A quantitative look inside the body: minimally invasive infrared analysis in vivo.

Today's minimally invasive biosensors are often based on chemical reagents and suffer from, e.g., oxygen dependence, toxic reaction products, excess analyte consumption, and/or degradation of the reagents. Here, we show the first successful analyte quantification by means of a minimally invasive sensor in vivo, which does not use chemical reactions. The concentration of glucose is determined continuously in vivo using transcutaneous, fiber-based mid-infrared laser spectroscopy. When comparing the infrared data measured in vivo with the 127 reference readings of glucose obtained in vitro, an overall standard deviation of 17.5% and a median of the absolute values of the relative deviations of 11.0% are achieved. The encouraging results open up the path toward a reagent-free long-term implant for the continuous surveillance of metabolites. In addition, the high sampling rate facilitates important research in body metabolism as well as its application outside the field of medicine such as real-time analyte sensing during fermentation.

Evaporation from open microchannel grooves.

The evaporation of water from open u-shaped microchannel grooves was investigated with particular emphasis on the roles of channel width and air flow conditions. Given the small dimensions of the microchannels, all measurements were conducted in a range where convection and diffusion are of equal importance and known correlations for the calculation of mass transfer coefficients cannot be applied. The evaporation rates were measured using a new optical method and a gravimetric method. Both measurement methods yielded mass transfer coefficients that are in agreement with each other. The observed relation between mass transfer coefficient, air velocity and channel width vastly differs from the predictions obtained from macroscopic structures. With respect to diagnostic devices we conclude that analyte concentration in an open microchannel groove strongly increases even within short times due to the evaporation process and we show that wider channels are more favourable in terms of minimizing the relative evaporation rate.

Effective fragment potential study of the influence of hydration on the vibrational spectrum of glucose.

The standard agent glucose has been the subject of numerous experimental and theoretical studies, especially in the aqueous environments which are present in most biochemical processes. The impact of the solvation process on the vibrational spectra of glucose in the mid-infrared region is investigated in this work. The computational study focused both on the variation of the number of surrounding water molecules from 0 to 229 and on the number of single spectra included in the iterative averaging process. The calculations consisted of a combination of force field methods for the sampling of the configuration space and density functional theory for further geometry optimizations. Effective fragment potentials (EFPs) were employed for the description of the solvent as a compromise between accuracy and computational complexity. A correlation between the experimental data and the number of surrounding water molecules could not be observed for an averaging over a small set of computed single spectra. The inclusion of an additionial polarizable continuum model (PCM) also showed no further impact. However, an increase in the number of underlying single spectra in the averaging process increased the correlation between simulations and the experiment substantially. Especially for 18 explicit EFP water molecules, an inclusion of 80 single spectra delivered a Pearson's correlation coefficient r ≈ 0.94.

Continuous glucose monitoring by means of mid-infrared transmission laser spectroscopy in vitro.

The continuous surveillance of glucose concentration reduces short-term risks and long-term complications for people with diabetes mellitus, a disorder of glucose metabolism. As a first step towards the continuous monitoring of glucose, reagent-free transmission spectroscopy in the mid-infrared region has been carried out in vitro using a quantum cascade laser and an optical silver halide fiber. A 30 µm gap in the fiber allowed for transmission spectroscopy of aqueous glucose solutions at a wavelength of 9.69 µm, which is specific to a molecular vibration of glucose. A noise-equivalent concentration as low as 4 mg/dL was achieved at an average power of 1.8 mW and an integration time of 50 s. This is among the most precise of glucose measurements using mid-infrared spectroscopy. Even with the very low average laser power of 0.07 mW the sensitivity of previous results (using a fiber optical evanescent field analysis) has been improved upon by almost one order of magnitude. Finally, the impact of potentially interfering substances such as other carbohydrates was analyzed.

Experimental evaluation of a robust optimization method for IMRT of moving targets.

Internal organ motion during radiation therapy, if not considered appropriately in the planning process, has been shown to reduce target coverage and increase the dose to healthy tissues. Standard planning approaches, which use safety margins to handle intrafractional movement of the tumor, are typically designed based on the maximum amplitude of motion, and are often overly conservative. Comparable coverage and reduced dose to healthy organs appear achievable with robust motion-adaptive treatment planning, which considers the expected probability distribution of the average target position and the uncertainty of its realization during treatment delivery. A dosimetric test of a robust optimization method for IMRT was performed, using patient breathing data. External marker motion data acquired from respiratory-gated radiotherapy patients were used to build and test the framework for robust optimization. The motion trajectories recorded during radiation treatment itself are not strictly necessary to generate the initial version of a robust treatment plan, but can be used to adapt the plan during the course of treatment. Single-field IMRT plans were optimized to deliver a uniform dose to a rectangular area. During delivery on a linear accelerator, a computer-driven motion phantom reproduced the patients' breathing patterns and a two-dimensional ionization detector array measured the dose delivered. The dose distributions from robust-optimized plans were compared to those from standard plans, which used a margin expansion. Dosimetric tests confirmed the improved sparing of the non-target area with robust planning, which was achieved without compromising the target coverage. The maximum dose in robust plans did not exceed 110% of the prescription, while the minimum target doses were comparable in standard and robust plans. In test courses, optimized for a simplified target geometry, and delivered to a phantom that moved in one dimension with an average amplitude of 17 mm, the robust treatment design produced a reduction of more than 12% of the integral dose to non-target areas, compared to the standard plan using 10 mm margin expansion.

Tumor trailing strategy for intensity-modulated radiation therapy of moving targets.

Internal organ motion during the course of radiation therapy of cancer affects the distribution of the delivered dose and, generally, reduces its conformality to the targeted volume. Previously proposed approaches aimed at mitigating the effect of internal motion in intensity-modulated radiation therapy (IMRT) included expansion of the target margins, motion-correlated delivery (e.g., respiratory gating, tumor tracking), and adaptive treatment plan optimization employing a probabilistic description of motion. We describe and test the tumor trailing strategy, which utilizes the synergy of motion-adaptive treatment planning and delivery methods. We regard the (rigid) target motion as a superposition of a relatively fast cyclic component (e.g., respiratory) and slow aperiodic trends (e.g., the drift of exhalation baseline). In the trailing approach, these two components of motion are decoupled and dealt with separately. Real-time motion monitoring is employed to identify the "slow" shifts, which are then corrected by applying setup adjustments. The delivery does not track the target position exactly, but trails the systematic trend due to the delay between the time a shift occurs, is reliably detected, and, subsequently, corrected. The "fast" cyclic motion is accounted for with a robust motion-adaptive treatment planning, which allows for variability in motion parameters (e.g., mean and extrema of the tidal volume, variable period of respiration, and expiratory duration). Motion-surrogate data from gated IMRT treatments were used to provide probability distribution data for motion-adaptive planning and to test algorithms that identified systematic trends in the character of motion. Sample IMRT fields were delivered on a clinical linear accelerator to a programmable moving phantom. Dose measurements were performed with a commercial two-dimensional ion-chamber array. The results indicate that by reducing intrafractional motion variability, the trailing strategy enhances relevance and applicability of motion-adaptive planning methods, and improves conformality of the delivered dose to the target in the presence of irregular motion. Trailing strategy can be applied to respiratory-gated treatments, in which the correction for the slow motion can increase the duty cycle, while robust probabilistic planning can improve management of the residual motion within the gate window. Similarly, trailing may improve the dose conformality in treatment of patients who exhibit detectable target motion of low amplitude, which is considered insufficient to provide a clinical indication for the use of respiratory-gated treatment (e.g., peak-to-peak motion of less than 10 mm). The mechanical limitations of implementing tumor trailing are less rigorous than those of real-time tracking, and the same technology could be used for both.