Technical Field

The present disclosure generally relates to apparatus and methods to store specimen containers in a temperature controlled environment, and to monitor one or more parameters within the temperature controlled environment to prevent exposure of biological samples within the specimen containers to parameters that put the viability of the biological samples at risk.

BACKGROUND

Description of the Related Art

Long-term preservation of cells and tissues through cryopreservation has broad impacts in multiple fields including tissue engineering, fertility and reproductive medicine, regenerative medicine, stem cells, blood banking, animal strain preservation, clinical sample storage, transplantation medicine, and in vitro drug testing. This can include the process of vitrification in which a biological specimen or sample (for example, an oocyte, an embryo, a biopsy) contained in or on a storage device (for example, a cryopreservation straw, cryopreservation tube, stick or spatula) is rapidly cooled by placing the biological specimen and the storage device in a substance, such as liquid nitrogen. This results in a glass-like solidification or glassy state of the biological specimen (for example, a glass structure at the molecular level), which maintains the absence of intracellular and extracellular ice (for example, reducing cell damage and/or death) and, upon thawing, improves post-thaw cell viability. To ensure viability, the vitrified biological specimens must then be continuously stored in a liquid nitrogen dewar or other container containing the liquid nitrogen, which is at a temperature of negative 190 degrees Celsius.

There are, however, a number of concerns in how these biological specimens are being stored, identified, managed, inventoried, retrieved, etc. For example, each harvested embryo is loaded on a rigid specimen holder (for example, embryo straw, stick or spatula). In the case of a tubular specimen holder, the tube may be closed (for example, plugged) at one end and open at the other end. The cryopreservation storage devices (for example, specimen holders) containing or holding the embryos are cooled as quickly as possible by plunging the cryopreservation storage device with the biological material into a liquid nitrogen bath in a cryogenic freezer at a temperature of approximately negative 190 degrees Celsius, for example to achieve vitrification. More particularly, multiple cryop reservation storage devices are placed in a goblet for placement in the liquid nitrogen storage tank or freezer. The goblet attaches to the liquid nitrogen storage tank such that the multiple cryopreservation storage devices are suspended in the liquid nitrogen. Labels that are manually written-on using a suitable marker pen or printed using a custom printer are attached to the straw and/or the goblet. Such labels can include identification information corresponding to the individual that the embryo was harvested from and other suitable information (for example, a cryopreservation storage device number, a practitioner number, etc.).

Access to the biological specimens are required during normal operation. For example, a particular biological specimen or specimens may be required to perform a procedure (for example, implantation of a fertilized egg). Retrieval of cryopreservation storage devices and associated biological specimens from the cryogenic refrigerator or cryogenic tank in which the biological specimens are stored exposes the retrieved biological specimens to non-cryogenic conditions (for example, temperatures above negative 190° C, and depending on a duration of the exposure places the biological specimens at risk. Due to the way biological specimens are stored (for example, cryop reservation storage devices arrayed in cassettes, cassettes arrayed in stacks), retrieval of one or more desired biological specimens often requires retrieval of additional biological specimens that are not needed at that time, exposing such to risk. Additionally, transport of biological specimens from a cryogenic refrigerator to a site of an intended use (for example, fertilization, implantation) exposes the biological specimens to risk.

With regard to storage and management of these biological specimens, facilities employ personnel that are required to maintain the liquid nitrogen storage tanks (for example, by refilling them with liquid nitrogen when needed) and manage the inventory of stored biological specimens (for example, by performing periodic accountings). There is, however, little recordkeeping with regard to the proper storage of these biological specimens. For example, subsequent identification or otherwise handling of the vitrified biological specimen or sample can involve removal of the specimen from temperature-controlled storage and exposure of the sample to ambient temperature, thus potentially risking the viability of the sample.

BRIEF SUMMARY

Accordingly, it is desirable to provide new apparatus and methods for transferring biological specimens (for example, eggs, sperm, embryos) to and from a temperature controlled environment, and storage of the biological specimens within the temperature controlled environment. It is also desirable to provide new apparatus and methods to validate that the stored biological specimens were maintained at proper conditions (for example below a certain temperature) throughout the storage and retrieval process while maintaining records of the conditions for each of the stored biological specimens.

A cryogenic storage system to store specimen containers in a temperature controlled environment includes a cryogenic storage tank. The cryogenic storage tank includes at least one wall that forms an interior of the cryogenic storage tank and that thermally insulates the interior of the cryogenic storage tank from an exterior thereof to provide the temperature controlled environment. The cryogenic storage tank includes an opening that provides ingress into and egress out of the temperature controlled environment. The cryogenic storage system further includes at least a first temperature sensor positioned to sense a temperature in a first region of the temperature controlled environment in the interior of the cryogenic storage tank. The cryogenic storage system further includes at least a first level sensor positioned to sense a level of a cryogenic medium within the temperature controlled environment in the interior of the cryogenic storage tank.

According to one embodiment, the first region of the cryogenic storage system includes an upper region of the temperature controlled environment and the first temperature sensor is positioned to sense the temperature in the upper region of the temperature controlled environment. The cryogenic storage system further includes a second temperature sensor positioned to sense a temperature in a second region of the temperature controlled environment in the interior of the cryogenic storage tank, wherein the second region is a lower region of the temperature controlled environment, and the lower region spaced relatively below the upper region of the temperature controlled environment.

According to one embodiment, the at least a first temperature sensor and the at least a first level sensor each measure conditions in the interior of the cryogenic storage tank. The cryogenic storage system, in response to the measured conditions crossing a certain threshold, produces notifications or alerts prompting corrective action to restore the conditions to acceptable values by recrossing the certain threshold.

According to one embodiment, the cryogenic storage system creates a record for each of the specimen containers stored within the temperature controlled environment. The record includes one or more conditions associated with each of the respective specimen containers. The one or more conditions includes a temperature of a region within the interior of the temperature controlled environment over a period of time in which the respective specimen container was positioned within the region. The one or more conditions includes removal of the respective specimen container from the temperature controlled environment and the length of time from removal to re-entry of the respective specimen container back into the temperature controlled environment.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elements or acts. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale, and some of these elements are arbitrarily enlarged and positioned to improve drawing legibility. Further, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the drawings. Figure 1 is an isometric view of a cryogenic storage system, according to at least one implementation, the cryogenic storage system including or interfacing with a transfer system to facilitate transfer of biological specimens (for example, eggs, sperm, embryos) between a cryogenic freezer or storage tank that holds a liquid nitrogen bath and a portable thermally insulated carrier, and/or to facilitate identification of stored biological specimens and evidence chain-of-custody during handling.

Figure 2 is an isometric view of a storage cassette holding a plurality of specimen containers, with two of the specimen containers removed from the storage cassette to better illustrate aspects of those storage containers.

Figure 3 is an isometric view of a storage cassette, according to another implementation.

Figure 4 is an isometric view of a portable thermally insulated cryogenic carrier that carries or holds a number of carrier cassettes positioned with respect to an antenna array of a reader of a transfer system, according to at least one implementation.

Figure 5 is a side elevation view of a cryogenic storage system, according to at least one implementation, the cryogenic storage system including or interfacing with at least one sensor to measure at least one parameter with a temperature controlled environment of the cryogenic storage system.

Figure 6 is an isometric view of a storage cassette holding a plurality of specimen containers, according to at least one implementation.

Figure 7 is side view of one of the specimen containers illustrated in Figure 6.

Figure 8 is a screen print showing a tank status window of a user interface at a first time, according to at least one implementation.

Figure 9 is a screen print showing a tank status window of a user interface at a second time, according to at least one implementation.

Figure 10 is a screen print showing a tank status window of a user interface at a third time, according to at least one implementation. DETAILED DESCRIPTION

In the following description, certain specific details are set forth in order to provide a thorough understanding of various disclosed embodiments. However, one skilled in the relevant art will recognize that embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc. In other instances, well-known structures associated with computer systems, actuator systems, and/or communications networks have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. In other instances, well-known computer vision methods and techniques for generating perception data and volumetric representations of one or more objects and the like have not been described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to.”

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

The headings and Abstract of the Disclosure provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

Figure 1 shows a cryogenic storage system 100, according to at least one illustrated embodiment. The cryogenic storage system 100 may take one of a large variety of forms, typically including a cryogenic storage tank or freezer 102, which can store a number of containers in a cryogenic environment, for example immersed in a bath of liquid nitrogen at a temperature at or below about negative 190°C. The cryogenic storage tank or freezer 102 may be highly thermally insulated, and may, for example, include stainless steel interior and exterior walls with a vacuum and/or other thermal insulating material therebetween.

As illustrated in Figures 2 and 3, the containers stored by the cryogenic storage tank or freezer 102 are formed as specimen containers 200 (only one called out). These specimen containers 200 may be stored in storage cassettes 202 or storage cassettes 302 for long term storage via a cryogenic refrigerator, such as the cryogenic storage tank or freezer 102. Each specimen container 200 may include a vial 204 (only one called out), a cap 206 (only one called out), one or more wireless transponders (for example, radio frequency identification (RFID) transponders) 208 (only one called out), an elongated specimen holder 209 (for example, straw, rod, spatula), one or more machine-readable symbols 210 (only one called out), or any combination thereof.

The specimen containers 200 may be sized to store specimens of biological tissue, for instance eggs, sperm or embryos, for example on the elongated specimen holder 209. Various implementations of specimen containers are described in U.S. patent application 63/026,526, filed May 18, 2020; U.S. patent application 62/936,133, filed November 15, 2019; U.S. patent application 62/927,566, filed October 29, 2019; U.S. patent application 62/900,281 , filed September 13, 2019; U.S. patent application 62/880,786, filed July 31 , 2019; U.S. patent application 62/879,160, filed July 26, 2019; U.S. patent application 62/741 ,986, filed October s, 2018; and U.S. patent application 62/741 ,998, filed October 5, 2018.

The specimen containers 200 are typically arrayed in the storage cassette 202, 302 for example arrayed in a two-dimensional array (for example, 7 by 7, 10 by 10, 8 by 12, 14 by 14). The storage cassettes 202, 302 are typically stored in the cryogenic storage tank or freezer 102 in vertical stacks, the vertical stacks also called racks. The stacks or racks of storage cassettes 202, 302 may be annularly arrayed in the cryogenic storage tank or freezer 102 about a central axis of the cryogenic storage tank or freezer 102. The cryogenic storage tank or freezer 102 may include a turntable or convey in the interior thereof, on which the stacks or racks of storage cassettes 202, 302 are carried. This allows respective stacks or racks of storage cassettes 202 to be aligned with an opening 116 of the cryogenic refrigerator for placement or removal.

The storage cassette 302 maintains cryogenic conditions for an array of the specimen containers 200, for example 49 separate ones of the specimen containers 200, according to at least one implementation. As shown in the illustrated embodiment, the storage cassette 302 may include a bulk container 312 that delineates an interior compartment 328. The interior compartment 328 may have an interior compartment profile, and the bulk container 312 may have an opening 330 at the top thereof.

The storage cassette 302 may further include a thermal shunt 332 with a substrate 334. According to one embodiment, the substrate 334 includes a metal. As shown, the substrate 334 may include a first major face 336 and a second major face 338, the second major face 338 opposed from the first major face 336 across a thickness of the substrate 334. The substrate 334 may have an array of a plurality of through holes 340 that extend through the thickness of the substrate 334. Each of the through holes 340 of the substrate 334 may be shaped and sized to receive at least a portion of the specimen containers 200.

As shown, the substrate 334 may be closely receivable in the interior compartment 328 of the bulk container 312. The thermal shunt 332 may have an outer profile that is asymmetrical to ensure that the thermal shunt 332 is positioned correctly in the interior compartment 328 of the bulk container 312. The thermal shunt 332 may be made of any of a variety of materials, preferably having a relatively large thermal mass as compared to the materials to be stored in the storage cassette 302. Suitable materials for the thermal shunt 332 may include, for example, slabs of non-ferrous metals, or metal impregnated polymers where the metal is a non-ferrous metal or the metal is in the form of small pieces, particles or strands that are sufficiently small and discontinuous as to prevent or retard the formation of currents therethrough. In at least some implementations, the thermal shunt 332 takes the form of an aluminum plate, slab, or slug. The storage cassette 302 may further include a thermally insulative material 342 closely receivable in the interior compartment 328 of the bulk container 312, the thermally insulative material 342 may have an array of a plurality of through holes 344 that extend there through. The thermally insulative material 342 reduces heat transfer (via conduction, convection, or both) outward from the thermal shunt 332 toward an external environment of the storage cassette 302.

According to one embodiment, each of the through holes 344 of the thermally insulative material 342 may be shaped and sized to receive at least a portion of the specimen containers 200. According to one embodiment, the thermally insulative material 342 may include a first portion 346 and a second portion 348. As shown the first portion 346 and the second portion 348 may be securable to one another, for example with one or more fasteners 350.

The thermally insulative material 342 and the thermal shunt 332 may be stacked in the interior compartment 328 of the bulk container 312 such that each of the through holes 344 of the thermally insulative material 342 is axially aligned with a respective one of the through holes 340 of the thermal shunt 332. The through holes 340 and 344 may have matching shapes, or alternatively, the through holes 340 may have a shape that is different from that of the through holes 344. The through holes 340, the through holes 344, or both the through holes 340 and 344 may be circular. The through holes 340, the through holes 344, or both the through holes 340 and 344 may be square with rounded corners.

Returning to Figure 1 , the cryogenic storage tank or freezer 102 includes an opening 116 and a door or cover 118 to selectively open and close the opening 116, to respectively provide access to the interior of the cryogenic storage tank or freezer 102 from an exterior thereof, and to prevent access, as well as hermetically seal the interior from the exterior to maintain the cryogenic temperature in the interior of the cryogenic storage tank or freezer 102. The stacks or racks of storage cassettes 202, 302 may be selectively placed into the interior of the cryogenic storage tank or freezer 102 for storage at cryogenic temperatures and removed from the interior of the cryogenic storage tank or freezer 102 for use via the opening 116. According to one embodiment, the cryogenic storage tank or freezer 102 may include one or more insulated sleeves deployable to surround the one or more of the stacks or racks of storage cassettes 202, 302. The one or more insulated sleeves may be deployed when the stacks or racks of storage cassettes 202, 302 are being handled or accessed for insertion and removal from the cryogenic storage tank or freezer 102. For example is one of the storage cassettes 202, 302 in a first rack is being handled, insulated sleeves may be deployed to surround the other racks.

According to one embodiment, the cryogenic storage tank or freezer 102 may include one or more breakaway or removable panels. Thus, in the event of a failure, (for example, a power outage) the inside of the temperature controlled environment 17 may be accessed quickly to facilitate removal of the storage cassettes 20 enabling the storage cassettes 20 to be quickly placed in another temperature controlled environment. According to one embodiment, at least a portion of the cryogenic storage tank or freezer 102 may be transparent so as to enable vision of the storage cassettes 20 within the temperature controlled environment 17 from outside the temperature controlled environment 17.

In some implementations, the stacks or racks of storage cassettes 202, 302 are manually removed from the cryogenic storage tank or freezer 102 when needed, and manually placed in the cryogenic storage tank or freezer 102 to store the specimens in the specimen containers 200 at cryogenic temperatures. In other implementations, the cryogenic storage system 100 includes a picker or elevator 120 to automatically remove selected ones of the stacks or racks of storage cassettes 202, 302 from the cryogenic storage tank or freezer 102 when needed, and to automatically place the storage cassettes 202, 302 with the specimen containers 200 in the cryogenic storage tank or freezer 102 to store the specimens in the specimen containers 200 at cryogenic temperatures.

The storage and retrieval mechanism (for example, turntable, picker or elevator) of the cryogenic storage tank or freezer 102 can automatically replicate movements of a human, and hence is denominated as a robot or robotic system. Whether manually moved or automatically moved, it is typically important to minimize exposure of the specimens to temperatures higher than about negative 190°C (for example, ambient room temperature or about 23 °C).

A transfer system 122 may facilitate a transfer of specimen containers 200 from the storage cassettes 202 to carrier cassettes and/or to portable thermally insulated cryogenic carriers in which the carrier cassettes are carried. The transfer system 122 may be part of the cryogenic storage system 100, or may be provided as a separate system that interfaces with the cryogenic storage system 100. For example, the transfer system 122 may interface with a conventional commercially available cryogenic automated storage system (for example, the Bistore III Cryo - 190°C System sold by Brooks Life Sciences)).

The transfer system 122 includes one or more readers 124 (only one shown in Figure 1 ) operable to read information from one or more wireless transponders physically associated with respective specimen containers 200, storage cassettes 202, and/or carrier cassettes 302 (Figure 3). As explained in detail herein, the readers 124 may include one or more antennas, for example a two- dimensional array of antennas 126, and one or more transmitters, receivers, transceivers (collectively radios), operable to cause the antennas to emit interrogation signals and to receive response signals in response to the interrogations signals. The reader(s) 124 may take the form of an RFID reader or interrogator. The transfer system 122 may include one or more dedicated user interface components (for example, touch screen display, speakers, microphones), or may employ a user interface component of the cryogenic storage system 100, for example one or more touch screen displays 128.

Portions of the cryogenic system 100 may be of a conventional design. For example, the cryogenic storage tank or freezer and/or the picker or elevator may take the form of a commercially available automated storage system (for example, the Bistore III Cryo -190°C System sold by Brooks Life Sciences). Some, or even all, of the cryogenic system 100 may include structures and methods for described herein, and thus are not known by the applicant to be either conventional or commercially available. For example, the transfer system 122 including the reader 124 is operable to work with a portable thermally insulated cryogenic carrier 400 (Figure 4, described below), and to facilitate transfer of the specimen containers 200 between the storage cassette 202, 302 and a portable carrier.

Figure 4 shows a portable thermally insulated cryogenic carrier 350 that carries or holds a number of the carrier cassettes 202, 302a, 302b (a smaller version of the storage cassette 302 described above) positioned with respect to an antenna array 126 of the reader 124 of the transfer system 122, according to at least one illustrated implementation.

The portable thermally insulated cryogenic carrier 350 is shown without a cover, and with the carrier cassettes 302a, 302b removed to better illustrate various features. In use, the portable thermally insulated cryogenic carrier 300 may hold a liquid nitrogen bath in the interior thereof, and the carrier cassettes 302a, 302b may be positioned at least partially immersed in the liquid nitrogen bath in the interior of the portable thermally insulated cryogenic carrier 350, with a cover positioned to close the opening at the top of the portable thermally insulated cryogenic carrier 350.

The antenna array 126 and/or the reader 124 may be supported by a platform or frame 356. The platform or frame 356 may have a lip 358 that allows the platform or frame 356 to be hung from a structure (for example, edge, handle) of the cryogenic storage tank or freezer 102, advantageously allowing the antenna array 126 and/or the reader 124 to be positioned proximate the cryogenic storage tank or freezer 102 to facilitate transfers between. This also advantageously allows simplified retrofit of the processor-based transfer system 122 to the cryogenic storage tank or freezer 102. Alternatively or additionally, the platform or frame 356 may be secured to the cryogenic storage tank or freezer 102 via other structures, for example fastened there to via fasteners (for example, bolts, screws, rivets), adhered thereto by adhesive or epoxy, or soldered thereto via a solder joint.

Referring to Figures 5 to 7, the cryogenic storage system 100 at least partially encloses a temperature controlled environment 17, for example formed at least partially by the cryogenic storage tank or freezer 102. The cryogenic storage tank or freezer 102 is sized to store a number of storage cassettes 20, each carrying a number of specimen containers 22, within the temperature controlled environment 17 such that biological specimen contained within each of the specimen containers 22 are maintained at or below a threshold temperature.

According to one embodiment, the storage cassettes 20 may be similar to the storage cassettes 202 (shown in Figure 2) or the carrier cassettes 302 (shown in Figure 3) such that the disclosures of each apply to the storage cassettes 20. Similarly, according to one embodiment, the specimen container 22 may be similar to the specimen container 200 (shown in Figure 2) such that the disclosure of the specimen container 200 applies to the specimen container 22.

The cryogenic storage tank may include a bottom surface 24 and a top surface 26 that each form a portion of a boundary for the temperature controlled environment 17. As shown, the top surface 26 may face the bottom surface and be spaced from the bottom surface 24 so as to define a height of the temperature controlled environment 17. The top surface 26 may include the opening 116 (as shown in Figure 1 ) that provides passage into and egress out of the temperature controlled environment 17 for the storage cassettes 20.

The cryogenic storage system 100 may include at least one temperature sensor 28 positioned so as to measure a temperature within the temperature controlled environment 17. According to one embodiment the at least one temperature sensor 28 may be positioned within the temperature controlled environment 17, for example carried by the cryogenic storage tank or freezer 102. According to one embodiment the at least one temperature sensor 28 is closer to the top surface 26 (or the opening 116) than the at least one temperature sensor 28 is from the bottom surface 24.

Such placement may be beneficial as the top of the temperature controlled environment 17 may be more susceptible to a rise in temperature. This susceptibility may be due to the proximity of the opening 116 near the top of the temperature controlled environment 17, as well as the tendency for cryogenic medium to sink towards the bottom of the temperature controlled environment 17 in addition to other factors.

One or more of the at least one temperature sensor 28 may be positioned so as to measure a temperature in a first region (a subset) of the temperature controlled environment 17. Another of the at least one temperature sensor 28 may be positioned so as to measure a temperature in a second region of the temperature controlled environment 17. The first region may be relatively higher (above) the second region. One or more of the regions within the temperature controlled environment 17 may include a plurality of the at least one temperature sensor 28, such that a backup or redundant sensor is present in the event of a failure of the other at least one temperature sensor 28 in the same region.

A plurality of the at least one temperature sensor 28 may be positioned equidistant from the top surface 26, for example such that each of the plurality of the at least one temperature sensor 28 are at the same height. A plurality of the at least one temperature sensor 28 may be radially spaced about a central axis of the cryogenic storage tank or freezer 102, for example such that the plurality of the at least one temperature sensors 28 are equidistant from one another.

According to one embodiment, the at least one temperature sensor 28 may include a subset of temperature sensors 28 that are positioned closer to the bottom surface 24 than the subset of temperature sensors 28 is from the top surface 26. Accurate temperature readings at various positions within the temperature controlled environment 17 may ensure a consistent temperature throughout the temperature controlled environment 17 and may assist in identification of a localized problem, for example a leak, within the cryogenic storage tank or freezer 102.

The cryogenic storage system 100 may include at least one level sensor 30 positioned so as to measure an amount of cryogenic medium inside the cryogenic storage tank or freezer 102. According to one embodiment, the at least one level sensor 30 may be positioned within the temperature controlled environment 17, for example carried by the cryogenic storage tank or freezer 102 such that the at least one level sensor 30 is closer to the bottom surface 24 than the at least one level sensor 30 is from the top surface 26. According to one embodiment, the at least one level sensor 30 includes a pressure sensor positioned at the lowest point within the temperature controlled environment 17, for example on the bottom surface 24 of the cryogenic storage tank or freezer 102, such that the pressure sensor measures the mass of the cryogenic medium inside the cryogenic storage tank or freezer 102. According to one embodiment, the at least one level sensor 30 may be positioned within the temperature controlled environment 17, for example carried by the cryogenic storage tank or freezer 102 such that the at least one level sensor 30 is closer to the top surface 26 than the at least one level sensor 30 is from the bottom surface 24. The at least one level sensor 30 may include a float valve type structure, for example with the sensor itself positioned outside the temperature controlled environment 17 while a float and part of arm extend into the temperature controlled environment 17.

According to one embodiment, the at least one level sensor 30 may be an optical sensor, which shoots a beam (for example, an infrared beam) across a width of the temperature controlled environment 17, or shoots the beam longitudinally (vertically) and measures time of flight for return of reflection off a top surface of the cryogenic medium (for example, liquid nitrogen), or includes a transmitter at one location (for example, proximate the top of the temperature controlled environment 17) and a receiver opposed (for example, proximate the bottom of the temperature controlled environment 17) and measures time to transmit or attenuation or phase shift to determine the amount of cryogenic medium within the temperature controlled environment 17.

According to one embodiment, the at least one level sensor 30 may include a fill sensor that detects the presence of cryogenic medium when the fill sensor is submerged in the cryogenic medium. As the level of the cryogenic medium drops such that the fill sensor is no longer submerged in the cryogenic medium, the fill sensor detects this change in status. The at least one level sensor 30 may include: one or more fill sensors positioned closer to the bottom surface 24 than the one or more fill sensors are from the top surface 26, one or more fill sensors positioned closer to the top surface 26 than the one or more fill sensor are from the bottom surface 24, or a combination of fill sensors some of which are positioned closer to the top surface 26 and others of which are positioned closer to the bottom surface 24.

The cryogenic storage system 100 may include a port 32 that provides passage of cryogenic medium into the temperature controlled environment 17 along a path remote from the opening 116. The port 32 may include another of the at least one temperature sensor 28 positioned to measure temperature of a medium passing through the port 32. The port 32 may be coupled to a bypass 34 such that: 1 ) upon the temperature sensor 28 of the port 32 measuring a temperature of a medium passing through the port 32 within a permitted temperature range, the bypass 34 is closed and the path to the temperature controlled environment 17 is open; and 2) upon the temperature sensor 28 of the port 32 measuring a temperature of the medium passing through the port 32 outside of a permitted temperature range the bypass 34 is open and the path to the temperature controlled environment 17 is blocked.

Opening and closing of the bypass 34 and the path may be implemented by a valve 36. According to one embodiment, the valve 36 may be actuated in response to a signal sent from the temperature sensor 28 of the port 32. For example, if a supply of cryogenic medium, for example liquid nitrogen, is connected to the port 32 such that the liquid nitrogen flows through the port 32, the temperature sensor 28 of the port 32 will detect that the temperature of the cryogenic medium is within the permitted temperature range and the valve 36 will be oriented such that the bypass 34 is blocked and the path to the temperature controlled environment 17 is open. If, on the other hand, a supply of a non-cryogenic medium is connected to the port 32, the temperature sensor 28 of the port 32 will detect that the temperature of the medium is outside the permitted temperature range and the valve 36 will be oriented such that the bypass 34 is open and the path to the temperature controlled environment 17 is blocked, thus preventing the temperature controlled environment 17 from being negatively impacted.

According to one embodiment, the at least one level sensor 30 may be communicatively coupled to the port 32 such that upon the at least one level sensor 30 measuring the amount of cryogenic medium inside the cryogenic storage tank or freezer 102 as being below a first threshold, the port 32 opens thereby allowing an additional amount of the cryogenic medium to enter the cryogenic storage tank or freezer 102. The at least one level sensor 30 may be communicatively coupled to the port 32 such that upon the at least one level sensor 30 measuring the amount of cryogenic medium inside the cryogenic storage tank or freezer 102 as being above a second threshold, the port 32 closes thereby preventing any additional amount of the cryogenic medium from entering the cryogenic storage tank or freezer 102.

The cryogenic storage system 100 may include a processor-based control system including at least one processor and at least one nontransitory memory communicatively coupled to the at least one processor and storing processor-executable instructions, for example as described below. The at least one temperature sensor 28 may be coupled to the at least one processor such that the at least one temperature sensor 28 is operable to provide a signal representative of a temperature in the temperature controlled environment 17 to the at least one processor. Similarly, the at least one level sensor 30 may be coupled to the at least one processor such that the at least one level sensor 30 is operable to provide a signal representative of the amount of cryogenic medium inside the cryogenic storage tank to the at least one processor.

The cryogenic storage system 100 may include at least one user interface system communicatively coupled to the at least one processor such that the at least one processor executes processor-executable instructions to present a user interface. The at least one user interface system may include one or more display screens, one or more touch-sensitive display screens, one or more speakers, one or more microphones, one or more keyboards, one or more pointer devices, one or more haptic interfaces, or any combination thereof.

According to one embodiment, the at least one processor is operable to execute the processor-executable instructions, which cause the at least one processor to perform at least one of: receiving the signal representative of the temperature over a period of time to form a time domain representation of the temperature in the temperature controlled environment 17; and receiving the signal representative of the level of the cryogenic fluid in the cryogenic storage tank or freezer 102 over the period of time to form a time domain representation of the level of the cryogenic fluid in the cryogenic storage tank or freezer 102. The at least one processor may be further operable to execute the processor-executable instructions, which cause the at least one processor to perform outputting one or more status indications to the at least one user interface system, the one or more status indications based at least in part on the time domain representation of the temperature, the time domain representation of the level, or both.

According to one embodiment, the one or more status indications may include an estimated amount of time remaining before the temperature in the temperature controlled environment 17 crosses a threshold value. The threshold value may be a maximum temperature at which a specimen within the specimen containers 22 remains cryo-stable, or may be based on the maximum temperature at which a specimen within the specimen containers 22 remains cryo-stable with a factor of safety built in, for example negative 175 degrees Celsius.

The processor-based control system may help predict future maintenance for the cryogenic storage system 100, such maintenance including refilling of cryogenic medium and repair/replacement of components prior to failure. Thus, the one or more status indications may include an estimated amount of time remaining before the level of the cryogenic fluid in the cryogenic storage tank or freezer 102 crosses a second threshold value. According to one embodiment, the one or more status indications may include a predicted amount of time until equipment failure.

The at least one processor may be operable to execute processorexecutable instructions that cause the at least one processor to perform outputting an alert to a first recipient of a set of recipients based at least in part on the time domain representation of the temperature, the time domain representation of the level, or both. The at least one processor may be further operable to execute processor-executable instructions that cause the at least one processor to perform outputting of the alert to a second recipient of the set of recipients if an acknowledgement is not received within a first defined time period from the first recipient.

The at least one processor may be further operable to execute processor-executable instructions that cause the at least one processor to perform outputting of the alert to a third recipient if the acknowledgement is not received within a second defined time period from either the first recipient or the second recipient, the third recipient excluded from the set of recipients. The third recipient may be an administer, manager, or other individual that represents an escalation beyond the original set of recipients.

The at least one processor may be operable to execute processorexecutable instructions that cause the at least one processor to perform initiating a reordering process of the cryogenic medium when a value representative of the amount of the cryogenic medium inside the cryogenic storage tank or freezer 102, or a value representative of a predicted amount of the cryogenic medium in the cryogenic storage tank or freezer 102 at a future time, falls below a defined threshold. The at least one processor may be operable to execute processorexecutable instructions that cause the at least one processor to perform initiating a backup system to increase the amount of the cryogenic fluid in the cryogenic storage tank or freezer 102 when a value representative of the amount of the cryogenic fluid in the cryogenic storage tank or freezer 102, or a value representative of a predicted amount of the cryogenic fluid in the cryogenic storage tank at a future time, falls below a defined threshold.

The at least one processor may be operable to execute processorexecutable instructions that cause the at least one processor to perform detection of intrusions to the cryogenic storage system, for example by an unauthorized user. According to one embodiment, a temperature measurement by one of the at least one temperature sensors 28 at a respective location in the temperature controlled environment 17 may be associated with one or more of the specimen containers 22 nearest the respective location.

According to one embodiment, the at least one processor may logically associate in a nontransitory processor-readable medium, the temperature of the specimen container 22 with the specimen container 22. This association may include storing temperatures of the specimen container 22 at each time period during a range of time periods, or simply setting a flag or other indicator that indicates whether a threshold temperature of the specimen container 22 was exceeded at any time during the time period, whether a threshold temperature was exceeded for a first defined duration at any time during the time period, or whether a threshold temperature was exceeded for a cumulative of two or more distinct durations during the time period. The data related to the association may be stored in a data store that stores information for the specimen containers 22 associated with two, three, or more different subjects or patients. According to one embodiment the at least one processor may store temperature data in memory that is physically associated with the respective specimen container 22, for example, stored in a read/writable memory of a wireless (for example, RFID) transponder physically coupled to or physically incorporated into a portion (for example, the vial, the cap, or the straw) of the specimen container 22.

The cryogenic storage system 100 may include one or more position sensors 40 that identify the current position of the robot used to retrieve the storage cassettes 20. The cryogenic storage system 100 may include an uninterrupted power supply 42, such that an unexpected loss of power during a storage/retrieval event will not prevent completion of the storage/retrieval event including maintaining the chain-of-custody of the specimen containers 22 involved in the storage/retrieval event.

Figures 8 through 10 show an exemplary user interface to facilitate operation of the process-based transfer system 122. Such can be thought of a backend system, operable to store, retrieve and inventory specimens retained on specimen holders or “cryodevices” which are in turn stored in specimen containers marked with wireless transponders and/or machine-readable symbols. These specimen containers may hold one or multiple sample holders, and are generally logically associated with a particular patient. The specimen containers are transferable between storage cassettes for storage in a cryogenic refrigerator and carrier cassettes for storage in a portable thermally insulated carrier used, for instance, to transport the specimens to and from a patient.

Figure 8 shows a tank status window 700 of a user interface for a cryogenic robot system at a first time, the tank status window 700 providing a status of a cryogenic tank (for example the cryogenic storage tank or freezer 102), according to at least one illustrated implementation. The at least one processor of the cryogenic storage system 100 may cause presentation of the tank status window 700 via a display monitor, heads up display, or other user interface device based on signals sent by the at least one temperature sensor 28, the at least one level sensor 30, or both. The tank status window 700 may include a tank identification 702, a temperature indicator 704 of a liquid nitrogen bath, a level indicator 706 of the liquid nitrogen bath, or any combination thereof. The tank identification 702 may be located within a panel of the tank status window 700 that includes the temperature indicator 704 and the level indicator 706 as shown. According to one embodiment, the tank identification 702 may be located in a separate panel of the tank status window 700, for example such that the tank identification is positioned below the temperature indicator 704 and the level indicator 706. The tank status window 700 may provide one or more indicators that both the temperature and level are within acceptable conditions, for example via a message (for example, “Everything is safe”) 708, a graphical indicator (for example, checkmark with the word “safe”) 710a, 710b, a color (for example, green) 712, or any combination thereof.

The tank status window 700 may, for example, be presented as a default window, for instance as a “screensaver” window when not otherwise interacting with the user interface. Additionally, or alternatively, the tank status window 700 may be presented at other times, for example in response to performing an initialization or a status check. The tank status window 700 may, for example, be presented continuously, or as an alert in response to occurrence of certain conditions (for example, temperature above one or more defined thresholds, fluid below one or more defined thresholds). Additionally, one or more alerts may be issued, for example via text message, electronic mail, etc.

Figure 9 shows the tank status window 800, which is similar to the tank status window 700 of Figure 8, of a user interface for a cryogenic robot system at another time, the tank status window 800 providing a status of a cryogenic tank (for example the cryogenic storage tank or freezer 102), according to at least one illustrated implementation. The processor-based transfer system 122 of the cryogenic system 100 causes presentation of the tank status window 800 via a display monitor, heads up display, or other user interface device.

The tank status window 800 includes a tank identification 802, a temperature indicator 804 of a liquid nitrogen bath, a level indicator 806 of the liquid nitrogen bath, or any combination thereof. The tank identification 802 may be located within a panel of the tank status window 800 that includes the temperature indicator 804 and the level indicator 806 as shown. According to one embodiment, the tank identification 802 may be located in a separate panel of the tank status window 800, for example such that the tank identification is positioned below the temperature indicator 804 and the level indicator 806.

The tank status window 800 may provide one or more indicators that both the temperature and level are approaching or at marginal conditions, for example via a message (for example, “WARNING! Your immediate attention is needed”) 808, a graphical indicator (for example, exclamation symbol and the word Warning) 810a, 810b, a color (for example, yellow) 812, or any combination thereof. In particular, the tank status window 800 of Figure 8 provides a first level of warning regarding conditions in the cryogenic tank or bath deteriorating (for example, temperature approaching or at a first temperature threshold or level of fluid approaching or at a first fluid level threshold). According to one embodiment, the tank status window 800 may indicate a critical condition.

The at least one processor of the cryogenic storage system 100 may cause presentation of the tank status window 800 via a display monitor, heads up display, or other user interface device based on signals sent by the at least one temperature sensor 28, the at least one level sensor 30, or both. According to one embodiment, the tank status window 800 includes information that indicates an action needed to prevent a potential future problem. For example, the at least one level sensor 30 may determine that the amount of cryogenic medium in the temperature controlled environment 17 is dropping and that a refill will be needed within a certain amount of time to prevent an unsafe rise in temperature.

The tank status window 800 may, for example, be presented as a default window, for instance as a “screensaver” window when not otherwise interacting with the user interface. The tank status window 800 may, for example, be presented continuously, or as an alert in response to occurrence of certain conditions (for example, temperature above one or more defined thresholds, fluid below one or more defined thresholds). Additionally, one or more alerts may be issued, for example via text message, electronic mail, etc.

Figure 10 shows the tank status window 900 of the user interface for a cryogenic robot system at yet another time, the tank status window 900 providing a status of a cryogenic tank (for example the cryogenic storage tank or freezer 102), according to at least one illustrated implementation. The processor-based transfer system 122 of the cryogenic system 100 causes presentation of the tank status window 900 via a display monitor, heads up display, or other user interface device.

The tank status window 900 may include a tank identification 902, for example a specific one of the cryogenic storage tank or freezer 102, being monitored, a temperature indicator 904 of liquid nitrogen within the tank 902, a level indicator 906 of the liquid nitrogen within the tank 902, or combination thereof. The tank identification 902 may be located within a panel of the tank status window 900 that includes the temperature indicator 904 and the level indicator 906 as shown. According to one embodiment, the tank identification 902 may be located in a separate panel of the tank status window 900, for example such that the tank identification is positioned below the temperature indicator 904 and the level indicator 906.

The tank status window 900 may provide one or more indicators that both the temperature and level are at or below acceptable conditions, for example via a message (for example, “WARNING! TAKE IMMEDIATE ACTION!”) 908, a graphical indicator (for example, exclamation symbol and the word Warning) 910a, 910b, a color (for example, red) 912, or any combination thereof. In particular, the tank status window 900 of Figure 10 provides a second level of warning, more dire than the first level of warning, regarding conditions in the cryogenic tank or bath deteriorating (for example, temperature approaching or at a second temperature threshold or level of fluid approaching or at a second fluid level threshold). According to one embodiment, the tank status window 900 may indicate a failure condition.

As shown, the one or more indications may include an estimated amount of time remaining 814a before the temperature in the temperature controlled environment 17 crosses a threshold value. The threshold value may be a maximum temperature at which a specimen within the specimen containers 22 remains cryostable, or may be based on the maximum temperature at which a specimen within the specimen containers 22 remains cryo-stable with a factor of safety built in, for example negative 175 degrees Celsius. The estimated amount of time remaining 814a before the temperature in the temperature controlled environment 17 crosses a threshold value may be based on the history of the temperature within the cryogenic storage tank or freezer 102, for example how fast the temperature is increasing or how long the temperature has been increasing.

As shown, the one or more indications may include an estimated amount of time remaining 814b before the amount of cryogenic medium (for example liquid nitrogen) in the temperature controlled environment 17 crosses a threshold value. The threshold value may be a minimum amount at which all of the biological samples within the specimen containers 22 remain submerged in the cryogenic medium. The estimated amount of time remaining 814b before the amount of cryogenic medium in the temperature controlled environment 17 crosses the threshold value may be based on the history of the amount of cryogenic medium within the cryogenic storage tank or freezer 102, for example how fast the amount is decreasing or for how long the amount has been decreasing.

The at least one processor of the cryogenic storage system 100 may cause presentation of the tank status window 900 via a display monitor, heads up display, or other user interface device based on signals sent by the at least one temperature sensor 28, the at least one level sensor 30, or both. According to one embodiment, the tank status window 900 includes information that indicates an action needed to prevent a potential future problem. For example, the at least one level sensor 30 may determine that the amount of cryogenic medium in the temperature controlled environment 17 is dropping and that a refill will be needed within a certain amount of time to prevent an unsafe rise in temperature.

The tank status window 900 may, for example, be presented as a default window, for instance as a “screensaver” window when not otherwise interacting with the user interface. The tank status window 900 may, for example, be presented continuously, or as an alert in response to occurrence of certain conditions (for example, temperature above one or more defined thresholds, fluid below one or more defined thresholds). Additionally, one or more alerts may be issued, for example via text message, electronic mail, etc.

The estimated amount of time remaining 814a and 814b may be present at all times (for example in each of tank status windows 700, 800, and 900), according to one embodiment. Alternatively, the estimated amount of time remaining 814a and 814b may be present only at certain times, for example when the value for the estimated time crosses a certain threshold.

The various implementations and embodiments described above can be combined to provide further implementations and embodiments. All of the commonly assigned U.S. patent application publications, U.S. patent applications, foreign patents, and foreign patent applications referred to in this specification and/or listed in the Application Data Sheet, including but not limited to U.S. patent application 63/082,640, filed September 24, 2020; U.S. patent application 63/026,526, filed May 18, 2020; U.S. patent application 16/842,034, filed April 7, 2020; U.S. patent application 16/842,030, filed April 7, 2020; U.S. patent application 16/840,720, filed April 6, 2020; U.S. patent application 16/840,718, filed April 6, 2020; U.S. patent application 62/936,133, filed November 15, 2019; U.S. patent application 62/927,566, filed October 29, 2019; U.S. patent application 62/900,281 , filed September 13, 2019; U.S. patent application 62/880,786, filed July 31 , 2019; U.S. patent application 62/879,160, filed July 26, 2019; U.S. patent application 62/741 ,986, filed October s, 2018; and U.S. patent application 62/741 ,998, filed October 5, 2018, are each incorporated herein by reference, in their entirety. These and other changes can be made to the embodiments in light of the above-detailed description.

In general, in the following claims, the terms used should not be construed to limit the claims to the specific implementations and embodiments disclosed in the specification and the claims, but should be construed to include all possible implementations and embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.