Patent ID: 12251086

DETAILED DESCRIPTION

As discussed above, more consistent processes for preserving tissue obtained via biopsy are needed. Such devices and methods are discussed in the present disclosure.

Within examples, a monitoring system includes a light source (e.g., a laser), a light detector (e.g., a photodiode), a processor, and a non-transitory computer readable medium storing instructions that, when executed by the processor, cause the monitoring system to perform functions. The functions include illuminating, via the light source, a biological sample (e.g., biopsied breast tissue) that is within a container while a fixation process is performed on the biological sample. For example, the biological sample is placed within a transparent container and is immersed in formalin. The formalin binds to and preserves proteins within the biological sample for subsequent evaluation. The degree to which the formalin binds to and preserves proteins within the biological sample is generally dependent on the duration the biological sample is immersed within the formalin and on the temperature of the formalin solution during that duration.

The functions also include determining, via the light detector, that an optical transmittance of the biological sample satisfies a condition. The optical transmittance of the biological sample can be used as a proxy for the degree of formalin fixation that has occurred in the biological sample. For example, the intensity of the light generated by the light source and incident upon the biological sample is compared to the intensity of the light transmitted through the container and the biological sample. Once the intensity of the transmitted light becomes less than or equal to a predetermined threshold value that corresponds with a desired level of formalin fixation, the monitoring system can responsively cease the fixation process. For example, the monitoring system can flush the formalin out of the container or cool the biological sample and/or the formalin to a temperature at which the formalin binding process substantially stops.

The monitoring system can be modular, for example, the container can be separable from the rest of the monitoring system such that the biological sample within the container can be transported and/or stored within the container prior to or after fixation of the biological sample. In some examples, the container is disposable.

FIG.1is a block diagram of a monitoring system100. The monitoring system100includes one or more of each of the following: a light source102, a light detector104, a pump106, a port108, a beam splitter110, a thermoelectric cooling module112, an actuator114, and a computing device200.

The light source102can be a laser or a broadband light source such as a tungsten-halogen light source. The light source102could also take the form of one or more light-emitting diodes (LEDs).

The light detector104can be a spectrometer or a photodiode, for example. Additionally, the light detector104could include an array of photodiodes or an area-based image sensor (e.g., a camera). The light detector104generally faces the light source102.

The pump106generally takes the form of a diaphragm pump, but other examples are possible. The pump106is configured to pump liquid to and from various chambers, containers, or reservoirs of the monitoring system100, as described in more detail below.

The port108forms a fluid connection to a container that holds a biological sample. Other ports108form a fluid connection to reservoirs within the monitoring system100that hold fluids such as water, paraffin, or formalin.

The valve(s)109can be used in conjunction with the pump106and the port(s)108to control the direction and flow of various fluids such as water, paraffin, or formalin.

The beam splitter110typically takes the form of two triangular prisms adhered to each other. The discontinuity of the joined surfaces of the prisms can be used to split an incident light beam into a transmitted beam and a reflected beam (e.g., having equal intensity).

The thermoelectric cooling module112takes the form of a junction of two different semiconductor or metal materials having differences in free electron density inherently or due to doping. When an electric current passes through the junction, a temperature gradient is generated between the two materials, which can be used to cool nearby objects such as a biological sample.

The actuator114is manually or electrically operated to clasp a biological sample (e.g., from a core needle). For example, the actuator114takes the form of a flat plate attached to a piston. In another example, the actuator114takes the form of a (e.g., flexible) membrane supported by one or more stiff (e.g., metal shafts) that are electromagnetically moved to clasp or release the biological sample.

FIG.2is a block diagram of the computing device200. The computing device200includes one or more processors202, a non-transitory computer readable medium204, a communication interface206, a display208, and a user interface210. Components of the computing device200are linked together by a system bus, network, or other connection mechanism212.

The one or more processors202can be any type of processor(s), such as a microprocessor, a digital signal processor, a multicore processor, etc., coupled to the non-transitory computer readable medium204.

The non-transitory computer readable medium204can be any type of memory, such as volatile memory like random access memory (RAM), dynamic random access memory (DRAM), static random access memory (SRAM), or non-volatile memory like read-only memory (ROM), flash memory, magnetic or optical disks, or compact-disc read-only memory (CD-ROM), among other devices used to store data or programs on a temporary or permanent basis.

Additionally, the non-transitory computer readable medium204can be configured to store instructions214. The instructions214are executable by the one or more processors202to cause the computing device200to perform any of the functions or methods described herein.

The communication interface206can include hardware to enable communication within the computing device200and/or between the computing device200and one or more other devices. The hardware can include transmitters, receivers, and antennas, for example. The communication interface206can be configured to facilitate communication with one or more other devices, in accordance with one or more wired or wireless communication protocols. For example, the communication interface206can be configured to facilitate wireless data communication for the computing device200according to one or more wireless communication standards, such as one or more Institute of Electrical and Electronics Engineers (IEEE) 801.11 standards, ZigBee standards, Bluetooth standards, etc. As another example, the communication interface206can be configured to facilitate wired data communication with one or more other devices. The communication interface206can also include analog-to-digital converters (ADCs) or digital-to-analog converters (DACs) that the computing device200can use to control various components of the monitoring system100.

The display208can be any type of display component configured to display data. As one example, the display208can include a touchscreen display. As another example, the display208can include a flat-panel display, such as a liquid-crystal display (LCD) or a light-emitting diode (LED) display.

The user interface210can include one or more pieces of hardware used to provide data and control signals to the computing device200. For instance, the user interface210can include a mouse or a pointing device, a keyboard or a keypad, a microphone, a touchpad, or a touchscreen, among other possible types of user input devices. Generally, the user interface210can enable an operator to interact with a graphical user interface (GUI) provided by the computing device200(e.g., displayed by the display208).

FIG.3shows functionality of the monitoring system100. A container404receives a biological sample402from a core needle or from a storage chamber within the monitoring system100. For example, the actuator114(not shown inFIG.3) can be used to clasp the biological sample402from the core needle as the core needle is inserted into the container404.

In another example, the pump106and the port108(not shown inFIG.3) can be used, via air or fluid pressure, to move the biological sample402from the storage chamber to the container404to be clasped by the actuator114and thereafter fixated and monitored.

The biological sample402is typically human tissue such as breast tissue biopsied using the core needle. The container404can be formed of partially or fully transparent plastic or glass. The container404is also fluid tight such that it is capable of additionally housing a liquid410(e.g., a formalin solution) that acts on the biological sample402to perform the fixation process. The liquid410is generally used as a fixative to prepare the biological sample402for examination. The pump106and/or the port108can be used to move the liquid410into the container404to immerse the biological sample402and perform the fixation process. The liquid410can be any liquid configured to perform the fixation process and preserve the biological sample402.

The light source102illuminates the biological sample402that is within the container404(e.g., a microfluidic or a millifluidic container) while the fixation process is performed on the biological sample402(e.g., while the biological sample402is immersed within the liquid410). For example, the light source102generates a light414and the beam splitter110splits the light414into a reference beam416and a sample beam418. Thus, the biological sample402is illuminated with the sample beam418that travels through the wall of the container404. The light414typically includes wavelengths ranging from 750 nm to 1000 nm, for example 800 nm to 816 nm, 792 nm to 824 nm, or a single wavelength approximately equal to 808 nm. However, the light414can include any wavelengths that are ultraviolet, visible, and/or infrared (e.g., near infrared).

Next, the monitoring system100(e.g., continuously) determines an optical transmittance of the biological sample402as the fixation process progresses. In practice, the optical transmittance will be a property of the container404and the liquid410as well, but the optical transmittance of the container404and the liquid410will generally not change over time. Generally, the optical transmittance of the biological sample402will decrease as the fixation process progresses, after an initial increase in the optical transmittance of the biological sample402. The monitoring system100determines the optical transmittance of the biological sample402by comparing a first intensity of a portion420of the sample beam418that transmits through the biological sample402, the liquid410, and the container404to a second intensity of the reference beam416. The optical transmittance of the biological sample402is generally equal to the (e.g., time varying) first intensity of the portion420divided by the (e.g., time varying) second intensity of the reference beam416.

FIG.4shows example data415that depicts the transmittance of the biological sample402(e.g., human breast tissue) with respect to fixation time and shows example data417that depicts the rate of change of the transmittance with respect to fixation time. The data415corresponds to the vertical axis on the left and the data417corresponds to the vertical axis on the right.

The monitoring system100determines that the optical transmittance of the biological sample402satisfies a condition. More specifically, the monitoring system100determines that the optical transmittance of the biological sample402is less than a threshold value413after some time passes (e.g., after four hours of fixation). More specifically, the monitoring system100determines that the optical transmittance attained a maximum412and determines that the optical transmittance of the biological sample402became less than the threshold value413after the optical transmittance attained the maximum412. In some examples, the fixation process causes the transmittance of the biological sample402to exhibit an increase prior to the transmittance exhibiting a larger decrease, as shown inFIG.4.

The threshold value413can be defined in various ways.FIG.4shows the threshold value413corresponding to a transmittance that is 10% of the maximum412(e.g., a 90% decrease relative to the maximum412). In other examples, threshold levels of 15%, 5%, or 1% could be used as the threshold value413.

In other examples, the threshold value can correspond to the transmittance at which the rate of change417has remained within a predetermined range of values for a predetermined amount of time. For example, the monitoring system100can identify the threshold value419based on the threshold value419corresponding to the value423on the rate of change curve417. As such, the predetermined amount of time in this example would be the amount of time that passes between the value421and the value423(e.g., approximately 2 hours) and the predetermined range of rate of change would be −0.1 to 0.1. Other examples are possible.

The monitoring system100then ceases the fixation process in response to determining that the optical transmittance of the biological sample402satisfies the condition (e.g., that the optical transmittance of the biological sample402is less than the threshold value413). For example, the monitoring system100, via the pump106and the port108, remove the liquid410from the container404by flushing the container with aqueous or preserving solution.

Referring toFIG.5, the biological sample402can be embedded within paraffin411for storage and/or cooled to a temperature that is less than or equal to 4° C., via the thermoelectric cooling module112. The container404is generally sealed after ceasing the fixation process.

In some examples, the monitoring system100includes multiple light sources102with multiple corresponding light detectors104configured for monitoring fixation of multiple biologic samples402simultaneously.

The upper panel ofFIG.6shows the container404after receiving the biological sample402but before the actuator114has clasped the biological sample402. The lower panel ofFIG.6shows the container404after the actuator114has clasped the biological sample402. InFIG.6, the actuator114is manually or electrically operated to clasp the biological sample402. For example, the actuator114takes the form of a flat plate attached to a piston.

The upper panel ofFIG.7shows the container404after receiving the biological sample402but before the actuator114has clasped the biological sample402. The lower panel ofFIG.7shows the container404after the actuator114has clasped the biological sample402. InFIG.7, the actuator114takes the form of a membrane supported by one or more stiff (e.g., metal) shafts115that are electromagnetically moved to clasp or release the biological sample402via solenoids117. In some examples, the membrane is flexible and conformable to the biological sample102.

AlthoughFIG.6andFIG.7show the light sources102and the light detectors104being oriented to emit and detect the light414as it travels vertically with respect toFIG.6andFIG.7, the light sources102and the light detectors104can be re-oriented to detect the light414as it travels into or out of the page with respect toFIG.6andFIG.7. In this orientation, the light sources102and the light detectors104can be positioned adjacent to the actuator114without the actuator114interfering with the light414.

FIG.8is a block diagram of a method700. As shown inFIG.8, the method700includes one or more operations, functions, or actions as illustrated by blocks302,304, and306. Although the blocks are illustrated in a sequential order, these blocks may also be performed in parallel, and/or in a different order than those described herein. Also, the various blocks may be combined into fewer blocks, divided into additional blocks, and/or removed based upon the desired implementation.

At block302, the method300includes illuminating the biological sample402that is within the container404while a fixation process is performed on the biological sample402. More details regarding block302can be found above with reference toFIG.3.

At block304, the method300includes determining that the optical transmittance of the biological sample402satisfies a condition. More details regarding block304can be found above with reference toFIG.4.

At block306, the method300includes ceasing the fixation process in response to determining that the optical transmittance of the biological sample402satisfies the condition. More details regarding block304can be found above with reference toFIG.5.

While various example aspects and example embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various example aspects and example embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.