Table 1.
Overview of microfluidic systems that study the role of the bone microenvironment in breast cancer metastasis, highlighting biomaterials used.
| Area of research | Relevant cells used | Cell growth surface | Key findings | Reference |
|---|---|---|---|---|
| Role of bone cells and mineralization in adhesion of BCCs | Murine RAW264.7 (OCs), MDA-MB-231, MCF-7 | 3D HAp-mineralized, porous scaffolds made of PLG microspheres | HAp enhances BCCs proliferation and adhesion to the matrix. HAp upregulates the secretion of IL-8 by BCCs, which induces inflammatory response, angiogenesis and osteoclastic resorption. |
(79) |
| Role of bone structure and mineralization parameters in adhesion of BCCs | hMSCs, MDA-MB-231, MCF-7 | 3D porous chitosan scaffolds containing HAp with different crystallinities, concentrations and grain sizes (micron/nano) | BCCs adhesion was increased in scaffolds containing 10% nano-crystalline HAp compared to those containing microcrystalline HAp. Coculture with hMSCs in HAp-containing scaffolds induced the upregulation of expression of the metadherin gene in BCCs (enhances metastatic potential and chemoresistance of BCCs). |
(78) |
| MDA-MB-231 | Porous PVA scaffolds generated via foaming and freezing and then mineralized via immersion in modified HBSS for 14 days. | The greater the extent of mineralization of the scaffold, the greater the adsorption of serum proteins leading to higher BCC adhesion and proliferation. | (88) | |
| Role of bone mineralization in adhesion of BCCs | MDA-MB-231 | 3D porous scaffolds containing HAp nanoparticles. HAp was aged for different lengths of time to increase crystalline development and added to the scaffold. | The smaller and less crystalline the HAp nanoparticles, the greater the adhesion of BCCs. Larger, more crystalline HAp particles stimulate more IL-8 production. | (76) |
| Role of bone structure in adhesion and survival of BCCs | hMSCs, MDA-MB-231 | Scaffold was 3D printed with different geometries created: either large or small square or hexagonal pores. Printable ink consisted of HAp nanoparticles suspended in PEG/PEG-DA hydrogel. | Different geometries of 3D scaffolds influenced BCC adhesion, with the small square matrices displaying greater cell numbers than the others. BCCs were less responsive to 5-FU in 3D HAp scaffolds with their optimized geometry. | (89) |
| Role of bone cells in survival of BCCs | Human fetal osteoblast cell line (hOBs), MDA-MB-231 | Porous constructs were 3D printed to allow for BCCs to form spheroids within the scaffold | Enhanced BCCs proliferation on HAp-containing matrices. BCCs co-cultured with hOBs directly affected the morphology, proliferation and IL-8 secretion by OBs. | (90) |
| Role of bone in colonization by BCCs | ECs, MSCs, MDA-MB-231 | Decellularised bone matrix within a microfluidic chip | Interstitial flow promotes colonization of BCCs in the bone microenvironment and BCCs exposed to interstitial flow display a slow-proliferative state linked with chemoresistance. | (91) |
| MDA-MB-231 and murine MC3T3-E1 | Collagen-HAp composite in a PDMS device. | Osteoblastic tissue was invaded by BCCs, which eroded apical collagen and consumed the surrounding matrix. | (92) | |
| Role of bone in extravasation of BCCs | hMSCs, HUVECs, MDA-MB-231 | Cells grew in a PDL-coated PDMS channels, with a thin Matrigel layer coating the central media channel | BCCs extravasated significantly more in the bone-like microenvironment compared to collagen-only controls. Extravasation rate was associated with paracrine signaling via CXCL5 and CXCR2. |
(93) |
| hMSCs, OBs, HUVECs, MDA-MB-231 | Cells mixed into a fibrin gel within a PDMS microfluidic device. | BCCs responded to the bone stromal cells via paracrine signaling, and this increased extravasation rate. Extravasation rate in bone-like environments was significantly higher relative to muscle-like microenvironments or controls. | (94) | |
| HDMECs, MDA-MB-231 | Cells were seeded directly into a PDMS microfluidic device with no additional biomaterials | CXCL12 acts through CXCR4 on HDMECs to promote the adhesion of circulating BCCs, which promotes extravasation. | (95) | |
| hOBs, HDMECs, MSCs, HLF, MDA-MB-231 | Multilayer microfabrication method used. Cells were seeded into rat tail collagen type I to introduce into PDMS microfluidic device | Bone-like microenvironment promoted extravasation of bone-tropic BCCs, suggesting OBs influence selective extravasation of BCCs. | (96) |
BCCs, breast cancer cells; FBs, fibroblasts; hMSCs, human mesenchymal stem cells; hOBs, human osteoblasts; ECs, endothelial cells; HDMECs, human dermal microvascular endothelial cells; HAp, hydroxyapatite; HLF, human lung fibroblasts; HBSS, Hanks' Balanced Salt Solution; HUVECs, human umbilical vein endothelial cells; IL-8, interleukin-8; OCs, osteoclasts; PLG, poly(lactic-co-glycolic acid); PEG, poly(ethylene glycol); PEG-DA, poly(ethylene glycol) diacrylate; PDL, Poly-D-lysine; PDMS, polydimethylsiloxane; PVA, polyvinyl acetate; 5-FU, 5-fluorouracil.