Noninvasive depth estimation using tissue optical properties and a dual-wavelength fluorescent molecular probe in vivo

Translation of fluorescence imaging using molecularly targeted imaging agents for real-time assessment of surgical margins in the operating room requires a fast and reliable method to predict tumor depth from planar optical imaging. Here, we developed a dual-wavelength fluorescent molecular probe with distinct visible and near-infrared excitation and emission spectra for depth estimation in mice and a method to predict the optical properties of the imaging medium such that the technique is applicable to a range of medium types. Imaging was conducted at two wavelengths in a simulated blood vessel and an in vivo tumor model. Although the depth estimation method was insensitive to changes in the molecular probe concentration, it was responsive to the optical parameters of the medium. Results of the intra-tumor fluorescent probe injection showed that the average measured tumor sub-surface depths were 1.31 ± 0.442 mm, 1.07 ± 0.187 mm, and 1.42 ± 0.182 mm, and the average estimated sub-surface depths were 0.97 ± 0.308 mm, 1.11 ± 0.428 mm, 1.21 ± 0.492 mm, respectively. Intravenous injection of the molecular probe allowed for selective tumor accumulation, with measured tumor sub-surface depths of 1.28 ± 0.168 mm, and 1.50 ± 0.394 mm, and the estimated depths were 1.46 ± 0.314 mm, and 1.60 ± 0.409 mm, respectively. Expansion of our technique by using material optical properties and mouse skin optical parameters to estimate the sub-surface depth of a tumor demonstrated an agreement between measured and estimated depth within 0.38 mm and 0.63 mm for intra-tumor and intravenous dye injections, respectively. Our results demonstrate the feasibility of dual-wavelength imaging for determining the depth of blood vessels and characterizing the sub-surface depth of tumors in vivo

Dissociation of Cerebral Blood Flow and Femoral Artery Blood Pressure Pulsatility After Cardiac Arrest and Resuscitation in a Rodent Model: Implications for Neurological Recovery.

Background Impaired neurological function affects 85% to 90% of cardiac arrest (CA) survivors. Pulsatile blood flow may play an important role in neurological recovery after CA. Cerebral blood flow (CBF) pulsatility immediately, during, and after CA and resuscitation has not been investigated. We characterized the effects of asphyxial CA on short-term (<2 hours after CA) CBF and femoral arterial blood pressure (ABP) pulsatility and studied their relationship to cerebrovascular resistance (CVR) and short-term neuroelectrical recovery. Methods and Results Male rats underwent asphyxial CA followed by cardiopulmonary resuscitation. A multimodal platform combining laser speckle imaging, ABP, and electroencephalography to monitor CBF, peripheral blood pressure, and brain electrophysiology, respectively, was used. CBF and ABP pulsatility and CVR were assessed during baseline, CA, and multiple time points after resuscitation. Neuroelectrical recovery, a surrogate for neurological outcome, was assessed using quantitative electroencephalography 90 minutes after resuscitation. We found that CBF pulsatility differs significantly from baseline at all experimental time points with sustained deficits during the 2 hours of postresuscitation monitoring, whereas ABP pulsatility was relatively unaffected. Alterations in CBF pulsatility were inversely correlated with changes in CVR, but ABP pulsatility had no association to CVR. Interestingly, despite small changes in ABP pulsatility, higher ABP pulsatility was associated with worse neuroelectrical recovery, whereas CBF pulsatility had no association. Conclusions Our results reveal, for the first time, that CBF pulsatility and CVR are significantly altered in the short-term postresuscitation period after CA. Nevertheless, higher ABP pulsatility appears to be inversely associated with neuroelectrical recovery, possibly caused by impaired cerebral autoregulation and/or more severe global cerebral ischemia

Portable, High-Bandwidth Frequency-Domain Photon Migration Instrument for Tissue Spectroscopy

We describe a novel frequency-domain photon migration instrument employing direct diode laser modulation and avalanche photodiode detection, which is capable of noninvasively determinating the optical properties of biological tissues in near real time. An infinite medium diffusion model was used to extract absorption and transport scattering coefficients from 300-kHz to 800-MHz photon-density wave phase data. Optical properties measured in tissue-simulating solutions at 670 nm agreed to within 10% of those expected

A High-Bandwidth Frequency-Domain Photon Migration Instrument for Clinical Use

We have developed a high-bandwidth frequency-domain photon migration (FDPM) instrument which is capable of noninvasively determining the optical properties of biological tissues in near-real-time. This portable, inexpensive, diode-based instrument is unique in the sense that we employ direct diode laser modulation and avalanche photodiode detection. Diffusion models were used to extract the optical properties (absorption and transport scattering coefficients)of tissue-simulating solutions.from the 300 kHz to I GHz photon density wave data

Frequency-Domain Photon Migration in Turbid Media

An analytical model is presented for the propagation of diffuse photon density waves in turbid media. The frequency- and wavelength-dependence of photon density waves are measured using Frequency-domain Photon Migration (FDPM). Media optical properties, including absorption, transport, and fluorescence relaxation times are calculated from experimental results

Properties of Photon Density Waves in Multiple-Scattering Media

Amplitude-modulated light launched into multiple-scattering media, e.g., tissue, results in the propagation of density waves of diffuse photons. Photon density wave characteristics in turn depend on modulation frequency (ω) and media optical properties. The damped spherical wave solutions to the homogeneous form of the diffusion equation suggest two distinct regimes of behavior: (1) a highfrequency dispersion regime where density wave phase velocity Vp has a ω dependence and (2) a low-frequency domain where Vp is frequency independent. Optical properties are determined for various tissue phantoms by fitting the recorded phase (Φ) and modulation (m) response to simple relations for the appropriate regime. Our results indicate that reliable estimates of tissuelike optical properties can be obtained, particularly when multiple modulation frequencies are employed

Spatiotemporal propagation of cerebral hemodynamics during and after resuscitation from cardiac arrest

Cardiac arrest (CA) affects over 500,000 people in the United States. Although resuscitation efforts have improved, poor neurological outcome is the leading cause of morbidity in CA survivors, and only 8.3% of out-of-hospital CA survivors have good neurological recovery. Therefore, a detailed understanding of the brain before, during, and after CA and resuscitation is critical. We have previously shown, in a preclinical model of asphyxial CA, that measurement of cerebral blood flow (CBF) is essential to better understand what happens to the brain during CA and resuscitation. We have shown that CBF data can be used to predict the time when brain electrical activity resumes. Moreover, we have described CBF characteristics after resuscitation, including the hyperemic peak and stabilized hypoperfusion. Overall, our previous work focused on the study of the temporal evolution of CBF dynamics. To provide a more complete picture of CBF dynamics associated with CA and resuscitation, we postulate that both the temporal and spatial evolution of CBF dynamics must be understood. To investigate spatiotemporal dynamics, we used laser speckle imaging (LSI) to image rats (n = 6) that underwent either 5- or 7-min asphyxial CA, followed by cardiopulmonary resuscitation (CPR) until return of spontaneous circulation (ROSC). During induction of global cerebral ischemia through CA, we have observed two periods during which a decrease in CBF propagates in space in a cranial window over the right hemisphere. The first period of time is during CA and the second is after the hyperemic peak, before stabilized hypoperfusion occurs post-ROSC. Figure 1 shows a representative rat blood flow maps of the spatial propagation during CA (top row) and after ROSC (bottom row). For each row, the leftmost image shows CBF at t = 0min, and each subsequent image to the right is the time after the initial image. The arrows on the images represent the propagation direction in which CBF decreases. In this example, during CA, the propagation direction is down and to the left (posterior-medial anatomically), while after ROSC it is down and to the right (posterior-laterally, anatomically). Please click Additional Files below to see the full abstract

Optical Properties of Human Uterus at 630 nm

The optical properties of normal and fibriotic human uteri were determined using frequency-domain and steady-state techniques