ABSTRACT
Metastasis is a complex and multifactorial process highly dependent on the interaction between disseminated tumor cells and the pre-metastatic niche. The metastatic sites detected in the bone of patients affected by neuroblastoma (NB), a malignancy of the developing sympathetic nervous system, are particularly aggressive. To improve our current knowledge of metastatic tumor cell biology and improve treatment success, appropriate in vitro and in vivo models that more closely resemble the native metastatic niche are needed. In this study, the impact of the geometry of synthetic ß-tricalcium-phosphate (ß-TCP) structures on the interaction of NB tumor cells with the stromal component has been examined. The tumor microenvironment is dynamically shaped by the stroma, which sustains the growth of NB cells inside the metastatic niche. The 3D growth conditions are a determining factor for the cell proliferation rate in ß-TCP. With respect to planar counterparts, channeled 3D ß-TCP structures stimulate more interleukin-6 and Fibronectin production and define Connexin 43 distribution inside the cells. Together, these results highlight how the biomechanical properties of the 3D microenvironment enable tumor cells to form spheroid-shaped arrangements. This, in turn, facilitates their pro-migratory and pro-invasive patterns and mimics the in vivo situation by translating realistic mechanobiological cues to the metastatic NB.
Subject(s)
Cues , Neuroblastoma , Cell Line, Tumor , Humans , Printing, Three-Dimensional , Tumor MicroenvironmentABSTRACT
Titanium-based alloys, for example, Ti6Al4V, are frequently employed for load-bearing orthopedic and dental implants. Growth of new bone tissue and therefore osseointegration can be promoted by the implant's microtopography, which can lead to improved long-term stability of the implant. This study investigates the effect that an organized, periodical microstructure produced by an electron beam (EB) technique has on the viability, morphology, and osteogenic differentiation capacity of human mesenchymal stromal cells (hMSC) in vitro. The technique generates topographical features of 20 µm in height with varying distances of 80-240 µm. Applied alterations of the surface roughness and local alloy composition do not impair hMSC viability (>94%) or proliferation. A favorable growth of hMSC onto the structure peaks and well-defined focal adhesions of the analyzed cells to the electron beam microstructured surfaces is verified. The morphological adaptation of hMSC to the underlying topography is detected using a three-dimensional (3D) visualization. In addition to the morphological changes, an increase in the expression of osteogenic markers such as osteocalcin (up to 17-fold) and osteoprotegerin (up to sixfold) is observed. Taken together, these results imply that the proposed periodical microstucturing method could potentially accelerate and enhance osseointegration of titanium-based bone implants.
