Design and validation of a fiber optic point probe instrument for therapy guidance and monitoring

Abstract in Undetermined ABSTRACT. Optical techniques for tissue diagnostics currently are experiencing tremendous growth in biomedical applications, mainly due to their noninvasive, inexpensive, and real-time functionality. Here, we demonstrate a hand-held fiber optic probe instrument based on fluorescence/reflectance spectroscopy for precise tumor delineation. It is mainly aimed for brain tumor resection guidance with clinical adaptation to minimize the disruption of the standard surgical workflow and is meant as a complement to the state-of-the-art fluorescence surgical microscopy technique. Multiple light sources with fast pulse modulation and detection enable precise quantification of protoporphyrin IX (PpIX), tissue optical properties, and ambient light suppression. Laboratory measurements show the system is insensitive to strong ambient light. Validation measurements of tissue phantoms using nonlinear least squares support vector machines (LS-SVM) regression analysis demonstrate an error of <5% for PpIX concentration ranging from 400 to 1000 nM, even in the presence of large variations in phantom optical properties. The mean error is 3% for reduced scattering coefficient and 5% for blood concentration. Diagnostic precision of 100% was obtained by LS-SVM classification for in vivo skin tumors with topically applied 5-aminolevulinic acid during photodynamic therapy. The probe could easily be generalized to other tissue types and fluorophores for therapy guidance and monitoring

Luminescence Spectroscopy For Biomedical Applications

This work presents optical methods utilizing visible light for characterization of biological tissue during diagnostics and treatment processes. The main aim has been to improve the therapeutic outcome of treatment modalities in in vivo studies. An optical probe instrument based on fluorescence/reflectance spectroscopy was developed for noninvasive monitoring of photosensitizerconcentration in the course of a photodynamic therapy (PDT) procedure. Furthermore, upconverting nanoparticles were exploited as probes for fluorescent imaging with direct applications in preclinical research. Photodynamic therapy (PDT) is a minimally invasive treatment modality that uses light, a photosensitizing drug and oxygen to ablate malignant tumours and other diseased tissues. PDT has been investigated for treating malignancies in numerous organs and has become a promising modality for some types of malignancies including some skin tumours and prostate cancers. PDT is, however, a highly complex treatment modality with many parameters influencing the treatment outcome. Improvements in dosimetry for PDT are ongoing, with thegoal to better correlate the clinical outcome to what is planned prior to the treatment of PDT. Accurate dosimetry and treatment planning require knowledge of tissue optical properties and an accurate model for the light propagation in the tissue. In the present work, we present a technique, to combine fluorescence and reflectance spectroscopy to yield improvements in the accuracy ofthe treatment planning. These improvements are further facilitated by multivariate analysis of the recorded data. Extracting the intrinsic fluorescence as well as optical properties of the tissue is demonstrated. This technique does not require a priori knowledge of the optical properties of the sample. The application of luminescence spectroscopy as an effective tool that allows detailedobservations of tissues to be made via labelling with exogenous probes, is growing remarkably in popularity. Lanthanide doped upconverting nanoparticles (UCNPs) have recently been developed as light-triggered luminescent probes in various biomedical applications. UCNPs have the ability to convert near-infrared (NIR) radiation with low photon energy into visible radiations withhigher energy per photon via a non-linear optical process. In this work, the non-linear dependency on the excitation intensity was compensated to improve the accuracy of measurements of the quantum efficiencies of UCNPs. Recently, UCNPs have evolved as an alternative fluorescent label to traditional fluorophores for imaging both in vitro and in vivo. Their great potential stems fromtheir properties which include high penetration depth into the tissue, low background signal and photostability. The aim of this work was also to optimize the excitation wavelength to achieve significant signal gain in deep tissues

Potential biomedical use of diode-laser-induced luminescence from upconverting nanoparticles

The intention with this chapter is to briefly review the capabilities made possible in the field of biomedical diagnostics and treatment by employing upconverting nanoparticles (UCNPs), as well as the importance of appropriate light sources for such applications. The field of UCNPs in biomedicine has grown rapidly the last decade, since they first were made sufficiently small and bright to be of real interest for biomedical applications. This research has been reviewed previously, while this chapter will focus on recent advances in the use of UCNPs for preclinical applications and diagnostic assays using laser diode excitation

Improving penetration depth in biological imaging using Nd3+/Yb3+/Er3+-doped upconverting nanoparticles

We have synthesized and evaluated in tissue phantom measurements a new type of Nd-codoped upconverting nanoparticles. They provide improved signal strengths from deep regions in a tissue phantom as compared to conventional upconverting nanoparticles, a result also suggesting they will provide less issues with heating the tissue during measurements

Increasing depth penetration in biological tissue imaging using 808-nm excited Nd3+/Yb3+/Er3+-doped upconverting nanoparticles

Ytterbium (Yb3+)-sensitized upconverting nanoparticles (UCNPs) are excited at 975 nm causing relatively high absorption in tissue. A new type of UCNPs with neodymium (Nd3+) and Yb3+ codoping is excitable at a 808-nm wavelength. At this wavelength, the tissue absorption is lower. Here we quantify, both experimentally and theoretically, to what extent Nd3+-doped UCNPs will provide an increased signal at larger depths in tissue compared to conventional 975-nm excited UCNPs. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License

Deep tissue imaging using Nd-doped upconverting nanoparticles

Deep tissue excitation of upconverting nanoparticles is limited for biomedical applications by water absorption. By modifying the nanoparticles to shift the excitation wavelength, we demonstrate better depth sensitivity

Development of a novel combined fluorescence and reflectance spectroscopy system for guiding high-grade glioma resections _ Confirmation of capability in lab experiments

Total resection of glioblastoma multiform (GBM), the most common and aggressive malignant brain tumor, is challenging among other things due to difficulty in intraoperative discrimination between normal and residual tumor cells. This project demonstrates the potential of a system based on a combination of autofluorescence and diffuse reflectance spectroscopy to be useful as an intraoperative guiding tool. In this context, a system based on 5 LEDs coupled to optical fibers was employed to deliver UV/visible light to the sample sequentially. Remitted light from the tissue; including diffuse reflected and fluorescence of endogenous and exogenous fluorophores, as well as its photobleaching product, is transmitted to one photodiode and four avalanche photodiodes. This instrument has been evaluated with very promising results by performing various tissue-equivalent phantom laboratory and clinical studies on skin lesions

Novel combined fluorescence/reflectance spectroscopy system for guiding brain tumor resections - hardware considerations

Glioblastoma multiforme (GBM) has long been known as the most common and aggressive form of brain malignancy. The morphological similarities of the malignant and surrounding tissue cause difficulties to distinct the tumors during surgery. In order to achieve better results in resecting malignant brain tumors, a fiber based optical system which can be used intraoperative is developed in this project. In this context, the system hardware details, system controlling interfaces and laboratory testing results are presented. Based on the results obtained from various tests with tissue-equivalent phantoms, the system is proved to have stable performance, robust structure, and have good linearity as well as high sensitivity to low PpIX concentration under strong ambient light conditions

Beam-profile-compensated quantum yield measurements of upconverting nanoparticles

The quantum yield is a critically important parameter in the development of lanthanide-based upconverting nanoparticles (UCNPs) for use as novel contrast agents in biological imaging and optical reporters in assays. The present work focuses on the influence of the beam profile in measuring the quantum yield (φ) of nonscattering dispersions of nonlinear upconverting probes, by establishing a relation between φ and excitation light power density from a rate equation analysis. A resulting 60% correction in the measured φ due to the beam profile utilized for excitation underlines the significance of the beam profile in such measurements, and its impact when comparing results from different setups and groups across the world