Fate of Nanoparticles in Neural Environments

Our goal is to develop an advanced in vitro system for nano-neurotoxicology that employs neural progenitor cells and tissue-engineering hydrogels. This work will enable rapid screening of engineered nanoparticles for neurotoxic hazards.

Engineered nanoparticles (NPs) have been shown to rapidly translocate along sensory nerves to the central nervous system (in animal models), cross the placental barrier (in humans), and are expected to cross the blood-brain barrier. In vivo studies are not practical for neurotoxic hazard assessment, however in vitro studies have well-known limitations including monocultures that limit cell-cell interactions and a stiff plastic environment that alters cell behavior.

Nanotoxicology studies have been criticized for employing doses that exceed what could be realistically encountered. High doses may drive an acute cellular response whereas lower, more realistic doses are likely to have subtle effects requiring functional endpoints. There remains an immediate need for improved in vitro methods for assessing neurotoxic hazards.

• Over 300 US companies are involved in nanoparticle-based product development. Nanotechnology innovations are expected to be a major driver of the world economy in the next decade. Market size estimates range from conservative ($5B) to astronomical ($3T).
• The inability to screen large batches of nanoparticles for health hazards has been identified as a major barrier to the nanotechnology industry and screening tools have been identified as a research need. Source: Nanotechnology Research Directions for Societal Needs in 2020 (WTEC Report 2010)
• Products utilizing nanomaterials are already on the market despite very limited environmental health and safety data. Perceptions (real or imagined) of health and safety risks can derail further product development. One high-dose investigation of titania nanoparticles led to the headline “Nanoparticles Damage Brain Cells.” Source: Environmental Health News 2008

Neurite Outgrowth in Progenitor Cell Cultures. Neural progenitor cells differentiate into neurons and glial cells (astrocytes and oligodendrocytes). We recently demonstrated that lithium chloride, a known neurotoxin, inhibits neurite outgrowth in differentiating progenitor cell cultures and can serve as a control for nanoparticle studies.

From K.M. Jeerage, T.L. Oreskovic, Submitted to Neurotoxicology (2011)

Nanoparticle Uptake by Neural Cells. Bioavailability is expected to impact the ability of nanoparticles to interfere with cellular processes. Quantitative fluorescence measurements show that neural progenitor cells have significantly different uptake of carboxyl-terminated quantum dots than model neural cells.

From K.M. Jeerage, T.L. Oreskovic, E. Mansfield, MRS Workshop on Functionalized Nanobiomaterials (2010)