Patent Application
20110137178
The present disclosure relates to exemplary embodiments of apparatus and methods for imaging particular cells, including but not limited to eosinophils, and more particularly to such exemplary apparatus and methods which can use, e.g., confocal microscopy to image particular cells including eosinophils.
Eosinophilic esophagitis (EoE) is a disease that afflicts both children and adults, thought to be caused by food allergy, and characterized by the presence of eosinophils within the esophageal squamous epithelium. EoE is now known to be common and rapidly increasing in incidence. EoE patients can experience symptoms ranging from nausea and vomiting to dysphagia and food impaction. It is generally thought that if left untreated, the eosinophilic inflammation may lead to significant and permanent damage, including fibrosis of the lamina propria, strictures, and perforations. As a result, EoE patients are currently treated until both symptoms and esophageal eosinophils abate.
While corticosteroids are effective for EoE, the disease usually returns when the drug is discontinued. The other therapy for EoE is aggressive dietary restriction. Once on a restricted diet, foods are gradually reintroduced until the diet becomes acceptable or symptoms and/or esophageal eosinophils recur. Since the only objective method for diagnosing EoE is histopathologic assessment of multiple upper endoscopic biopsies, monitoring the esophagus during therapy and the food reintroduction process involves a high number of repeat endoscopies. This process is time consuming and frustrating for patients and their families. Because endoscopic biopsy requires conscious sedation, it can also be costly, placing a substantial financial burden on our health care system. Given the rapid increase in the number of patients with this disease, there is a compelling need for a less invasive and more cost effective ways for identifying eosinophils in the esophagus.
Confocal microscopy has been developed for imaging at the cellular level in tissue. Recently, it has been determined that reflectance confocal microscopy (RCM) is capable of imaging eosinophils within the esophagus. One exemplary embodiment of RCM is termed spectrally encoded confocal microscopy (SECM), which has the advantages that it can be miniaturized and incorporated into a small-diameter, flexible probe and can obtain images at very high speeds (e.g., 10-100× faster than video rate), a feature that enables microscopic screening of entire luminal organs in realistic procedural times.
One objective of this invention is to provide an accurate and inexpensive diagnostic tool for EoE. It is possible to accomplish this goal utilizing RCM and SECM technology so that it can be incorporated into a small, flexible transnasal or transoral probe capable of automatically scanning the esophagus to identify eosinophils. This device can be utilized in the outpatient setting without requiring sedation, endoscopy, or biopsies, thereby decreasing the inconvenience and cost of monitoring eosinophil counts in patients undergoing therapy for EoE.
Eosinophilic esophagitis (EoE or EE) is an inflammatory disease of the esophagus that is primarily caused by food allergy. Approximately 50-70% of patients with EoE have another concomitant atopic disease. EoE affects both children and adults, is more common in Caucasians (>90%) and in males (2-4:1 ratio). The distinguishing feature of EoE is eosinophil infiltration within the esophageal squamous epithelium that does not resolve following acid reduction therapy and is not present elsewhere throughout the GI tract. Patients with EoE can experience a variety of unpleasant symptoms such as chest pain, nausea, vomiting, dysphagia, food impaction, and failure to thrive. While the natural history of this disease is not fully understood; experts fear that longstanding eosinophilic inflammation may give rise to permanent esophageal damage, leading to fibrosis of the lamina propria, esophageal narrowing, stricture, and perforation.
The significance of EoE was underappreciated for twenty years. Over the past decade, however, pioneering work by a number of investigators has brought the importance of this disease to light. During this period, the number of patients found to have EoE has risen dramatically. Emerging data suggests that the prevalence of EoE may approach 0.01-0.1% of the general population, possibly higher than that of other inflammatory bowel diseases such as Crohn's. The incidence of EoE is also rapidly increasing, mirroring the increase in atopic disease incidence found in Western countries over the same time period. Recognition of EoE is now much greater than before; this, combined with its high prevalence and incidence has pediatric and adult gastroenterologists struggling to cope with an influx of patients presenting with this disease.
Recently, diagnosis of EoE can require an upper endoscopy with biopsy. At upper endoscopy, EoE patients can have findings of diminished vascularity, longitudinal furrowing, friability, microabscesses (white specks), exudates, esophageal rings (trachealization of the esophagus), narrow-caliber esophagus, strictures, and food impaction. The accuracy of endoscopy alone for EoE is modest, however, as these findings may be seen in other diseases and the esophagus may be endoscopically normal in up to 30% of cases. The only objective method for EoE diagnosis is endoscopic biopsy. The current standard of care is pinch biopsies obtained at the distal (˜5 cm from the gastroesophageal junction (GEJ)) and proximal (˜15 cm from the GEJ) portions of the esophagus. Biopsies are taken from sites with abnormal endoscopic findings and also from locations that do not show visual evidence of disease. The number of biopsies that are obtained is also important as a recent study showed that the histopathologic diagnosis of EoE was only correctly rendered in 55% of patients with one biopsy, but increased to 100% after 5 biopsies.1 Finding greater than 15 eosinophils per high power field (HPF=400×) in any one of the biopsy specimens renders a diagnosis of EoE. Other histopathologic findings, such as eosinophil degranulation, microabscesses, superficial layering of the eosinophils, basal layer hyperplasia, and increased numbers of mast cells and other leukocytes are also seen in EoE, but are currently not required for diagnosis.
Primary EoE diagnosis can require pathologic findings of elevated esophageal eosinophils in the absence of acid reflux and without the involvement of other segments of the GI tract. As a result, at the time of first diagnosis, biopsies are also acquired from the stomach and duodenum.3 In addition, for primary diagnosis, the biopsies are usually repeated following one month of proton pump inhibitors (PPI) to rule out GERD etiology. Follow up diagnosis by endoscopic biopsy is much more common and utilized to manage multiple therapy decisions and regimens throughout the course of the disease.
Both pharmacologic and dietary therapy can relieve symptoms and return the esophagus to histologic normalcy. The only established pharmacologic therapy is corticosteroids. Systemic steroids are recommended for urgent relief of acute symptoms and oral or swallowed topical routes of administration for maintenance. The primary complication of oral and topical corticosteroids is esophageal candidiasis, which has been observed in up to 20% of patients. The main limitation of corticosteroids is that EoE universally recurs when they are withdrawn, and as a result, if corticosteroids are the only line of therapy, they must be continued throughout the duration of the disease. Follow up endoscopic intervals with biopsy to determine when the steroid dosages must be adjusted or discontinued are currently under debate.4 The long term effects of corticosteroids for maintenance of remission in EoE patients are also not well understood.4 Other newer agents, such as anti-IL-5 and IL-13, which are antibodies to cytokines that regulate eosinophil chemotaxis, are currently under investigation.
Another effective therapy option for EoE patients is strict dietary elimination to remove the offending antigen. The most effective diet is the elemental diet, which provides nutrients as small molecular weight compounds, including proteins as amino acids or peptides, carbohydrates as oligosaccharides or monosaccharides, and fats as medium-chain triglycerides. In pediatric studies, administration of an elemental diet has been shown to resolve EoE in up to 98% of cases. However, the elemental diet is very restrictive, poorly tolerated, and may have to be administered by a feeding tube. As a result, less stringent elimination diets have been proposed, such as the six-food elimination diet (milk, egg, soy, wheat, shellfish, and nuts), which in one study effectively treated EoE in approximately 75% of patients. Methods for finding the culprit dietary antigen, such as skin prick and allergy patch testing (APT) have been proposed, but are not yet accurate enough to be recommended for managing the diets of EoE patients. Dietary elimination is very difficult for patients to tolerate and as a result, foods are gradually reintroduced into the diet until symptoms and/or esophageal eosinophils recur.
Because of the impact of EoE on quality of life and the concern that this disease may progress to esophageal fibrosis with unknown long-term risks, experts recommend that EoE be treated until symptoms and the eosinophilic infiltrate are resolved. Management of these patients requires many repeat endoscopic biopsies during the food reintroduction and/or corticosteroid dosing process to assess esophageal eosinophils. This process is inconvenient and taxing to patients and their families. It is also associated with a small but real risk of complications associated with endoscopy. In addition, at an average of currently about $1000 per procedure, endoscopic biopsy for EoE monitoring can be a significant expense to our health care system. These considerations have led to a preference to determine less invasive and more cost effective ways to obtain esophageal eosinophil counts.
Sedation, via IV administration of sedatives and narcotic analgesics, is the single most important contributor to the high cost of upper endoscopy and is estimated to account for 30-50% of the total procedural cost. Because of the mortality and morbidity associated with complications related to sedation, patients must undergo continuous cardiopulmonary monitoring and nursing support during the endoscopic procedure. Post-procedural recovery also contributes to the expense, as it requires additional nursing, monitoring, and patient care in a large and specialized physical space. After discharge, patients frequently need to be escorted home, and adults lose at least a day's work. Finally patient tolerance for sedated procedures is lower than for unsedated procedures. In addition to the expense of sedation, other modifiable costs of upper endoscopy include physician time and biopsy processing; assessing esophageal eosinophils would undoubtedly be less expensive if a nurse or technician could conduct the procedure. Biopsies can add to the cost at about $150 per specimen. Taking these factors into account, up to half of the total cost of upper endoscopy can be a result of sedation.
Blood biomarkers that may be surrogates for esophageal eosinophils are actively being investigated to overcome the high cost and inconvenience limitations of endoscopic biopsy. Research into the pathophysiology of this disease has indicated that EoE results from a TH2 inflammatory process, mediated by IL-5 and IL-13 and dependent on Eotaxin-3. In addition to these cytokines, peripheral blood eosinophils, serum IgE, CD23, and Eosinophil Derived Neurotoxin have also been proposed as potential biomarker surrogates for biopsy eosinophil levels. While some correlations between these biomarkers and EoE have been found, research in this area is early and important parameters such as the cost of these tests, robust cutoff values, and effects of age, symptoms, and gender have yet to be determined. It may be preferable to determine whether the specificity of these biomarkers for esophageal eosinophils, especially in patients who are likely to have other coexistent atopic diseases, is sufficient for guiding therapy decisions.
Unsedated transnasal procedures.
For example, transnasal and transoral access to the esophagus can be attained in the outpatient setting without sedation for both adult and pediatric patient populations. When passing a catheter in the unsedated patient, transnasal access is generally better tolerated than the transoral approach because of a more vigorous gag reflex encountered in transoral procedures. Standard transnasal procedures, such as nasogastric tube (NG tube) insertion, are conducted in millions of patients annually with few if any major complications. With NG tube insertion, a flexible, 10-18F (3-6 mm) diameter tube is first measured from the nares to the xiphoid process. It is then lubricated with a anesthetic gel and inserted into one of the patient's nares that has been previously anesthetized with a topical lidocaine spray. The tube is aimed down and back and advanced; as the tube passes the posterior pharynx, the patient is asked to swallow or sip water through a straw to suppress the gag reflex. When the tube passes the pharynx, it is easily advanced through the esophagus to the stomach. Confirmation that the tube is in the stomach can be accomplished by injecting air through the tube and auscultating with a stethoscope or by measuring the pH of aspirated fluid. The tube can then be retracted into the esophagus. Following the procedure, patients can usually resume regular activity immediately.
Reflectance confocal microscopy (RCM), can be suited for imaging esophageal eosinophils in EoE patients, as it is a non-invasive optical imaging method that enables the visualization of cellular structures at approximately 1 μm resolution, and does not require the administration of exogenous contrast agents. RCM rejects or ignores multiply scattered light from tissue and detects the singly backscattered photons that contain structural information by employing confocal selection of light reflected from a tightly focused beam. Most commonly, RCM is implemented by rapidly scanning a focused beam in a plane parallel to the tissue surface, resulting in transverse or en face images of tissue. The large numerical aperture (NA>0.3) of the objective lens used in RCM yields a very high spatial resolution. The imaging depth of penetration of RCM (several hundred micrometers) is well suited to the detection of EoE, which typically manifests near the luminal surface.
All internal organ confocal microscopy imaging modalities proposed to date provide microscopic images under endoscopic guidance and only at discrete locations—the so-called “point sampling” method. Point sampling can be inherent to RCM since it has an extremely limited field of view (in the range of about 200-500 μm), which is less than that of a pinch biopsy used for EoE diagnosis. With the transnasal approach proposed here, the diagnostic probe can be inserted without endoscopic guidance and the data acquired automatically. As a result, relatively large areas of the esophagus should be imaged in order to be certain that this “unguided” method captures information from areas that contain elevated eosinophils and that are representative of the overall disease state.
This mode of operation may need a paradigm shift, which can be termed “Comprehensive Volumetric Microscopy (CVM),” or the capability to obtain microscopic images of the epithelium of large mucosal areas in three-dimensions. Others in the field are now recognizing the value of this concept; interesting mosaicing approaches have been devised to stitch multiple confocal images together, covering a few mm2, but this technology is still far from the comprehensive imaging that is required to scan a sufficient (10+ cm) length of the esophagus for eosinophils.
For CVM, imaging speeds should be increased by at least an order of magnitude above video rate, due to the tremendous bandwidth of the microscopic information and the constraint of obtaining this data in a realistic procedural time (<10 min). In addition, a RCM probe must be developed to automatically scan the microscope over these large tissue surface areas rapidly and with a high degree of precision. Recently, CVM can be implemented using a second-generation form of OCT, called optical frequency domain imaging (OFDI), and rapid helically scanning catheters. This research has enabled the acquisition of three-dimensional microscopic images of the entire distal esophagus (6.0 cm length) in a few minutes and long (˜10 cm) segments of coronary arteries in patients in less than 5 seconds. While OFDI systems and method shows can be very helpful for various clinical applications, the use of approximately 10 μm resolution by such exemplary systems and methods may not be sufficient for identifying individual cells.
Exemplary embodiments of RCM apparatus and methods of esophageal eosinophils has not been previously described. Thus, according to the exemplary embodiments of the present disclosure, as shown in
While RCM apparatus and methods has been described as it is applied in the skin, small confocal microscopy probes for internal organ imaging were not developed to technical challenges associated with miniaturizing a scanning microscope. One difficulty can be the development of a mechanism for rapidly raster-scanning the focused beam at the distal end of a small-diameter, flexible probe. A variety of approaches have been attempted to address this problem, including the use of distal micro electro mechanical systems (MEMS) beam scanning devices, and proximal scanning of single-mode fiber bundles. Another challenge can be the miniaturization of high NA objectives used for optical sectioning.
This exemplary need has led to a development of an exemplary embodiment of an apparatus and a method of RCM according to the present disclosure, which can be termed spectrally encoded confocal microscopy (SECM) that can be configured to rapidly obtain higher-resolution CVM images via, e.g., a small-diameter probe.
According to one exemplary embodiment of the present disclosure, exemplary RCM techniques, methods and apparatus according to the present disclosure can be configured to identify esophageal eosinophils.
One of the objects of exemplary embodiments of the present disclosure is to determine the presence or absence of esophageal eosinophils in human patients. Another object of the present disclosure is to count, in a manual, semi-automatic, or computer processing manner, the number of eosinophils in human patients. A further object of the present disclosure is to obtain cross-sectional images of tissue at the cellular level to enable the counting of eosinophils. Another object of the exemplary embodiments of the present disclosure present disclosure is to identify other cells, such as leukocytes, including mast cells, lymphocytes, basophils, and neutrophils, that may also be elevated in EoE. A further object of the exemplary embodiments of the present disclosure present disclosure is to provide a device for evaluating other histologic features of EoE in vivo, including basal layer hyperplasia, abscess, eosinophil degranulation, and lamina propria fibrosis.
Still another object of the present disclosure is to provide an exemplary embodiment of an RCM or SECM apparatus and transnasal probe for imaging esophageal eosinophils.
For example, a transnasal or transoral RCM probe can be designed and fabricated based on the nasogastric (NG) tube, e.g., a predicate device. A pressure sensor can be utilized to facilitate placement of the RCM probe's optics near the gastroesophageal junction. The probe's optics can scan from the distal to proximal esophagus, creating a three-dimensional RCM image that covers a surface area of a surface area of the esophagus that may range from 0-1000 mm2. In addition, a faster and higher resolution RCM system can be provided to facilitate the scan to be completed in a few minutes.
Thus, in accordance with the exemplary embodiments of the present disclosure, it is possible to provide devices and methods which can measure esophageal eosinophils directly, and without the cost and complexities of endoscopic biopsy. The exemplary embodiments can use reflectance confocal microscopy techniques, e.g., implemented through a flexible, small-diameter (approximately 3 mm) transnasal probe. The exemplary device can be configured or structured to be deployed without sedation in the outpatient setting and operated by a technician. Once inserted, images from the entire length of the esophagus can be automatically obtained and analyzed by a computer to provide eosinophil counts. The exemplary embodiments of the present disclosure can provide a cost-effective and less invasive tissue image-based biomarker for EoE that can be used to follow these patients during their therapeutic course. Additionally, the exemplary device can be utilized to study this disease to answer questions about the pathophysiology and natural history of EoE.
The exemplary embodiments of the present disclosure can be utilized, e.g., in research and clinical applications for other diseases associated with elevated tissue eosinophils. For instance, certain subtypes of asthma are characterized by the presence of airway eosinophilia and the technology developed here may provide a new means for personalizing and monitoring the response to asthma therapy. Improving understanding, diagnosis, and therapeutic monitoring of other eosinophilic diseases such as eosinophilic gastritis, gastroenteritis, and colitis, as well as hypereosinophilic syndromes, would also be facilitated by the exemplary embodiments of the present disclosure for visualizing these cells in vivo.
Figure According to further exemplary embodiments of the present disclosure, the transnasal SECM systems, apparatus and methods cancan facilitate a clinical use thereof, and detect esophageal eosinophils over large surface areas. This exemplary capability can greatly improve the management of EoE patients, in accordance with current guidelines. Given the relative newness of this disease entity, however, today's guidelines are primarily based on Class 3 evidence such as case reports and individual clinical experiences. Because of the ability of the exemplary SECM systems, apparatus and methods can according to the present disclosure to longitudinally monitor esophageal eosinophils in a minimally invasive manner, they can be used to determine the role of eosinophils in precipitating symptoms and long-term complications.
Thus, an exemplary embodiment of apparatus and method according to the present disclosure can be provided. For example, using at least one first arrangement, it is possible to direct at least one first electro-magnetic radiation to at least one portion of tissue within a body. Using at least one second arrangement, it is possible to receive at least one second electro-magnetic radiation provided from the portion, which is based on the first electro-magnetic radiation. Further, using at least one third arrangement, it is possible to differentiate at least one particular cell which is eosinophil, mast cell, basophil, monocyte and/or nutrophil from other cells in the portion based on the second electro-magnetic radiation.
According to one exemplary embodiment of the present disclosure, the second electro-magnetic radiation can be reflected from the portion(s). The third arrangement can be configured to image the particular cell(s). The third arrangement can be configured to image the particular cell(s) over a region of the tissue that greater than an are of 1 mm2. The third arrangement can also be configured to image the particular cell(s) in three-dimensions, and/or to image a cross-section of the particular cell(s). The tissue can be a luminal organ, and the luminal organ can be an esophagus and/or a pulmonary airway.
According to another exemplary embodiment of the present disclosure, the first arrangement and/or the second arrangement can be provided in a catheter. The catheter can be structured and/or sized to be inserted to reach the tissue transorally or transnasally, and/or can have a cross-sectional diameter of less than 5 mm. The catheter can include a balloon arrangement, and the balloon arrangement can contain an auto-focusing arrangement which is configured to auto-focus on the portion. The catheter can be facilitated in a nasogastric tube, and/or can include a wound cable. In addition or as an alternative, the catheter can include a further arrangement which is configured to measure pressure of the tissue within a body. The catheter can have a portion to be inserted into the body which is substantially flexible.
In yet another exemplary embodiment of the present disclosure, the particular cell(s) can include a plurality of particular cells, and the arrangement can be further configured to determine a number of the particular cells, and/or automatically count the number of the particular cells. Further, the second arrangement can be configured to receive a confocal light and/or a spectrally encoded confocal light. In addition, the second arrangement can be configured to receive and detect a florescent electro-magnetic radiation.
According to a further exemplary embodiment of the present disclosure, the first arrangement and/or the second arrangements can include a further arrangement which is configured to spectrally disperse the first electro-magnetic radiation and/or the second electro-magnetic radiation, respectively. The first arrangement and/or the arrangement can contain at least one optical fiber arrangement which has multiple wave-guiding regions. The optical fiber arrangement can include a double-clad fiber core. Further, the first arrangement can be configured to transmit a broadband light and/or light whose frequency changes over time. Further, the third arrangement can be additionally configured to differentiate basal layer hyperplasia, abscess, eosinophil degranulation and/or lamina propria fibrosis from other cells. The particular cell(s) to be differentiated can be or include eosinophil. In addition, the third arrangement can differentiate the particular cell(s) based on (a) a strength of a signal from a cytoplasm and/or (ii) a shape of a nucleus of the particular cell.
These and other objects, features and advantages of the exemplary embodiment of the present disclosure will become apparent upon reading the following detailed description of the exemplary embodiments of the present disclosure, when taken in conjunction with the appended claims.
Further objects, features and advantages of exemplary embodiments of the present disclosure can become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the present disclosure, in which:
Throughout the figures, the same reference numerals and characters, unless otherwise stated, are used to denote like features, elements, components or portions of the illustrated embodiments. Moreover, while the subject disclosure will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments. It is intended that changes and modifications can be made to the described embodiments without departing from the true scope and spirit of the subject disclosure.
Described herein is a feasibility of a transnasal SECM device for eosinophil counting, including results from a esophageal biopsy study, descriptions of OFDI clinical esophageal imaging devices, and a bench top SECM probe prototype that incorporates the key components required for the implementation of a transnasal SECM probe.
Externally from the probe (e.g., within the console of the exemplary system/apparatus), the spectrum of the returned electro-magnetic radiation can measured and/or converted into a confocal reflectance as a function of transverse displacement within the sample using a detector or a spectrometer or other spectral detecting arrangement/system 220 which is/are known to those having ordinary skill in the art. Spectral decoding of a line in the image can be performed very rapidly, e.g., at rates of up to about 400 kHz, which can be approximately 25 times that of video rate confocal microscopy systems, and over about 250 times faster than some endoscopic RCM systems. The other transverse axes of the image can be obtained by relatively slow and straightforward mechanical actuation, such as helical scanning, that can be used for a wide variety of endoscopic probes. Similarly to other RCM techniques, images obtained by exemplary SECM systems, apparatus and methods can facilitate a visualization of subcellular-level microstructure, as shown in
Exemplary embodiments of systems, methods utilizing SECM techniques and/or structures according to the present disclosure can be used to diagnose Barrett's esophagus, including dysplasia and early-stage adenocarcinoma. In order to determine the accuracy of SECM for diagnosis, it is possible to SECM images of excised upper GI biopsy samples to histopathology, which also facilitates a visualization of eosinophils.
An exemplary embodiment of a SECM system according to the present disclosure can be provided that can have optical specifications for utilization of the exemplary transnasal device can used for exemplary histopathology correlation procedures. The exemplary SECM system can utilize an exemplary wavelength-swept source (central wavelength=1320 nm; bandwidth=70 nm; repetition rate=5 kHz) and an objective lens with an effective NA of 0.5.73 An exemplary single-mode illumination and multi-mode detection imaging configuration can be used to reduce laser speckle noise. The transverse and axial resolutions of the exemplary SECM system can be, e.g., 2.3 μm and 9.7 μm, respectively.
In one of the exemplary biopsies imaged in this exemplary analysis (as shown in
The nuclei shown in
After confirming that eosinophils are visible by the exemplary SECM system, apparatus and method, a protocol can be modified to image biopsies from pediatric patients with suspicion of EoE. An exemplary pediatric biopsy can be obtained from a pediatric patient with a history of EoE. As shown in
Exemplary optical coherence tomography or exemplary optical frequency domain imaging probes for imaging large regions of the esophagus can be provided.
Exemplary SECM Probe with Exemplary Components
An exemplary embodiment of a probe according to the present disclosure can be provided to facilitate a comprehensive SECM imaging of the distal esophagus. With such exemplary probe (e.g., as shown in
An exemplary 1/e2 diameter of the collimated beam on the grating-lens pair can be 4.0 mm. As a result, the effective NA of the exemplary system/apparatus can be approximately 0.4, thus producing an exemplary possible spot diameter of approximately 1.2 μm, and a confocal parameter of approximately 2.5 μm. The measured transverse line spread function full-width-half-maximum (FWHM) and axial FWHM from a mirror scanned through the focus can be measured to be approximately 2.1 μm and approximately 5.5 μm, respectively. The field of view can be approximately 500 μm. These exemplary measurements can be slightly lower than theoretical values, likely due to aberrations in the optical path.
Exemplary embodiments for qualitative identification of eosinophils and automatic quantification of eosinophils can include an identification based on signal strength (as shown in
Transverse Vs. Cross-Sectional Image Planes
Generally, pathologists can view biopsies in a cross-sectional orientation. It is possible to obtain SECM and histology images and/or data along the transverse aspect of the biopsy, which can be perpendicular to the cross-sectional plane, as shown in
A schematic diagram of the transnasal device according to an exemplary embodiment of the present disclosure is shown in
The exemplary PS-NG tube 1510 and the exemplary SECM probe 1520 can be advanced to a stomach 1560 using standard NG tube placement techniques as described herein. Following a confirmation that the device is in the stomach 1560, the exemplary device can be withdrawn while recording continuous pressure measurements with a pressure sensor 1570, in a manner identical or similar to that of single-sensor esophageal manometry. The target location can be the lower esophageal sphincter (LES) 1580. Once the LES 1580 is identified, the exemplary SECM probe 1520 can be positioned ˜5 cm 1590 proximal to the LES 1580, and SECM imaging will commence. Following the exemplary imaging procedure, the entire device can be removed from the patient. This exemplary device can be cost effective, as the PS-NG tube can be sterilized and reused. If the PS-NG tube 1510 is closed, the SECM probe may likely not contact the patient and can therefore be reused without requiring sterilization between cases.
There can be different types of pressure sensors that may be incorporated into the wall of the PS-NG tube, including hydraulic, solid state, piezoresistive, and optical sensors. It can be preferable to use optical pressure sensors, as they can be extremely small, are accurate and robust, and will not require delivery of fluid or electrical current through the PS-NG tube. One exemplary optical pressure sensor is a Fabry-Perot diaphragm filter placed at the tip of an optical fiber 1600, as shown in
This exemplary pressure apparatus can comprises a 125-μm diameter single- or multi-mode optical fiber with a 250-μm diameter Fabry-Perot diaphragm filter at the tip, as shown in
A detailed schematic diagram of an exemplary embodiment of the SECM probe according to the present disclosure is shown in
Within the housing 1715, the illumination light from the DCF 1705 can be collimated by a singlet lens 1725. As shown in
The objective lens 1740 can be assembled at an angle so that each wavelength can illuminate a distinct transverse and axial (e.g., depth) location within the esophageal wall. This exemplary configuration can facilitate a simultaneous acquisition of images at many depth locations during a single helical scan as shown in an imaging line 1750. A solid immersion layer 1755, which can comprise a plastic epoxy that has a similar refractive index to the PS-NG tube 1720, can reside between the objective lens 1740 and the inner sheath 1745. The solid immersion layer 1755 can further reduce aberrations caused by the PS-NG tube 1720. A lubricant 1760 can be used between the SECM probe's optical window and the PS-NG tube 1720 to reduce friction during the rotation and translation.
An exemplary rotary junction (as shown
Current laser technology facilitates faster wavelength tuning over a broader bandwidth. It is possible to decrease the total time of exemplary screening procedure. Compared with prior SECM system, the exemplary embodiment of the system according to the present disclosure can be configured to image, e.g., more than fifty times faster (e.g., 254 kHz vs. 5 kHzA-line rate). In order to increase imaging speed, it is possible to provide an exemplary laser configuration for high-speed operation and will incorporate new digital data acquisition hardware. Exemplary characteristic of the scanning spectral filter of the exemplary wavelength swept lasers have been reviewed to increase the free-spectral-range of its operation while not decreasing the transmission line width. When operating the filter in this way, the laser sweep speed can be doubled and the emission duty cycle reduced by one-half. In other words, the output from the laser can be a single, fast wavelength scan followed by an equal duration interval of no emission. In order to complete the duty cycle and achieve a doubling of the repetition rate, the direct laser output can be divided into two paths having a relative delay equal to the duration of the emission. The light from the two paths can then be recombined, in a manner similar to the buffering method proposed by Huber et al. To compensate for loss in this multiplexing operation, it is possible to incorporate a buffer semiconductor optical amplifier to restore the average output power to, e.g., approximately 80 mW.
Table 1 depicts exemplary specifications and objective performance targets (OPTs) for the exemplary SECM probe and system. The OPTs for meeting the goals of certain exemplary embodiments of the present disclosure can be based on the a configuration of a confocal microscopy to be used for endoscopic imaging of the esophagus. The outer diameter of the transnasal probe can be approximately 3.3 mm (10F) and the rigid length approximately 10 mm, which should facilitate a convenient transnasal access for small children and adults. The longitudinal, pullback scan length of approximately 10 cm matches the typical distance between proximal and distal biopsies utilized in the standard endoscopic biopsy procedure. For an objective lens NA of, e.g., 0.46 and a DCF inner cladding mode number of, e.g., 16 in this exemplary design, it is possible to achieve a transverse resolution of approximately 1.4 μm and an axial resolution of approximately 13.5 μm, values that can be similar to those of the bench top SECM system, which was demonstrated to have a capability to visualize of eosinophils in our preliminary studies (see
Sensitivity, defined here as the minimum detectable reflectance (SNR>1), is a key system parameter that affects image quality and penetration depth. It has been shown that, e.g., 10−4 to 10−7 of the incident light is reflected from skin at depths up to 300 μm. Since skin attenuates light more than the non-keratinized epithelial mucosa of the esophagus, and taking into account the differences in wavelengths and objective lens NA's between the two systems, it is estimated that 130 μm within tissue, the SECM probe's objective can collect approximately 3×10−3 to 3×10−6 of the illuminating light. Given that the exemplary source can emit, e.g., 80 mW, and an exemplary maximum 10-dB double pass insertion loss (e.g., 6 dB from probe, 4 dB from fiber optics and rotary junction), it is therefore estimates that our reflected power will range from approximately 25 μW (max) to 25 nW (min) on the detector. The noise at the detector can consist of shot noise, relative intensity noise (RIN), and thermal/electrical noise. At higher detected sample powers, the RIN noise dominates shot noise due to the narrow line width (˜0.6 nm) of our swept source.105
For example, dual-lumen 10F (OD=3.3 mm) transnasal tubes, marked externally every cm, can be custom extruded. A variety of wall thicknesses and materials, including polyurethane, polyvinyl chloride (PVC), Tygon and silicone, can be provided to determine an appropriate combination of flexibility and maneuverability. The PS-NG tube together with the inserted SECM probe can be tested for flexibility and trackability and can be compared with commercially available NG tubes to ensure that it has the correct mechanical characteristics for transnasal or transoral insertion. It is possible to additionally test the ability of our SECM probe to be retracted within the PS-NG.
Small diameter pressure sensors can comprise coated, buffered, and bare fibers can be tested for flexibility and durability. Trackability and pushability can be tested with sensors inserted into the lumen PS-NG tube. Pressure measurements can be tested and calibrated with the sensor outside the tube and inside the tube using varying, known pressures within a hermetically-sealed phantom. Different materials protecting the diaphragm can be tested for stability, sterilizability, and capability to accurately and reliably transduce external pressures.
It is possible to provide exemplary optical components to miniaturize the SECM probe. In order to minimize the probe diameter and length, e.g., a collimation lens (e.g. singlet; BK7; OD=1.2 mm; f=5 mm) can be fabricated. A compensation plate (e.g. LASF35; OD=1.2 mm; f=233 mm) can be manufactured and used for the compensation of the astigmatism that is induced by non-symmetric light path through the PS-NG tube to the esophagus. A custom objective lens (doublet; LASF18 and LASF35; OD=1.2 mm; f=1.1 mm; NA=0.46) can be fabricated to have diffraction-limited optical performance for the spectral region that can be used for SECM imaging. The grating (groove density=1240 Ipmm) can be designed and fabricated to have maximum diffraction efficiency for the 1st order at the spectrum between 1220 nm to 1380 nm. It is possible to provide exemplary probe optics (
A variety of cylindrical phantoms can be constructed to verify the probe. Exemplary resolution phantoms can consist of hollow cylinders with resolution standards affixed to the interior surface. Imaging cylindrical intralipid/gelatin phantoms and swine esophageal epithelia ex vivo can test penetration depth. Finally, segments of freshly excised swine and cadaver esophagus can be imaged using the probe.
It is possible to provide an exemplary mechanical housing and the transparent sheath for the probe assembly.
DCF. Various exemplary DCFs can be provided which can include, e.g., the core-inner cladding mode ratio required to meet the axial and transverse resolution OPTs.
Wound cable. Exemplary multi-layer wound drive shafts can be used to helically scan distal optics within exemplary catheter designs. A custom wound cable can be provided for a motion transduction accuracy and repeatability through the catheter. For example, wound cables with multi-layer configurations can be provided to reduce or minimize translational and rotational distortion in the SECM images.
Lubricant. Normal saline can be used as the lubricant between the SECM probe and the PS-NG tube. Different lubricants with higher refractive indices that better match that of the PS-NG tube can be also tested to further improve the optical performance.
Probe-console interface. The optical rotary junction (
Exemplary Console. An exemplary embodiment of an imaging laser can be configured for power, spectrum, instantaneous line width, and repetition rate. The exemplary optics can be provided for appropriate throughput and efficiency. The optical layout can be assembled on a small breadboard for incorporation into the cart.
Software. Software can be provided to control the rotary junction and read and display the data from the pressure sensors. For example, Signatec PDA16 data acquisition software can be programmed to control the new boards and process the digitized data into images. Software can be provided for real time display of the pressure sensor's reading and integrated into the graphical user interface. Multi-resolution SECM image navigation and automated eosinophil counting can be incorporated into the existing code and user interface.
Sterilization and reuse. It is possible to use the exemplary embodiment of transnasal probe configuration according to the present disclosure so that they can be sterilized and reused, which will lower the cost of the exemplary device/apparatus, and thus the exemplary monitoring procedure. For example, it is possible to keep the external surface smooth and free of defects and will utilize materials that are stable following CIDEX or ETO sterilization procedures.
For the certain patients in which transnasal procedures are contraindicated, the PS-NG tube can be placed transorally. For safety reasons, it is can be preferable for the NG tube to not enter the airways. The exemplary approach for verifying the position of the tube can include finding an acidic pH from an aspirate. It is possible to provide another lumen in the wall of the PS-NG tube for fluid aspiration. Alternatively, it is possible to make the PS-NG tube open at the distal end, and use the SECM lumen to conduct the fluid aspiration. In this case, it is possible to either use additional sheath between the SECM probe and the PS-NG tube or make the SECM probe sterilizable. Depending on the dimension and shape of the esophagus, according to one exemplary embodiment, a contact may not be maintained between the PS-NG tube and the esophageal wall for a portion of the imaging area. An alternative approach can be to provide a balloon-centering SECM catheter and introduce the catheter through the PS-NG tube for imaging (e.g., see
The optics of the balloon-centering SECM probe can be similar to that of the existing design with the exception that an autofocusing mechanism can be added (
Exemplary Miniaturization. It is possible to stamp an epoxy-based grating on an angle-polished cylinder
Motion artifacts. If significant longitudinal motion during sequential circumferential scans can be encountered, the scans may not line up. It is possible to correct for this occurrence by using cross-correlation techniques on adjacent scans prior to reconstructing the SECM dataset.
Exemplary Imaging penetration depth. The ranging depth of the SECM probe can be, e.g., about 130 μm. Since the eosinophilic infiltrate of EoE can typically manifests near the luminal surface, is likely that images obtained over this depth will provide sufficient information regarding the distribution of eosinophils to make a correct diagnosis. If it is determined that larger imaging penetration depth is preferred, it is possible to modify the exemplary design to increase the chromatic aberration of the objective lens, which will increase the ranging depth. An alternative approach can be to utilize a Fresnel objective lens. These configuration that enlarge the imaging penetration depth can also increase the number of discrete depth locations that can be imaged, possibly resulting in a prolonged acquisition time.
Exemplary Axial resolution. If cross-sectional imaging is used to render an accurate eosinophil count and multi-mode detection through the DCF may not provide high enough axial resolution to visualize eosinophils on cross-sectional reformatted images, different DCF configuration with smaller number of modes can be used. For example, decreasing the number of modes from about 16 to 10 can increase the speckle contrast only by about 6% while improving the axial resolution by 27%.
Increase of Speed of acquisition. The exemplary configuration can scan, e.g., a 1000 mm2 area of the esophagus at about 10 different optical sections in about 2.9 minutes which is well tolerated by adult patients. If this imaging duration is determined to be too long, it can be reduced by decreasing the number of optical sections, critically sampling the data, or decreasing the pullback length. For example, one approach for reducing the total imaging time can be, e.g., to image two 1 cm longitudinal segments in the proximal and distal esophagus, a modification that can lower the acquisition time to approximately 30 seconds.
It is possible that that the exemplary unsedated transnasal SECM can be as accurate as endoscopic biopsy for counting esophageal eosinophils. This can be tested by comparing unsedated transnasal SECM to upper endoscopic biopsy, e.g., in 300 patients undergoing evaluation for EoE. In addition, information on patient tolerance of the exemplary SECM procedure can be obtained.
Unsedated transnasal SECM imaging. Prior to sedation and upper endoscopy, many or all patients can be imaged using the exemplary transnasal SECM probe and system described herein. An alternative embodiment according to the present disclosure can utilize a transoral probe described herein. Exemplary methods for insertion using intraesophageal pressure guidance can be similar or identical to those described herein above. When the probe is located at approximately 5 cm from the GEJ, helical SECM imaging will commence. The exemplary optics configuration within the exemplary probe can pull back in a helical scan from the distal to the proximal esophagus over a length of, e.g., about 10 cm at a rate of about 0.5 mm/second, resulting in a pullback duration of, e.g., about 2.9 minutes. The exemplary SECM data can be processed in real-time and viewed immediately after the pullback has completed to confirm that the data is of diagnostic quality. The exemplary optics configuration of the transnasal probe can be repositioned, and the exemplary imaging procedure repeated if necessary or desired. Following the exemplary imaging procedure, the exemplary transnasal probe can then be removed from the patient. Eosinophils may be identified and counter as per patient, imaging region, or one or more high power fields as per the methods described herein. Other features of EoE, including basal layer hyperplasia, degranulation, abscess, lamina propria fibrosis may be then rendered on the SECM or RCM dataset using qualitative user-applied criteria, semiautomatic, or automatic image processing arrangement. This information can be subsequently used to render a diagnosis of EoE or provide additional information regarding the diagnostic status of the patient.
Accordingly, exemplary embodiments of the present disclosure can provide a less invasive technology for monitoring esophageal eosinophils. Such advances can decrease the cost and of eosinophil monitoring and will increase patient tolerance for follow up eosinophil evaluation procedures. Further, the exemplary technology can be of utility to determine the pathophysiology and natural history disease in future research.
The foregoing merely illustrates the principles of the invention. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. Indeed, the arrangements, systems and methods according to the exemplary embodiments of the present disclosure can be used with any OCT system, OFDI system, SD-OCT system or other imaging systems, and for example with those described in International Patent Application PCT/US2004/029148, filed Sep. 8, 2004, U.S. patent application Ser. No. 11/266,779, filed Nov. 2, 2005, and U.S. patent application Ser. No. 10/501,276, filed Jul. 9, 2004, the disclosures of which are incorporated by reference herein in their entireties. It will thus be appreciated that those skilled in the art will be able to devise numerous systems, arrangements and methods which, although not explicitly shown or described herein, embody the principles of the invention and are thus within the spirit and scope of the present disclosure. In addition, to the extent that the prior art knowledge has not been explicitly incorporated by reference herein above, it is explicitly being incorporated herein in its entirety. All publications referenced herein above are incorporated herein by reference in their entireties.
This application is based upon and claims the benefit of priority from U.S. Patent Application Ser. No. 61/249,207, filed on Oct. 6, 2009, the entire disclosure of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61249207 | Oct 2009 | US |
