Single-cell analysis is rapidly gaining prominence in biology and medicine. The ability to profile elemental content at the level of an individual cell offers new insight into health, disease, and cellular function. However, existing techniques have long struggled with the fundamental challenge of how to preserve fragile mammalian cells during sample introduction for inductively coupled plasma mass spectrometry (ICP-MS).
A new study from Chiba University, Japan, published in the Journal of Analytical Atomic Spectrometry, demonstrates a transformative approach that addresses this limitation head-on. By integrating a piezoelectric microdroplet generator (µDG) into the sample introduction system of an ICP-MS instrument, researchers have developed a method that preserves cell integrity and enables precise quantification of elemental content in individual mammalian cells.
The Need for Gentler Sample Introduction
ICP-MS is a powerful tool for detecting trace elements in biological samples, with single-cell ICP-MS (scICP-MS) extending this capability to individual cells. Traditional scICP-MS workflows use a pneumatic nebulizer to atomize the sample into a mist. While effective for hardier cells such as yeast or bacteria, this method exposes larger mammalian cells to intense shear forces that rupture membranes and distort elemental profiles.
Chemical fixation, often used to toughen cells before nebulization, introduces its own problems. It alters the distribution and concentration of intracellular elements, particularly ions such as phosphorus and sulfur, thereby compromising the accuracy of downstream analysis.
To avoid these issues, researchers led by Assistant Professor Yu-ki Tanaka sought a sample introduction method that maintains both structural and elemental integrity of unfixed mammalian cells.
Microdroplets Deliver a Solution
The team replaced the conventional nebulizer with a µDG—an instrument that gently ejects uniform droplets containing single cells into the ICP-MS system. These droplets travel through a custom T-shaped glass interface and are carried into the plasma using a controlled argon and helium gas flow. This approach significantly reduces physical stress on cells and eliminates the need for fixation.
The impact was immediate. K562 leukemia cells were delivered to the ICP-MS with a significant increase in efficiency using the µDG system. More importantly, microscopic examination showed the cells remained structurally intact throughout the process.
“We have expanded the potential of scICP-MS technology to mammalian cultured cells, developing a robust analytical technique for measuring elemental content,” reports Tanaka.
Precision Elemental Analysis at the Single-Cell Level
To validate their approach, the researchers quantified five essential elements—magnesium (Mg), phosphorus (P), sulfur (S), zinc (Zn), and iron (Fe)—within individual K562 cells. The results demonstrated excellent agreement with values obtained via traditional solution nebulization ICP-MS following acid digestion.
The calibration process used ion-containing microdroplets of known concentration to generate linear standard curves. Despite the larger droplet sizes compared to traditional methods, efficient ionization occurred without the need for additional heating or desolvation devices.
The team also demonstrated long-term stability of the µDG system and validated it across a range of particle types, including nanoparticles and yeast cells, further establishing its versatility for elemental quantification in diverse samples.
Applications and Outlook
Single-cell elemental analysis has far-reaching implications. Trace metals such as iron, magnesium, and zinc play critical roles in cellular metabolism, signal transduction, and disease development. Accurate measurement at the single-cell level enables researchers to uncover heterogeneity within cell populations and gain a deeper understanding of how elemental imbalances contribute to conditions such as cancer or neurodegeneration.
The µDG-ICP-MS platform is particularly promising for clinical diagnostics and environmental exposure studies. Blood cells, for instance, can serve as easily accessible indicators of systemic health. Elemental fingerprints from patient samples could one day guide personalized treatment strategies or monitor disease progression.
“This approach opens the door to evaluating health conditions by analyzing elemental composition at the cellular level,” notes Tanaka. “We believe scICP-MS can become a core technology in diagnostics and prognostics.”
Conclusion
By combining precision microdroplet technology with the high sensitivity of ICP-MS, this new methodology overcomes a major barrier in single-cell analysis. It can enable reliable elemental profiling of delicate mammalian cells without chemical fixation or structural damage. As this technology matures, it is positioned to expand the capabilities of elemental bioanalysis in medicine, toxicology, and beyond.