Millimeters In Depth Research Articles

878 Development of a Near Infrared Somatostatin Receptor Type 2 (SSTR2)-Targeted Probe for Fluorescence-Guided Surgery in Meningiomas

INTRODUCTION: Meningioma frequently recur at the primary resection site requiring improvement in the intraoperative tumor visualization and surgical technique. To guide the resection, this study aims to develop a highly specific and sensitive optical method for intraoperative meningioma imaging. By suitable cameras fluorescent dyes in the near infrared (NIR, 700-1000nm) can be detected up to few millimeters in depth in real time. METHODS: We invented a SSTR2 targeting probe by linking a somatostatin analogue (TATE, Tyr(3)Thr(8)-Octreotid) to a new developed dye (sNIR). In the optical characterization, our probe showed similarities to indocyanine green and stability as well as bleaching kinetic were investigated in vitro. The probe was intravenously injected in native mice and detected by a custom-built camera setup to evaluate pharmacokinetics and biodistribution, focusing on physiologically SSTR2 overexpressing organs that were validated by immunohistochemistry (IHC). As proof-of-principle, fluorescence-guided meningioma resection was performed in an ectopic and orthotopic IOMM-Lee mouse model. RESULTS: Our probe is stable in aqueous solution up to 12h with favorable optical properties regarding pharmacokinetics, biodistribution and photostability compared to its IRDye800 analogue. In vivo, we observed a highly specific signal uptake in the gastric epithelium, pancreas and pituitary (all are overexpressing SSTR2) compared to autofluorescence and negative controls. Given the intermediate SSTR2 expression in the meningioma mouse model, we could still detect a mean tumor-to-brain ratio of 6.12 (n = 5; SD 1.8) allowing the fluorescence-guidance to be feasible. CONCLUSIONS: Our preclinical results indicate that the new SSTR2-targeted fluorescent probe is stable in various media over time and capable of specifically targeting the SSTR2 in vitro and in vivo potentially enabling sensitive and specific meningioma fluorescent-guided surgery in the future.

Small animal cerebral microvascular imaging with super-resolution ultrasound: Techniques and applications

Super-resolution ultrasound (SR-US) is an emerging microvascular imaging technology that provides a micron-scale spatial resolution with tens of millimeters of depth of imaging penetration. The unmatched combination of high spatial resolution and deep imaging penetration opened new doors for many brain imaging applications that benefit from cerebrovascular biomarkers. Recently, SR-US has found its niche in small animal brain applications thanks to its unique capabilities of extending the optical-imaging-level spatial resolution to subcortical, deep brain regions. In this presentation, I will first introduce existing SR-US imaging techniques that are tailored to small animal brain imaging applications. Topics include fast SR-US methods, 3D SR-US imaging, and phase aberration correction for intact skull imaging. I will then focus on reviewing brain imaging applications that use SR-US to characterize cerebral mirovasculature in the aging, stroke, and Alzheimer’s Disease brain. Finally, I will introduce the new functional super-resolution imaging technique that combines SR-US with functional ultrasound (fUS) to realize whole-brain neural activity recording at a micron-scale spatial resolution.

KS04.5.A Development of a somatostatin receptor type 2 (SSTR2)-targeted probe for near infrared fluorescence guided meningioma surgery

Abstract Background Meningioma mostly recur at the primary resection bed requiring improvement in the intraoperative tumor visualization and surgical technique. This study aims to develop a highly specific and sensitive optical probe for intraoperative meningioma imaging to guide the tumor resection. Fluorescent dyes in the near infrared (NIR I, 700-1000nm) and shortwave infrared (NIR II, 1000-2000nm) allow detection by suitable cameras up to few millimeters in depth in real time. Our objective is to invent a fluorescent NIR I and II probe specifically targeting the somatostatin receptor type 2 (SSTR2) reliably overexpressed in meningioma independently of WHO grade and subtype. Material and Methods By linking a somatostatin analogue (TATE, Tyr(3)Thr(8)-Octreotid) to a new developed dye (sNIR), we synthesized a SSTR2 specific probe. Its optical properties are comparable to indocyanine green and stability as well as bleaching kinetic were observed in vitro. The probe was intravenously injected in native mice to evaluate pharmacokinetics and biodistribution and detected by a custom-built camera setup focusing on physiologically highly expressing SSTR2 tissues validated by immunohistochemistry (IHC). As proof-of-principle fluorescence guided tumor resection was performed in an ectopic and orthotopic meningioma IOMM-Lee mouse model. Results The SSTR2-sNIR probe is stable in aqueous solution up to 12h with favorable optical properties regarding kinetics, biodistribution and photostability compared to its IRDye800 analogue. In vivo, we observed a highly specific physiological signal uptake in the gastric epithelium, the pancreas and pituitary (they are highly expressing SSTR2 on IHC) compared to autofluorescence and negative controls (unlabeled dye and scrambled version). Given the moderate SSTR2 expression in the preclinical meningioma model we could still detect a mean tumor-to-brain ratio of 6.12 (n = 5; SD 1.8) in the orthotopic meningioma mouse model, allowing the fluorescence guidance to be feasible. Conclusion Our preclinical results demonstrate that the innovative SSTR2-targeted fluorescent probe is stable in various biological media over time and capable of specifically targeting the SSTR2 in vitro and in vivo potentially enabling sensitive and specific meningioma fluorescent guided surgery in the future.

Manually scanned single fiber optical coherence tomography for skin cancer characterization

Optical coherence tomography (OCT) is a cross-sectional imaging modality based on low coherence light interferometry. Within dermatology, it has found applications for in vivo diagnostic imaging purposes, as well as to guide Mohs micrographic surgery (MMS), due to its ability to visualize skin morphology up to several millimeters in depth. However, standard OCT probes have a large footprint and capture an extended area of the skin, making it difficult to precisely pinpoint clinically relevant location being imaged. Mohs surgeons stand to benefit from a handheld in vivo imaging device that can accurately trace surgical margins. In this study, we demonstrate the use of a single fiber OCT (sfOCT) instrument. Our imaging system features a miniature common path single fiber probe, and a novel speckle decorrelation technique that generates distortion free 2D images from manual scanning.By manually moving the single-fiber probe across the region of interest, the user can perform a lateral OCT scan while visualizing the location of the probe during data acquisition. Using the sfOCT, we have identified normal skin morphology, qualitatively correlated features of basal cell carcinoma and squamous cell carcinoma with histopathology, and quantified the disruption of the dermo-epidermal junction OCT pattern in skin tumors—each demonstrating the potential of utilizing sfOCT to differentiate tumor from normal skin. Using this imaging tool, a Mohs surgeon can enhance determination of surgical margins for the first stage of MMS, potentially decreasing the time and number of stages required for complete tumor removal.

Proposal of a new CT arthrographic classification system of osteochondral lesions of the talus

BackgroundSurgical treatment of osteochondral lesions of the talus (OLT) is warranted if medical treatments fail, achieving good results in around 85% of cases. Numerous classification systems, based on all possible imaging modalities (radiography, MRI, CT scan, scintigraphy, and CT arthrography), have been proposed to guide surgical treatments, but none has proven to be superior. A recent study demonstrated the prognostic value of CT arthrography by accurately describing the subchondral bone plate. A systematic review of the literature has brought new criteria to predict good outcome following bone marrow stimulation surgical techniques: lesions should measure less than 1 centimeter in size and 5 millimeters in depth. Based on these data, we are proposing a new simple, 3-stage CT arthrographic classification system of OLT. Materials and methodsAfter a brief overview of the classification, 60 CT-arthrographies of ankles with OLT were organized according to this new CT arthrographic classification system by four surgeons (two juniors and two seniors). Two imaging assessments were performed one month apart. Statistical analysis was performed using the Fleiss’ kappa coefficient to determine the inter- and intraobserver agreement. ResultsAn excellent inter- and intraobserver agreement was found with overall Fleiss’ kappa coefficients of 0.897 and 0.847, respectively. ConclusionThe results of our study showed an excellent inter- and intraobserver agreement for this new CT arthrographic classification system of OLT. The principal advantage of this new classification system, based on the latest data in the literature, is its ability to easily distinguish lesions that are more amenable to bone marrow stimulation techniques. Level of evidenceII.

Molecular Probes for Evaluation of Oxidative Stress by In Vivo EPR Spectroscopy and Imaging: State-of-the-Art and Limitations

Oxidative stress, defined as a misbalance between the production of reactive oxygen species and the antioxidant defenses of the cell, appears as a critical factor either in the onset or in the etiology of many pathological conditions. Several methods of detection exist. However, they usually rely on ex vivo evaluation or reports on the status of living tissues only up to a few millimeters in depth, while a whole-body, real-time, non-invasive monitoring technique is required for early diagnosis or as an aid to therapy (to monitor the action of a drug). Methods based on electron paramagnetic resonance (EPR), in association with molecular probes based on aminoxyl radicals (nitroxides) or hydroxylamines especially, have emerged as very promising to meet these standards. The principles involve monitoring the rate of decrease or increase of the EPR signal in vivo after injection of the nitroxide or the hydroxylamine probe, respectively, in a pathological versus a control situation. There have been many successful applications in various rodent models. However, current limitations lie in both the field of the technical development of the spectrometers and the molecular probes. The scope of this review will mainly focus on the latter.

PREDICTION AND INVESTIGATION OF SURFACE ROUGHNESS WHILE TURNING SG IRON WITH CUBIC BORON NITRIDE (CBN) AND TUNGSTEN CARBIDE INSERTS

This work compares the effect of cubic boron nitride (CBN) and multilayer (TiCN+Al2O3+TiN) coated tungsten carbide (WC) tools during the turning of spheroidal graphite (SG) nodular iron. Nodular irons have more ductility which is required in mechanical components that demand high fatigue resistance like crankshafts, cam shafts, bearing caps and clutch housings. The impact of various process parameters like the depth of cut, cutting speed and feed on the surface roughness (Ra) of SG iron is studied and optimized using the response surface model. The chip morphology is also discussed for evaluation of the quality of the turned surface. The experimental outcomes reveal that the WC tool offers a high surface finish at the optimal combination of the cutting speed at 102 meter/minute, feed at 0.051 millimeter/revolution and depth of cut at 0.5 millimeter and that, for the CBN insert, at 245 meter/minute of cutting speed, 0.051 millimeter/revolution of feed and 0.75 millimeter of depth of cut.

Can chondral healing be improved following microfracture? The effect of adipocyte tissue derived stem cell therapy

BackgroundWe aimed to investigate the effect of adipose tissue-derived mesenchymal stem cells (ADSCs) on chondral healing using the microfracture (MF) technique. MethodsThirty male rabbits were randomly divided into three groups. Standard cylindrical osteochondral defects (OCDs) were created in the weight-bearing areas of the medial condyles of all the right knees; the defects were four millimeters in diameter and two millimeters in depth. The control group (group A) was restricted to spontaneous healing. For group B, we performed MF with a 1.5-mm drill. For group C, we applied MF using the same method and then applied 3×106 ADSCs to the defect area. At eight weeks post-operation, the subjects were sacrificed, and the distal femoral joint surfaces were evaluated histopathologically for chondral healing. The samples were scored according to the International Cartilage Repair Society (ICRS) scale. ResultsThe results for group C were significantly better than those for group A in terms of the surface properties (p=0.003). The matrix evaluation was better for group A than for group C (p=0.01). The cell distribution, cell viability and subchondral bone parameters were similar between the groups (p=0.198, p=0.387 and p=0.699). The cartilage mineralization parameter was better for group C than for group A (p=0.001). The signs of healing were better for group C than for group B, but the differences were not significant (p=0.185). ConclusionsImprovements with additional ADSC treatments were not statistically significant in cases in which ADSC treatment was compared with isolated MF treatment. Clinical RelevanceAdditional ADSCs treatment may have positive effect on chondral healing but it doesn’t seem significant.

Effect of temperature regime and compression in OCT imaging of skin in vivo

Abstract: Optical coherence tomography (OCT) is a modern technique for imaging of internal structures of biotissue of up to several millimeters in depth with a resolution of several micrometers. However, various external conditions can distort the diagnostic capabilities of an OCT image. Mechanical compression and temperature regime are the two conditions which mostly affect the diagnostic OCT images obtained with a contact probe. It is shown here that the application of compression to human skin induces a decrease in contrast of the stratum corneum-epidermis junction and an increase in contrast of the epidermis-dermis junction. With regard to these junctions, a preliminary change of biotissue temperature induces additional changes in the contrast, with opposing effects in case of heating and cooling.

Non-invasive parenchymal, vascular and metabolic high-frequency ultrasound and photoacoustic rat deep brain imaging.

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central nervous system of small animals. However, transdermal and transcranial neuroimaging is frequently affected by low sensitivity, image aberrations and loss of space resolution, requiring scalp or even skull removal before imaging. To overcome this challenge, a new protocol is presented to gain significant insights in brain hemodynamics by photoacoustic and high-frequency ultrasounds imaging with the animal skin and skull intact. The procedure relies on the passage of ultrasound (US) waves and laser directly through the fissures that are naturally present on the animal cranium. By juxtaposing the imaging transducer device exactly in correspondence to these selected areas where the skull has a reduced thickness or is totally absent, one can acquire high quality deep images and explore internal brain regions that are usually difficult to anatomically or functionally describe without an invasive approach. By applying this experimental procedure, significant data can be collected in both sonic and optoacoustic modalities, enabling to image the parenchymal and the vascular anatomy far below the head surface. Deep brain features such as parenchymal convolutions and fissures separating the lobes were clearly visible. Moreover, the configuration of large and small blood vessels was imaged at several millimeters of depth, and precise information were collected about blood fluxes, vascular stream velocities and the hemoglobin chemical state. This repertoire of data could be crucial in several research contests, ranging from brain vascular disease studies to experimental techniques involving the systemic administration of exogenous chemicals or other objects endowed with imaging contrast enhancement properties. In conclusion, thanks to the presented protocol, the US and PA techniques become an attractive noninvasive performance-competitive means for cortical and internal brain imaging, retaining a significant potential in many neurologic fields.

Non-invasive Parenchymal, Vascular and Metabolic High-frequency Ultrasound and Photoacoustic Rat Deep Brain Imaging

Photoacoustics and high frequency ultrasound stands out as powerful tools for neurobiological applications enabling high-resolution imaging on the central nervous system of small animals. However, transdermal and transcranial neuroimaging is frequently affected by low sensitivity, image aberrations and loss of space resolution, requiring scalp or even skull removal before imaging. To overcome this challenge, a new protocol is presented to gain significant insights in brain hemodynamics by photoacoustic and high-frequency ultrasounds imaging with the animal skin and skull intact. The procedure relies on the passage of ultrasound (US) waves and laser directly through the fissures that are naturally present on the animal cranium. By juxtaposing the imaging transducer device exactly in correspondence to these selected areas where the skull has a reduced thickness or is totally absent, one can acquire high quality deep images and explore internal brain regions that are usually difficult to anatomically or functionally describe without an invasive approach. By applying this experimental procedure, significant data can be collected in both sonic and optoacoustic modalities, enabling to image the parenchymal and the vascular anatomy far below the head surface. Deep brain features such as parenchymal convolutions and fissures separating the lobes were clearly visible. Moreover, the configuration of large and small blood vessels was imaged at several millimeters of depth, and precise information were collected about blood fluxes, vascular stream velocities and the hemoglobin chemical state. This repertoire of data could be crucial in several research contests, ranging from brain vascular disease studies to experimental techniques involving the systemic administration of exogenous chemicals or other objects endowed with imaging contrast enhancement properties. In conclusion, thanks to the presented protocol, the US and PA techniques become an attractive noninvasive performance-competitive means for cortical and internal brain imaging, retaining a significant potential in many neurologic fields.

Total skin electron beam therapy using an inclinable couch on motorized table and a compensating filter.

Total skin electron beam is a specialized technique that involves irradiating the entire skin from the skin surface to only a few millimetres in depth. In the Stanford technique, the patient is in a standing position and six different directional positions are used during treatment. Our technique uses large electron beams in six directions with an inclinable couch on motorized table and a compensating filter was also used to spread the electron beam and move its intensity peak. Dose uniformity measurements were performed using Gafchromic films which indicated that the surface dose was 2.04 ± 0.05 Gy. This technique can ensure the dose reproducibility because the patient is fixed in place using an inclinable couch on a motorized table.

High-resolution optoacoustic mesoscopy with a 24 MHz multidetector translate-rotate scanner

Optoacoustic (photoacoustic) mesoscopy aims at high-resolution optical imaging of anatomical, functional, and cellular parameters at depths that go well beyond those of optical-resolution optical or optoacoustic microscopy i.e., reaching several millimeters in depth. The approach utilizes tomography to achieve ultrasonic-diffraction resolution and operates at high-ultrasound frequencies (20 to 200 MHz) induced by few-nanosecond laser pulse excitation of tissues. We investigated here the performance of optoacoustic mesoscopy implemented at 24 MHz center frequency and its ability to resolve optical absorption contrast in the mouse kidney ex vivo. The developed system achieved better than 30 μm in-plane resolution and 110 μm elevation resolution over a cylindrical volume of 9-mm diameter and 9-mm height. This unprecedented combination of resolution and depth was achieved by implementing a translate-rotate detection geometry and by tomographic reconstruction. The approach yielded images of optically absorbing structures with a level of detail never-before visualized in an intact mouse kidney and allows insights into their unperturbed architecture. We discuss the ability to offer multispectral acquisitions and enable in vivo imaging.

Groove Marks in the Lower Pecos Canyonlands

Groove marks are an extremely enigmatic style of rock art. Incised groove marks are deep narrowly incised lines, usually in the shape of a "V" or "W" that rarely are more than six millimeters in depth and two to three millimeters wide. Several functional hypotheses have been introduced to explain the purpose of this rock art style. In 2010, the author designed an experimental study designed to test one long held hypothesis that suggests groove marks in limestone were formed by sharpening bone implements. The experiment conducted in the ethnoarchaeology lab at the University of Nevada, Las Vegas demonstrated that groove marks most likely were not used as a way to sharpen bone awls in limestone. Instead, the experiment suggests that archaeological groove marks in the Lower Pecos Canyonlands were created with chert flakes.

Identification of a New Source of Contamination of Quercus sp. Oak Wood by 2,4,6-Trichloroanisole and Its Impact on the Contamination of Barrel-Aged Wines

Thanks to practical experience in various wineries in recent years, it is now clear that, similarly to the well-known phenomenon in corks, there are several sources of unpredictable contamination of oak wood by 2,4,6-trichloroanisole (TCA). TCA affects staves in the same barrel very sporadically, with extremely limited contaminated areas on the surface that may reach several millimeters in depth. The precise origin of the TCP and TCA in oak wood is not known at this stage. Available data indicate that the phase where stavewood is naturally dried and seasoned is the source of these undesirable organochlorine contaminants. The strictly chemical formation of 2,4,6-trichlorophenol (TCP), derived from organochlorine biocides, was demonstrated to be impossible under traditional cooperage conditions, and its accumulation remained highly improbable. Similarly to previous discoveries in corks, all the analyses of oak wood suggested that the TCP was of biochemical origin. The capacity to biomethylate chlorophenols is well-known and relatively widespread among the usual microflora in stavewood, but the precise origin of the intermediary leading to TCP formation is still unknown. One probable hypothesis is that this reaction involves chloroperoxidase (CPO). Several ideas have been proposed, but the microorganisms responsible for the formation of the TCA precursor in oak wood have not yet been identified. The extent of this problem is still severely underestimated by coopers and barrel-users, due to the extremely unpredictable, localized contamination of the staves.

Temperature Field Simulation for Aluminum Alloy Surface Modification by Scanning Electron Beam

According to the actual experimental condition and theoretical analysis, a finite element model was established to describe the surface modification process of scanning electron beam of 6A02 aluminum alloy. The phase change process and thermal radiation were considered in the simulation. The temperature simulation revealed the ultrahigh rate of the heating and cooling, rapid melting and re-solidification within seconds in the range of millimeters in depth. The calculated melting zone was an irregular semicircle, the x-axis length was about 2.9mm, and the axial depth was about 1.4mm. This research will predict the melting condition.

Prediction of hardness–depth profile from indentations at surface of materials

Surface treatments are used to increase the resistance of the surface of mechanical parts. Unlike thin films, surface hardened materials may cover several tenths of millimetres in depth. The effectiveness of such treatments is studied by analysing the hardness–depth profile. In this paper, the authors describe a method to evaluate the hardness profile with depth based on the estimation of the contribution of deeper zones of the hardened material to the hardness of the surface through the practice of a series of indentations on the surface with increasing loads. This model allows estimating the hardness of virtual layers through a step by step calculation process at increasing depths under the surface of the material. The model was satisfactorily tested on stainless steel previously surface treated through ion nitriding with a duplex process consisting in ion nitriding followed by the irradiation with high energy short duration plasma beams of argon.

‘Two is better than one’—probes for dual-modality molecular imaging

Molecular or personalised medicine is the future of patient management and healthcare, and molecular imaging plays a key role towards this goal. However, amongst molecular imaging techniques, no single modality is perfect and sufficient to gain all the necessary information. For instance, optical fluorescence imaging is difficult to quantify--especially in tissue more than a few millimetres in depth within a subject; magnetic resonance imaging (MRI) has superb resolution but low sensitivity and positron emission tomography (PET) has very high sensitivity but poor resolution. The combination of multiple molecular imaging techniques can therefore offer synergistic advantages over any modality alone. However, the problem cannot be solved by simply adding two different classes of imaging probes together, unless they happen to have identical pharmacodynamic properties. Therefore, multi-modal contrast agents or imaging probes have been developed to solve this problem. Despite the great wealth of information that such probes can provide, their development is far from trivial and represents an important challenge to synthetic chemists. In this feature article, we provide an overview of recent findings in the synthesis, evaluation and application of dual-modality molecular imaging probes.

Electron scattering filter design for a single field rotational total skin irradiation

The aim of radiotherapy treatment of cutaneous T-cell lymphoma is to irradiate the skin with an appropriately homogeneous dose distribution up to a few millimetres in depth. This can be achieved by applying one of the total skin electron irradiation techniques. An aluminium/polystyrene foam electron scattering filter was designed so that the incident beam is broadened and degraded sufficiently to achieve a mean dose uniformity in a rectangular field of 180 cm height and 40 cm width. This paper reports on the development and construction of the electron scattering filter for use with a Varian 2100C accelerator, without MLCs, with a dose uniformity, over a useful field dimension of 180 cm height and 40 cm width, of +/- 7% about the mean, and an x-ray contamination of less than 2.4% beyond a depth of 3 cm.

Micromachining using ultrasonic impact grinding

Although largely unknown in the MEMS community, micromachining using ultrasonic impact grinding (UIG) is a fascinating yet easy fabrication scheme to achieve virtually any shape, such as a shallow or deep reservoir, a channel, a via, etc, in silicon, glass and other commonly used ceramic and semiconductor materials in the MEMS field. Because of the patterning and masking issues, etching even shallow channels or vias in a pre-processed silicon/glass/ceramic substrate is somewhat difficult, if not impossible. However, by using UIG one can achieve such structures, up to millimeters in depth in virtually no time. Furthermore, in silicon substrates, the orientation or any other physical dimension of the feature will no longer be constrained as in anisotropic etching by the crystallographic planes and directions; and in amorphous glass or ceramic substrates, features with vertical walls can be achieved, otherwise usually accomplished only by expensive laser ablation. Thus, the authors believe that this UIG process could open up many avenues to easily and quickly achieve the larger MEMS structures as well as packaging for both prototype and for production in silicon, glass and ceramic.