Development of a multi-route physiologically based pharmacokinetic (PBPK) model for nanomaterials: a comparison between a traditional versus a new route-specific approach using gold nanoparticles in rats.

BACKGROUND: Physiologically based pharmacokinetic (PBPK) modeling is an important tool in predicting target organ dosimetry and risk assessment of nanoparticles (NPs). The methodology of building a multi-route PBPK model for NPs has not been established, nor systematically evaluated. In this study, we hypothesized that the traditional route-to-route extrapolation approach of PBPK modeling that is typically used for small molecules may not be appropriate for NPs. To test this hypothesis, the objective of this study was to develop a multi-route PBPK model for different sizes (1.4-200 nm) of gold nanoparticles (AuNPs) in adult rats following different routes of administration (i.e., intravenous (IV), oral gavage, intratracheal instillation, and endotracheal inhalation) using two approaches: a traditional route-to-route extrapolation approach for small molecules and a new approach that is based on route-specific data that we propose to be applied generally to NPs. RESULTS: We found that the PBPK model using this new approach had superior performance than the traditional approach. The final PBPK model was optimized rigorously using a Bayesian hierarchical approach with Markov chain Monte Carlo simulations, and then converted to a web-based interface using R Shiny. In addition, quantitative structure-activity relationships (QSAR) based multivariate linear regressions were established to predict the route-specific key biodistribution parameters (e.g., maximum uptake rate) based on the physicochemical properties of AuNPs (e.g., size, surface area, dose, Zeta potential, and NP numbers). These results showed the size and surface area of AuNPs were the main determinants for endocytic/phagocytic uptake rates regardless of the route of administration, while Zeta potential was an important parameter for the estimation of the exocytic release rates following IV administration. CONCLUSIONS: This study suggests that traditional route-to-route extrapolation approaches for PBPK modeling of small molecules are not applicable to NPs. Therefore, multi-route PBPK models for NPs should be developed using route-specific data. This novel PBPK-based web interface serves as a foundation for extrapolating to other NPs and to humans to facilitate biodistribution estimation, safety, and risk assessment of NPs.

Toxicity assessment of six titanium dioxide nanoparticles in human epidermal keratinocytes.

PURPOSE: The aim of this study was to evaluate and compare the toxicity of six different types of titanium dioxide (TiO2) nanoparticles (NP) on human epidermal keratinocytes (HEK). MATERIALS AND METHODS: Six TiO2 NP (A (10 nm), A*(32 nm), B (27.5 nm), C (200 nm), C*(30-40 nm), and D*(200-400 nm)) were suspended in water or culture medium and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In addition, these NP were assayed with cell viability, cytokine release and cellular uptake in HEK. RESULTS: TiO2NP did not change in shape in the culture medium when visualized by TEM. There was an increase in agglomeration with all TiO2NP in the medium when measured by DLS. Since TiO2NP interfered with the CellTiter 96®AQueous One and MTT assays but had a minimal effect on alamar Blue (aB). The aB viability assay was selected to assess all six types of TiO2NP and sample B had a statistically significant decrease in viability at 0.4 mg/ml. A slight increase in TNF-α was noted in sample A*, C, and D* at as low as 0.05 mg/ml. Sample A* and B at certain concentrations showed an increase in Interleukin (IL)-6. IL-10 and IL-1ß release for all TiO2NP were noted around the detection limit with no significant changes compared to control. A statistically significant decrease in IL-8 was noted for all TiO2NP at the highest concentrations due to the adsorption of IL-8 by TiO2. All TiO2NP were localized within cytoplasmic vacuoles of HEK and the element Ti was detected by energy-dispersive x-ray spectroscopy analysis. CONCLUSIONS: Based on cell viability, only sample B was slightly cytotoxic to HEK and samples B and A* have the potential to cause inflammation indicated by an increase in IL-6.

Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern).

Threshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual 'dose' applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool.

Biocompatibility analysis of an electrically-activated silver-based antibacterial surface system for medical device applications.

The costs associated with the treatment of medical device and surgical site infections are a major cause of concern in the global healthcare system. To prevent transmission of such infections, a prophylactic surface system that provides protracted release of antibacterial silver ions using low intensity direct electric current (LIDC; 28 µA system current at 6 V) activation has been recently developed. To ensure the safety for future in vivo studies and potential clinical applications, this study assessed the biocompatibility of the LIDC-activated interdigitated silver electrodes-based surface system; in vitro toxicity to human epidermal keratinocytes, human dermal fibroblasts, and normal human osteoblasts, and antibacterial efficacy against Staphylococcus aureus and Escherichia coli was evaluated. The study concluded that the technological applications of the surface system for medical devices and surgical tools, which contact human tissues for less than 1.5 h, are expected to be self-sterilizing without causing toxicity in vivo.

An artificial intelligence-assisted physiologically-based pharmacokinetic model to predict nanoparticle delivery to tumors in mice.

The critical barrier for clinical translation of cancer nanomedicine stems from the inefficient delivery of nanoparticles (NPs) to target solid tumors. Rapid growth of computational power, new machine learning and artificial intelligence (AI) approaches provide new tools to address this challenge. In this study, we established an AI-assisted physiologically based pharmacokinetic (PBPK) model by integrating an AI-based quantitative structure-activity relationship (QSAR) model with a PBPK model to simulate tumor-targeted delivery efficiency (DE) and biodistribution of various NPs. The AI-based QSAR model was developed using machine learning and deep neural network algorithms that were trained with datasets from a published "Nano-Tumor Database" to predict critical input parameters of the PBPK model. The PBPK model with optimized NP cellular uptake kinetic parameters was used to predict the maximum delivery efficiency (DEmax) and DE at 24 (DE24) and 168 h (DE168) of different NPs in the tumor after intravenous injection and achieved a determination coefficient of R2 = 0.83 [root mean squared error (RMSE) = 3.01] for DE24, R2 = 0.56 (RMSE = 2.27) for DE168, and R2 = 0.82 (RMSE = 3.51) for DEmax. The AI-PBPK model predictions correlated well with available experimentally-measured pharmacokinetic profiles of different NPs in tumors after intravenous injection (R2 ≥ 0.70 for 133 out of 288 datasets). This AI-based PBPK model provides an efficient screening tool to rapidly predict delivery efficiency of a NP based on its physicochemical properties without relying on an animal training dataset.

Meta-Analysis of Nanoparticle Distribution in Tumors and Major Organs in Tumor-Bearing Mice.

Low tumor delivery efficiency is a critical barrier in cancer nanomedicine. This study reports an updated version of "Nano-Tumor Database", which increases the number of time-dependent concentration data sets for different nanoparticles (NPs) in tumors from the previous version of 376 data sets with 1732 data points from 200 studies to the current version of 534 data sets with 2345 data points from 297 studies published from 2005 to 2021. Additionally, the current database includes 1972 data sets for five major organs (i.e., liver, spleen, lung, heart, and kidney) with a total of 8461 concentration data points. Tumor delivery and organ distribution are calculated using three pharmacokinetic parameters, including delivery efficiency, maximum concentration, and distribution coefficient. The median tumor delivery efficiency is 0.67% injected dose (ID), which is low but is consistent with previous studies. Employing the best regression model for tumor delivery efficiency, we generate hypothetical scenarios with different combinations of NP factors that may lead to a higher delivery efficiency of >3%ID, which requires further experimentation to confirm. In healthy organs, the highest NP accumulation is in the liver (10.69%ID/g), followed by the spleen 6.93%ID/g and the kidney 3.22%ID/g. Our perspective on how to facilitate NP design and clinical translation is presented. This study reports a substantially expanded "Nano-Tumor Database" and several statistical models that may help nanomedicine design in the future.

Lack of hydroxylated fullerene toxicity after intravenous administration to female Sprague-Dawley rats.

Hydroxylated fullerenes (C60OH(x)) or fullerols are water-soluble carbon nanoparticles that have been explored for potential therapeutic applications. This study assesses acute in vivo tolerance in 8-wk-old female Sprague-Dawley rats to intravenous (iv) administration of 10 mg/kg of well-characterized C60(OH)30. Complete histopathology and clinical chemistries are assessed at 8, 24, and 48 h after dosing. Minor histopathology changes are seen, primarily in one animal. No clinically significant chemistry changes were observed after treatment. These experiments suggest that this fullerol was well tolerated after iv administration to rats.

In vitro biodistribution of silver nanoparticles in isolated perfused porcine skin flaps.

Nanomaterials increasingly are playing a role in society for uses ranging from biomedicine to microelectronics; however, pharmacokinetic studies, which will be necessary for human health risk assessments, are limited. Currently the most widely used nanoparticle in consumer products is silver (Ag). The objective of the present study was to quantify the local biodistribution of two types of Ag nanoparticles, Ag-citrate and Ag-silica, in the isolated perfused porcine skin flap (IPPSF). IPPSFs were perfused for 4 h with 0.84 µg ml(-1) Ag-citrate or 0.48 µg ml(-1) Ag-silica followed by a 4-h perfusion with media only during a washout phase. Arterial and venous concentrations of Ag were measured in the media by inductively coupled plasma optical emission spectrometry (ICP-OES). Venous concentrations of Ag for both types of nanoparticles were best fit with a two compartment model. The normalized volumes of distribution estimated from the noncompartmental analysis of the venous concentrations indicated distribution of Ag greater than the vascular space; however, because total Ag was measured, the extravascular distribution could be attributed to diffusion of Ag ions. The estimated clearance for both types of Ag nanoparticles was 1 ml min(-1) , which was equal to the flap perfusion rate, indicating no detectable elimination of Ag from the system. Four hours after infusion of the Ag nanoparticles, the recovery of Ag in the venous effluent was 90 ± 5.0% and 87 ± 22% of the infused Ag for Ag-citrate and Ag-silica, respectively.

Acute vascular effects of nanoparticle infusion in isolated perfused skin.

The majority of studies on the effect of nanomaterials on biological function involves either isolated in vitro cell systems or are concerned with in vivo effects after inhalational or dermal exposure. The current work reports on an intriguing observation of the vascular effects seen in an ex vivo perfused tissue preparation, the isolated perfused porcine skin flap (IPPSF), in studies conducted to assess nanomaterial biodistribution. Compared with a relatively large dataset involving organic chemical infusions (n = 53), infusion of six different nanoparticles of diverse sizes and composition (silica or dextran coated Fe(2)O(3), silica or citrate coated silver, PEG or carboxylated quantum dots [QD]) resulted in statistically significant post-infusion flap weight gain and an increase in arterial perfusion pressure (especially with QD-PEG). In contrast, infusion with nC(60) nanoparticles did not produce these effects. These observations suggest certain nanoparticle infusions may be associated with acute vascular physiologic effects that merit further attention. FROM THE CLINICAL EDITOR: In this study utilizing a perfused porcine skin flap, specific nanoparticle infusions were demonstrated to be associated with significant acute vascular physiological effects.

Predicting Nanoparticle Delivery to Tumors Using Machine Learning and Artificial Intelligence Approaches.

Background: Low delivery efficiency of nanoparticles (NPs) to the tumor is a critical barrier in the field of cancer nanomedicine. Strategies on how to improve NP tumor delivery efficiency remain to be determined. Methods: This study analyzed the roles of NP physicochemical properties, tumor models, and cancer types in NP tumor delivery efficiency using multiple machine learning and artificial intelligence methods, using data from a recently published Nano-Tumor Database that contains 376 datasets generated from a physiologically based pharmacokinetic (PBPK) model. Results: The deep neural network model adequately predicted the delivery efficiency of different NPs to different tumors and it outperformed all other machine learning methods; including random forest, support vector machine, linear regression, and bagged model methods. The adjusted determination coefficients (R2) in the full training dataset were 0.92, 0.77, 0.77 and 0.76 for the maximum delivery efficiency (DEmax), delivery efficiency at 24 h (DE24), at 168 h (DE168), and at the last sampling time (DETlast). The corresponding R2 values in the test dataset were 0.70, 0.46, 0.33 and 0.63, respectively. Also, this study showed that cancer type was an important determinant for the deep neural network model in predicting the tumor delivery efficiency across all endpoints (19-29%). Among all physicochemical properties, the Zeta potential and core material played a greater role than other properties, such as the type, shape, and targeting strategy. Conclusion: This study provides a quantitative model to improve the design of cancer nanomedicine with greater tumor delivery efficiency. These results help to improve our understanding of the causes of low NP tumor delivery efficiency. This study demonstrates the feasibility of integrating artificial intelligence with PBPK modeling approaches to study cancer nanomedicine.

Biocorona modulates the inflammatory response induced by gold nanoparticles in human epidermal keratinocytes.

The functional activities of gold nanoparticles (AuNPs) on biological systems depend on their physical-chemical properties and their surface functionalizations. Within a biological environment and depending on their surface characteristics, NPs can adsorb biomolecules (mostly proteins) present in the microenvironment, thereby forming a dynamic biomolecular corona on the surface. The presence of this biocorona changes the physical-chemical and functional properties of the NPs and how it interacts with cells. Here, we show that primary human epidermal keratinocytes (HEK) exposed in culture to branched polyethyleneimine (BPEI)-AuNPs, but not to lipoic acid (LA)-AuNPs, show potent particle uptake, decreased cell viability and enhanced production of inflammatory factors, while the presence of a human plasma-derived biocorona decreased NPs uptake and rescued cells from BPEI-AuNP-induced cell death. The mechanistic study revealed that the intracellular oxidative level greatly increased after the BPEI-AuNPs treatment, and the transcriptomic analysis showed that the dominant modulated pathways were related to oxidative stress and an antioxidant response. The stress level measured by flow cytometry also showed a significant decrease in the presence of a biocorona. Further anaylsis discovered that nuclear factor erythroid-2 related factor (Nrf2), a major regulator of anti-oxidant and anti-inflammatory genes, as the key factor related to the AuNPs induced oxidative stress and inflammation. This study provides futher understanding into the mechanisms on how NPs-induced cellular stress and reveals the protective effects of a biocorona on inflammatory responses in HEK at the molecular level, which provides important insights into the biological responses of AuNPs and their biocorona.

The synergistic strategies for the immuno-oncotherapy with photothermal nanoagents.

Immuno-oncotherapy has shown great promise for the cure of late-stage and metastatic cancer. Great efforts have tried to improve the overall response rate (ORR) and to reduce the immune-related adverse events (irAEs). Antigen presentation, T cell activation and killing are interlocking and distinct steps to initiate effective anti-tumor immune responses. Aiming to overcome the tumor immune evasion whose mechanisms include limited release of neoantigen, suppressed infiltration of antigen-presenting cells (APCs) and T cells, and the expression of immune checkpoints (ICPs), combinational therapeutic strategies have shown great potential by activating the anti-tumor immune responses together with deactivating immunosuppressive conditions simultaneously. In this direction, photothermal therapy (PTT) has attracted attention due to the efficient ablation of tumor cells, of which the released immunogenic tumor debris can activate host immune responses. The combination of immunoadjuvants and/or ICP inhibitors can boost the anti-tumor immune responses, realizing PTT-synergized immuno-oncotherapy. In this regard, numerous multifunctional nanomaterials have been designed with integration of photothermal and immuno-oncotherapeutic agents into one package via well-designed surface modification and functionalization. This review summarizes the recent studies on the synergistic strategies for the immuno-oncotherapy based on photothermal nanoagents and the mechanisms that trigger the systemic anti-tumor immune responses and PTT-synergized immuno-oncotherapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Skin penetration and kinetics of pristine fullerenes (C60) topically exposed in industrial organic solvents.

Pristine fullerenes (C60) in different solvents will be used in many industrial and pharmaceutical manufacturing and derivatizing processes. This report explores the impact of solvents on skin penetration of C60 from different types of industrial solvents (toluene, cyclohexane, chloroform and mineral oil). Yorkshire weanling pigs (n=3) were topically dosed with 500 microL of 200 microg/mL C60 in a given solvent for 24 h and re-dosed daily for 4 days to simulate the worst scenario in occupational exposures. The dose sites were tape-stripped and skin biopsies were taken after 26 tape-strips for quantitative analysis. When dosed in toluene, cyclohexane or chloroform, pristine fullerenes penetrated deeply into the stratum corneum, the primary barrier of skin. More C60 was detected in the stratum corneum when dosed in chloroform compared to toluene or cyclohexane. Fullerenes were not detected in the skin when dosed in mineral oil. This is the first direct evidence of solvent effects on the skin penetration of pristine fullerenes. The penetration of C60 into the stratum corneum was verified using isolated stratum corneum in vitro; the solvent effects on the stratum corneum absorption of C60 were consistent with those observed in vivo. In vitro flow-through diffusion cell experiments were conducted in pig skin and fullerenes were not detected in the receptor solutions by 24 h. The limit of detection was 0.001 microg/mL of fullerenes in 2 mL of the receptor solutions.

Fabrication of microneedles using two photon polymerization for transdermal delivery of nanomaterials.

Microneedle devices for transdermal delivery of nanoscale pharmacologic agents were fabricated out of organically-modified ceramic (Ormocer) materials using two photon polymerization. Out-of-plane hollow microneedle arrays with various aspect ratios were fabricated using this rapid prototyping process. Human epidermal keratinocyte (HEK) viability on Ormocer surfaces fabricated using two photon polymerization was similar to that on control surfaces. Nanoindentation studies were performed to determine hardness and Young's modulus values for Ormocer materials. Microneedies were shown to enable more rapid distribution of the PEG-amine quantum dot solution to the deep epidermis and dermis layers of porcine skin than topical administration. Our results suggest that two photon polymerization may be used to create microneedle arrays for transdermal delivery of nanoscale pharmacologic agents.

Interactions of aluminum nanoparticles with human epidermal keratinocytes.

Aluminum nanoparticles (Al NP) have been used in applications as diverse as drug delivery, material surface coatings and an ingredient for solid rocket fuel in military explosives and artillery. Although Al NP are used in many civilian and military applications, the health and safety implications of these nanosize particles are not known. To understand the interactions and biological activity of Al NP in human cells, cultured human neonatal epidermal keratinocytes (HEK) were exposed for 24 h to 50 and 80 nm Al NP in concentrations from 4.0 to 0.0004 mg ml(-1) to assess the cytotoxicity and inflammatory potential. UV-Vis measurements and nanoparticle controls revealed that the Al NP interact with the assay dyes. Viability did not decrease in HEK exposed to both the 50 and the 80 nm Al NP at all treatment concentrations with MTT, CellTiter 96 AQueous One (96 AQ) and alamar Blue (aB) viability assays. The 96 AQ and aB assays interact with the Al NP less than MTT, and proved to be the best assays to use with these Al NP. TEM depicted Al NP localized within the cytoplasmic vacuoles of the cells. Cytokine data was variable, indicating possible nanoparticle interactions with the cytokine assays. These studies illustrate the difficulties involved in assessing the biological safety of nanomaterials such as Al NP due to media- and temperature-dependent particle agglomeration and nanoparticle interactions with biomarkers of cytotoxicity.

Meta-Analysis of Nanoparticle Delivery to Tumors Using a Physiologically Based Pharmacokinetic Modeling and Simulation Approach.

Numerous studies have engineered nanoparticles with different physicochemical properties to enhance the delivery efficiency to solid tumors, yet the mean and median delivery efficiencies are only 1.48% and 0.70% of the injected dose (%ID), respectively, according to a study using a nonphysiologically based modeling approach based on published data from 2005 to 2015. In this study, we used physiologically based pharmacokinetic (PBPK) models to analyze 376 data sets covering a wide range of nanomedicines published from 2005 to 2018 and found mean and median delivery efficiencies at the last sampling time point of 2.23% and 0.76%ID, respectively. Also, the mean and median delivery efficiencies were 2.24% and 0.76%ID at 24 h and were decreased to 1.23% and 0.35%ID at 168 h, respectively, after intravenous administration. While these delivery efficiencies appear to be higher than previous findings, they are still quite low and represent a critical barrier in the clinical translation of nanomedicines. We explored the potential causes of this poor delivery efficiency using the more mechanistic PBPK perspective applied to a subset of gold nanoparticles and found that low delivery efficiency was associated with low distribution and permeability coefficients at the tumor site (P < 0.01). We also demonstrate how PBPK modeling and simulation can be used as an effective tool to investigate tumor delivery efficiency of nanomedicines.

Amino/Amido Conjugates Form to Nanoscale Cobalt Physiometacomposite (PMC) Materials Functionally Delivering Nucleic Acid Therapeutic to Nucleus Enhancing Anticancer Activity via Ras-Targeted Protein Interference.

Aberrant splicing and protein interaction of Ras binding domain (RBD) are associated with melanoma drug resistance. Here, cobalt or nickel doped zinc oxide (ZnO) physiometacomposite (PMC) materials bind to RNA and peptide shown by Ninhydrin staining, UV-vis, Fourier transform infrared, and circular dichroism spectroscopy. PMCs deliver splice switching oligomer (SSO) into melanoma cells or 3-D tumor spheroids shown by flow cytometry, fluorescence microscopy, and bioluminescence. Stability in serum, liver, or tumor homogenate up to 48 h and B16F10 melanoma inhibition ≥98-99% is shown. These data suggest preclinical potential of PMC for delivery of SSO, RBD, or other nucleic acid therapeutic and anticancer peptides.

Microfabricated curtains for controlled cell seeding in high throughput microfluidic systems.

A microfabricated cell curtain is presented that facilitates cellular assays. The cell curtain is defined as a poly(dimethylsiloxane) (PDMS) wall that extends from the ceiling of a cell culture microchamber to within microns of the chamber floor. Curtain use is demonstrated by observing monolayer human epidermal keratinocyte (HEK) colonies for 48 h longer than possible with non-curtained microfluidic chambers. The curtains were further characterized by integrating them into a 96 chamber high throughput microfluidic cell culture device. As proof of concept, this device was used to assay a range of ethanol dilutions spanning 0-22% in cell culture medium. Cells exposed to 12% ethanol or less for 30 min would recover to 85% viability at 24 h, while cells exposed to higher concentrations had viabilities below 10%. The data also showed that cells exposed to 6% ethanol or less grew in population size, 8% ethanol exposure stunted growth, and higher concentrations led to population loss. Curtain use permitted high initial cell seeding densities and increased the amount of time cells can be cultured compared to multi-well plates.

Expression of proinflammatory cytokines by human mesenchymal stem cells in response to cyclic tensile strain.

Mesenchymal stem cells produce proinflammatory cytokines during their normal growth. Direct or indirect regulation of bone resorption by these cytokines has been reported. However, the effects of osteogenic conditions-chemical and/or mechanical-utilized during in vitro bone tissue engineering on expression of cytokines by hMSCs have not been studied. In this study, we investigated the effects of cyclic tensile strain, culture medium (with and without dexamethasone), and culture duration on the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) by bone marrow derived human mesenchymal stem cells (hMSCs). Human MSCs seeded in three-dimensional Type I collagen matrices were subjected to 0%, 10%, and 12% uniaxial cyclic tensile strains at 1 Hz for 4 h/day for 7 and 14 days in complete growth or dexamethasone-containing osteogenic medium. Viability of hMSCs was maintained irrespective of strain level and media conditions. Expression of either TNF-alpha or IL-1 beta was not observed in hMSCs under any of the conditions investigated in this study. Expression of IL-6 was dependent on culture medium. An increase in IL-6 expression was caused by both 10% and 12% strain levels. Both 10% and 12% strain levels caused an increase in IL-8 production by hMSCs that was dependent on the presence of dexamethasone. IL-6 and IL-8 expressions by hMSCs were induced by cyclic tensile strain and osteogenic differentiating media, indicating that IL-6 and IL-8 may be functioning as autocrine signals during osteogenic differentiation of hMSCs.

Cyclic tensile strain increases interactions between human epidermal keratinocytes and quantum dot nanoparticles.

The effects of quantum dots (QD) on cell viability have gained increasing interest due to many recent developments utilizing QD for pharmaceutical and biomedical applications. The potential use of QD nanoparticles as diagnostic, imaging, and drug delivery agents has raised questions about their potential for cytotoxicity. The objective of this study was to investigate the effects of applied strain on QD uptake by human epidermal keratinocytes (HEK). It was hypothesized that introduction of a 10% average strain to cell cultures would increase QD uptake. HEK were seeded at a density of 150,000 cells/mL on collagen-coated Flexcell culture plates (Flexcell Intl.). QD were introduced at a concentration of 3 nM and a 10% average strain was applied to the cells. After 4h of cyclic strain, the cells were examined for cell viability, QD uptake, and cytokine production. The results indicate that addition of strain results in an increase in cytokine production and QD uptake, resulting in irritation and a negative impact on cell viability. Application of physiological load conditions can increase cell membrane permeability, thereby increasing the concentration of QD nanoparticles in cells.