganic component of bone, may be implicated in these processes. However, it is currently unclear how the nanoscale materials properties of bone mineral, such as particle size and crystallinity, which change as a result of osteolytic bone remodeling, affect metastatic breast cancer. We have developed a two-step hydrothermal synthesis method to obtain HA nanoparticles with narrow size distributions and varying crystallinity. These nanoparticles were incorporated into gas-foamed/particulate leached poly(lactide-co-glycolide) scaffolds, which were seeded with metastatic breast cancer cells to create mineral-containing scaffolds for the study of breast cancer bone metastasis. Our results suggest that smaller, poorly-crystalline HA nanoparticles promote greater adsorption of adhesive serum proteins and enhance breast tumor cell adhesion and growth relative to larger, more crystalline nanoparticles. Conversely, the larger, more crystalline HA nanoparticles stimulate enhanced expression of the osteolytic factor interleukin-8 (IL-8). Our data suggest an important role for nanoscale HA properties in the vicious cycle of bone metastasis and indicate that mineral-containing tumor models may be excellent tools to study cancer biology and to define design parameters for non-tumorigenic mineral-containing or mineralized matrices for bone regeneration.

SUBMITTER: Pathi SP

PROVIDER: S-EPMC3613283 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis.

Pathi Siddharth P SP Lin Debra D W DD Dorvee Jason R JR Estroff Lara A LA Fischbach Claudia C

Biomaterials 20110420 22

Breast cancer frequently metastasizes to bone, where it leads to secondary tumor growth, osteolytic bone degradation, and poor clinical prognosis. Hydroxyapatite Ca(10)(PO(4))(6)(OH)(2) (HA), a mineral closely related to the inorganic component of bone, may be implicated in these processes. However, it is currently unclear how the nanoscale materials properties of bone mineral, such as particle size and crystallinity, which change as a result of osteolytic bone remodeling, affect metastatic brea ...[more]

PMID: 21507478

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Project description:Our long-term goal is to develop smart biomaterials that can facilitate regeneration of critical-size craniofacial lesions. In this study, we tested the hypothesis that biomimetic scaffolds electrospun from chitosan (CTS) will promote tissue repair and regeneration in a critical size calvarial defect. To test this hypothesis, we first compared in vitro ability of electrospun CTS scaffolds crosslinked with genipin (CTS-GP) to those of mineralized CTS-GP scaffolds containing hydroxyapatite (CTS-HA-GP), by assessing proliferation/metabolic activity and alkaline phosphatase (ALP) levels of murine mesenchymal stem cells (mMSCs). The cells' metabolic activity exhibited a biphasic behavior, indicative of initial proliferation followed by subsequent differentiation for all scaffolds. ALP activity of mMSCs, a surrogate measure of osteogenic differentiation, increased over time in culture. After 3 weeks in maintenance medium, ALP activity of mMSCs seeded onto CTS-HA-GP scaffolds was approximately two times higher than that of cells cultured on CTS-GP scaffolds. The mineralized CTS-HA-GP scaffolds were also osseointegrative in vivo, as inferred from the enhanced bone regeneration in a murine model of critical size calvarial defects. Tissue regeneration was evaluated over a 3 month period by microCT and histology (Hematoxylin and Eosin and Masson's Trichrome). Treatment of the lesions with CTS-HA-GP scaffolds induced a 38% increase in the area of de novo generated mineralized tissue area after 3 months, whereas CTS-GP scaffolds only led to a 10% increase. Preseeding with mMSCs significantly enhanced the regenerative capacity of CTS-GP scaffolds (by ?3-fold), to 35% increase in mineralized tissue area after 3 months. CTS-HA-GP scaffolds preseeded with mMSCs yielded 45% new mineralized tissue formation in the defects. We conclude that the presence of HA in the CTS-GP scaffolds significantly enhances their osseointegrative capacity and that mineralized chitosan-based scaffolds crosslinked with genipin may represent a unique biomaterial with possible clinical relevance for the repair of critical calvarial bone defects.

Dataset Information

Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis.

Publications

Hydroxyapatite nanoparticle-containing scaffolds for the study of breast cancer bone metastasis.

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