(Invited) Resonator and SERS Sensing in the Field of Drug Delivery
Authors: Boisen Anja 
Published: July 2021

Introduction

Our research center of excellence IDUN combines research in nanosensors/centrifugal microfluidics and microfabricated devices for oral drug delivery. This allows us to explore the synergy between sensor development and search for new pharmaceutical delivery tools and materials. Our developed nanosensors get access to unique polymers and biomolecules and are able to characterize, among others, small volumes of materials and molecules, which are today not possible to analyze by any standard technologies. We will show examples of recent findings and results within drug/polymer characterization (1) and process monitoring (2) using nanomechanical sensors. Also, new applications within therapeutic drug monitoring using Surface Enhanced Raman Scattering (SERS) will be presented as well as sensor integration with centrifugal microfluidics platforms.

Resonators

By monitoring the resonance frequency shift of micrometer sized strings or cantilevers coated with thin layers of polymers, it is possible to monitor phase transitions using only ng of material. We have been able to observe beta relaxation of polymers (3) and drugs (2), see figure 1. These systems also allowed us to monitor degradation of biomaterials used in the fabrication of the microcontainers (4). Also, strings are inherently sensitive to temperature changes (5). The resonant frequency detunes as a function of temperature and temperature changes down to 10-5 °C can be detected. The effect has been used to perform photothermal IR spectra on samples deposited on resonating strings and resonating filters. This has been used to for example study the amorphous and crystalline forms of indomethacin (1). As an alternative to cleanroom fabricated resonators we have used single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom processing. This method additionally makes it possible to study the behavior of single crystals, which would otherwise be extremely difficult/impossible. This method has, among others, allowed us to study new phenomena in the hydration/dehydration of drugs (6).

Centrifugal microfluidics

The optics and mechanics from a DVD player can be used to realize compact and sensitive sensor systems. By rotating a polymer disc with integrated microfluidic channels it is possible to manipulate liquid samples such as blood – performing crucial operations like separation, valving and mixing. We integrate sensor elements such as cantilevers, nanoparticles, resonating strings and SERS substrates with centrifugal microfluidics (7). The sensors are read out by a DVD pick-up head, which can perform transmission/absorption measurements and can detect nm deflections. Also, electrodes and spectrometers are integrated on a disc platform, facilitating electrochemical/Raman measurements. Our nanopillar SERS substrate can be used for sample filtration and separation. Here the nanopillars function similarly to a filter paper in chromatography and can be used to distinguish e.g. different components in a urine sample as well as drug residuals. A SERS chip is placed in a centrifugal microfluidics platform, whereby the sample can be initially centrifuged. Subsequently half the SERS chip is exposed to the centrifuged liquid. Hereby, liquid can travel up the chip by the so-called wicking effect, and depending on affinity of molecules to the surface, different molecules will travel different lengths. Hereby, a separation is secured and the different molecules are read-out as bands on the SERS chip.

Acknowledgements

This research has received funding from the ERC grant agreement n° 320535 and from the Center of Excellence ’IDUN’ granted by Danish National Research Foundation, DNRF122/the Velux Foundations.

References

[1] M. Kurek et al. Nanomechanical Infrared Spectroscopy with Vibrating Filters for Pharmaceutical Analysis. Angew. Chemie 129, 3959–3963 (2017).

[2] M. Karl et al.Ultrasensitive Microstring Resonaotrs for Solid State Thermomechanical Analysis of Small and Large Molecules, Journal of the American Chemical Society 140 (50), 17522-17531 (2018).

[3] S. Bose et al. Micromechanical fast quasi-static detection of α and β relaxations with nanograms of polymer. J. Polym. Sci. Part B Polym. Phys. 53, 1035–1039 (2015).

[4] A.C. Ceccacci et al. Blu-Ray-based micromechanical characterization platform for biopolymer degradation assessment. Sensors Actuators B Chem. 241, 1303–1309 (2017).

[5] T. Larsen, T. et al. Ultrasensitive string-based temperature sensors. Appl. Phys. Lett. 98, 121901 (2011)

[6] P. O. Okeyo et al. Single particles as resonators for thermomechanical analysis. Nat. Commun.
11, 1235 (2020).

[7] O. Durucan et al., Nanopillar-Assisted SERS Chromatography, ACS Sensors, 2018

Figure 1