The rapid growth of nanotechnology (reported from the Congressional Research Service on August 29, 2013 projected a $3.1 trillion nanotechnology product revenue by 2015), high-cost in animal research, and increasing emphasis on animal well-being present a grand challenge and urgent need to develop viable in vitro means to understand the health risks of nanomaterials. Our long-term goal is to develop reliable in vitro methods to access the health effects of manufactured nanomaterials (NMs), and with this knowledge, to improve the materials' biocompatibility, and develop therapeutic strategies for disease prevention and intervention. This R21 plan proposes a completely new approach for investigation of nanomaterials-cell interactions that are of in vivo relevancy. A microfluidic delivery system will be integrated with the existing instrument of combined laser scanning confocal microscope and atomic force microscope (AFM) in the PI's laboratory. The microfluidic system enables delivery of nanomaterials with designed functionality and quantity to the designated sites of living cells, such as near membrane and intracellularly. The responses of cells will be monitored in situ using high resolution AFM imaging and single cell mechanics (PI team, US patent, 2012), from which significant responses will be identified. The nanomaterials treatments will then be replicated and monitored by confocal imaging to further reveal the nanoparticle-cell interactions intracellularly. The outcomes shall deepen our understanding of nanomaterials-cell interactions and demonstrate the concept that better in vivo mimetics may be achieved by eliminating the changes in NMs' states due to the delivery pathways such as interactions with culture media. Upon completion of this R21 research, we envision that cell mechanics (as a readout of cellular response) in conjunction with accurate delivery could be automated using Microelectromechanical systems (MEMs) platform, which has sufficient simplicity and throughput for R&D activities. Overall, this R21 shall provide a platform technology to enable important advances to reach the eventual goal of understanding and predicting nanotoxicity without using animal models.
The rapid growth of nanotechnology (reported from the Congressional Research Service on August 29, 2013 projected a $3.1 trillion nanotechnology product revenue by 2015), high-cost in animal research, and increasing emphasis on animal well-being present a grand challenge and urgent need to develop viable in vitro means to understand the health risks of nanomaterials. Toward this need, two primary approaches have been taken to study toxicity of nanomaterials: (a) in vivo toxicity, i.e., using animal models and collecting data from human subjects; and (b) in vitro toxicity assays, i.e., using living cells tha can be cultured repeatedly in laboratories. In contrast to the toxicity of small molecular drugs and chemicals, using in vitro cytotoxicity assays to access or predict nanotoxicity in vivo is heavily criticized due to the vastly different pathways nanomaterials go through which could lead to different nanomaterials-cell interactions in vivo versus in vitro. One key complexity concerns the structural and chemical changes during nanomaterial transport inside bodies, for example, nanoparticles could pick up proteins during transport. This R21 proposes a vastly new and different approach to ensure that the physiochemical state of nanomaterials will be preserved from initial state to the sites where nanomaterials meet cells. This is achieved by the integration of microfluidic delivery to the team's existing instrument of combined atomic force and laser scanning confocal microscope. This accurate control allows better mimetics of in vivo situations by preserving the designed size, chemical state and dosage. This approach also allows systematic and reliable investigations of nanoparticles-cell interactions and will hopefully reveal the cause and threshold of cytotoxicity. Once this new approach is validated and demonstrated via this R21 project, we shall continue on to reach our long-term goal: to develop reliable in vitr methods to access the health effects of manufactured nanomaterials (NMs), and with this knowledge, to improve the materials' biocompatibility, and to develop therapeutic strategies for disease prevention and intervention.
| Zhang, Jiali; Piunova, Victoria A; Liu, Yang et al. (2018) Controlled Molecular Assembly via Dynamic Confinement of Solvent. J Phys Chem Lett 9:6232-6237 |
| Karsai, Arpad; Slack, Teri Jo; Malekan, Hamed et al. (2016) Local Mechanical Perturbation Provides an Effective Means to Regulate the Growth and Assembly of Functional Peptide Fibrils. Small 12:6407-6415 |
| Zhao, Jianli; Sun, Shasha; Swartz, Logan et al. (2015) ""Size-Independent"" Single-Electron Tunneling. J Phys Chem Lett 6:4986-90 |
