ModelingIn VitroCellular Responses to Silver Nanoparticles

Abstract

Engineered nanoparticles (NPs) have been widely demonstrated to induce toxic effects to various cell types. In vitro cell exposure systems have high potential for reliable, high throughput screening of nanoparticle toxicity, allowing focusing on particular pathways while excluding unwanted effects due to other cells or tissue dosimetry. The work presented here involves a detailed biologically based computational model of cellular interactions with NPs; it utilizes measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. This new model is implemented for macrophages and parameterized using in vitro measurements of changes in cellular viability and mRNA levels of cytokines: TNF, IL-1b, IL-6, IL-8, and IL-10. The model includes in vitro cellular dosimetry due to nanoparticle transport and transformation. Furthermore, the model developed here optimizes the essential cellular parameters based on in vitro measurements, and provides a “stepping stone” for the development of more advanced in vivo models that will incorporate additional cellular and NP interactions.

Physiologically based mathematical models of nanomaterials for regulatory toxicology: A review

“… MN (size) Endpoint Biological level Species Reference nano-Al (80 nm) Functional viability Alveolar macrophages cell dynamics Rat [41] polyamidoamine dendrimer (PAMAM) Uptake/cytotoxicity (sub-)Cellular responses (e.g. ROS, apoptosis) for human keratinocyte and murine macrophages Human Murine [42] nano-Ag carbon black (10–20 nm) Pulmonary function Alveolar tissue Mouse [43] nano-Ag citrate-coated and PVP-coated In vitro inflammatory response Immune cell – macrophages and human monocyte-derived macrophages for cytokine study Human [44] …”

“…Finally, Mukherjee et al [44] developed a mathematical model that predicts the in vitro inflammatory response (i.e. expression levels of cytokines) of immune cells exposed to citrate-coated and PVP-coated nano-Ag in a culture system.…”

“…The available TD models focus on cellular, sub-cellular or tissue levels. Two out of four models focus on alveolar cells or tissue [41] , [43] , one is developed for macrophages [44] and one for different cell lines [42] .…”

Nanosized Minicells Generated by Lactic Acid Bacteria for Drug Delivery

“…Therefore, it is a difficult to scale up nanoparticle production leading to limitation in market production. More importantly, the human immune system may be defenseless against particles on the nanoscale [80][81][82]. As a result, tiny solid particles can cause irritation in the lungs and potentially cause lung damage and cancer.…”

Modeling In Vivo Interactions of Engineered Nanoparticles in the Pulmonary Alveolar Lining Fluid

“…Consequently, any analysis of the residence time distribution, clearance and biological response of NPs in any tissue system requires a detailed characterization of their form, size and surface reactivity, as these change dynamically with time. The effects of transformation processes were investigated for an in vitro culture of alveolar macrophages [ 14 ], demonstrating that NP dosimetry to cells is significantly different when relevant transformation processes are considered. Hinderliter et al [ 6 ] also showed that the actual amount and form of the NPs reaching the cells over time are markedly different when NP diffusion and settling area are taken into account.…”