Abstract
Despite decades of research into the interaction between cells and nanoparticles, there is a lack of consensus regarding how specific physicochemical characteristics of the nanoparticles, including chemical composition, crystallinity, size, morphology, charge, and aspect ratio, among others, govern their internalization and intracellular fate. Methodological novelties offer new perspectives on the same old problematics, and often translate into an improved understanding of the given topic. Inspired by an analogy with the theme of the movie, Lisbon Story, a conceptually unconventional method for gaining insight into the interaction between nanoparticles and cells is proposed here. It involves the random, “Take 1” capture of an atomic force micrograph showing the interaction of human mesenchymal stem cells and clusters of spherical hydroxyapatite nanoparticles with a broad distribution of sizes and shapes, the blowup of its segments, and their detailed qualitative inspection. This method led to the derivation of three illustrative hypotheses, some of which were refuted and some corroborated. Specifically, the presupposition that there is an inverse relationship between the cellular uptake efficiency and the size of nanoparticle clusters was confirmed, both empirically and through a literature meta-analysis, but the idea that the geometry of these clusters affects the uptake was refuted. The definite presence of morphological determinants of the cellular uptake at the level of elementary particles, not clusters thereof, however, was confirmed in an alternative experiment. Likewise, immunofluorescent studies demonstrated that relatively large and irregularly shaped nanoparticle clusters do get internalized and localized to the perinuclear area, where they engage in an intimate interaction with the cell nucleus. The proposed enhancement of the binding between cells and biomaterials by increasing the surface ruffling consequential to the nanoparticle uptake - in analogy with the enhanced cell adhesion achieved by introducing topographic irregularities to smooth biomaterial surfaces - was also confirmed by showing that the uptake improves the stem cell adhesion. The uptake also augmented the stem cell viability and the proliferative capacity of cells reseeded with this internal nanoparticle cargo on a fresh surface, albeit with moderate levels of statistical significance and the caveat of its presumed dependence on the cell type, the nanoparticle chemistry and dose, and the overall stage in the transition of the multipotent cells toward an osteoprogenitor lineage.
Highlights
Despite decades of research into the interaction between cells and nanoparticles, the literature is pervaded with insufficiently comprehensive, methodologically limited reports that frequently contradict each other’s findings with regard to the effect of specific physicochemical characteristics ofAppl
Even when comparisons are limited to a single cell type, such as mesenchymal stem cells (MSCs), which lie at the focus of this study, there are still considerable incoherencies pervading the literature
The findings presented here, with respect to the relationship between the cellular uptake and the cell adhesion, viability, and proliferation, should be treated with caution because they may not necessarily apply to different nanoparticle chemistries, cell types, or growth conditions
Summary
Despite decades of research into the interaction between cells and nanoparticles, the literature is pervaded with insufficiently comprehensive, methodologically limited reports that frequently contradict each other’s findings with regard to the effect of specific physicochemical characteristics ofAppl. For each report demonstrating that eukaryotic cells have a greater affinity for smaller nanoparticles [1,2,3], two reports can be found that demonstrate the opposite, namely a direct proportionality between the cell viability and the particle size [4,5,6,7,8,9]. While some reports provide evidence in favor of the inverse dependence of the degree of differentiation of MSCs on the particle size [16,17], other reports demonstrate the direct dependence [18,19], with the rest of the studies providing mixed findings, such as the greatest effect of particles in the medium size ranges [20,21], or the different effect of differently sized particles on markers dominant in early, middle, and later stages of the differentiation process [22,23]
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