Two-layer reconstruction of Raman spectra in diffusive media based on an analytical model in the time domain.

We derive and validate an analytical model that describes the migration of Raman scattered photons in two-layer diffusive media, based on the diffusion equation in the time domain. The model is derived under a heuristic approximation that background optical properties are identical on the excitation and Raman emission wavelengths. Methods for the reconstruction of two-layer Raman spectra have been developed, tested in computer simulations and validated on tissue-mimicking phantom measurements data. Effects of different parameters were studied in simulations, showing that the thickness of the top layer and number of detected photon counts have the most significant impact on the reconstruction. The concept of quantitative, mathematically rigorous reconstruction using the proposed model was finally proven on experimental measurements, by successfully separating the spectra of silicone and calcium carbonate (calcite) layers, showing the potential for further development and eventual application in clinical diagnostics.

Hybrid heterogeneous phantoms for biomedical applications: a demonstration to dosimetry validation.

Phantoms simultaneously mimicking anatomical and optical properties of real tissues can play a pivotal role for improving dosimetry algorithms. The aim of the paper is to design and develop a hybrid phantom model that builds up on the strengths of solid and liquid phantoms for mimicking various anatomical structures for prostate cancer photodynamic therapy (PDT) dosimetry validation. The model comprises of a photosensitizer-embedded gelatin lesion within a liquid Intralipid prostate shape that is surrounded by a solid silicone outer shell. The hybrid phantom was well characterized for optical properties. The final assembled phantom was also evaluated for fluorescence tomographic reconstruction in conjunction with SpectraCure's IDOSE software. The developed model can lead to advancements in dosimetric evaluations. This would improve PDT outlook as a clinical treatment modality and boost phantom based standardization of biophotonic devices globally.

Perspectives on interstitial photodynamic therapy for malignant tumors.

SIGNIFICANCE: Despite remarkable advances in the core modalities used in combating cancer, malignant diseases remain the second largest cause of death globally. Interstitial photodynamic therapy (IPDT) has emerged as an alternative approach for the treatment of solid tumors. AIM: The aim of our study is to outline the advancements in IPDT in recent years and provide our vision for the inclusion of IPDT in standard-of-care (SoC) treatment guidelines of specific malignant diseases. APPROACH: First, the SoC treatment for solid tumors is described, and the attractive properties of IPDT are presented. Second, the application of IPDT for selected types of tumors is discussed. Finally, future opportunities are considered. RESULTS: Strong research efforts in academic, clinical, and industrial settings have led to significant improvements in the current implementation of IPDT, and these studies have demonstrated the unique advantages of this modality for the treatment of solid tumors. It is envisioned that further randomized prospective clinical trials and treatment optimization will enable a wide acceptance of IPDT in the clinical community and inclusion in SoC guidelines for well-defined clinical indications. CONCLUSIONS: The minimally invasive nature of this treatment modality combined with the relatively mild side effects makes IPDT a compelling alternative option for treatment in a number of clinical applications. The adaptability of this technique provides many opportunities to both optimize and personalize the treatment.

Fluorescence intensity and lifetime imaging of free and micellar-encapsulated doxorubicin in living cells.

Frequency domain fluorescence lifetime imaging microscopy (FLIM) has been used in combination with laser scanning confocal microscopy to study the cellular uptake behavior of the antitumor drug doxorubicin (DOX) and micellar-encapsulated DOX (PLyAd-DOX). The endocytosis uptake process of PLyAd-DOX was monitored over 72 hours using confocal microscopy, with a maximum fluorescence recorded at incubation periods around 24 hours. The micellar structure was not found to release the encapsulated DOX during the time course of imaging. FLIM revealed single lifetime distributions of PLyAd-DOX during accumulation in the cytoplasm. The free DOX in contrast was observed both in the cytoplasm and the nuclear domain of the cell, showing bimodal lifetime distributions. There was a marked dependence of the measured free-DOX lifetime on concentration within the cell, in contrast to reference experiments in aqueous solution, where no such dependence was found. The results suggest the formation of macromolecular structures inside the living cells.

Computer simulation analysis of source-detector position for percutaneously measured O2 -gas signal in a three-dimensional preterm infant lung.

Further improvements in the clinical care of our most vulnerable patients-preterm infants-are needed. Novel diagnostic and surveillance tools facilitate such advances. The GASMAS technique has shown potential to become a tool to, noninvasively, monitor gas in the lungs of preterm infants, by placing a laser source and a detector on the chest wall skin. It is believed that this technology will become a valuable clinical diagnostic tool for monitoring the lung function of these patients. Today, the technology is, for this application, in an early stage and further investigations are needed. In the present study, a three-dimensional computer model of the thorax of an infant is constructed, from a set of CT images. Light transport simulations are performed to provide information about the position dependence of the laser- and detector probe on the thorax of the infant. The result of the simulations, based on the study method and the specified model used in this work, indicates that measurement geometries in front and on the side of the lung are favorable in order to obtain a good gas absorption signal.

Development of a 3-dimensional tissue lung phantom of a preterm infant for optical measurements of oxygen-Laser-detector position considerations.

There is a need to further improve the clinical care of our most vulnerable patients-preterm infants. Novel diagnostic and treatment tools facilitate such advances. Here, we evaluate a potential percutaneous optical monitoring tool to assess the oxygen and water vapor content in the lungs of preterm babies. The aim is to prepare for further clinical studies by gaining a detailed understanding of how the measured light intensity and gas absorption signal behave for different possible geometries of light delivery and receiver. Such an experimental evaluation is conducted for the first time utilizing a specially developed 3-dimensional-printed optical phantom based on a geometry model obtained from computer tomography images of the thorax (chest) of a 1700-g premature infant. The measurements yield reliable signals for source-detector distances up to about 50 mm, with stronger gas absorption signals at long separations and positions related to the lower part of the lung, consistent with a larger relative volume of this. The limitations of this study include the omission of scattering tissue within the lungs and that similar optical properties are used for the wavelengths employed for the 2 gases, yielding no indication on the optimal wavelength pair to use.

Realtime light dosimetry software tools for interstitial photodynamic therapy of the human prostate.

Photodynamic therapy (PDT) for the treatment of prostate cancer has been demonstrated to be a safe treatment option capable of inducing tissue destruction and decreasing prostate specific antigen (PSA) levels. However, prostate-PDT results in large intra- and interpatient variations in treatment response, possibly due to biological variations in tissue composition and short-term response to the therapeutic irradiation. Within our group, an instrument for interstitial PDT on prostate tissue has been developed that combines therapeutic light delivery and monitoring of light transmission via numerous bare-ended optical fibers. Here, we present algorithms that utilize data on the light distribution within the target tissue to provide realtime treatment feedback based on a light dose threshold model for PDT. This realtime dosimetry module is implemented to individualize the light dose and compensate for any treatment-induced variations in light attenuation. More specifically, based on the light transmission signals between treatment fibers, spatially resolved spectroscopy is utilized to assess the effective attenuation coefficient of the tissue. These data constitute input to a block-Cimmino optimization algorithm, employed to calculate individual fiber irradiation times provided the requirement to deliver a predetermined light dose to the target tissue while sparing surrounding sensitive organs. By repeatedly monitoring the light transmission signals during the entire treatment session, optical properties and individual fiber irradiation times are updated in realtime. The functionality of the algorithms is tested on diffuse light distribution data simulated by means of the finite element method (FEM). The feasibility of utilizing spatially resolved spectroscopy within heterogeneous media such as the prostate gland is discussed. Furthermore, we demonstrate the ability of the block-Cimmino algorithm to discriminate between target tissue and organs at risk (OAR). Finally, the realtime dosimetry module is evaluated for treatment scenarios displaying spatially and temporally varying light attenuation levels within the target tissue. We conclude that the realtime dosimetry module makes it possible to deliver a certain light dose to the target tissue despite spatial and temporal variations of the target tissue optical properties at the therapeutic wavelength.

Feasibility of white-light time-resolved optical mammography.

We demonstrate the feasibility of white-light time-resolved optical mammography. The instrumentation is based on supercontinuum light generated in photonic crystal fiber and 32-channel parallel time-correlated single-photon-counting detection. Total measurement time is of the order of 10 min for typical clinical applications. Preliminary measurements performed on volunteers show the ability of the system to determine tissue constituent concentrations and structure over the entire breast area. Furthermore, measurements on a tissue-like sample demonstrate detection and characterization of inclusions.

Online dosimetry for temoporfin-mediated interstitial photodynamic therapy using the canine prostate as model.

Online light dosimetry with real-time feedback was applied for temoporfin-mediated interstitial photodynamic therapy (PDT) of dog prostate. The aim was to investigate the performance of online dosimetry by studying the correlation between light dose plans and the tissue response, i.e., extent of induced tissue necrosis and damage to surrounding organs at risk. Light-dose planning software provided dose plans, including light source positions and light doses, based on ultrasound images. A laser instrument provided therapeutic light and dosimetric measurements. The procedure was designed to closely emulate the procedure for whole-prostate PDT in humans with prostate cancer. Nine healthy dogs were subjected to the procedure according to a light-dose escalation plan. About 0.15 mg/kg temoporfin was administered 72 h before the procedure. The results of the procedure were assessed by magnetic resonance imaging, and gross pathology and histopathology of excised tissue. Light dose planning and online dosimetry clearly resulted in more focused effect and less damage to surrounding tissue than interstitial PDT without dosimetry. A light energy dose-response relationship was established where the threshold dose to induce prostate gland necrosis was estimated from 20 to 30 J/cm2.

Characterization of normal breast tissue heterogeneity using time-resolved near-infrared spectroscopy.

In recent years, extensive efforts have been made in developing near-infrared optical techniques to be used in detection and diagnosis of breast cancer. Variations in optical properties of normal breast tissue set limits to the performance of such techniques and must therefore be thoroughly examined. In this paper, we present intra- and intersubject as well as contralateral variations of optical and physiological properties in breast tissue as measured by using four-wavelength time-resolved spectroscopy (at 660, 786, 916 and 974 nm). In total, 36 volunteers were examined at five regions at each breast. Optical properties (absorption, mu(a), and reduced scattering, mu'(s)) are derived by employing diffusion theory. The use of four wavelengths enables determination of main tissue chromophores (haemoglobin, water and lipids) as well as haemoglobin oxygenation. Variations in all evaluated properties seen over the entire breast are approximately twice those for small-scale heterogeneity (millimetre scale). Intrasubject variations in optical properties are almost in all cases below 20% for mu'(s), and 40% for mu(a). Overall variations in water, lipid and haemoglobin concentrations are all in the order of 20%. Oxygenation is the least variable of the quantities evaluated, overall intrasubject variations being 6% on average. Extracted physiological properties confirm differences between pre- and post-menopausal breast tissue. Results do not indicate systematic differences between left and right breasts.