Cartridge for tissue storage for imaging

Abstract

A cartridge for storing an unlabeled tissue imaged by an optical imaging system, comprising: a container for storing the unlabeled tissue and connecting to the optical imaging system; an optical substrate provided on the bottom surface of the container, through which the optical imaging system is configured to image the unlabeled tissue and generate a virtually stained histological image of the unlabeled tissue; and a lid provided on the upper surface of the container, the lid comprising a film for pressing the unlabeled tissue against the optical substrate so that the entire cut end of the unlabeled tissue is flat against the optical substrate.

Description

Technical Field

[0001] The present disclosure relates to a tissue storage cartridge for imaging, and more particularly, to a cartridge for storing unlabeled tissue that is imaged by an optical imaging system configured to generate a virtual stained histological image of the unlabeled tissue. However, embodiments herein are also applicable to molecular diagnostics.

Background Art

[0002] Surgical resection is an essential part of the treatment of most solid cancerous tumors and involves the surgeon removing the tumor and the surrounding tissue. A "surgical margin" (or "margin") can refer to the boundary of the excised tissue. A "negative surgical margin" can refer to a surgical margin that does not overlap the cancerous tumor or is sufficiently distant from the cancerous tumor. A "positive surgical margin" can refer to a surgical margin that overlaps the cancerous tumor or is not sufficiently distant from the cancerous tumor.

[0003] During surgical resection, it can be difficult for the surgeon to accurately determine the amount of surrounding tissue to be excised such that an appropriate surgical margin is achieved and it can be difficult to determine whether a negative margin exists. Thus, many initial resection surgeries result in positive margins that necessitate additional surgeries.

[0004] After surgical resection of tissue, histopathological evaluation is performed on the resected tissue to determine whether the resection margin is negative or positive. Generally, histopathological evaluation of tissue includes steps of chemically stabilizing the resected tissue with a fixative, embedding the resected tissue in paraffin, slicing the resected tissue, placing the resected tissue on a slide glass, staining the resected tissue with dyes (e.g., hematoxylin and eosin), and performing optical microscopic qualitative analysis of the histological image of the stained tissue. The above-mentioned techniques are time-consuming, expensive, error-prone, and cannot be performed during surgery.

[0005] In some cases, intraoperative evaluation of the resection margin is enabled by frozen section analysis. Frozen section analysis includes steps of embedding the resected tissue in a special medium, cooling the resected tissue, freezing the resected tissue, slicing the resected tissue, staining the resected tissue, placing the stained tissue, and analyzing the histological image of the stained tissue. In the above-mentioned techniques, the surgical time is prolonged, cell morphology is deteriorated, and artifacts that affect the pathological diagnosis of tissue are introduced. Thus, frozen section analysis often includes an unacceptably high false positive rate.

[0006] Therefore, there is a need for a technique to provide intraoperative evaluation of the resection margin in an accurate, safe, and time-saving manner.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0008] Embodiments of the present disclosure relate, among other things, to a cartridge for storing an unlabeled tissue that is imaged by an optical imaging system configured to generate a virtual stained histological image of the unlabeled tissue. Each embodiment disclosed herein may include one or more of the features described in relation to any of the other disclosed embodiments.

[0009] The accompanying drawings, which are incorporated herein and constitute a part of this specification, illustrate embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. As described above, various histological imaging techniques are time-consuming, error-prone, and often cannot be performed during surgery. Therefore, confirmation of a negative margin during surgery can be very difficult or impossible with conventional imaging techniques.

[0010] The present disclosure provides a cartridge for storing an unlabeled tissue imaged by an optical imaging system configured to generate a virtually stained histological image of the unlabeled tissue. However, embodiments herein are also applicable to imaging of labeled tissues (e.g., molecular imaging using labeled antibodies, molecular imaging using labeled antigens, molecular imaging using labeled oligonucleotides, fluorescence imaging, etc.).

[0011] The cartridge includes a container for storing an unlabeled tissue and for connecting to an optical imaging system. Further, the cartridge includes an optical substrate through which the optical imaging system is configured to image the unlabeled tissue to generate a virtually stained histological image of the unlabeled tissue. Further, the cartridge includes a lid having a membrane for pressing the unlabeled tissue against the optical substrate such that the entire cut end of the unlabeled tissue is flat against the optical substrate.

[0012] During surgery, tissue may be excised from a patient and the excised unlabeled tissue placed in the cartridge. The cartridge may then be connected to an optical imaging system. The optical imaging system can generate a virtually stained histological image of the true cut end of the unlabeled tissue during surgery while the cartridge maintains the orientation of the tissue when it was excised from the patient. In this way, it is possible to more accurately, quickly, and during surgery determine whether a cut end negativity exists in the excised tissue sample, thereby improving the safety and effectiveness of surgical resection of cancerous tumors.

[0013] In some embodiments, "un-labelled tissue" refers to tissue that has not been stained by a stain used in histology. For example, un-labelled tissue has not been stained by stains such as hematoxylin, eosin, acid dyes, basic dyes, periodic acid-Schiff reaction stains, Masson stains, Alcian blue stains, Van Gieson stains, reticulin stains, Giemsa stains, toluidine blue stains, silver and gold stains, chromic potassium alum stains, haemotoxylin stain, Isamin blue stain, osmium stains, PAS, T-blue, congo red, crystal violet, etc. In some embodiments, "virtually-stained histological image" refers to an image that mimics the staining of un-labelled tissue. In other words, a virtually-stained histological image shows how un-labelled tissue would look, or could potentially look, if it were stained.

[0014] FIG. 1A is a diagram of a cartridge for storing un-labelled tissue. As shown in FIG. 1A, the cartridge 100 may include a container 110, an optical substrate 120, a lid 130, a membrane 140, and a cap 150. As further shown in FIG. 1A, the cartridge 100 may store un-labelled tissue 160.

[0015] The container 110 may store un-labelled tissue 160 and may be connected to an optical imaging system 200 (shown in FIG. 2) configured to generate a virtually-stained histological image of the un-labelled tissue 160. The container 110 may include a top surface 110-1, a bottom surface 110-2, and a side surface 110-3. The bottom surface 110-2 and the side surface 110-3 of the container 110 may form a cavity in which the un-labelled tissue 160 is placed and stored. The container 110 may be made of any suitable material (e.g., plastic, metal, etc.) and may have any suitable shape (e.g., circular, hexagonal, square, etc.).

[0016] The optical substrate 120 may be provided on the bottom surface 110-2 of the container 110. With the optical substrate 120, the optical imaging system 200 may image the non-labeled tissue 160 through the optical substrate 120 to generate a virtual stained histological image 240 of the non-labeled tissue 160 (as shown in FIG. 2). The optical substrate 120 may be formed from any suitable material and may have any suitable shape. For example, the optical substrate 120 may be composed of an optically transparent material configured to be suitable for the operating wavelength of the optical imaging system 200. As a specific example, based on the excitation wavelength of the optical imaging system 200 in the range of 250 nm to 270 nm, the optical substrate 120 may be ultraviolet fused silica or quartz. Further, the optical substrate 120 may be configured to allow photons of a specific wavelength to pass through based on a specific configuration of the optical imaging system 200.

[0017] In addition to or instead of this, the optical substrate 120 may be provided with an anti-reflection coating. In some implementations, the anti-reflection coating is for single use only and thus may not need to comply with sterilization or cleaning protocols. Thus, the disposable nature of the optical substrate 120 can prevent the cartridge 100 from being used multiple times, thereby preventing or reducing the risk of contamination and false negatives or false positives.

[0018] In addition to, or alternatively to, this, the optical substrate 120 may comprise a Fabry - Pérot etalon 180 (such as shown in FIGS. 1B and 1C) to enable the optical imaging system 200 to acquire all photoacoustic data streams. The optical imaging system 200 may use the Fabry - Pérot etalon 180 to acquire ultrasonic propagation data used in conjunction with photon absorption remote sensing data streams (e.g., emission, non - emission, and scattering) and assist in the image reconstruction of an image of the unlabeled tissue 160. The Fabry - Pérot etalon 180 may be provided on the upper surface 120 - 1 of the optical substrate 120 that contacts the unlabeled tissue 160. Alternatively, the Fabry - Pérot etalon 180 may be provided on the bottom surface 120 - 2 of the optical substrate 120. The Fabry - Pérot etalon 180 is placed on the surface of the optical substrate. The Fabry - Pérot etalon 180 can be deposited on the surface of the glass using thin - film deposition techniques. Acoustic waves 172 are generated by an initial pressure (generated from the absorption of the excitation light from the excitation laser 176) that modulate the thickness of the thin film of the Fabry - Pérot etalon 180, which are detected as a modulation on the detection laser 178. The detection laser collection unit 174 can be set to acquire the emission / non - emission channel 182 at the depth of focus into the tissue, and the Fabry - Pérot etalon channel 184 at the first and second surfaces of the Fabry - Pérot etalon 180.

[0019] In addition to, or instead of, this, the cartridge 100 may comprise a transducer 186 (as shown in FIG. 1D) to enable the optical imaging system 200 to acquire an ultrasonic data stream. The ultrasonic data stream can assist in examining signals at a greater depth than can be addressed using photon absorption remote sensing, and the ultrasonic data stream can enable the optical imaging system 200 to reconstruct and collect depth scan information. The transducer 186 may be provided on the optical substrate 120. Instead of this, the transducer 186 may be provided in mechanical contact with the cartridge 100. In addition to this, the cartridge 100 may include a liquid buffer. In this case, the ultrasonic wave 172 may pass through the liquid buffer and reach the transducer 186.

[0020] In addition to, or alternatively to, this, the cartridge 100 may comprise an electrical via 188 that enables current to pass through the transducer 186 of the cartridge 100 without causing a leak in the casing in the cartridge 100 (as shown in FIG. 1D). Further, the electrical via 188 may interconnect the cartridge 100 to the cartridge plate 230 of the optical imaging system 200. In this case, an interlock may be provided by an electrical loop to prevent operation of the optical imaging system 200 in a situation where the cartridge 100 is not properly connected to the optical imaging system 200. Since the transducer 186 may be sensitive to time-of-flight, the system may be capable of reconfiguring and collecting depth scans. The physical transducer 186 may be incorporated within the cartridge (either on the container wall or on the optical substrate 120). The transducer 186 may have physical electrical contacts for connection to connectors. FIG. 1D shows three options for the location of the transducer 186 and subsequent electrical via 188. The electrical via 188 may also be incorporated within the optical substrate 120 or on the wall of the cartridge so as to increase the distance from the location of the actual transducer 186. It is possible to add a liquid to the cartridge to enable improved acoustic wave propagation.

[0021] The lid 130 may be provided on the upper surface of the container 110 and may include a film 140 for pressing the non-labeled tissue 160 against the optical substrate 120 such that the entire stump 170 of the non-labeled tissue 160 is flat against the optical substrate 120. As used herein, "flat" may refer to the surface of the non-labeled tissue 160 being in contact with the surface of the optical substrate 120 (e.g., upper surface 120-1) such that there is no gap between the surface of the non-labeled tissue 160 and the surface of the optical substrate 120. For example, as shown in FIG. 1, the film 140 may receive an external pressure 105 (i.e., pressure from outside the cartridge 100) and transmit an internal pressure 115 (pressure from within the cartridge 100) to the non-labeled tissue 160 to press the non-labeled tissue 160 against the optical substrate 120. The film 140 may receive the external pressure 105 from a human operator, a pressure assembly 600 (described in more detail in connection with FIG. 6), etc. Based on the acting pressure, the film 140 can be shaped to fit the surface of the non-labeled tissue 160 and press the non-labeled tissue 160 against the optical substrate 120. The lid 130 may be formed from any suitable material and may be of any suitable shape. Further, the film 140 may be formed from any suitable material and may be of any suitable shape. The external pressure 105 can be used in conjunction with an internal vacuum, for example, to evacuate air pockets and remaining undesirable fluids. The vacuum may not be sufficient to flatten the tissue, so it is possible to use the external pressure 105 thereafter. Alternatively, the external pressure 105 (repeating thumping) can be used to move fixed air bubbles, and the vacuum can be used to draw out those air bubbles.

[0022] The cap 150 may be provided on the bottom surface of the container 110 and may protect the optical substrate 120. The cap 150 may be formed from any suitable material and may be of any suitable shape. The optical imaging system 200 can automatically remove the cap 150 by mechanical action so that the optical substrate 120 is not inadvertently damaged during installation of the cartridge 100 of the unlabeled tissue 160. In situations where an "upper cap" (not shown) is provided above the lid 130 (for example, when the membrane is permeable), the cap 150 may be referred to as a "bottom cap". The "upper cap" may seal the unit for proper storage of fresh tissue. When the membrane is completely impermeable to fluid transfer, the upper cap may not be required at this time.

[0023] A surgeon, medical professional, or other entity may excise the unlabeled tissue 160 from a patient and place the unlabeled tissue 160 on the optical substrate 120 within the container 110. By way of example, the unlabeled tissue 160 may be rinsed before being placed in the container 110, fixed before being placed in the container 110, or placed directly in the container 110 without any treatment (e.g., immediately after excision without any intervening processing steps between excision and placement in the container). In some embodiments, the unlabeled tissue 160 may be placed in the cartridge within a threshold time frame (e.g., within 1 minute, within 5 minutes, within 10 minutes, etc.) after being excised from the patient.

[0024] In some embodiments, fluid may be added into the cartridge 100 to assist imaging. By way of example, the fluid may be saline, water, methanol, ethanol, acetic acid, acetic acid and ethanol, formaldehyde, paraformaldehyde, picrate, hepes-glutamate buffered organic solvent, aluminum chloride, etc. In addition to, or instead of, this, a fixing medium (e.g., formalin, paraffin, etc.) may be added to the cartridge 100 (e.g., pumped through the fluid port 185), and the unfixed tissue 160 may be preserved during storage of the unfixed tissue 160 after imaging of the unfixed tissue 160.

[0025] As shown in FIG. 1E, the fluid port 185 may be provided at the upper position 190. It is possible to add or remove fluid through the fluid port 185. When a vacuum is applied to the fluid port 185, the flexible membrane 140 is pressed, and the membrane 140 can take a shape conforming to the tissue 160, and the tissue 160 can be pressed. In some embodiments, a fluid channel 188 may fluidly connect the fluid port 185 to the container 110.

[0026] As shown in FIG. 1F, the fluid port 185 may be provided at the bottom position. In this case, the fluid port 185 is on the bottom side 192. The port 185 can engage a quick disconnect fitting on the machine side. In this way, it is possible to draw a vacuum from the bottom side / machine side, add liquid from the bottom side / machine side, or both, thereby clearing the user side (no obstacles to the user's fluid or tubing). A check valve can be added to allow only one-way flow as desired.

[0027] As shown in FIG. 1G, the fluid port 185 may be provided at the upper position 190. When no vacuum is applied, the membrane 140 does not deform. When a vacuum is applied to the port, the membrane 140 is deformed against the tissue 160. The membrane can deform plastically or elastically.

[0028] As shown in FIG. 1H, an external pressure 105 can be applied (through the membrane 140) to the dorsal / upper side of the tissue, which serves two functions. That is, 1) additional pressure is applied to promote the contact between the tissue / optical substrate 120, and 2) pressure is applied in such a way as to promote the bubbles 194 to leave the tissue / glass interface. Combining with a vacuum can also help the bubbles 194 to escape. The pressure can be static or alternating ("repeatedly striking") to facilitate the emergence of the bubbles 194. In both cases, it is possible to use an overview camera (210) to identify the locations where pressure needs to be applied to move the bubbles 194 from the optical substrate-tissue interface 120. Instead of the overview camera, it is possible to activate an optical imaging head (220) to view the bubbles 194. For example, a scattered image using a detection wavelength can clearly show the presence of the bubbles 194.

[0029] As shown in FIG. 1I, an external pressure array 107 can also be used in combination with a vacuum. For example, the external pressure array 107 can be a spring-loaded actuator, a pogo pin array, etc. In the case of a pogo pin array, the pins can be individually actuated to drive the bubbles 194 away from the optical substrate-tissue interface 120 or to apply pressure / force only over a specific area.

[0030] As shown in FIG. 1J, in the uncompressed state, the deep stump 163 of the excised tissue 196 is in contact with the optical substrate 120, and the peripheral stump 164 is lifted. All the stumps can be mapped based on standard anatomical orthotopia. The excised tissue 196 may be displayed in top view, side view, and bottom view (as shown from left to right in FIGS. 1J, 1K, and 1L). The excised tissue may contain a visible cancer 197.

[0031] As shown in FIG. 1K, the stump section 1 (161) is made completely flat with respect to the optical substrate, and pressure is first applied to the left side so as to be in focus. The stump section 1 (161) is the first scan region.

[0032] As shown in FIG. 1L, when the first scan is completed, the stump section 2 (162) is made completely flat with respect to the optical substrate, and then pressure is applied to the right side so as to be in focus. The stump section 2 (162) is the second scan region.

[0033] As shown in FIG. 1M, it is desirable that the optical substrate 120 be flat along the z = 0 plane so that the tissue interface remains at the focus in the light beam for ideal imaging. When pressure or vacuum is applied, the optical substrate 120 (and the tissue interface) may deform and the image may become out of focus (blurred). By knowing the discrete values of the pressure or vacuum applied, it is possible to pre-determine the "bending" profile 198 of the optical substrate 120, and during the scan, it is possible to move the tissue sample up and down along the bending profile 198 so that the image does not become blurred. Alternatively, a combination of pressure and vacuum can be "offset" from each other so that the optical substrate and the tissue remain flat.

[0034] Figure 2 is a diagram of a cartridge that connects to an optical imaging system. As shown in Figure 2, the cartridge 100 may be connected to the optical imaging system 200. For example, as shown, the cartridge 100 may be connected to the cartridge plate 230 of the optical imaging system 200. The optical imaging system 200 may include, among other things, a camera head 210, an imaging head 220, and a cartridge plate 230. The optical imaging system 200 may be configured to move the cartridge plate 230 so that the cartridge 100 is positioned above the camera head 210 or the imaging head 220 to enable imaging of the unlabeled tissue 160. As further shown in Figure 2, the optical imaging system 200 may be configured to generate a virtual stained histological image 240 of the unlabeled tissue 160. In addition to, or instead of, this, the optical imaging system 200 may be configured to generate other types of images of the unlabeled tissue 160.

[0035] In some implementations, the optical imaging system 200 may be an imaging system using photoacoustic remote sensing, such as an imaging system using photon absorption remote sensing. In this case, the optical imaging system 200 may use a picosecond-scale pulsed excitation laser 176 (shown in FIG. 1B), and the pulsed excitation laser 176 is focused on the unlabeled tissue 160 to generate radiative effects (e.g., light emission), non-radiative effects (e.g., heat and pressure), and scattering effects in the unlabeled tissue 160. Further, the optical imaging system 200 can capture photons and convert the photons into various forms of emission (e.g., non-radioactive and radioactive) from the unlabeled tissue 160, while the scattered photons continue to move through other parts of the unlabeled tissue 160 and continue to interact with other parts of the unlabeled tissue 160. Furthermore, the optical imaging system 200 may be an imaging system using photoacoustic remote sensing, such as a photo-thermal imaging system. In this case, the optical imaging system 200 may use a second confocal detection beam to record the non-radiative effects, thereby enabling the detection of temperature or pressure changes. The optical imaging system 200 can record the changes as a modulation of the backscattering intensity and directly correlate the modulation with the local non-radiative absorption contrast. The non-perturbed backscattering (pre-excitation event) simultaneously acquires the optical scattering contrast. In this way, the optical imaging system 200 may combine the acquired contrasts or visualize the acquired contrasts separately.The optical imaging system 200 may be configured to implement one or more techniques as described in U.S. Patent No. 10,117,583, issued November 6, 2018; U.S. Patent No. 10,327,646, issued June 25, 2019; U.S. Patent No. 10,627,338, issued April 21, 2020; U.S. Patent Application Publication No. 2020 / 0359903, published November 19, 2020; U.S. Patent Application Publication No. 2021 / 0199566, published July 1, 2021; U.S. Patent Application Publication No. 2021 / 0404948, published December 30, 2021; U.S. Patent No. 11,122,978, issued September 21, 2021; International Publication No. 2021 / 255695, published December 23, 2021; and PCT Application No. PCT / IB2022 / 054433, filed May 12, 2022, the entire disclosures of which are incorporated herein by reference.

[0036] To generate a virtually stained histological image 240 of the unlabeled tissue 160, the optical imaging system 200 can use ultraviolet light to virtually stain the unlabeled tissue 160 and then color-match the virtually stained unlabeled tissue 160 to hematoxylin and eosin staining. In this way, the optical imaging system 200 can generate substantially similar histological images during surgery compared to the time-consuming and error-prone tissue processing and staining workflows as described above. The virtually stained histological image 240 may be an image of the unlabeled tissue 160 that includes a mimicked hematoxylin staining that stains cell nuclei in a dark blue-violet color and a mimicked eosin staining that stains cytoplasm and extracellular matrix in a pink hue.

[0037] Figure 3A is a diagram of a cartridge for storing unlabeled tissue that includes a notch. As shown in Figure 3A, the unlabeled tissue 160 may include a notch 310. The notch 310 may be a formation in the unlabeled tissue 160 that enables maintenance of the orientation of the unlabeled tissue 160 with respect to the patient. For example, as shown in Figure 3B, the notch 310 may correspond to the vertical (up - down) direction of the patient. In other examples, the notch may correspond to a horizontal direction within the patient, such as, for example, an outer - inner direction, or a front - back direction. After the unlabeled tissue 160 is excised from the patient, the notch 310 may be formed in the unlabeled tissue 160, such as by applying the notch 310 to the unlabeled tissue 160 or cutting the notch 310 into the unlabeled tissue 160, and the unlabeled tissue 160 may then be placed in the cartridge 100. Since the unlabeled tissue 160 is not processed compared to other techniques, the notch 310 has a low risk of being lost or damaged.

[0038] Figure 3B is a diagram of a display that includes a tissue image and an image of the patient's orientation. As shown in Figure 3B, the display 320 may display a tissue image 330, a tissue image axis 340, a patient image 350, a tissue image 360, and a direction indicator 370.

[0039] The tissue image 330 may be an image of the unlabeled tissue 160 imaged by the optical imaging system 200. The optical imaging system 200 may image the unlabeled tissue 160, detect the notch 310, and based on the notch, display the unlabeled tissue 160 on the display 320 in an orientation corresponding to the orientation of the unlabeled tissue 160 with respect to the patient. For example, as shown in Figure 3B, the notch 310 may correspond to the vertical direction of the patient. Thus, as illustrated, the display 320 may display the tissue image 330 such that the notch 310 is arranged in the vertical direction.

[0040] The tissue image 330 may include a tissue image axis 340 superimposed on the tissue image 330. The tissue image axis 340 may include a vertical axis (up-down axis) and a horizontal axis (outer-inner axis) as shown. The optical imaging system 200 may correspond the tissue image axis 340 to the notch 310. That is, as shown, the vertical axis of the tissue image axis 340 may be in the same plane as the direction indicated by the notch 310. For example, as shown in FIG. 3B, the notch 310 may correspond to the vertical direction of the patient. Thus, as shown, the display 320 may display the tissue image axis 340 on the tissue image 330 such that the vertical axis of the tissue image axis 340 is aligned with the notch 310.

[0041] The patient image 350 may be a representation of a body part of the patient and may include a tissue image 360 superimposed on the representation of the body part at the corresponding position where the unlabeled tissue 160 was excised from the patient. For example, as shown in FIG. 3B, the patient image 350 includes a tissue image 360 provided on the right cheek of the patient.

[0042] The optical imaging system 200 may receive information for identifying the location where the unlabeled tissue 160 was excised from the patient, and generate a patient image 350 and a tissue image 360 based on the location-identifying information. For example, the optical imaging system 200 may receive information based on an image acquired by the optical imaging system 200, based on user input, based on information stored on the cartridge 100, based on artificial intelligence (AI) techniques, based on analyzing the unlabeled tissue 160, etc. Further, the optical imaging system 200 may generate the patient image 350 such that the tissue image 360 is overlaid on the patient image 350 at a location corresponding to the location where the unlabeled tissue 160 was excised from the patient. Conventional workflows use ink to indicate the orientation of the sample. Nominally, these inks are not good for PARS because they absorb the excitation wavelength and / or the detection wavelength. In some implementations, the ink has an absorption spectrum outside the desired excitation wavelength and / or detection wavelength so that the ink does not interfere with the optical measurement. In some implementations, the surgeon may use an ink specific to PARS. In this way, the surgeon does not need to change the way of applying the ink of the present invention.

[0043] The orientation indicator 370 may be an indicator indicating the orientation of the unlabeled tissue 160 with respect to the patient, determined by the notch 310. For example, as shown in FIG. 3B, the optical imaging system 200 may overlay an orientation indicator 370 indicating the vertical direction on the tissue image 360 and the patient image 350.

[0044] Figure 4A is a diagram of a piece of paper that includes orientation marks. In addition to the function of the orientation marks, the paper also serves the functions of a blotting cloth and a cutting surface. As shown in FIG. 4, the paper 400 may include orientation marks 410. The paper 400 may be the paper on which the unlabeled tissue 160 is placed after being excised from a patient and before being placed in the cartridge 100. The orientation marks 410 may be marks that enable the orientation of the unlabeled tissue 160 with respect to the patient to be maintained. For example, as shown in FIG. 4A, the orientation marks 410 depicted as "I" and "III" may correspond to the vertical direction (e.g., bottom - top) of the patient, and the orientation marks 410 depicted as "IIII" and "II" may correspond to the horizontal direction (e.g., front - back or outside - inside) of the patient. The unlabeled tissue 160 is placed on the paper 400 and is oriented with respect to the orientation marks 410 so that the orientation of the unlabeled tissue 160 with respect to the patient can be confirmed.

[0045] Figure 4B is a diagram of a cartridge that includes orientation marks. As shown in Figure 4B, the optical substrate 120 may include orientation marks 420 that enable maintenance of the orientation of the unlabeled tissue 160 with respect to the patient. For example, the orientation marks 420 depicted as "I" and "III" may correspond to the vertical direction (e.g., bottom - top) of the patient, and the orientation marks 420 depicted as "IIII" and "II" may correspond to the horizontal direction (e.g., front - back or outside - inside) of the patient. The paper 400 may include orientation marks 410 that correspond to the orientation marks 420 provided on the optical substrate 120. In particular, the paper 400 may have exactly the same markings in exactly the same orientation as the orientation marks 420 on the optical substrate 120. The unlabeled tissue 160 may then be transferred to the optical substrate 120 by the same person or entity that performed the excision, or by a different person or entity, while maintaining the orientation of the unlabeled tissue 160 with respect to the orientation marks 420. For example, the excised unlabeled tissue 160 may be placed on the paper 400 in the intended orientation with respect to the orientation marks 410 of the paper 400 by a surgeon, and then an assistant, technician, nurse, other doctor may transfer the unlabeled tissue 160 to the optical substrate 120 by visually aligning the markers of the paper 400 with the orientation marks 420 of the cartridge 100, for example, to maintain the orientation intended by the surgeon.

[0046] In this way, the optical imaging system 200 can detect the orientation mark 420 and display the unlabeled tissue 160 on the display 320 in an orientation corresponding to the orientation of the unlabeled tissue 160 with respect to the patient. In addition to this, the optical imaging system 200 may superimpose the orientation mark on the image displayed by the display 320. The orientation mark 420 is depicted as being provided on the optical substrate 120, but the orientation mark 420 may be provided on any of the other components of the cartridge 100, such as the lid 130, the container 110, or the cap 150. For example, the cap 150 may be in a predetermined position when the unlabeled tissue 160 is disposed within the cartridge 100, the cap 150 may have the orientation mark 420, the orientation mark 420 is large, visible to the human naked eye, and coincides with the orientation mark 420 on the paper 400. When the cap 150 is key-fixed to the cartridge 100, the alignment of the unlabeled tissue 160 with respect to the cartridge 100 can be maintained even after the cap 150 is removed.

[0047] Figures 5A and 5B are diagrams of a cartridge containing a unique identifier. As shown in Figures 5A and 5B, the container 110 may include a unique identifier 500. The unique identifier 500 may be an identifier that can be electronically tracked. For example, the unique identifier 500 may be electronically tracked by an optical imaging system 200 via communication technologies such as a Quick Response (QR) code, Radio Frequency Identification (RFID), Near Field Communication (NFC), Bluetooth (registered trademark), or a barcode. As an example, based on the container 110 being connected to the optical imaging system 200, the optical imaging system 200 (e.g., the camera head 210) may read the unique identifier 500 provided on the bottom surface of the container 110 and obtain the unique identifier 500. It is also possible to use a detection laser as a scattering microscope that can also image barcodes (two-dimensional or one-dimensional). In this case, a visible camera may not be required. Figures 5A and 5B depict the unique identifier 500 as being provided in the form of a QR code (registered trademark) on the bottom surface of the container 110, but the unique identifier 500 may be provided at any position on any other component of the cartridge 100, such as the lid 130, the optical substrate 120, or the cap 150. The unique identifier 500 may be correlated with a patient name, a patient identifier, a tissue identifier, etc.

[0048] In addition to, or instead of, this, the unique identifier 500 may be an interlock for the operation of the optical imaging system 200. For example, the operation of the imaging head 220 of the optical imaging system 200 may be stopped until the cartridge 100 is connected to the optical imaging system 200 and the unique identifier 500 is detected by the optical imaging system 200. Instead of this, the cartridge 100 may be provided with another type of interlock at various positions or on another component of the cartridge 100. For example, the cartridge 100 may be provided with a mechanical feature that engages with the optical imaging system 200 when the cartridge 100 is connected to the optical imaging system 200.

[0049] In addition to, or alternatively to, this, the unique identifier 500 may be a control mechanism that prevents the cartridge 100 from being used multiple times. For example, the optical imaging system 200 may detect the unique identifier 500 and determine whether the cartridge 100 has already been used for imaging. Based on determining that the cartridge 100 has already been used for imaging, the optical imaging system 200 may prevent additional imaging of the unlabeled tissue 160 provided in the cartridge 100. In this way, the unique identifier 500 can prevent, i.e., reduce the number of, false positives or false negatives that occur based on cross-contamination.

[0050] In addition to, or alternatively to, this, the unique identifier 500 may include information that enables the optical imaging system 200 to apply an appropriate amount of pressure or displacement to the cartridge 100 to press the unlabeled tissue 160 against the optical substrate 120 so that the entire cut end of the unlabeled tissue 160 is flat against the optical substrate 120. For example, the unique identifier 500 may include information identifying a pressure value applied to the cartridge 100, a displacement value of the cartridge 100, an AI algorithm executed by the optical imaging system 200 to apply pressure to the cartridge 100, and the like. The identifier may also be associated with the country in which it is marketed. The identifier can also be associated with an IDE or RUO for regulatory approval.

[0051] FIG. 6A is a diagram of a cartridge that connects to a pressure assembly of an optical imaging system. FIG. 6B is a diagram of a pressure assembly of an optical imaging system that connects to a membrane of the cartridge. FIG. 6C is a diagram of pins and pads of a pressure assembly of an optical imaging system. As shown in FIGS. 6A-6C, the pressure assembly 600 may be configured to apply pressure to the unlabeled tissue 160 to press the unlabeled tissue 160 against the optical substrate 120 such that the entire stump 170 of the unlabeled tissue 160 is flat against the optical substrate 120. In some implementations, the pressure assembly 600 may be external to the cartridge 100. For example, the optical imaging system 200 may include the pressure assembly 600. Alternatively, the pressure assembly 600 may be internal to the cartridge 100. Individual actuators in the pressure assembly can be individually addressed to actuate only one at a time (or combinations of multiple) simultaneously.

[0052] As shown in FIGS. 6A-6C, as an example, the pressure assembly 600 may include an array of pins 610 and corresponding pads 620. By using the pins 610 and pads 620, the pressure assembly 600 can exert different pressures at different displacements (different locations along the surface of the membrane 140 and / or the lid 130). For example, the pads 620 may collectively cover the entire surface, substantially the entire surface, or another portion of the unlabeled tissue 160. Additionally, each pad 620 may individually cover a subset of the surface of the unlabeled tissue 160. Further, the pressure applied to each pad 620 via each respective pin 610 may be adjusted and varied such that the same or different pressures can be applied to each pad 620. In this way, the pressure applied to the surface of the unlabeled tissue 160 may be consistent across the entire surface of the unlabeled tissue 160 (e.g., when each pad 620 applies the same pressure), or may vary across the surface of the unlabeled tissue 160 (e.g., when one or more pads 620 apply different pressures). In this way, the pressure assembly 600 may press the unlabeled tissue 160 such that the entire stump 170 of the unlabeled tissue 160 is flat against the optical substrate 120.

[0053] In some implementations, as shown in FIGS. 1J-1L, the optical imaging system 200 and / or the cartridge 100 may be configured to apply a positive pressure to the bottom surface of the optical substrate 120 to counteract bending of the optical substrate 120 and maintain flatness of the entire stump 170 of the unlabeled tissue 160 against the optical substrate 120.

[0054] The optical imaging system 200 may be configured to control the pressure assembly 600 to change the applied pressure such that the entire stump 170 of the unlabeled tissue 160 becomes flat against the optical substrate 120. In some implementations, the optical imaging system 200 may control the pressure assembly 600 to apply a specific pressure based on information obtained from the unique identifier 500 of the cartridge 100. For example, the unique identifier 500 may include pressure information that identifies a specific pressure to be applied based on a specific type of unlabeled tissue 160 to be imaged. The pressure information may include information that identifies a specific pressure to be applied by each group of pins 610 and pads 620 of the pressure assembly 600. For example, the pressure information may include a matrix of pressures to be applied to the unlabeled tissue 160 corresponding to the group consisting of pins 610 and pads 620. In other words, the pressure information may identify the specific pressure to be applied by each pad 620 of the pressure assembly 600, and each pad 620 corresponds to a specific subset of the surface of the unlabeled tissue 160. The pressure information may be pre-determined or may be determined using AI technology or the like.

[0055] In addition to, or instead of, this, the optical imaging system 200 may change the applied pressure based on an image of the unlabeled tissue 160. For example, the optical imaging system 200 (e.g., the camera head 210) may image the unlabeled tissue 160, and the optical imaging system 200 may control the pressure assembly 600 to change the applied pressure such that the entire stump 170 of the unlabeled tissue 160 becomes flat against the optical substrate. In some implementations, the AI algorithm executed by the optical imaging system 200 may control the pressure assembly 600 to perform the aforementioned operations.

[0056] As shown in FIG. 6D, before the pressure assembly 600 contacts the membrane, the location and orientation of the pad array may already match the pin array 610. That is, the pins 610 engage the pads 620 before the membrane is stretched.

[0057] As shown in FIG. 6E, the pad array 620 is attached to a membrane rather than pins. In this way, a small permanent toroidal joint in the pressure assembly 600 is not necessary. Further, the pad array 620 can retain its shape after pressure is applied, which can hold the tissue in its orientation at that time even in some cases after the pressure assembly 600 is disengaged.

[0058] As shown in FIG. 6F, each pad 620 includes a cup-like depression and each pin 610 includes a rounded tip, which forms a toroidal joint upon contact. As shown in FIG. 6G, the space inside the cartridge is sealed. Vent holes may be required to allow air and fluid to flow. Another hole may be used to add fixative or embedding media. Ports can be incorporated into the pressure assembly 600 and the ports can be connected when the pressure assembly 600 engages the lid 130.

[0059] FIG. 7 is a diagram of a cartridge with fiducials. As shown in FIG. 7, the optical substrate 120 may include fiducials 700 that assist in aligning the camera head 210 and the imaging head 220 of the optical imaging system 200 and ensure that PARS acquisition is centered on an appropriate interrogation window. The fiducials 700 may be laser etched onto the optical substrate 120 or deposited onto the optical substrate 120 using photolithography tools (e.g., thin metal deposited and etched on a wafer level or die level). The fiducials 700 may be located outside the imaging window of the non-labeled tissue 160 (e.g., the outer annular ring of the optical substrate 120) so as not to interfere with PARS imaging of the tissue and to allow high laser densities to be used without damaging the optical substrate 120. The fiducials may be of the correct shape / size so as to have sufficient optical resolution for the visible camera to resolve. In some implementations, three or more fiducials are required to establish the x,y orientation. When the fiducials are scanned by the PARS head, the fiducials need to be within the optical field of the imaging system.

[0060] In some implementations, the fiducials 700 may be optical resolution targets that assist in both the axial auto-alignment (focusing direction) and the lateral alignment of the detection beam and the excitation beam of the optical imaging system 200. By measuring the fiducials in all four quadrants, the optical imaging system 200 may automatically level the cartridge plate 230 with respect to the beam and ensure that the focal plane is consistent across the entire field of view of the non-labeled tissue 160 during scan acquisition.

[0061] By using scattered images from both the excitation laser and the detection laser, the fiducial 700 may be optically resolved, and when done at the start of each new PARS acquisition, the fiducial image quality can serve as a beam health metric to ensure that the excitation and detection beams remain focused together over time to avoid system drift. If either the excitation or detection scattered image deviates or comes into focus, the optical imaging system 200 may activate an alarm indicating that the optical imaging system 200 requires realignment.

[0062] In some implementations, when an active alignment system is implemented by the optical imaging system 200, the scattered image of the fiducial 700 can be used to manipulate the beam to reacquire alignment of the optical imaging system 200.

[0063] In light of the above, during surgery, tissue may be excised from a patient and placed in the cartridge 100. The cartridge 100 may then be connected to the optical imaging system 200. The optical imaging system 200 can generate a virtually stained histological image 240 of the true stump 170 of the non-labeled tissue 160 while maintaining the orientation of the tissue excised from the patient in the cartridge 100. Further, in this way, the embodiments herein enable more accurately, quickly, and during surgery to confirm whether a stump negative exists, thereby improving the safety and effectiveness of surgical resection of cancerous tumors.

[0064] FIG. 8 is a diagram of components of an optical imaging system. As shown in FIG. 8, optical imaging system 200 may include a bus 810, a processor 820, a memory 830, a storage component 840, an input component 850, an output component 860, and a communication interface 870. In addition to the components described in connection with FIGS. 2 and 6A-6C (e.g., camera head 210, imaging head 220, and pressure assembly 600), optical imaging system 200 may include the aforementioned components.

[0065] Bus 810 includes components that enable communication between components of optical imaging system 200. Processor 820 may be implemented in hardware, firmware, or a combination of hardware and software. Processor 820 may be a central processing unit (CPU), a graphics processing unit (GPU), an acceleration processing unit (APU), a microprocessor, a microcontroller, a digital signal processor (DSP), a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), or another type of processing component.

[0066] Processor 820 may include one or more processors that can be programmed to execute functions. Memory 830 may include random access memory (RAM), read only memory (ROM), and / or another type of dynamic or static storage device (e.g., flash memory, magnetic memory, and / or optical memory) that stores information and / or instructions for use by processor 820. Storage component 840 may store information and / or software related to the operation and use of optical imaging system 200. For example, storage component 840 may include a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optical disk, and / or a solid state disk), a compact disk (CD), a digital versatile disk (DVD), a floppy disk®, a cartridge, a magnetic tape, and / or another type of non-transitory computer-readable medium, along with a corresponding drive.

[0067] The input component 850 may include components that enable the optical imaging system 200 to receive information via user input (e.g., a touch screen display, keyboard, keypad, mouse, button, switch, and / or a microphone for receiving a reference sound input). In addition to, or instead of, this, the input component 850 may include sensors for detecting information (e.g., a global positioning system (GPS) component, an accelerometer, a gyroscope, and / or an actuator). The output component 860 may include components that provide output information from the optical imaging system 200 (e.g., a display 320, a speaker for outputting sound at an output sound level, and / or one or more light emitting diodes (LEDs)).

[0068] The communication interface 870 may include components such as a transceiver that enable the optical imaging system 200 to communicate with other devices via a wired connection, a wireless connection, or a combination of a wired connection and a wireless connection (e.g., a transceiver and / or a separate receiver and transmitter). The communication interface 870 may enable the optical imaging system 200 to receive information from another device and / or provide information to another device. For example, the communication interface 870 may include an Ethernet (registered trademark) interface, an optical interface, a coaxial interface, an infrared interface, a radio frequency (RF) interface, a universal serial bus (USB) interface, a Wi-Fi interface, a cellular network interface, etc.

[0069] The optical imaging system 200 may perform one or more processes described herein. The optical imaging system 200 may perform these processes based on a processor 820 that executes software instructions stored by a non-transitory computer-readable medium such as a memory 830 and / or a storage component 840. The computer-readable medium is defined herein as a non-transitory memory device. The memory device may include a memory space within a single physical memory device or a memory space distributed across multiple physical memory devices. The software instructions may be read into the memory 830 and / or the storage component 840 from another computer-readable medium or from another device via a communication interface 870. When executed, the software instructions stored in the memory 830 and / or the storage component 840 may cause the processor 820 to perform one or more processes described herein.

[0070] In addition to, or instead of, software instructions, a hardwired circuit may be used to perform one or more processes described herein, either alone or in combination with software instructions. Accordingly, the implementations described herein are not limited to any particular combination of hardware circuitry and software.

[0071] The number and arrangement of components shown in FIG. 8 are provided as an example. In practice, the optical imaging system 200 may include additional components, fewer components, different components, or components arranged differently than those shown in FIG. 8. In addition to, or instead of, this, a set of components of the optical imaging system 200 (e.g., one or more components) may perform one or more functions described as being performed by another set of components of the optical imaging system 200.

[0072] FIG. 9 is a flowchart of a process for preparing an unlabeled tissue for imaging. As shown in FIG. 9, a process 900 for preparing an unlabeled tissue 160 for imaging may include a step of excising the unlabeled tissue 160 from a patient (operation 910), a step of forming a notch in the unlabeled tissue 160 (operation 920), and a step of transferring the unlabeled tissue 160 to a paper 400 including an orientation mark 410 corresponding to the orientation mark 420 of the cartridge 100 (operation 930). For example, a surgeon or other medical personnel may excise the unlabeled tissue 160 from the patient, form a notch in the unlabeled tissue 160, and place the unlabeled tissue 160 on the paper 400. In some cases, the process 900 may be performed within a threshold time frame (e.g., 1 minute, 5 minutes, 10 minutes, etc.). Alternatively, the notch may also be made during actual excision (i.e., a surgeon or medical personnel can make a notch while the tissue is still on / inside the patient).

[0073] FIG. 10 is a flowchart of a process for preparing a cartridge for imaging. As shown in FIG. 10, process 1000 may include a step (operation 1010) of obtaining a unique identifier 500 of cartridge 100 that includes non-labeled tissue 160. For example, optical imaging system 200 may detect unique identifier 500 via RFID, via QR, etc., by reading a serial number. As further shown in FIG. 10, process 1000 may include a step (operation 1020) of determining the pressure or vacuum to apply to non-labeled tissue 160 based on unique identifier 500. For example, optical imaging system 200 may determine pressure or vacuum information such as internal pressure, external pressure, pressing settings compliant with a standard, vacuum settings, pressure of pressure assembly 600, positive pressure, etc. As a specific example, optical imaging system 200 may determine information identifying the pressure or vacuum applied by each respective group of pins 610 and pads 620 of pressure assembly 600. As further shown in FIG. 10, process 1000 may include a step (operation 1030) of adding buffer solution to cartridge 100 and a step (operation 1040) of sealing cartridge 100.

[0074] FIG. 11 is a flowchart of a process for detecting an interlock between a cartridge and an optical imaging system. As shown in FIG. 11, process 1100 may include a step of detecting an interlock between cartridge 100 and optical imaging system 200 (operation 1110). For example, optical imaging system 200 may detect a mechanical feature that engages with optical imaging system 200 when cartridge 100 connects to optical imaging system 200, and detect the interlock based on detecting the mechanical feature. Alternatively, optical imaging system 200 may optically detect cartridge 100, such as via camera head 210, and detect the interlock based on optically detecting cartridge 100. In addition to or instead of this, optical imaging system 200 may detect a unique identifier 500 of cartridge 100 and detect the interlock based on optically detecting the unique identifier 500 of cartridge 100.

[0075] As further shown in FIG. 11, process 1100 may include a step of applying pressure or vacuum to non-labeled tissue in cartridge 100 (operation 1120). For example, optical imaging system 200 may apply pressure or vacuum to non-labeled tissue in cartridge 100. As a specific example, optical imaging system 200 may control pressure assembly 600 to apply pressure or vacuum to non-labeled tissue 160. In this case, optical imaging system 200 may determine pressure or vacuum information, control each pin 610 and pad 620 of pressure assembly 600, and apply a specific pressure or vacuum to a group of each pin 610 and pad 620 of pressure assembly 600 to apply a consistent or varying pressure or vacuum to the surface of non-labeled tissue 160.

[0076] FIG. 12 is a flowchart of a process for imaging tissue. As shown in FIG. 12, process 1200 may include a step of reading a quick response code of cartridge 100 (operation 1210). For example, optical imaging system 200 may read a QR code (registered trademark) provided on cartridge 100 and execute operations 1220-1260 based on the reading of the QR code (registered trademark).

[0077] As further shown in FIG. 12, process 1200 may include a step of applying pressure to unlabeled tissue 160 in cartridge 100 (operation 1220). For example, optical imaging system 200 may apply pressure to unlabeled tissue 160. As a specific example, optical imaging system 200 may determine pressure information and control each group of pins 610 and pads 620 of pressure assembly 600 to apply a consistent or varying pressure to the surface of unlabeled tissue 160. Using visible camera (210), the system can confirm whether air exists between the optical substrate and the tissue. Alternatively, the scattered image from imaging head (220) can give a very clear indication (usually a very high signal) that the tissue is not flat against the optical substrate. In this example, if the scattered image at 210 captures an air pocket after a full scan, more pressure (or vacuum) can be applied to the area of the air pocket to remove the air and bring the tissue into contact with the sample, and the system can rescan that area. In this case, the newly scanned area can be stitched to the full scan to create an image completely free of air pockets.

[0078] As further shown in FIG. 12, process 1200 may include a step of determining whether the unlabeled tissue is flat (operation 1230). For example, optical imaging system 200 may determine whether unlabeled tissue 160 is flat with respect to optical substrate 120. Again, herein, "flat" may refer to the surface of unlabeled tissue 160 being in contact with the surface of optical substrate 120 (e.g., top surface 120-1) such that there is no gap between the surface of unlabeled tissue 160 and the surface of optical substrate 120. Optical imaging system 200 may determine that unlabeled tissue 160 is flat based on an image acquired by optical imaging system 200, detecting that there is no gap between the surface of unlabeled tissue 160 and the surface of optical substrate 120, determining that there are no air bubbles between the surface of unlabeled tissue 160 and the surface of optical substrate 120, applying a specific pressure to unlabeled tissue 160, etc.

[0079] As further shown in FIG. 12, if the unlabeled tissue is not flat (operation 1230-NO), then process 1200 may include returning to operation 1220. For example, optical imaging system 200 may repeatedly adjust the pressure applied to unlabeled tissue 160 until unlabeled tissue 160 is flat with respect to optical substrate 120.

[0080] As further shown in FIG. 12, process 1200 may include a step of detecting the boundary of the unlabeled tissue (operation 1240). For example, optical imaging system 200 may use camera head 210 and / or imaging head 220 to detect the boundary of unlabeled tissue 160. When imaging head 220 is used to detect the boundary, it is possible to use a low-resolution scattered image that can be fast.

[0081] As further shown in FIG. 12, process 1200 may include a step of setting a scan range (operation 1250). For example, the optical imaging system 200 may set the scan range of the optical imaging system 200 based on the detected boundary of the unlabeled tissue 160.

[0082] As further shown in FIG. 12, process 1200 may include a step of displaying an image of the unlabeled tissue and orienting the image of the unlabeled tissue with respect to the patient (operation 1260). For example, the optical imaging system 200 may display, via the display 320, the tissue image 330, the tissue image axis 340, the patient image 350, the tissue image 360, and / or the direction indicator 370, in a manner similar to that described above in connection with FIG. 3B.

[0083] FIG. 13 is a flowchart of a process for adjusting the imaging head of an optical imaging system. As shown in FIG. 13, process 1300 may include a step of automatically leveling the cartridge plate (operation 1310). For example, the optical imaging system 200 may measure the fiducial 700 in all four quadrants and automatically level the cartridge plate 230 with respect to the beam to ensure consistent focus across the entire field of view of the unlabeled tissue 160 during scan acquisition.

[0084] As further shown in FIG. 13, process 1300 may include a step of measuring the fiducial image quality (operation 1320). By using the scattered images from both the excitation laser and the detection laser, the fiducial 700 may be optically resolved. When performed at the start of each new PARS acquisition, the fiducial image quality can act as a beam health metric to ensure that the excitation beam and the detection beam remain focused together over time to avoid system drift. If either the scattered image of excitation or detection is off or in focus, the optical imaging system 200 may activate an alarm indicating that the optical imaging system 200 requires realignment.

[0085] FIG. 14 is a flowchart of a process for storing tissue in a cartridge. As shown in FIG. 14, process 1400 may include a step of adding a fixing medium to the cartridge (operation 1410) and a step of storing the cartridge (operation 1420). For example, a fixing medium (e.g., formalin, paraffin, etc.) may be added to the cartridge 100, and the cartridge 100 may be stored for later use, additional imaging, etc. In some implementations, the system can automatically detect air bubbles, analyze the air bubbles, and provide the user with instructions on how to adapt the mechanical fixation of the sample to better place the tissue.

[0086] It is to be understood that the principles of the present disclosure are described herein with reference to exemplary embodiments for specific applications, but the present disclosure is not limited thereto. Those skilled in the art and those having access to the teachings provided herein will recognize that all additional modifications, uses, embodiments, and equivalent substitutions are within the scope of the embodiments described herein. Therefore, the embodiments should not be regarded as limited by the foregoing description.

Claims

[Claim 1] A system for optical imaging of label-free tissues, An optical imaging system configured to image the unlabeled tissue to generate a virtually stained histological image of the unlabeled tissue, or to perform molecular detection or molecular diagnosis, The system comprises a cartridge for storing the unlabeled tissue imaged by the optical imaging system, and the cartridge is A container for storing the unlabeled tissue and for connecting to the optical imaging system, An optical substrate provided on the bottom surface of the container, wherein the optical imaging system is configured to image the unlabeled tissue through the optical substrate, A system comprising: a lid provided on the upper surface of the container, the lid having a film for pressing the unlabeled tissue against the optical substrate such that the entire cut end of the unlabeled tissue is flat with respect to the optical substrate.

Images