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The objective of this paper is to demonstrate flex-embedded and surface-assembled photonic devices, inductive telemetry, and passive integration to form next-generation miniaturized biophotonic sensors. A hybrid combination of embedding and surface-assembled devices on flex is pursued to reduce the lateral and thickness dimensions of biophotonic systems. Embedding of premanufactured discrete passive devices is demonstrated by inserting in cavities, followed by printed fan-out connections to form the bridge connects between devices and other system components. Initial prototypes showed functional response to color shifts and reliability under bending loads on tissue phantoms. Measurements also confirmed responses to muscle activity as seen through changes in the backscattered light intensity during fist-closure with human subject hands. Initial bending test and reliability after water immersion indicate the stability of the chosen material systems towards flexible and wearable applications. This system concept can eventually be integrated with other system components such as RF transceivers for data telemetry, leading to completely autonomous wireless photosensors for wearable and implantable systems.

Miniaturized 3D package integration with piezo-magnetostrictive telemetry is analyzed towards advanced wireless medical systems. The paper is composed of three aspects. The first is to analyze telemetry using a multiferroic or piezo-magnetostrictive power interface. Parametric analysis was performed to estimate the impact of material, geometry and input magnetic fields. The second aspect is the process integration of devices and telemetry interfaces in 3D embedded packages for smallest form-factors. The telemetric interface and sensor devices are packaged in a flexible substrate with 3D interconnections, leading to miniaturized solutions. The sensor-communication and the power source flex layers are separately fabricated and connected with via-fill layers that are flex-compatible. Flex integration allows the devices to be functional on curved surfaces. In the final part, coupled magnetostrictive and piezoelectric films were considered to power devices in neural recording, neurostimulation and biophotonic systems. Power analysis requirements and piezo-magnetostrictive solutions for these specific scenarios is shown to illustrate the geometric compatibility towards emerging needs.

To evaluate the effects of closed endotracheal tube suctioning on systemic oxygen saturation, cerebral regional oxygen saturation, and somatic regional (renal) oxygen saturation and hemodynamic variables in children.Prospective observational.A tertiary care PICU.Children aged 0-18 years, requiring invasive mechanical ventilation and with an arterial line.Closed endotracheal suction.The study included 19 sedated and intubated children, 0-18 years old. They were enrolled in an ongoing prospective observational study. We used near-infrared spectroscopy for cerebral regional oxygen saturation and somatic regional (renal) oxygen saturation. The timing of each closed endotracheal tube suctioning event was accurately identified from video recordings. We extracted systemic oxygen saturation, cerebral regional oxygen saturation, somatic regional (renal) oxygen saturation, heart rate, and systolic blood pressure and diastolic blood pressure for 5 minutes before and 5 minutes after each event and used these data for analysis. One-minute average values of these variables were used for repeated-measures analysis. We analyzed 287 endotracheal tube suctioning episodes in 19 children. Saline was instilled into the endotracheal tube during 61 episodes. The mean heart rate (107.0 ± 18.7 vs 110.2 ± 10.4; p0.05), mean arterial blood pressure (81.5 ± 16.1 vs 83.0 ± 15.6 mm Hg; p0.05), and the mean cerebral regional oxygen saturation (64.8 ± 8.3 vs 65.8 ± 8.3; p0.05) were increased after suctioning. The mean systemic oxygen saturation (96.9 ± 2.7 vs 96.7 ± 2.7; p = 0.013) was decreased, whereas the mean somatic regional (renal) oxygen saturation was not significantly different after endotracheal tube suctioning. Repeated-measures analysis revealed transient increases in heart rate, respiratory rate, systolic blood pressure, and diastolic blood pressure; a sustained increase in cerebral regional oxygen saturation; and transient decreases in systemic oxygen saturation and somatic regional (renal) oxygen saturation. Saline instillation did not affect oxygenation or hemodynamic variables.Closed endotracheal tube suctioning in sedated children is associated with transient but clinically insignificant changes in heart rate, blood pressure, cerebral regional oxygen saturation, systemic oxygen saturation, and somatic regional (renal) oxygen saturation. Saline instillation during endotracheal tube suctioning had no adverse effects on systemic or cerebral oxygenation.

Heart rate variability (HRV) has been used as prognostic tool in various disorders in pediatric and adult patients. In our study we aimed to evaluate heart rate variability indices and their association with neurological outcome in three children with anoxic brain injury following drowning. Three children included in the study were admitted following drowning and required mechanical ventilation and targeted temperature management. All physiologic data, including electrocardiography (ECG) and EEG were collected for a period of 3–5 days after enrollment. ECG signals were analyzed in both time and frequency domains. The spectral power of the low-frequency (LF) band (0.04–0.15 Hz) and that of the high-frequency (HF) band (0.15–0.4 Hz), the standard deviation of the average R to R ECG intervals (SDANN) were calculated. Mean low-frequency/high-frequency power ratios (LF/HF) were compared using a two-tailed t -test and ANOVA with Tukey–Kramer multiple comparisons. The power in the LF band, the LF/HF power ratio, and the SDANN, were lower in children who had a poor outcome, and during periods of isoelectric or burst suppression EEG patterns.

Current clinical practice in focal epilepsy involves brain source imaging (BSI) to localize brain areas where from interictal epileptiform discharges (IEDs) emerge. These areas, named irritative zones, have been useful to define candidate seizures-onset zones during pre-surgical workup. Since human histological data are mostly available from final resected zones, systematic studies characterizing pathophysiological mechanisms and abnormal molecular/cellular substrates in irritative zones—independent of them being epileptogenic—are challenging. Combining BSI and histological analysis from all types of irritative zones is only possible through the use of preclinical animal models. Here, we recorded 32-channel spontaneous electroencephalographic data from rats that have focal cortical dysplasia (FCD) and chronic seizures. BSI for different IED subtypes was performed using the methodology presented in Bae et al. (2015). Post-mortem brain sections containing irritative zones were stained to quantify anatomical, functional, and inflammatory biomarkers specific for epileptogenesis, and the results were compared with those obtained using the contralateral healthy brain tissue. We found abnormal anatomical structures in all irritative zones (i.e., larger neuronal processes, glioreactivity, and vascular cuffing) and larger expressions for neurotransmission (i.e., NR2B) and inflammation (i.e., ILβ1, TNFα and HMGB1). We conclude that irritative zones in this rat preclinical model of FCD comprise abnormal tissues disregarding whether they are actually involved in icto-genesis or not. We hypothesize that seizure perpetuation happens gradually; hence, our results could support the use of IED-based BSI for the early diagnosis and preventive treatment of potential epileptic foci. Further verifications in humans are yet needed.

Background Optical spectroscopy can be used to assess the pathophysiological characteristics of diseased and injured biological tissue in vivo in a non-destructive way. It is often used in conjunction with a contact optical probe for the purposes of operating and sensing in a sterile field. Since the probe is often held by the hand of an investigator during data acquisition, any hand instability can affect the quality of acquired data and, hence, degrade the accuracy of diagnosis. This study was designed to quantitatively characterize these artifacts, and then propose an effective engineering solution to remove them. Methods Time-dependent diffuse reflectance spectra ( Rd ( λ , t )) were acquired from the normal cortex region of pediatric patients undergoing epilepsy surgery. They were acquired at a rate of 33Hz, and their range was 400 and 900nm. Two distinct ways of collecting data were tested: one with the fiber optical probe held by the surgeon's hand during data acquisition, and the other with the probe held by a specially designed probe holder. The probe holder was designed and constructed to minimize the variations in probe contact pressure and contact point for the full duration of any given investigation. Spectral data acquired using versus not using the probe holder were characterized and compared in the time, wavelength, and frequency domains, using both descriptive and inferential statistics. Results Hand motion manifested as strong random variations in Rd ( λ , t ) which impacted temporal and frequency characteristics of Rd ( λ , t ). The percentage standard deviation %STD of Rd ( λ , t ) acquired without probe holder could be as high as 60%, and they are significantly higher than those with probe holder at all wavelengths. This difference is especially prominent between 400 and 600nm. Rd ( λ , t ) acquired without the probe holder also processed a higher spectral power energy in the frequency domain than those with the probe holder. The correlation analysis revealed that the hand motions induced synchronistic variations in Rd ( λ , t ) between 600 and 800nm, but this synchronicity is not obvious between 400 and 600nm. Conclusion The results of this investigation demonstrate the nature and the magnitude of hand motion induced artifacts in in vivo diffuse reflectance spectra and propose one potential solution ( i.e. , a probe holder) to remove them. These findings allow us to improve the quality of time-dependent, diffuse reflectance signals acquired to study the dynamic characteristics of biological tissues, like brain, in vivo .

The applicability of optical spectroscopy for intraoperative detection of brain tumors/tumor margins was investigated in a pilot clinical trial consisting of 26 brain tumor patients. The results of this clinical trial suggest that brain tumors and infiltrating tumor margins (ITM) can be effectively separated from normal brain tissues in vivo using combined autofluorescence and diffuse-reflectance spectroscopy. A two-step empirical discrimination algorithm based on autofluorescence and diffuse reflectance at 460 and 625 nm was developed. This algorithm yields a sensitivity and specificity of 100 and 76%, respectively, in differentiating ITM from normal brain tissues. Blood contamination was found to be a major obstacle that attenuates the accuracy of brain tumor demarcation using optical spectroscopy. Overall, this study indicates that optical spectroscopy has the potential to guide brain tumor resection intraoperatively with high sensitivity.

Purpose: Promising results of optical signals have been reported in the literature for the diagnosis of Barrett’s esophagus, oral cavity lesions, brain tumor margins, cervical intraepithelial neoplasia, skin cancer and bladder cancer. The potential usefulness of these techniques in renal tissues and neoplasms has not been described to date. This initial study examined the feasibility of using fluorescence and diffuse reflectance spectroscopy to differentiate between malignant and benign renal tissues. Materials and Methods: An ex vivo study was conducted to identify optical characteristics of various renal tissue types. Pathologically confirmed benign and malignant renal samples were obtained from nephrectomy specimens from patients undergoing radical nephrectomy. Fluorescence and diffuse reflectance spectra were measured from benign and malignant renal tissues. Results: All renal tissues, malignant or benign, contain 2 primary emission peaks—a strong one at approximately 285 nm excitation, approximately 340 nm emission (Peak A), and a weak one at approximately 340 nm excitation, approximately 460 nm emission (Peak B). Peak A of normal renal tissue typically locates at the shorter excitation wavelength region than that of malignant tissue. The intensity of Peak B from benign tissues tends to be greater than that from malignant renal tissues. Diffuse reflectance intensities from malignant renal tissues between 600 and 800 nm are markedly greater than those from normal renal tissue. Empirical discrimination algorithms developed based on selected fluorescence and diffuse reflectance spectral characteristics yields accurate differentiation between benign and malignant renal tissues. Conclusions: Highly accurate differentiation between normal human renal tissues and renal cell cancers is feasible using combined fluorescence and diffuse reflectance spectroscopy in an ex vivo setting. If successful in future clinical studies, optical spectroscopy could aid in margin detection and tissue discrimination while performing nephron sparing surgery.

OBJECTIVE: Adult gliomas have indistinct borders. As the ratio of neoplastic cells to normal cells becomes lower, the ability to detect these cells diminishes. We describe a device designed to augment intraoperative identification of both solid tumor and infiltrating tumor margins. METHODS: A novel, intraoperative, optical spectroscopic tool, using both white light reflectance and 337-nm excitation fluorescence spectroscopy, is described. Discrimination algorithms have been developed to segregate neoplastic tissues from normal glial and neuronal elements. The spectroscopy device was used to measure 5 to 10 locations during glioma resection. Beneath the tool, a biopsy sample was obtained and the pathological results were reviewed in a blinded fashion. Samples were classified as solid tumor, infiltrating tumor, or normal gray or white matter. Comparisons were made between the optical spectra and the histopathological results of sampled areas in evaluating the sensitivity and specificity of the tool for tissue discrimination. RESULTS: Spectral data were obtained from 24 patients with glioma and from 11 patients with temporal lobe epilepsy. A sensitivity of 80% and a specificity of 89% in discriminating solid tumor from normal tissues were obtained. In addition, infiltrating tumor margins were distinguished from normal tissues with a sensitivity of 94% and a specificity of 93%. CONCLUSION: We have developed a handheld, optical spectroscopic device that may be used rapidly and in near real time with high sensitivity and reproducibility as an optical tissue discrimination tool in glioma surgery.

OBJECTIVE: Magnetic resonance imaging abnormalities in malignant brain tumors after irradiation may represent either recurrent tumor or radiation injury. Optical spectroscopy may represent a novel technique to identify radiation damage in brain tissues and to differentiate contrast-enhancing lesions from recurrent tumor. METHODS: Fluorescence and diffuse reflectance spectra were acquired from 90 patients: 15 undergoing surgical resection for presumed recurrent tumor after radiation therapy, 15 with epilepsy and hippocampal sclerosis, and 60 with tumors who had not received irradiation. Optical spectra were acquired from 6 to 10 sites and were compared with a biopsy obtained from beneath the optical spectroscopy probe; the data then were classified by a neuropathologist blinded to the spectroscopy data. A probe for the intraoperative collection of diffuse reflectance and fluorescence spectra was used. RESULTS: Thirteen of 15 patients (29 of 129 spectra) with previous irradiation showed a unique spectral feature characterized by a fluorescence peak centered at 500 nm (F500). All biopsy specimens showing histopathological signs of radiation injury had the F500 on their corresponding spectra (18 of 18). The F500 was identified in another 10% (11 of 111 spectra) of samples with previous irradiation but no histologically identifiable signs of radiation damage. The F500 was never seen in the normal temporal lobe of epilepsy patients with hippocampal sclerosis (0 of 105) and was seen in only 1.5% of tumor patients who did not undergo previous irradiation (6 of 433). CONCLUSION: Optical spectroscopy detects radiation damage in brain tissues. The F500 spectral peak may allow accurate selection of tissues for biopsy in evaluating patients with new, contrast-enhancing lesions in the setting of previous irradiation.

Background A current limitation of hepatic radiofrequency ablation (RFA) is an inability to detect ablation margins in real time. Thermal injury from RFA alters the biochemical properties governing tissue fluorescence. We hypothesized that the changes in hepatic fluorescence measured during hepatic RFA could be used to detect irreversible hepatocyte damage accurately and to determine ablation margins in real time. Methods RFA was performed on healthy pig livers and monitored in vivo simultaneously for fluorescence and temperature by a fiberoptic micro-interrogation probe connected to a spectroscopy system. Ablations were stopped based on previously established real-time fluorescence spectral data, not based on temperature or time. To determine where in the ablated tissue cell death occurred, biopsies for transmission electron microscopy were taken from 4 areas of 3 specimens: (1) nonablated liver, (2) hemorrhagic zone/normal liver interface, (3) hemorrhagic zone/coagulated zone interface, and (4) coagulated zone. In vitro fluorescence emission intensity was determined at each biopsy site. Results Peak hepatic fluorescence intensity occurred at 470 nm and decreased as RFA progressed. Transmission electron microscopy evidence of irreversible hepatocyte damage occurred at the interface of the coagulation zone and the hemorrhagic zone and correlated with a 87.5% ± 9% decrease in fluorescence emission intensity. Tissue fluorescent changes from thermal injury were unaffected by tissue cooling. Conclusion Fluorescence spectroscopy accurately detected hepatocellular thermal injury from RFA in real time and can detect irreversible cell damage during tissue thermal therapy.

Radiofrequency ablation (RFA) is an evolving technology used to treat unresectable liver tumors. Currently, there is no accurate method to determine RFA margins in real-time during the procedure. We hypothesized that a fiber-optic based spectroscopic monitoring system could detect thermal damage from RFA in real-time. Fluorescence (F) and diffuse reflectance (Rd) spectra were continuously acquired from within the expected ablation zone during canine hepatic RFA using a fiber-optic microinterrogation probe (MIP). The F and Rd spectral feedback were continuously monitored and ablations were stopped based on changes in spectra alone. After each ablation, the MIP tract was marked with India ink and the ablation zone was excised. The relationship of the MIP to the zone of ablation was examined grossly and microscopically. F and Rd spectral changes occurred in three characteristic phases as the ablation zone progresses past the MIP. Phase 1 indicates minimal deviation from normal lives. Phase 2 occurs as the MIP lies within the hemorrhagic zone of the ablated tissue. Phase 3 correlates with complete tissue coagulation. The absolute magnitude of spectral change correlates with the gross and histologic degree of thermal damage. Optical spectroscopy is a technology that allows real-time detection of thermal tissue damage. In this study, both F and Rd spectroscopy accurately defined the advancing hemorrhagic edge of the zone of ablation and the central coagulation zone. These results suggest that F and Rd spectroscopy can be used to create a real-time feedback system to accurately define RFA margins.

Thermal energy generated by radio-frequency current or other means may be employed in treating liver tumors by means of thermal coagulation when conventional resection is impossible. Currently, these thermal energy-based therapeutic procedures suffer from the lack of an adequate feedback control system, making it difficult to determine the optimal therapeutic endpoint. In this study, the potential of optical spectroscopy to provide such an objective endpoint for these procedures is presented. Freshly harvested canine liver samples were exposed to 50/spl deg/C, 60/spl deg/C, and 70/spl deg/C water baths for times ranging from 0 to 60 min. Transmission and reflectance were measured from each sample using an integrating sphere and the optical properties of each sample were accordingly derived. Excitation-emission matrices were recorded from the samples using a spectrofluorometer to identify the intrinsic fluorescence characteristics of native and thermally coagulated liver tissues. In addition, fluorescence and diffuse reflectance spectra were separately obtained from the samples prepared using a portable spectroscopic system. Results of this study show that fluorescence and optical properties of liver tissues exhibit clear and consistent changes through the thermal coagulation process. Specifically, the primary peak in the fluorescence spectra from liver tissues shifts from 480 nm in the native state to 510 nm in the fully coagulated state. In addition, a three- to fourfold increase in the absolute intensity of the diffuse reflectance spectra is observed upon complete coagulation of liver tissues. These dynamic spectral features indicate that fluorescence and diffuse reflectance spectroscopy may provide a direct measure of the biochemical and structural changes associated with tissue thermal damage in the liver.

Here we present a new methodology that investigates the intrinsic structural and hemodynamic characteristics of in vivo brain tissue, in a non-contact fashion, and can be easily incorporated in an intra-operative environment. Within this methodology, relative total diffuse reflectance spectra (RTD(λ)) were acquired from targets using a hybrid spectroscopy imaging system. A spectral interpretation algorithm was subsequently applied to RTD(λ) to retrieve optical properties related to the compositional and structural characteristics of each target. Estimation errors of the proposed methodology were computationally evaluated using a Monte Carlo simulation model for photon migration under various conditions. It was discovered that this new methodology could handle moderate noise and achieve very high accuracy, but only if the refractive index of the target is known. The accuracy of the technique was also validated using a series of tissue phantom studies, and consistent and accurate estimates of μs’(λ)/μa(λ) were obtained from all the phantoms tested. Finally, a small-scale animal study was conducted to demonstrate the clinical utility of the reported method, wherein a forepaw stimulation model was utilized to induce transient hemodynamic responses in somatosensory cortices. With this approach, significant stimulation-related changes (p < 0.001) in cortical hemodynamic and structural characteristics were successfully measured.

A simple but effective method of spectral processing was developed to minimize or remove the effects of the presence of superficial blood on tissue optical spectra and, hence, enhance the performance of optical-spectroscopic-based in vivo tissue diagnosis and surgical guidance. This spectral-processing algorithm was developed using the principles of absorption-induced light attenuation wherein the ratio of fluorescence intensity (F) and the hth power of diffuse reflectance intensity (Rd) at a given emission wavelength /spl lambda//sub m/ is immune to spectral distortions induced by the presence of blood on the tissue surface. Here, the exponent h is determined by the absorption coefficients of whole blood at the excitation and emission wavelengths. The theoretical basis of this spectral processing was verified using simulations and was experimentally validated. Furthermore, the optical spectra of brain tissues collected in vivo was processed using this algorithm to evaluate its impact on brain tissue differentiation using combined fluorescence and diffuse reflectance spectroscopy. Based on the simulation, as well as experimental results, it was observed that using F/Rd/sup h/ h can effectively reduce or remove spectral distortions induced by superficial blood contamination on tissue optical spectra. Thus, optical spectroscopy can also be used intraoperatively for applications such as surgical guidance of tumor resection.

Regenerative medicine is the process of replacing or regenerating animal cells, tissues, or organs to restore or establish normal function. This field has the potential to solve the problem of the shortage of organs available for donation and of organ transplant rejection. Recently, application of Complementary and Alternative Medicine (CAM) as a means to accelerate the process of regeneration is a new approach. The CAM therapies offer a natural and cost-effective intervention to change the course of chronic disease and may regenerate failing organ systems. The paper by Dr. Y.–J. Chen et al. explores how the Hepatitis B virus-encoded X regulates the expression of epidermal growth factor receptor, an important gene for growth of hepatocytes. Dr. H.–Y. Liu et al. demonstrated the regenerative potentials of deep sea water on osteogenesis, showing that deep sea water could potentially be applied in osteoporosis therapy. Dr. S. –H. Hsu et al. prepared peripheral nerve conduits containing the negatively charged Tremella fuciformis polysaccharide (TF) and successfully used the TF-immobilized conduits to repair a large (15 mm) critical gap defect in rats. Y. Lee et al. found that L-glutamate-induced neurotoxicity could be suppressed by the treatment with constituents of Rhodiola rosea, indicating that the Rhodiola rosea may have therapeutic potential for the treatment of inflammation and neurodegenerative disease. Dr. B.–Y. Yang et al. tried to apply percutaneous electrical stimulation to improve bone remodeling and bone healing in rats. X-ray and micro-CT showed that the electrical treatment could increase the amount of newly formed cranial bone. W. Liu et al. examined the contribution of side population (SP) cells from kidney and bone marrow to the reconstitution of kidney SP pools after ischemia-reperfusion injury (IRI). They found that following renal IRI, kidney SP cells were acutely depleted and then progressively restorated to baseline levels by both self-proliferation and extrarenal source, that is, bone marrow-derived cell homing. Dr. F. Yahya et al. showed that methanol extract of Bauhinia purpurea leaves could exert potential hepatoprotective activity in rats via its antioxidant activity and high phenolic content. T. Jayakumar et al. reviewed the effects of andrographolide, a major bioactive chemical constituent in Andrographis paniculata (Burm.f.) Nees, against cardiovascular disease, platelet activation, infertility, and NF-kB activation. Dr. H.–M. Chiang et al. showed the antioxidant activity of a Neonauclea reticulata water extract against ultraviolet B (UVB) irradiation in human skin fibroblast cell cultures (Hs68) by inhibiting MMP-1, -3, and -9 expressions and increasing levels of collagen activity. Dr. W.–Y. Su et al. developed a biphasic calcium phosphate cement, consisting of α-tricalcium phosphate (α-TCP) and hydroxyapatite (HAP), which is a potential biomaterial for bone repair. C. Y. Ho et al. showed that acupuncture and electroacupuncture could have positive effects on regeneration of median nerve in rats. J. Xiao et al. demonstrated that administration of garlic-derived antioxidant S-allylmercaptocysteine (SAMC) could ameliorate hepatic injury in a nonalcoholic fatty liver disease rat model. Dr. S.–C. Lee et al. investigated the effect of ferulic acid (FA) against peripheral nerve injury. They found that FA appears to promote peripheral nerve regeneration across a 15 mm critical defect gap in the rat sciatic nerve injury model. Suppression of macrophages by FA at the site of peripheral nerve injury may contribute to its nerve growth-promoting capability. By compiling these articles, we hope to stimulate our readers and researchers to provide continuing efforts to fully understand the effects of CAM therapies on regenerating tissues or organs. Yueh-Sheng Chen Wei-Chiang Lin Cheryl Miller

In this pilot study, we explored the potential of using a diffuse reflectance imaging system to extract interictal pathophysiological characteristics of epileptic cortex in an intraoperative setting. The imaging system was able to simultaneously measure diffuse reflectance signals at two distinct wavelengths (500 and 700 nm) from the entire exposed cortical surface. It was used to study ten pediatric patients during their epilepsy surgery. Diffuse reflectance images, Rd(x,y,λ,t) at 500 nm and 700 nm, were acquired at a 5 Hz rate for at least 200 seconds. Post imaging analysis identified a unique local frequency oscillation (LFO), below respiration rate, existed in Rd(x,y,500 nm,t) and Rd(x,y,700 nm,t). Mapping the spectral densities of LFOs over the cortical surface identified the spatial distribution of the LFOs. In almost all ten patients studied, the location demonstrating strong LFOs coincided with the epileptic cortex determined using ECoG. However, some LFOs were found in close proximity to functional areas according to fMRI. We further used the correlation coefficient map to identify those pixels with similar waveforms for better demarcation. These preliminary results support the feasibility of using wavelength-dependent diffuse reflectance imaging to intra-operatively detect epileptic cortex.

Low-frequency oscillations in cortical hemodynamics were observed from the cortex of pediatric patients undergoing epilepsy surgery; they may be used to identify the functional and/or the epileptic cortex intraoperatively.

This paper presents an electronic tongue system with blind source separation (BSS) and wireless sensor network (WSN) for remote multi-ion sensing applications. Electrochemical sensors, such as ion-sensitive field-effect transistor (ISFET) and extended-gate field-effect transistor (EGFET), only provide the combined concentrations of all ions in aqueous solutions. Mixed hydrogen and sodium ions in chemical solutions are observed by means of H + ISFET and H + EGFET sensor array. The BSS extracts the concentration of individual ions using independent component analysis (ICA). The parameters of ISFET and EGFET sensors serve as a priori knowledge that helps solve the BSS problem. Using wireless transceivers, the ISFET/EGFET modules are realized as wireless sensor nodes. The integration of WSN technology into our electronic tongue system with BSS capability makes distant multi-ion measurement viable for environment and water quality monitoring. Keywords: Electronic tongue, ion-sensitive field-effect transistor (ISFET), extended-gate field-effect transistor (EGFET), wireless sensor network (WSN), blind source separation (BSS), independent component analysis (ICA)

According to the Epilepsy Foundation, about 45,000 children under the age of 15 develop epilepsy each year. One of the long-standing challenges in the field of pediatric epilepsy research is to differentiate between normal and epileptic brain areas. This problem is especially important for children with intractable epilepsy, because surgical intervention must be used to alleviate their epileptic symptoms. Optical spectroscopy may be used to assess the pathophysiological characteristics of the epileptic brain tissue intraoperatively in a non-destructive manner, which, in turn, allows surgeons to plan an epilepsy surgery. Herein, the study is focused on demonstrating the feasibility of using time-dependent, diffuse reflectance spectroscopy specifically to detect pathophysiological characteristics associated with epileptic brain tissue. In a pediatric patient undergoing epilepsy surgery, time-dependent, diffuse reflectance spectra were measured from the epileptic cortex and the surrounding tissue using a fiber-optic spectroscopy system. The system was designed to acquire diffuse reflectance spectra from 300 - 1100 nm at a maximum acquisition rate of 33 Hz. Spectral and temporal variations in the acquired spectral sequences were compared to the corresponding electrocorticographic results, and thosevariations unique to the epileptic cortex were identified using statistical methods. Furthermore, these spectral variations were related to the physiological and morphological characteristics of the brain tissue. The preliminary results obtained from this in vivo study demonstrate the feasibility of differentiating epileptic cortex tissue from normal tissue using time-dependent, diffuse reflectance data.

The short- and long-term effects of probe contact pressure on in vivo diffuse reflectance and fluorescence spectroscopy were investigated using an animal model. Elevation in probe contact pressure induced major profile alterations in the diffuse reflectance spectra between 400 and 650 nm, and led to significant intensity increases in the fluorescence spectra. The pressure threshold that was required to induce statistically significant spectral alterations was dependent upon the type of tissue. The observed spectral alterations may be attributed to decreases in local blood volume, blood oxygenation, and tissue metabolism, resulting from high probe contact pressure.

Optical spectroscopy for in vivo tissue diagnosis is performed traditionally in a static manner; a snap shot of the tissue biochemical and morphological characteristics is captured through the interaction between light and the tissue. This approach does not capture the dynamic nature of a living organ, which is critical to the studies of brain disorders such as epilepsy. Therefore, a time-dependent diffuse reflectance spectroscopy system with a fiber-optic probe was designed and developed. The system was designed to acquire broadband diffuse reflectance spectra (240 ~ 932 nm) at an acquisition rate of 33 Hz. The broadband spectral acquisition feature allows simultaneous monitoring of various physiological characteristics of tissues. The utility of such a system in guiding pediatric epilepsy surgery was tested in a pilot clinical study including 13 epilepsy patients and seven brain tumor patients. The control patients were children undergoing suregery for brain tumors in which measurements were taken from normal brain exposed during the surgery. Diffuse reflectance spectra were acquired for 12 seconds from various parts of the brain of the patients during surgery. Recorded spectra were processed and analyzed in both spectral and time domains to gain insights into the dynamic changes in, for example, hemodynamics of the investigated brain tissue. One finding from this pilot study is that unsynchronized alterations in local blood oxygenation and local blood volume were observed in epileptogenic cortex. These study results suggest the advantage of using a time-dependent diffuse reflectance spectroscopy system to study epileptogenic brain in vivo.

The effects of myocardial infarction on in vivo diffuse reflectance and fluorescence characteristics of myocardial tissue were investigated. Spectral alterations induced by infarct development in myocardial tissue are reported.

The effects of probe contact pressure on in vivo diffuse reflectance and fluorescence spectroscopy was investigated. Spectral alterations induced by contact probe pressure and the minimal pressure required to induce such effects are reported here.

It is estimated that approximately 17,000 malignant brain tumors are diagnosed in adults and 1,500 in children every year in the United States. Although primary brain tumors account for only 1.4% of all cancers, the 5-year survival rate of these patients (35%) is low. The most common initial therapy received by brain tumor patients is surgical resection. Many studies have shown that the degree of resection significantly influences the time to recurrence and the overall survival of brain tumor patients. Currently, surgical navigation systems and ultrasonography are used intraoperatively to help neurosurgeons locate brain tumor and maximize resection. Despite the applications of these technologies, significant residual tumor mass is often found to be left behind in patients following brain tumor resection. Hence, there is a need for an objective, intraoperative real-time system that is capable of accurately differentiating brain tumors from normal brain tissue, and detecting tumor margins with sub-millimeter spatial resolution.

Recently, optical spectroscopy has shown considerable promise to be used as a potential clinical tool for human brain tumor detection and therapeutic guidance. Our group showed for the first time the possibility of using combined autofluorescence and diffuse reflectance spectroscopy and established its applicability for human brain tumor demarcation in previous in vitro and in vivo studies. We report in this paper the results of a clinical study designed to further evaluate the efficacy of the approach for demarcation of brain tumors and tumor margins from normal brain tissues in intra-operative clinical setting. Using a portable system, optical spectra were collected from the brain of 110 patients undergoing craniotomy at the Vanderbilt University Medical Center. Spectral measurements were taken from multiple sites of tumor core, tumor margin and normal areas of brain tissues and the resulting spectra were correlated with the corresponding histopathologic diagnosis. Using histology as the gold standard, a probabilistic multi-class diagnostic algorithm was developed to simultaneously distinguish tumor core and tumor margin from normal brain tissue sites using independent training and validation sets of data. An unbiased estimate of the accuracy of the model indicates that combined autofluorescence and diffuse reflectance spectroscopy was able to distinguish tumor core and tumor margin from normal brain tissues with an average predictive accuracy of ~88%.

Epileptogenic lesions and their margins are often difficult to define intraoperatively. We hypothesize that optical spectroscopy can detect unique pathophysiological features of epileptogenic lesions in children and hence differentiate them from normal brain. This hypothesis was tested by comparing the in vivo optical and fluorescence characteristics of epileptogenic brain lesions (non-neoplastic) with those of normal brain. Patients were recruited from those receiving epilepsy surgeries at Miami Children's Hospital. Using a portable spectroscopic system, optical characterization of brain was performed intraoperatively. Fluorescence spectra were measured at 337 nm excitation, and diffuse reflectance spectra were measured between 400 and 850 nm. To date, seven epilepsy patients have been enrolled in the study. A couple interesting trends have been observed in the recorded optical spectra. First, sites within the resection zone, as defined by the intracranial electroencephalogram data, often show higher diffuse reflectance signals than normal sites do. This is especially prominent around 500 nm and between 650 and 850 nm. Secondly, several investigated sites with abnormal electroencephalogram and/or pathology show a unique blue shift in their fluorescence spectra, which is not seen in other cases.

Tissue themial ablation techniques, especially radiofrequency ablation (RFA), have become important implements in the arsenal of therapies for treatment of primary and metastatic tumors of the liver. RFA can be performed percutaneously, laparoscopically, or during celiotomy as a primary therapy of an unresectable tumor. It may also be used as an adjunct to partial hepatectomy, which remains the gold standard for the treatment of hepatic tumors. The technique of RFA requires image guided placement of the needle electrode within the targeted tumor. The imaging techniques used are most often ultrasound or computed tomography (CT), but it can also be done using magnetic resonance imaging (MRI). Once activated, the RFA needle electrode causes destruction of the tumor cells via thermal conversion of the radiofrequency energy. The intrinsic electrical impedance of the tissue transforms the electrical current into heat, elevating the local tissue temperature and leading to coagulation necrosis. Clinically, RFA is a relatively safe procedure with a complication rate reported between 5 and 13% in most series (Bilchik et al. 2001; Curley et al. 2000; Wong et al. 2001). The efficacy of RFA, however, is not clear. There are no long term data regarding disease free survival, and the largest of clinical series report local recurrence rates as high as 39% (Bilchik et al. 1999; Curley et al. 1999; de Baere et al. 2000). Most clinicians believe that the large recurrence rates are due to either initial misplacement of the electrode or inadequate ablation of the tumor. The basic principles of oncologic surgery hold that a margin of non-cancerous tissue must be removed surrounding a tumor to insure

To complement a project towards the development of real-time optical biopsy for brain tissue discrimination and surgical resection guidance, the optical properties of various brain tissues were measured in vitro and correlated to features within clinical diffuse reflectance tissue spectra measured in vivo. Reflectance and transmission spectra of in vitro brain tissue samples were measured with a single-integrating-sphere spectrometer for wavelengths 400-1300 nm and converted to absorption and reduced scattering spectra using an inverse adding-doubling technique. Optical property spectra were classified as deriving from white matter, grey matter or glioma tissue according to histopathologic diagnosis, and mean absorption and reduced scattering spectra were calculated for the three tissue categories. Absolute reduced scattering and absorption values and their relative differences between histopathological groups agreed with previously reported results with the exception that absorption coefficients were often overestimated, most likely due to biologic variability or unaccounted light loss during reflectance/transmission measurement. Absorption spectra for the three tissue classes were dominated by haemoglobin absorption below 600 nm and water absorption above 900 nm and generally determined the shape of corresponding clinical diffuse reflectance spectra. Reduced scattering spectral shapes followed the power curve predicted by the Rayleigh limit of Mie scattering theory. While tissue absorption governed the shape of clinical diffuse reflectance spectra, reduced scattering determined their relative emission intensities between the three tissue categories.

Dynamics of fluorescence/diffuse reflectance characteristics and temperature of liver and kidney tissue undergoing radio-frequency ablation were studied in vivo. The results demonstrate the sensitivity and effectiveness of the optical-based method for tissue thermal damage assessment.

Thermotherapies such as radio-frequency ablation achieve necrosis of liver tumors through thermal coagulation and are frequently employed when surgical resection is impossible. Currently, thermotherapy procedures suffer from the lack of an adequate feedback control system, making it difficult to know precisely when to terminate therapy. In vitro and in vivo studies were performed on canine liver tissue to determine the feasibility of using fluorescence and diffuse reflectance spectroscopy to provide an objective endpoint for these procedures. The fluorescence and diffuse reflectance spectra of liver tissue exhibited consistent changes over the coagulation process. In vitro results showed a shift in the primary fluorescence peak from 490 nm in the native state to 510 nm in the fully coagulated state; in addition, a three- to four-fold increase in the absolute intensity of the diffuse reflectance spectra was observed upon complete coagulation. Similar spectral alterations were obtained in vivo. Based on our results, fluorescence and diffuse reflectance spectroscopy provide a direct way to assess the biochemical and structural changes associated with tissue thermal damage; hence, they can be developed into a feedback system for thermotherapies.

A silicon p-n junction biased in avalanche breakdown emits visible light and its integration offers the potential for VLSI-compatible optical interconnect systems, enabling next generation technologies and/or contact-less functional testing. The Si light emitters were stressed with AC and DC excitation and increased temperature to accelerate the aging. The results clearly show that the effects of AC and temperature stressing are negligible on light emission. DC stressing results in light coalescence for low values of current ( 40 mA), there is no significant variation of light emission. Changes in the light emission behavior for large and small values of DC excitation are consistent with a hydrogen migration model. The study revealed a strong dependence of light emission on the layout of test devices.

Spectral imaging as a modality combines two powerful techniques of imaging and fluorescence spectroscopy. By generating a 2-D image of an object with fluorescence information at every pixel, spectral imaging has the potential to provide clinicians with a valuable tool which can not only diagnosis the tissue but also provide an image of the boundary of where the normal and cancerous tissue intersect. The system used in these experiments was a modified spectral imaging system from Applied Spectral Imaging (SD-200, Carlsbad, CA). The system was mounted in an off-microscope configuration so that instead of performing microscopic measurements of tissue, macroscopic measurements on the order of several millimeters in size were collected. Preliminary results indicate that the spectra acquired from human brain tissues in vitro at individual pixels of the spectral image cube appear similar to that acquired using the single pixel system. Based on the findings of this study, spectral imaging has the potential to be a useful tool for tissue diagnostics and is currently limited by the speed of data acquisition and size of the data.© (2001) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

An optical spectroscopy-based system for intraoperative guidance of brain tumor resection is currently under development at Vanderbilt University and Vanderbilt University Medical Center. The effectiveness of brain tumor margin detection, especially the infiltrating type, using combined in vivo autofluorescence and diffuse reflectance spectroscopy was successfully demonstrated in a preliminary clinical trial (on a total of 26 brain tumor patients). In this trial, a two-step empirical discrimination algorithm based on autofluorescence and diffuse reflectance intensity at 460 nm and 625 nm yielded 100% sensitivity and 76% specificity in differentiating infiltrating tumor margins from normal brain tissues.

A pilot in vivo study was conducted to investigate the feasibility of using optical spectroscopy for brain tumor margin detection. Fluorescence and diffuse reflectance spectra were acquired using a portable clinical spectroscopic system from normal brain tissues, tumors, and tumor margins in 21 brain tumor patients undergoing craniotomy. Results form this study show the potential of optical spectroscopy in detecting infiltrating tumor margins of primary brain tumors.

In this study, the Z-scan technique was used to examine the thermal lens effect in turbid media containing micro-spheres suspended in water. The scattering coefficients of the turbid media were varied from 10 to 100 cm-1. The experimental results suggested that the nonlinear changes in the refractive index of the scattering medium induced by high power laser heating could significantly impact the propagation of laser beam through the scattering medium. Presence of thermally-induced nonlinear changes in refractive index of tissue during high power laser irradiation may significantly alter the distribution of laser light in tissue during laser therapy.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We have studied dynamic changes in optical properties of various tissues during argon and pulse Nd:YAG laser irradiation while monitoring tissue surface temperature. High power laser radiation induces reversible and/or irreversible changes in the optical behavior of the tissue. Reversible changes in diffuse reflectance and total transmittance can be as much as 15% and 20% of initial values, respectively. We are currently investigating the mechanism responsible for the observed reversible changes.

The concept of using diffuse reflectance spectroscopy to distinguish intraoperatively between pediatric brain tumors and normal brain parenchyma at the edge of resection cavities is evaluated using an in vivo human study. Diffuse reflectance spectra are acquired from normal and tumorous brain areas of 12 pediatric patients during their tumor resection procedures, using a spectroscopic system with a handheld optical probe. A total of 400 spectra are acquired at the rate of 33 Hz from a single investigated site, from which the mean spectrum and the standard deviation are calculated. The mean diffuse reflectance spectra collected are divided into the normal and the tumorous categories in accordance with their corresponding results of histological analysis. Statistical methods are used to identify those spectral features that effectively separated the two tissue categories, and to quantify the spectral variations induced by the motion of the handheld probe during a single spectral acquisition procedure. The results show that diffuse reflectance spectral intensities between 600 and 800 nm are effective in terms of differentiating normal cortex from brain tumors. Furthermore, probe movements induce large variations in spectral intensities (i.e., larger standard deviation) between 400 and 600 nm.

The objective of this in vitro tissue study is to investigate the feasibility of using optical spectroscopy to differentiate pediatric neoplastic and epileptogenic brain from normal brain. Specimens are collected from 17 patients with brain tumors, and from 26 patients with intractable epilepsy during surgical resection of epileptogenic cerebral cortex. Fluorescence spectra are measured at excitations of 337, 360, and 440 nm; diffuse reflectance spectra are measured between 400 and 900 nm from each specimen. Pathological analysis is performed to classify abnormalities in brain specimens, and its findings are correlated with spectral data. Statistically significant differences (p

Object Surgery is an important therapeutic modality for pediatric patients with intractable epilepsy. However, existing imaging and diagnostic technologies such as MR imaging and electrocochleography (ECoG) do not always effectively delineate the true resection margin of an epileptic cortical lesion because of limitations in their sensitivity. Optical spectroscopic techniques such as fluorescence and diffuse reflectance spectroscopy provide a nondestructive means of gauging the physiological features of the brain in vivo, including hemodynamics and metabolism. In this study, the authors investigate the feasibility of using combined fluorescence and diffuse reflectance spectroscopy to assist epilepsy surgery in children. Methods In vivo static fluorescence and diffuse reflectance spectra were acquired from the brain in children undergoing epilepsy surgery. Spectral measurements were obtained using a portable spectroscopic system in conjunction with a fiber optic probe. The optical investigations were conducted at the normal and abnormal cortex as defined by intraoperative ECoG and preoperative imaging studies. Biopsy samples were taken from the investigated sites located within the zone of resection. The optical spectra were classified into multiple subsets in accordance with the ECoG and histological study results. The authors used statistical comparisons between 2 given data subsets to identify unique spectral features. Empirical discrimination algorithms were developed using the identified spectral features to determine if the objective of the study was achieved. Results Fifteen pediatric patients were enrolled in this pilot study. Elevated diffuse reflectance signals between 500 and 600 nm and/or between 650 and 850 nm were observed commonly in the investigated sites with abnormal ECoG and/or histological features in 10 patients. The appearance of a fluorescent peak at 400 nm was observed in both normal and abnormal cortex of 5 patients. These spectral alterations were attributed to changes in morphological and/or biochemical characteristics of the epileptic cortex. The sensitivities and specificities of the empirical discrimination algorithms, which were constructed using the identified spectral features, were all > 90%. Conclusions The results of this study demonstrate the feasibility of using static fluorescence and diffuse reflectance spectroscopy to differentiate normal from abnormal cortex on the basis of intraoperative assessment of ECoG and histological features. It is therefore possible to use fluorescence and diffuse reflectance spectroscopy as an aid in epilepsy surgery.

Introduction Epileptogenic lesions and their margins are often difficult to define intraoperatively. Optical spectroscopy, especially diffuse reflectance and fluorescence spectroscopy, can characterize tissue in vivo. We hypothesize that optical spectroscopy can detect unique pathophysiological features of epileptogenic lesions and hence differentiate them from normal brain. This hypothesis was tested by comparing the in vivo optical and fluorescence characteristics of epileptogenic brain lesions (non-neoplastic) with those of normal brain. Methods Patients were recruited from those undergoing evaluation for surgical management of intractable epilepsy at Miami Children's Hospital. Fluoroscence and diffuse reflectance spectra were acquired from the brain using a fiberoptic spectroscopic system. Both static and dynamic spectral acquisition was performed; thus, the average and time dependent characteristics were assessed. Both hemo-dynamic and metabolic physiologic characteristics were retrieved from the spe...

Given the wavelength dependence of sample optical properties and the selective sampling of surface emission angles by noncontact imaging systems, differences in angular profiles due to excitation angle and optical properties can distort relative emission intensities acquired at different wavelengths. To investigate this potentiality, angular profiles of diffuse reflectance and fluorescence emission from turbid media were evaluated experimentally and by Monte Carlo simulation for a range of incident excitation angles and sample optical properties. For emission collected within the limits of a semi-infinite excitation region, normalized angular emission profiles are symmetric, roughly Lambertian, and only weakly dependent on sample optical properties for fluorescence at all excitation angles and for diffuse reflectance at small excitation angles relative to the surface normal. Fluorescence and diffuse reflectance within the emission plane orthogonal to the oblique component of the excitation also possess this symmetric form. Diffuse reflectance within the incidence plane is biased away from the excitation source for large excitation angles. The degree of bias depends on the scattering anisotropy and albedo of the sample and results from the correlation between photon directions upon entrance and emission. Given the strong dependence of the diffuse reflectance angular emission profile shape on incident excitation angle and sample optical properties, excitation and collection geometry has the potential to induce distortions within diffuse reflectance spectra unrelated to tissue characteristics.

The release of excitatory amino acids (EAAs) from injured neurons has been associated with secondary injury following head trauma. The development of a rapid and sensitive method for the quantification of EAAs may provide a means for clinical management of patients affected by head trauma. We explore the potential application of surface-enhanced Raman spectroscopy (SERS) for rapid quantification of the concentration of EAAs in aqueous silver colloids. The EAAs glutamate (Glu) and aspartate (Asp) are released following head injury and have been observed to exhibit SERS spectra that should enable them to be distinguished in a complex aqueous media. Of the two EAAs, the concentration of Glu has been shown to be more indicative of injury to the central nervous system. Using 30-s scans and a 50-mW argon laser, aqueous Glu is quantifiable from 0.4 to 5 micromol/L and is spectrally distinguishable from Asp. In addition, initial in vivo microdialysis experiments suggest that this SERS system is capable of measuring chemical changes following head trauma in the rat brain. Compared with current high-performance liquid chromatography (HPLC) techniques for amino acid detection, the short scanning and processing time associated with the SERS approach enables measurement on a near-real-time basis, providing clinical information in anticipation of pharmaceutical intervention.

The dynamics of the optical behavior of tissue during the photothermal interaction of laser radiation with tissue could significantly affect the optimization of light doses for effective and safe applications of lasers in medicine. Characterization of the dynamics of tissue optics during laser heating was performed by means of simultaneous measurements of the total transmittance, diffuse reflectance, and surface temperature of fresh and thermally coagulated human skin and canine aorta during long-pulsed Nd:YAG laser heating with a double integrating-sphere system and an infrared camera. Thermally induced changes in the optical properties of tissue caused a decrease in the total transmittance and an increase in the diffuse reflectance of both fresh and precoagulated skin and aorta samples. For fresh tissue, these changes were primarily reversible until photocoagulation occurred, then both the reversible, as well as the irreversible, changes were observed. However, for precoagulated tissue the reversible changes in the optical properties were dominant, whereas the irreversible changes were insignificant. Results from this study indicate the existence of the nonlinear behavior in the optics of turbid biological media during pulsed laser heating. Possible mechanisms responsible for this nonlinear optical behavior are discussed.

A pump (cw Ho-YAG laser) and probe (He-Ne laser) system was used to study the dynamics of the optical behavior of ocular tissue during laser heating. The nonlinear optical behavior of porcine corneal and vitreous-humor tissue was characterized in vitro by means of measurements of the radial profile of a He-Ne laser beam transmitted through the tissue. Temperature gradients in the tissue created by the absorption of pump radiation caused the probe beam to diverge. For constant laser power, the rate of divergence was made dependent on the spot size of the pump beam. The profile of the transmitted probe beam returned to its original magnitude and shape after the tissue was permitted to cool. This reversible change in optical behavior was attributed to the formation of a negative lens owing to thermally induced local gradients in the refractive index of the tissue.