The invention relates generally to diagnostic methods for real time diagnosis of biological cells and tissue. A diagnosis of abnormal tissue can be made by the detection of differences in properties of biological cells, properties such as cell density, size and composition. A diagnosis of abnormal tissue may also include a characterization of these differences in cellular properties. In addition to aiding a health care provider with making a diagnosis of abnormal tissue, an apparatus for diagnosis that provides real-time imaging ensures that the abnormal tissues is also completely removed during a surgical procedure so that the subject does not have to undergo multiple surgical procedures to remove all traces of the abnormal tissue. Typically it takes 2 to 5 days to obtain a conclusive answer on the surgical success which is determined after detailed pathology and histology analysis is performed on the sample. Real-time detection would give feedback to the surgeon during the surgery and thereby reducing the possibility that the subject will have to undergo a 2nd surgery due to the presence of “positive margins”, or not enough cancer-free margins on the excised tissue.
Current devices and methods for detecting abnormal tissue in a sample have several disadvantages. The methods currently used, include X-rays, ultrasound imaging, magnetic resonance imaging, thermal imaging, radiofrequency (RF) reflection and absorption, and electrical impedance techniques. Electrical impedance techniques has the disadvantage that the detection of abnormalities in the tissues and the cells is done by measuring the changes in electrical impedance of the tissue globally rather than measuring electrical impedance locally because the current devices and methods are positioned outside of the body when in use. Apparatuses that use global measures to detect changes in electrical impedance are less sensitive and have relatively poor spatial resolution. For example, in X-ray imaging the sensitivity of the device in imaging small-size cancer lumps such as lumps that are less than 3 mm in size is low. Additionally, in cases where there is a low relative amount of malignant cells adjacent to benign cells, the sensitivity of the X-ray is less than 30%. X-rays are also affected by any other objects that may absorb the X-rays, such as a dense tissue structures or bone located between the X-ray source and the detector. Additionally, an X-rays machine cannot be used inside the body.
Another technique for detecting the presence of abnormal tissue is the use of ultrasound waves to detect cancer cells. Ultrasound machines image tissue by looking at the reflection of the ultrasound waves of the denser cells. Also the elasticity differences between benign and malignant cells contribute to the image produced by ultrasound. The use of ultrasound is further limited in the minimum size of detectable abnormal tissue because ultrasound imaging of smaller sizes is subject to poorer signal to noise ratio. Similarly, it is also difficult to detect changes in cell density of the tissue in denser media.
Another imaging apparatus used to detect the presence of abnormal tissue is the MRI machine. Like the other imaging apparatuses previously mentioned, MRI images are also affected by cell density and composition. Further, the MRI image is strongly affected by the amount of background noise from the overall tissue scanned and is also limited by the size of abnormal tissue that is detectable. And like X-ray, MRI cannot be used inside of the body.
Other imaging methods include: thermal imaging techniques which detect changes in the temperature of tissues that have denser cell densities and which attract more blood flow to the area; RF reflection and absorption, which is also used to detect cancer cells by detecting variations in the reflection and absorption of RF in suspect tissues as compared to benign cells; electrical impedance techniques have also been developed to determine the malignancy of the cells within the organ by monitoring electrical responses from the outer surface of the tissue.
Sometimes a tissue requires further analysis. For example, it may be beneficial to know whether a sample of abnormal cells is benign or malignant. It may, therefore, be necessary to send the sample out for analysis to a pathology lab. In the pathology lab, cancerous cells are characterized using histological methods which can be time consuming and may involve complex sample preparation procedures that can last anywhere from 8-12 hours.
Because the current techniques mentioned above are typically capable only of being positioned outside of the body there may be difficulty in detecting small volumes of abnormal tissue or testing small sample areas. Also, positioning the detecting device outside of the body creates the potential for a greater amount of interference with neighboring tissue; makes it more difficult to reach the target tissue through structures in between the target tissue and the testing device; and increase the likelihood that the signal to noise ratio will be poor. In addition, the current methods for detecting abnormal tissue employ bulky machinery. Further, tissue samples are currently sent to pathology labs for testing which ultimately increases the time frame for making a diagnosis.
A method currently being used for detecting and identifying variations in samples is the optical detection of cellular variations. Optical techniques for diagnosing include the use of Surface Enhanced Raman Spectroscopy (SERS) as applied to tissues. Raman spectroscopy has been shown to have very good sensitivity down to the single cell level. In SERS electromagnetic radiation is introduced to a sample through an optical probe. Treating the surface of the structure for holding the sample with electrically conductive, metallic materials enhances the electromagnetic field experienced by the sample. The electromagnetic radiation interacts with the sample and is scattered and reflected back to a detector due to inherent properties of the sample. The scattered electromagnetic radiation can be used as an indicator of the characteristics of the tissue sample. This technique has been shown to have good sensitivity and specificity for cancer cells. However, the technique works on thin tissue sections and requires the use of a microscopy set-up.
Thus, there exists a need for optical devices and methods that detect in real-time the near-field effects of electromagnetic radiation on abnormal tissue with high sensitivity and precision and which is capable of being contained in a compact unit that is easily manipulated in reference to the sample. In addition to the advantage that the invention described herein provides real-time diagnosis of the sample being tested, an automated real-time diagnosis instrument will help to eliminate the possibility of human error or missing a critical volume of tissue.
An aspect of the invention is directed to an apparatus for the diagnosis of a biological sample. The apparatus is comprised of an optical probe; a probe head distally connectable to the optical probe, the optical probe further comprising at least one optical element for applying an electromagnetic radiation of a first wavelength to the biological sample, and one or more collection elements positioned proximate the at least one optical element; and an analyzer for analyzing a signal received from the biological sample by the one or more collection elements. The probe head can be removable from the probe, if desired. Alternatively, the probe head can be integrally formed with the probe. In some configurations, the apparatus further comprises a plurality of serially deployable probe heads, each probe head comprising one or more optical elements, the one or more collection elements positioned proximate the one or more optical elements. The collection element of the apparatus can be comprised of an optical fiber with cladding. Additionally, the collection element can further comprise a spectral filter where the spectral filter is selected from the group comprising: an interference filter, low pass filter, high-pass filter, band pass filter, and Rayleigh filter. The optical element of the apparatus can be comprised of an optical fiber with a clad segment and a bare clad-less segment. The clad-less segment of the optical element can have conductive islands of film deposited on its surface. In some cases the apparatus has an optical element with a cross-section less than 500 microns. In some cases the optical element of the apparatus is less than 5 m in length. The optical element may further be adapted to be in communication with an excitation source selected from one or more of a laser, a laser array, a light emitting diode, a diode array a broad light source, and a low pressure lamp. The apparatus can be configured to further comprise at least one of a spectrometer, an interference filter, a low-pass filter, a high-pass filter, and a band-pass filter. The analyzer of the apparatus can collect the resulting Raman scattering of the electromagnetic radiation generated by the optical element and analyze at least one signal received by the collection elements from the sample in real-time. The analyzer is further adapted and configured to identify a signature of the signal received from the biological sample. The signature of the biological sample is determined based on one or more of a density, shape, size, and chemical composition of the biological sample measured. In some configurations, the apparatus further comprises a photodetector where the photodetector collects the signal from the collection element and is at least one of a charge-coupled device camera, photodiodes, avalanche photodiodes, phototransistors, photomultipliers, charge injection device detector, and hybrid multiplier. In some configurations, the apparatus is adapted and configured to be handheld. In addition, the apparatus can be adapted and configured for use in situ. Alternatively, the apparatus can be adapted and configured for use with an endoscope. In another embodiment of the device, a metrology unit can also be provided with the device. When a metrology unit is used, the metrology unit scans an extracted biological sample in three dimensions at different locations. An apparatus with a metrology unit can further consist of a motorized stage adapted and configured to receive a mounted biological sample.
Another aspect of the invention is directed to an apparatus for in situ determination of surgical efficacy, comprising: an optical probe adapted and configured to engage a target tissue site of a mammal at a distal end, a probe head distally connectable to the optical probe, the optical probe further comprising at least one optical element for applying an electromagnetic radiation of a first wavelength to a tissue at a surgical site of a mammal, and one or more collection elements positioned proximate the at least one optical element; and an analyzer for comparing a signal received from the tissue at the tissue site by the one or more collection elements with a reference signal from a benign tissue sample. The probe head can be removable from the probe, if desired. Alternatively, the probe head can be integrally formed with the probe. In some configurations the apparatus comprises a plurality of serially deployable probe head each probe head comprising one or more optical elements, the one or more collection elements positioned proximate the one or more optical elements. The collection element of the apparatus can be comprised of an optical fiber with cladding. Additionally, the collection element can further comprise a spectral filter where the spectral filter is selected from the group comprising: an interference filter, low pass filter, high-pass filter, band pass filter, and Rayleigh filter. The optical element of the apparatus can be comprised of an optical fiber with a clad segment and a bare clad-less segment. The clad-less segment of the optical element can have conductive islands of film deposited on its surface. In some cases the apparatus has an optical element with a cross-section less than 500 microns. In some cases the optical element of the apparatus is less than 5 m in length. The optical element may further be adapted to be in communication with a an excitation source selected from one or more of a laser, a laser array a light emitting diode, a diode array a broad light source, and a low pressure lamp. The apparatus can be configured to further comprise a detector where the detector is at least one of a spectrometer, an interference filter, a low-pass filter, a high-pass filter, and a band-pass filter. The analyzer of the apparatus can collect the resulting Raman scattering of the electromagnetic radiation generated by the optical element and analyze at least one signal received by the collection elements from the tissue at a surgical site in real-time. The analyzer is further adapted and configured to identify a signature of the signal received from the biological sample. The signature of the biological sample is determined based on one or more of a density, shape, size, and chemical composition of the biological sample measured. In some cases, the apparatus can further comprise a detector where the detector is one or more of a charge-coupled device camera, photodiodes, avalanche photodiodes, phototransistors, photomultipliers, charge injection device detector, and hybrid multipliers. In some configurations, the apparatus is adapted and configured to be handheld. In addition, the apparatus can be adapted and configured for use in situ. Alternatively, the apparatus can be adapted and configured for use with an endoscope.
Also described herein is a method of diagnosing a biological sample real-time comprising: engaging the biological sample with an optical probe having a probe tip distally connectable to the optical probe, the optical probe further comprising at least one optical element adapted to apply electromagnetic radiation of a first wavelength to the biological tissue of a mammal, and one or more collection elements positioned proximate the one or more optical elements; and an analyzer for analyzing a signal received from the biological sample by the one or more collection elements; emitting electromagnetic radiation of a first wavelength; collecting a signal from the biological sample; analyzing the signal received from the biological sample to produce a result; and diagnosing the biological sample based on the result. The method may also further comprise the step of replacing the probe head with a second probe head and thereafter emitting electromagnetic radiation of a second wavelength, collecting the signal from the biological sample, analyzing the signal received from the biological sample to produce a result, and diagnosing the biological sample based on the result. The electromagnetic radiation of the first wavelength and the electromagnetic radiation of the second wavelength comprise the same wavelength. The step of engaging the biological sample can be done by applying the optical probe to a tissue site within a body of a mammal. Alternatively, the method may further comprise approaching a tissue site within a body of a mammal with the optical probe. Another alternative of the method further comprises inserting the optical probe into a body of a mammal through an endoscope. The method of diagnosing may further comprise the step of analyzing the signal in real-time. Additionally, the method of diagnosing further comprises the step of comparing the signal received from the biological sample to a signal of a reference sample. The reference sample could be a benign tissue sample and could be obtained from the same mammal.
Also contemplated is a kit for diagnosing a biological tissue comprising: an optical probe; and a probe head for use with the optical probe, the probe head comprising at least one or more optical elements adapted to apply electromagnetic radiation of a first wavelength, and one or more collection elements positioned proximate the at least one or more optical elements. The kit may further comprise a plurality of optical probe heads connectable to the optical probe.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
The devices, apparatuses, methods, and kits described herein are adapted and configured to rapidly determine the spatial location of abnormalities in a sample, such as a biological sample, or any soft material that can be probed. For example, the sample can come from any mammal or warm blooded animal which can serve as a sample donor. The devices, systems, methods, and kits described herein are able to discriminate between different types of cells using near-field Surface Enhanced Raman Spectroscopy (SERS) technology to identify the molecular signature of the biological cells. In Raman spectroscopy, the scattering of electromagnetic radiation by the sample is detected and the spectrum of radiation can be used to identify and characterize the sample. The optical device uses a fiber optic bundle array to guide electromagnetic radiation from an electromagnetic radiation source to the sample. The fiber optic bundle array further collects the scattered radiation from sample after being excited by the laser. The pattern of scattered radiation changes depending on the characteristics of the sample. As an example, in comparison to normal cells, cancer cells tend to be of different size and shape, their nuclei tend to be larger and more prominent, they form more dense collections of cells, they have irregular boundaries and surface topography, and they vary in chemical composition. These variations can all affect the spectral footprint of the cells being tested. The Raman spectrum from a benign reference sample of the patient's tissue can be used as a comparison for suspect samples. A comparison with a known benign sample can be used to characterize and identify abnormalities in the tissue. The statistical analysis of a collected Raman spectrum provides a unique signature of the sample based on the specific density, shape, size, and chemical composition of the measured sample.
The optical device and technique described herein can be used in the operating room during surgery to get a fast or real-time diagnosis of areas suspected of cancer or other abnormalities. In addition, the optical device and methods can be used as a time saving measure in pathology labs to characterize the sample before further histological processing.
Therefore, the present invention implements real-time diagnosis and characterization of abnormal tissues or cells in a sample where the detection and characterization of the abnormal tissues or cells can be performed either in vivo or inside the body, in vitro or outside the body, or in situ, in which the sample being tested is in an tissue extracted from a patient in which sample is located.
A diagram of the typical components of a Raman spectroscopy system used with the optical device described herein is shown in
A side view of an optical probe 310 is shown in
The fiber bundle array 316 consists of an illumination fiber 312, and at least one collection element 314. The illumination fiber 312 introduces excitation energy from the excitation energy source, such as a light source, to the sample. The illumination fiber is typically located at the center of the fiber bundle array 316 when more than one collection element 314 is present.
Once the sample is excited by the electromagnetic radiation, the radiation is scattered by the sample thereby generating a Raman spectrum for the sample. The resulting Raman spectrum is collected by at least one collection element 314. Typically the collection elements are fiber optic cables and multiple collection elements are embodied in the invention. When multiple collection elements are used, the collection elements comprise the remainder of the fiber bundle array. Similar to the illumination fiber, the collection elements 314 are cladded, to ensure that the optical signals remain internalized inside of their respective fibers.
The optical device described herein may consist of an optical probe head integrated with the fiber bundle array. The optical probe head may either combined with the fiber bundle cable to form a probe, where the probe head is permanently coupled to the fiber bundle array; the probe head alternatively may be fabricated from the illumination fiber by stripping the cladding from the illumination fiber. Alternatively, the probe head 318 can be interchangeable with other probe heads by detaching and reattaching different probe heads with the same fiber bundle array as shown in
Although the optical probe 410 can be used by manually holding the optical probe head, it may be beneficial to introduce the optical probe 410 to the sample through the use of a handheld device 400 as shown in
To use the device 400, the user grips the handle 432 of the device 400 and approaches the sample with the optical probe 410, so that the optical probe head 418 is sufficiently proximal to the sample. Typically the handheld device 400 is configured so that the optical probe 410 is rotatable with respect to the handle 432 to ensure that the proper areas of sample are stimulated and an adequate amount of Raman scattering is detected. Further, the neck of the 434 of the device 400 is typically translatable with respect to the handle 432. The optical probe 410 can then be translated either close to or further from the handle 432 of the device 400, in other words distal to or proximal to the sample, while the handle 432 of the device 400 remains stationary.
In order to fully connect the optical probe 410 to the handle 432 of the device 400, the bundle fiber array 416 is typically fed through the neck 434 of the device 400. The illumination fiber 412 of the bundle fiber array 416 is in communication with a light source. The light source can either be external to the handheld device or the light source can be an internal light source housed within the handle 432 of the device 400 as is shown in
The handheld device stimulates the sample with electromagnetic radiation or other excitation source and records the signals generated by the cells of the sample excited by the electromagnetic radiation. The signals generated by the sample when detected and recorded by the collection elements of the device can then be sent to the spectrometer which it typically located external to the handheld device. In this case, the collection fiber bundle would exit the device through the base 440 of the device 400. Alternatively, a small processor or data storage component could be housed in the handle of the device for storage of the signals detected until the data can be transferred to the spectrometer.
The optical probe head can be used in a handheld unit as previously described. Alternatively, a modified version of the optical probe head can be incorporated into other medical devices. For example, the optical probe head can be incorporated into an endoscope. An exemplary illustration of an endoscope 550 is shown in
In some cases when an optical probe head is used together with an instrument such as an endoscope, the bundle fiber array with a connector is introduced into the bore. The optical probe head 518 is then coupled to the bundle fiber array 516 through the connectors 524, 524′ as shown in
The optical device 600 described herein in some cases is used as part of a metrology apparatus 602 as shown in
The device can be used in vivo or in the body, in vitro or in isolated cells, or in situ, testing cells in removed intact tissue.
In addition to being used to diagnose a cancerous condition by detecting abnormalities in cells, the optical device measured herein can be used in the operating room by a surgeon in real-time to ensure complete removal of problematic tissue, such as cancer cells, during a surgical procedure.
Kits employing the devices, components, and materials of the invention can also be employed. A variety of kits are also contemplated. For example, a kit for diagnosing a biological tissue can comprise, for example, an optical probe and an optical probe head for use with the optical probe, the optical probe head comprising at least one or more optical elements adapted to apply electromagnetic radiation of a first wavelength, and one or more collection elements positioned proximate the at least one or more optical elements. Furthermore, the kit could include a plurality of optical probe heads connected to the probe. A kit including an embodiment of the invention previously described in some instances further includes a console component. The console component typically consists of a processor and some kind of display unit, such as a computer and a monitor. The optical characteristics detected by the device are typically displayed on the monitor.
A variety of methods are also contemplated. One method includes a method of diagnosing a biological sample in real-time. The method comprises: engaging the biological sample with an optical probe having an optical probe head distally connectable to the optical probe, the optical probe further comprising at least one optical element adapted to apply electromagnetic radiation of a first wavelength to the biological tissue of a mammal, and one or more collection elements positioned proximate the one or more optical elements; and an analyzer for analyzing a signal received from the biological sample by the one or more collection elements; emitting electromagnetic radiation of a first wavelength; collecting a signal from the biological sample; analyzing the signal received from the biological sample to produce a result; and diagnosing the biological sample based on the result. The method can further comprise engaging the biological sample by applying the optical probe to a tissue site within the body of the mammal. Alternatively, the method can further comprise engaging the biological sample by approaching the tissue site within the body of the mammal with the optical probe. Additionally, the optical probe can be inserted into the body of the mammal through an endoscope. The optical probe head can be replaced, if desired, with a second optical probe head. The second probe head can then emit electromagnetic radiation of a second wavelength and the signal from the biological sample in response to the electromagnetic wavelength of the second wavelength can be collected and analyzed to produce a result, and thereby the biological sample is able to be diagnosed. Furthermore, the electromagnetic radiation of the first wavelength and the electromagnetic radiation of the second wavelength are the same. Alternatively, the method can further comprise the step of analyzing the signal in real-time. Further, the signal received from the biological sample can be compared to a signal received from a reference sample. For example, the reference sample can be a benign tissue sample, the benign tissue sample having been obtained from the same mammal.
The optical device can be used to detect suspect areas of tissue during a lumpectomy. Once the surgeon excises the suspect breast tissue, either the surgeon, a pathologist, or lab technician in the operating room can use the handheld device as shown in
The optical device can also be used to detect cancerous tissue in vivo during a lumpectomy. During the lumpectomy, the surgeon will use the probe in the body cavity of the patient to assess if, once the suspect tissue has been excised, the remaining tissue in the breast is free of malignancy. Once the excision procedure is complete, the surgeon will use the device inside the body to scan the surface of the cavity. The results obtained from a benign tissue sample will be registered to form a baseline for the patient tissue response and the results from the suspect areas will be compared with the benign values. The console will display the variations in the tissue response. If the spectrum of scattered radiation from the sample varies from the spectrum from a benign sample, the surgeon will then note the area and will excise more tissue at the margins to ensure complete excision of the cancerous tissue before closing the patient.
As part of a typical cancer excision surgery the surgeons sometime excise sentinel lymph nodes and additional nodal areas to determine whether the cancer has metastasized. The optical probe can be used in vivo, to make sure that the node is cancer free before excising it. Additionally the device can be used in-vitro to find out if more lymph nodes need to be excised before the patient is closed.
Current methods for conducting a prostate cancer biopsy include taking tissue from 12 random sites in the prostate gland. The tissue taken during the biopsy is then sent to a lab and the results are obtained a few days later. If the areas of cancer are not within one of the 12 random sites, the procedure needs to be repeated again. Using the optical device described herein, in conducting a prostate cancer biopsy, the optical probe of the invention can be mounted in an endoscope and the organ suspected of cancer can be optically tested using the probe. The response can then be compared to the response from a benign area of the organ. If a noticeable deviation from the benign tissue response is detected, the surgeon will excise the tissue from this area to perform a permanent pathology.
The invention also can be used in a biopsy to determine whether a suspected area of tissue is malignant or not. Because the device operates in real time, the invention can help reduce the amount of benign biopsy procedures done today as well as reduce the cost of these procedures. It is found that more than 80% of biopsies result in the sample being benign tissue, therefore the device will be able to reduce the cost of these procedures to those tissue portions that are more likely to show malignancy.
The optical device can also be used with other devices for locating abnormal tissue. During a lumpectomy, the surgeon can probe the body cavity of a patient to localize the areas of abnormal tissue. The surgeon can use an electrical characterization device to narrow the surgical area. Once the area has been narrowed using the electrical device, the optical device can then be used to identify the locations of cancerous tissue without having to penetrate the tissue with a foreign object. The area can then be rescanned with the optical probe to determine if any abnormal tissue remains. If abnormal tissue is detected, the tissue can be excised. If no abnormal tissue is detected, the patient can then be closed by the surgeon.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
This application claims is a continuation application of U.S. patent application Ser. No. 12/525,006 with an International Filing Date of Jan. 31, 2008, which claims the benefit of PCT/US2008/052608 filed on Jan. 31, 2008, under 35 USC §365, this application also claims the benefit of U.S. Provisional Application No. 60/898,683, filed Feb. 1, 2007, entitled “Optical System for Identification and Characterization of Cancer Cells” which application is incorporated herein by reference.
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