Container for samples for cryogenic storage

Abstract

A container (100) for cryogenically stored biological samples (102) is disclosed, comprising an insulated housing comprising a cavity (108) for containing at least one cryogenically stored biological sample; and a sealed reservoir (106) at least partially surrounding the cavity, the sealed reservoir comprising a liquefied gas (120), such as liquid air, which is maintained mostly liquefied by means of a heat transfer engine (112), such as a Stirling cryocooler. A valve (114) can be provided to serve as both an overflow valve and an inlet valve. The inlet valve can be coupled to a sensor (122) for sensing the volume of liquefied gas within the sealed reservoir. The container can further comprise a heat exchanger (116) coupled to the heat engine and extending into the sealed reservoir.

Description

Technical Field

[0001] This invention relates to a container for cryogenically stored samples (e.g., biological samples), wherein the cryogenically stored samples can be maintained for extended periods, such as months, upon arrival at their destination, and may also be capable of controlled freezing and thawing rates. The container of this invention can also be used to transport other types of samples that require cryogenic storage without the need for conventional cryogenic materials such as liquid nitrogen or solid carbon dioxide. Background Technology

[0002] Cryogenic storage is a technique for preserving biological samples that involves cooling the samples to very low temperatures (e.g., -78.5°C to -196°C) and maintaining them for an extended period of time. By cooling biological samples to low temperatures, the kinetics of chemical or enzymatic reactions that would otherwise degrade the samples are slowed down to a point where the samples no longer degrade or degrade only at a very slow rate. As a result, biological samples can be stored for an extended period of time and then restored to ambient temperature as needed for use and / or analysis.

[0003] If the temperature of a cryopreserved sample is maintained at a sufficiently low temperature during transport, it can be transported. Allowing the sample to be heated above a certain temperature, such as above its glass transition point, may compromise its integrity. This is because the cryoprotectants used during cryopreservation have a degree of toxicity to the sample and diffuse more extensively, thus allowing for more chemical reactions that can affect the viability of stored cells. Prolonged exposure to cryoprotectants and the chemical reactions at higher temperatures, and their cumulative effects, can damage the cryopreservation material. Below the glass transition temperature, the viscosity of the system means that the cumulative effect is very small. During cryopreservation, controlled cooling from the cell's ambient temperature is necessary to minimize damage and optimize cell viability after thawing. Therefore, it is clear that to ensure sample integrity during transport, cryopreserved samples must be kept sufficiently cold so that the cumulative damaging effects are not significant during the intended transport and storage period.

[0004] Besides maintaining sufficiently low temperatures during transport, the transport containers and their contents must be compatible with the environments they pass through before, during, and after transport. Therefore, in the case of air transport, the use of phase change coolants such as liquid nitrogen is unacceptable for safety reasons if there is a risk of liquid nitrogen spillage. To avoid this problem, dry transport devices and Dewar containers with porous materials (such as molecular sieves or zeolites) have been developed to ensure cryogenic transport without the risk of liquid nitrogen spillage. In such Dewar containers, liquid nitrogen is absorbed into the porous material and retained therein until it vaporizes into gaseous nitrogen.

[0005] A problem associated with these dry transport devices is that porous materials are susceptible to contamination, such as particulate biomaterials from liquid nitrogen residue within the device. This requires sterilization between uses, making their use in sterile environments like operating rooms and cleanrooms highly undesirable. Furthermore, Dewar containers are vacuum-jacketed containers, and to ensure uniform pressure distribution across the container walls, their shape must be approximately cylindrical or spherical. Thicker materials are required to avoid catastrophic failures, thus reducing the effectiveness of using Dewar containers. This combination means that dry transport devices are typically in the form of cylindrical or spherical Dewar containers with a relatively narrow orifice at one end through which liquid nitrogen and samples are loaded. Typical dry transport devices have drilled holes that radiate radially from the central axis of the Dewar container opening. A porous material that absorbs liquid nitrogen is provided in a ring between the outer wall of the drilled holes and the innermost wall of the Dewar container. This indicates that the porous material (i.e., molecular sieve elements) cannot be easily removed and replaced, and in any case, the sample must be extracted first.

[0006] Simpler transport containers that incorporate phase change cooling materials (such as solid carbon dioxide) as coolants (cryoprotectants) can also be used to transport cryogenically stored samples. These containers consist of insulated containers (such as Dewar containers or insulated boxes) containing or immersing the sample in a bed of solid carbon dioxide. The problem with using such containers is that they can only maintain the sample at a relatively moderate cryogenic temperature for a limited period and are not suitable for transporting or storing over long periods without frequent refilling of the phase change cooling material. Solid carbon dioxide has a temperature of approximately -78.5°C, which is above the glass transition temperature of many cryoprotectants, and this temperature may not be low enough to prevent damage to the sample before, during, or after transport over longer timescales (days).

[0007] Advances in medicine mean there is an increasing need to transport and maintain cryogenically stored samples in environments where cryogenic materials (liquid nitrogen, solid carbon dioxide, etc.) and storage facilities are unavailable and / or impractical. For example, the field of immunotherapy is rapidly developing and has significant potential for therapeutic applications, such as in the treatment of cancers like leukemia and melanoma. In one approach, T cells are harvested from a patient's blood and then genetically engineered to introduce chimeric antigen receptors (CARs) onto their surface. The resulting chimeric antigen receptor T cells (CAR T cells) are then grown in a laboratory to provide a sufficient therapeutic quantity and subsequently infused into the original patient. The CAR T cells can then recognize relevant protein antigens on the surface of tumor cells and subsequently mobilize the patient's immune system to kill those cells. This process requires transferring blood and / or tissue samples to a laboratory capable of performing the genetic engineering and then growing the required number of CAR T cells. Furthermore, the CAR cells must then be transported back to the patient's own clinic and stored until the patient is ready for treatment. This typically requires storing cryopreserved (one or more) CAR T-cell samples at the clinic for several weeks or longer, and this necessitates the construction of local cryopreservation facilities or the provision of transport containers that can also be used as storage units upon arrival. The object of this invention is to provide such a transport container. Summary of the Invention

[0008] In a first aspect of the invention, a container for cryogenic storage of biological samples is provided, the container comprising: an insulating shell including a cavity for receiving at least one cryogenically stored biological sample; and a sealed reservoir at least partially surrounding the cavity of the shell, the sealed reservoir comprising a liquefied gas.

[0009] In a second aspect of the invention, a method is provided for monitoring the volume of a liquefied gas within a container of the type described herein, the method comprising: determining whether at least one sensor indicates that the volume of the liquefied gas is below a desired volume and / or that evaporating liquefied gas is flowing out of a sealed reservoir; and sending a control signal to activate a heat engine to condense any evaporating liquefied gas in the sealed reservoir of the container.

[0010] In a third aspect of the invention, a method for monitoring the integrity of a container of the type described herein is provided, the method comprising: determining whether the measured power consumption of the container's heat engine exceeds an expected power consumption; and if the measured power consumption exceeds the expected power consumption, outputting a report on the integrity of the container in response to the determination.

[0011] According to a relevant aspect of the invention, a non-transitory data carrier carrying code is provided, which, when implemented on a processor, causes the processor to perform any of the methods described herein.

[0012] As will be understood by those skilled in the art, embodiments of this technology can be embodied as systems, methods, or computer program products. Therefore, this technology can take the form of a completely hardware embodiment, a completely software embodiment, or an embodiment combining software and hardware aspects.

[0013] Furthermore, embodiments of this technology may take the form of a computer program product embodied in a computer-readable medium, on which computer-readable program code is embodied. The computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. The computer-readable medium may be, for example, but not limited to, electronic, magnetic, optical, electromagnetic, infrared, or semiconductor systems, apparatuses, or devices, or any suitable combination thereof.

[0014] Computer program code for performing the operations of this technology can be written in any combination of one or more programming languages, including object-oriented programming languages ​​and conventional procedural programming languages. Code components can be embodied as procedures, methods, etc., and can include sub-components, which can take the form of instructions or sequences of instructions at any level of abstraction, ranging from direct machine instructions of the native instruction set to high-level compiled or interpreted language constructs. Attached Figure Description

[0015] The technology is illustrated in the accompanying drawings by way of example, wherein: Figure 1 A shows a schematic diagram of a container for samples used for cryogenic storage; Figure 1 B shows Figure 1 A schematic diagram of the airflow mechanism of container A; Figure 2 It is used for monitoring Figure 1 A flowchart illustrating the example steps for determining the volume of liquefied gas within container A; Figure 3 It is used to monitor from Figure 1 A flowchart illustrating the example steps of the fluid flowing out of container A; and Figure 4 It is used for monitoring Figure 1 A flowchart illustrating the example steps for ensuring the integrity of container A. Detailed Implementation

[0016] Cryogenic storage of many types of biological materials is used for subsequent applications in medicine, biotechnology, and veterinary science. To ensure long-term viability, maintaining samples at temperatures below 150 K is considered essential. A simple method to achieve this cryogenicity is the use of liquid nitrogen (which has a boiling point of 77 K). After adding cryoprotectant additives and a controlled freezing rate, the sample is immersed in liquid nitrogen or in a gas phase above liquid nitrogen, typically contained in a Dewar flask. The liquid nitrogen evaporates and is replenished with fresh liquid nitrogen, which can be done manually or via an automated filling system from a large Dewar flask or storage tank. As an alternative to liquid nitrogen, mechanical cryostats operating at 120 K have been developed.

[0017] However, current cryogenic storage methods present numerous challenges. For instance, liquid nitrogen is expensive and may be difficult to obtain in some geographical locations. Health and safety issues may arise associated with the storage and handling of large volumes of liquid nitrogen. Furthermore, liquid nitrogen may contain very low levels of contaminants after manufacturing, and further contamination can occur during transportation and storage. Therefore, liquid nitrogen must always be considered as potentially contaminated by viable microorganisms. Contamination of liquid nitrogen by ice, inanimate debris, and viable microorganisms has been documented, and numerous reports have indicated that contamination has transferred from liquid nitrogen to its vapor. While it is theoretically possible to filter liquid nitrogen, this would require specialized equipment and validation of the filtration procedure to demonstrate that contaminants are removed each time it is performed. If validation is not feasible, liquid nitrogen cannot be used in cleanrooms without compromising air quality. Moreover, to achieve cryogenic temperatures, mechanical refrigeration still conventionally employs cascaded compressors, which tend to be large, noisy, and expensive.

[0018] In a broad sense, this technology relates to containers for cryogenic storage of biological samples, including a supply of liquefied gas to maintain the cryogenically stored biological samples at a desired temperature during sample storage and / or transport. The containers described herein include a sealed reservoir containing at least a liquefied gas for maintaining the cryogenically stored biological samples at the desired temperature, but without requiring direct contact between the liquefied gas and the sample. Evaporation of the liquefied gas within the sealed reservoir can be mitigated by providing means for condensing the evaporating liquefied gas within the container, such that the liquefied gas within the sealed reservoir is maintained at the required volume to maintain the sample within the container at the desired temperature. Embodiments of the container can advantageously remove or substantially reduce the possibility of contamination of the biological sample by the liquefied gas or by evaporated liquefied gas. Furthermore, by providing a sealed reservoir containing the liquefied gas within the container, it is possible to use the same liquefied gas supply for a considerable period of time, which addresses the problem of unavailability of liquefied gas in some geographical locations. Furthermore, since the same supply can be used and reused once provided in a sealed storage container, health and safety concerns can be reduced, as users of the container may not need to come into contact with the liquefied gas, especially when users put samples into or remove them from the container.

[0019] Figure 1 A schematic diagram shows a container 100 for storing and / or transporting a cryogenically stored sample 102, such that the cryogenically stored sample within the container 100 is maintained at the desired temperature for an extended period to ensure sample integrity. The cryogenically stored sample 102 can be a cryogenically stored biological sample or any type of sample that requires cryogenic storage without the use of conventional cryogenic materials such as liquid nitrogen or solid carbon dioxide.

[0020] Container 100 includes an insulating shell comprising a cavity 108 for receiving at least one cryogenically stored biological sample 102, and a sealed reservoir 106 at least partially surrounding the cavity 108 of the shell. In embodiments, the sealed reservoir 106 may include a liquefied gas 120 supplied within the sealed reservoir from at least one external source (not shown). The liquefied gas 120 may be any one or more of liquefied helium, liquefied nitrogen, liquefied air, and liquefied oxygen, but it will be understood that this is a non-exhaustive and non-limiting list of suitable materials. Additionally or alternatively, the sealed reservoir 106 may include a liquefied gas that has been absorbed into a suitable material.

[0021] The sealed reservoir 106 includes at least one valve 114. The at least one valve 114 may be an relief valve, a pressure relief valve, or a safety valve for controlling or limiting the pressure within the sealed reservoir 106. The relief valve may be designed to open automatically when a predetermined pressure is reached within the sealed reservoir 106. Relief valves may be provided in cases where the mechanism within the container cannot condense / reliquefy evaporated liquefied gas (which may cause gas buildup within the sealed reservoir 106), in cases of power interruption of the mechanism, or insulation failure of the container 100.

[0022] In an embodiment, at least one valve 114 may be or may include a flow sensor. The flow sensor can be used to determine whether gas is entering or leaving the sealed reservoir 106. For example, if it is determined that gas is leaving the sealed reservoir 106, this may indicate that a leak pressure release is occurring or a leak exists that allows gas to leak out of the sealed reservoir 106 (which may mean that the supply of liquefied gas 120 needs to be refilled more frequently). Flow sensor ( Figure 1 (Not shown in section A) can be coupled to a controller so that if the flow sensor indicates that gas is leaking from the sealed reservoir, the controller can take action to remedy the situation. For example, the controller can cause a refrigeration unit to be turned on to cool / condense the gas, thereby reducing or stopping the flow of gas from the sealed reservoir 106. This is described in more detail below.

[0023] At least one valve 114 may be an inlet valve for filling the sealed reservoir 106 with either a gas (which will condense within the reservoir to provide liquefied gas) or liquefied gas 120. Therefore, the inlet valve may be coupled to an external source of gas / liquefied gas 120, allowing the gas / liquefied gas to flow into the sealed reservoir 106. In an embodiment, the inlet valve may be coupled to at least one sensor 122 within the sealed reservoir 106. The at least one sensor 122 may be a sensor for sensing the volume of liquefied gas 120 within the sealed reservoir 106. The inlet valve 114 may be configured to automatically close when at least one sensor 122 indicates that the desired volume of liquefied gas 120 has been obtained in the sealed reservoir 106. In an embodiment, at least two “fill sensors” 122 may be present in the sealed reservoir 106—one for determining whether a minimum desired volume of liquefied gas 120 is present in the sealed reservoir 106, and the other for determining whether a maximum volume of liquefied gas 120 is present in the sealed reservoir 106. In such an embodiment, the inlet valve 114 may remain open until the sensor indicates that the maximum volume of liquefied gas 120 has been reached.

[0024] In an embodiment, liquefied air may be used in the sealed reservoir 106 to maintain the sample 102 in the chamber 108 at the desired cooling temperature. Liquefied air is air that has been cooled to a very low temperature so that it has condensed and become liquid. Air from the external environment can be pumped into the sealed reservoir 106 of the container 100, where it is cooled to form liquefied air. Air and liquefied air typically include nitrogen, oxygen, argon, and other inert gases. Using air or liquefied air as a means of cooling the sample 102 can be advantageous because it eliminates the need for a separate dedicated gas / liquid supply to the container 100 (e.g., a liquid nitrogen tank). Instead, air from the environment surrounding the container 100 can be introduced into the container and cooled (condensed) to a cryogenic temperature. This can reduce the operating costs of the container 100.

[0025] However, problems can arise when liquefied air begins to heat up and evaporate. The boiling point of liquid air lies between that of liquid nitrogen and liquid oxygen. As a result, as the liquid air boils and evaporates (e.g., due to the shutdown of cooling / condensing mechanisms), the nitrogen component evaporates faster than the oxygen component. This can cause the liquid air mixture to contain oxygen at concentrations as high as approximately 50%. Liquid oxygen contains 4000 times more oxygen by volume than ordinary air, and materials generally considered non-flammable (such as carbon, stainless steel, powdered aluminum, etc.) can burn in its presence. Therefore, it may be desirable to reduce, minimize, or eliminate the accumulation of liquid oxygen within the container.

[0026] Therefore, in an embodiment, at least one valve 114 may be coupled to an airflow mechanism for reducing or eliminating the buildup of liquid oxygen and frost within the container 100. Figure 1 Example airflow mechanism is shown in B. This airflow mechanism allows gas to flow into a sealed reservoir 106 of container 100 and allows gas (e.g., evaporated—and therefore hot—liquefied gas) to flow out of the sealed reservoir 106. The airflow mechanism may include a conduit 124 that can be coupled to valve 114. Figure 1 As shown in Figure B, the conduit 124 may be branched or shaped into a first branch and a second branch. An inlet is provided on the first branch of the conduit 124 to allow gas (e.g., air from the external environment) to flow into the sealed reservoir 106 of the container 100. A one-way valve 126 is provided along the first branch to prevent evaporated air from flowing from the sealed reservoir along the first branch and affecting the functionality of the inlet. An outlet is provided on the second branch of the conduit 124 to allow gas (including evaporated liquefied gas) to flow out of the sealed reservoir 106. A one-way valve 128 is provided along the second branch of the conduit 124 to prevent gas from outside the container 100 from flowing through the second branch and into the sealed reservoir.

[0027] In an embodiment, to reduce the accumulation of liquid oxygen within the sealed reservoir 106, the airflow mechanism may include a chamber 130 located between the inlet and a one-way valve 126 on the first branch of the conduit 124. The chamber 130 may contain an oxygen absorber. An oxygen absorber, or oxygen scavenger, is a material that helps remove or reduce oxygen levels. The oxygen absorber may be iron-based or non-ferrous. Therefore, oxygen from the gas (e.g., air) flowing into the inlet of the conduit 124 can be at least partially removed, reducing the potential accumulation of liquid oxygen when the gas condenses in the sealed reservoir 106. In an embodiment, the chamber 130 may be removably provided on the first branch of the conduit 124. This allows the entire chamber 130 to be removed, enabling the disposal of the oxygen absorber and replacement with fresh oxygen absorber material. In an embodiment, the entire chamber 130 may be disposed of and replaced with a new chamber 130 containing fresh oxygen absorber material. Additionally or alternatively, chamber 130 may be openable in situ to allow the oxygen scavenger to be removed and replaced with fresh material.

[0028] In an embodiment, to reduce frost buildup within the sealed reservoir 106 (which reduces the cooling potential of the condensate gas), the airflow mechanism may include a chamber 132 located on a first branch of the conduit 124. If chamber 130 is not provided, chamber 132 is located between the inlet and a one-way valve 126 on the first branch of the conduit 124. If chamber 130 is also present, chamber 132 is located between chamber 130 and the one-way valve 126 on the first branch of the conduit 124, i.e., after the chamber containing deoxygenating material. Chamber 132 contains a desiccant or other suitable material for absorbing moisture / water from the input gas. Removing moisture / water from the input air reduces the potential for frost or ice to form within container 100, and particularly in sealed reservoir 106. Frost or ice can reduce the cooling efficiency provided by the condensate gas by inhibiting heat transfer between sealed reservoir 106 and chamber 108. Chamber 132 may be removably provided on the first branch of the conduit 124. This allows the entire chamber 132 to be removed so that the desiccant can be disposed of and replaced with fresh desiccant. In an embodiment, the entire chamber 132 can be disposed of and replaced with a new chamber 132 containing fresh desiccant. Additionally or alternatively, the chamber 132 may be openable in situ to allow the desiccant to be removed and replaced with fresh material.

[0029] In an embodiment, a single valve 114 can be used as both a pressure reducing valve and an inlet valve.

[0030] Therefore, in an embodiment, at least one valve 114 is an inlet valve for filling a sealed reservoir with gas or liquefied gas. The inlet valve may be coupled to a gas flow mechanism to allow gas to flow into the sealed reservoir (where it may be condensed to provide liquefied gas) and to allow evaporated gas to flow out of the sealed reservoir. The gas flow mechanism may include at least one chamber located between the gas inlet and the inlet valve. At least one chamber may contain an oxygen scavenger or a desiccant. In an embodiment, a flow sensor may be provided within the inlet valve to detect the flow rate of fluid flowing into and / or out of the sealed reservoir, and in particular to detect the outflow of evaporated liquefied gas from the reservoir.

[0031] Container 100 may include a heat engine 112 for condensing gas in the sealed reservoir 106 to provide liquefied gas, and / or for cooling liquefied gas 120 in the sealed reservoir 106. The heat engine may be a refrigerator, a Kleemenco cycle refrigerator, a pulse tube refrigerator, an acoustic Stirling refrigerator, a Joule Thompson refrigerator, a Stirling refrigerator (also known as a Stirling engine), or any other suitable refrigeration device. In an embodiment, the heat engine may be a Stirling refrigerator with a cooling capacity of at least 20 W at 77 K. Heat engine 112 may be used to condense / reliquefy evaporated liquefied gas within the sealed reservoir 106 to maintain the level / volume of cryogenic agent within container 100.

[0032] The container 100 may include a heat exchanger 116 coupled to the heat engine 112. For example... Figure 1 As shown in Figure A, heat exchanger 116 can extend into sealed reservoir 106 to provide cooling to liquefied gas 120. Therefore, heat exchanger 116 can extract heat from the top of sealed reservoir 106 to cool liquefied gas 120 and condense any evaporated liquefied gas 120 that may rise to the top of sealed reservoir 106. Arrow 118 indicates the flow direction of the condensate formed when heat engine 112 and heat exchanger 116 are turned on.

[0033] When the liquefied gas in the sealed reservoir 106 evaporates, the evaporated liquefied gas rises to the top of the sealed reservoir 106, where it can approach the heat exchanger 116 coupled to the heat engine 112. The heat engine 112 can operate at a temperature below the saturation temperature (e.g., 77 K for liquefaction of liquid nitrogen at 1 bar) under the pressure of the liquefied gas in the sealed reservoir 106 to achieve liquefaction / condensation of the evaporated liquefied gas. When not used to liquefy the gas, the heat engine 112 can be used to lower the temperature of the liquefied gas within the sealed reservoir 106, and thereby reduce evaporation.

[0034] As described above, container 100 may include at least one sensor 122 in sealed reservoir 106 for sensing the volume or level of liquefied gas 120 within sealed reservoir 106. It will be understood that... Figure 1 The location of sensor 122 in A is illustrative rather than restrictive.

[0035] Container 100 may include at least one controller coupled to at least one sensor 122. Figure 1 (Not shown in A). The controller 100 can be configured to: determine whether at least one sensor 122 indicates that the volume of liquefied gas 120 is lower than the desired volume; and send a control signal to the heat engine 112 to start the heat engine, thereby condensing any evaporated liquefied gas in the sealed reservoir 106.

[0036] As described above, at least one valve 114 may be or may include a flow sensor capable of detecting gas flowing into and / or out of the sealed reservoir 106. The flow sensor may be coupled to a controller such that if the flow sensor indicates gas is leaking from the sealed reservoir, the controller can take action to remedy the situation. For example, the controller may signal heat engine 112 to open to cool / condense the gas, thereby reducing or stopping the flow of gas from the sealed reservoir 106. When the flow sensor indicates that the flow of gas from the sealed reservoir 106 has significantly decreased or stopped, the controller may signal heat engine 112 to close, as this may indicate that evaporated liquefied gas has condensed again in the sealed reservoir 106. The flow sensor allows the controller to provide a faster response than the level / volume sensor 122.

[0037] In an embodiment, the controller may be further configured to: after a specified time, determine whether at least one sensor 122 indicates that the volume of liquefied gas 120 is below the required volume; send a control signal to the heat engine 112 to shut it down; and output a message in response to the determination indicating that liquefied gas needs to be added to the sealed reservoir 106. The specified time may be the time after the expected volume is reached. This can be determined based on experiments / calibrations of the container 100. In an embodiment, the controller may be able to determine, based on data from at least one sensor 122, how much volume is insufficient in the sealed reservoir 106 (i.e., the difference between the required volume and the sensed volume), and how long the heat engine 112 must be turned on in order to reach the required volume. This can determine the specified time after which the sensors(s) can be polled again.

[0038] In one embodiment, container 100 may include a power meter ( Figure 1 (Not shown in A), the power meter is used to measure the power consumption of the heat engine 112 when the heat is turned on / used for cooling the sealed reservoir 106.

[0039] The aforementioned controller, or another controller, can be coupled to a power meter. The controller can be configured to: determine whether the measured power consumption of the heat engine 112 exceeds the expected power consumption; and if the measured power consumption exceeds the expected power consumption, output a report regarding the integrity of container 100 in response to this determination. In this way, the integrity of container 100 can be determined. For example, if it is determined that the heat engine 112 is using more power than expected, container 100 may not be properly insulated, or there may be a leak in the sealed reservoir, which is causing liquefied gas to evaporate or leak from container 100.

[0040] Container 100 may include a communication module ( Figure 1 (Not shown in A), this communication module is used to convey information to any one or more of the following: the container user; a remote server; the container manufacturer or supplier; an electronic display; or electronic equipment. For example, reports about the integrity of the container and / or messages about filling the storage tank with more liquefied gas can be conveyed to the user or a device / server outside the container 100, enabling relevant actions to be taken.

[0041] Container 100 may include a vacuum insulator / vacuum insulator layer 104. The vacuum insulator 104 may be provided by one or more vacuum-insulated plates. Figure 1 As shown in Figure A, a vacuum insulator surrounds the sealed reservoir 106 and the cavity 108 to prevent both the liquefied gas in the sealed reservoir 106 and the sample 102 in the cavity 108 from heating. In contrast, the sealed reservoir 106 at least partially surrounds the cavity 108, allowing the cold liquefied gas to maintain the cavity 108 and the sample 102 at the desired temperature.

[0042] Container 100 may include a removable insulating cover or covering 110, wherein the housing and cavity 108 may be sealed by the removable cover 110.

[0043] The container 100 described herein can be used to store cryogenically stored biological samples and / or to transport cryogenically stored biological samples.

[0044] Figure 2 It is used for monitoring Figure 1A flowchart illustrating the example steps for determining the volume of liquefied gas within container A. In step S200, at least one sensor 122 is used to sense / measure the volume of liquefied gas in sealed reservoir 106. A controller or processor (or (one or more) similar components) uses the sensor data to determine whether the sensed volume of liquefied gas is below a desired volume (step S202). The desired volume is the volume required to ensure that the cavity 108 of container 106, and therefore the sample 102, is at the temperature required to ensure sample integrity. If the sensed volume is equal to or greater than the desired volume, the process returns to step S200. If the sensed volume is below the desired volume, the controller sends a control signal to activate heat exchanger 112 to thereby condense any evaporated liquefied gas in sealed reservoir 106 and lower the temperature in the reservoir (step S204).

[0045] After a specified time T, the controller may send a control signal to shut down the heat generator 112 (step S206). Data from at least one sensor 122 may be read again to determine the current volume of liquefied gas in the sealed reservoir 106 (step S208). The specified time may be the time after which the desired volume is expected to be reached. This can be determined based on experiments / calibrations of the container 100. In an embodiment, the controller may be able to determine, based on data from at least one sensor 122, how much volume is insufficient in the sealed reservoir 106 (i.e., the difference between the desired volume and the sensed volume) and how long the heat generator 112 must be turned on in order to reach the desired volume. This can determine the specified time after which the sensors(s) can be polled again. (As mentioned above, in addition to or instead of the level / volume sensor 122, a flow sensor in valve 114 may be used to determine when the heat generator 112 may need to be turned on to counteract the evaporation of liquefied gas in the sealed reservoir 106. The flow sensor may provide a better and faster response than the level / volume sensor 122.)

[0046] In step S210, the controller determines whether the sensed volume is still below the required volume. If the sensed volume is at least equal to the required volume, the process returns to step S200. If the sensed volume is still below the required volume, the controller can be configured to output a message or control signal indicating that liquefied gas needs to be added to the sealed reservoir 106 (i.e., the sealed reservoir 106 needs to be filled with more liquefied gas from an external source) (step S212). As described above, this can be achieved by using a communication module to communicate with the user of the container or with an external device / server. In an embodiment, in step S212, if liquefied gas needs to be added to the container, the controller can cause a warning light or the like to appear or an alarm to sound. After the reservoir has been filled (either using gas condensed into the provided liquefied gas or using liquefied gas), such that the required volume of liquefied gas has been achieved, the process returns to step S200.

[0047] Figure 3 It is used to monitor from Figure 1 A flowchart illustrating an example step of fluid flowing out of container A, specifically evaporated liquefied gas, from the sealed reservoir 106 of container 100. In step S300, a flow sensor in valve 114 is used to detect / sensor the outflow of evaporated liquefied gas from the sealed reservoir 106. In response to the flow sensor data, a controller or processor (or similar component(s)) instructs the refrigerator / heat engine 112 to turn on to cool the liquefied gas in the sealed reservoir and condense any evaporated liquefied gas in the sealed reservoir, thereby stopping or substantially reducing the outflow of evaporated liquefied gas from the sealed reservoir 106 (step S302).

[0048] The controller continues to receive data from the flow sensor, or polls the flow sensor regularly, to determine whether the gas flowing out of the sealed reservoir 106 has significantly decreased or stopped (step S304). If the flow sensor data indicates that the gas flowing out of the sealed reservoir 106 (through valve 114) has significantly decreased or stopped, the controller instructs the heat engine 112 to shut down (step S306), and the process returns to step S300. However, if the flow sensor data indicates that the gas continues to flow out of the sealed reservoir 106 at an unacceptable rate, the controller determines whether a specified time T has elapsed since the heat engine 112 was turned on (step S308). Time T may be a time determined experimentally / calibrated based on the container 100, and is the time taken for the condensation of the liquefied gas to substantially complete its evaporation. Alternatively, time T may be the maximum time that the heat engine 112 can operate, for example for the power efficiency of the container.

[0049] If time T has not been reached in step S308, the controller allows the heat engine 112 to continue operating (step S310). However, if time T has been reached in step S308, but gas is still flowing from the sealed reservoir 106, the controller may first instruct the heat engine 112 to shut down (step S312), and then may be configured to output a message or control signal indicating that liquefied gas needs to be added to the sealed reservoir 106 (i.e., the sealed reservoir 106 needs to be filled with more liquefied gas from an external source) (step S314). As described above, this can be achieved by using a communication module to communicate with the user of the container or with an external device / server. In an embodiment, in step S314, if liquefied gas needs to be added to the container, the controller may display a warning light or the like or sound an alarm. After the reservoir has been filled (either using gas condensed into the provided liquefied gas or using liquefied gas), resulting in the desired volume of liquefied gas, the process returns to step S300.

[0050] In an embodiment, Figure 2 and Figure 3 The methods shown can be combined.

[0051] Therefore, in an embodiment, a method for monitoring the volume of liquefied gas within a container is provided, the method comprising: determining whether at least one sensor indicates that the volume of liquefied gas is below a desired volume and / or that evaporating liquefied gas is flowing out of a sealed reservoir; and sending a control signal to activate a heat engine to condense any evaporating liquefied gas in the sealed reservoir of the container.

[0052] The method may further include: after a specified time, determining whether at least one sensor indicates that the volume of liquefied gas is still below the required volume; sending a control signal to shut down the heat engine; and in response to the determination, outputting a message indicating that liquefied gas needs to be added to a sealed storage tank.

[0053] The method may further include: after a specified time, determining whether at least one sensor indicates that the evaporated liquefied gas is still flowing out of the sealed reservoir; sending a control signal to shut down the heat engine; and in response to the determination, outputting a message indicating that liquefied gas needs to be added to the sealed reservoir.

[0054] Figure 4 It is used for monitoring Figure 1A flowchart illustrating example steps for assessing the integrity of container A. As described above, the controller may be coupled to a power meter, which measures the power consumption of the heat engine 112 during operation. Therefore, in step S400, the process involves measuring the power input to or consumed by the heat engine 112. The controller may be configured to determine whether the measured power consumption of the heat engine 112 exceeds the expected power consumption (step S402). If the measured power consumption is equal to or less than the expected power consumption, the process may return to step S400. If the measured power consumption exceeds the expected power consumption, the controller may output a report regarding the integrity of container 100 (step S404). In this way, the integrity of container 100 can be determined. For example, if it is determined that the heat engine 112 is using more power than expected, container 100 may not be properly insulated, or there may be a leak in the sealed reservoir, causing liquefied gas to evaporate or leak out of container 100.

[0055] Therefore, in an embodiment, a method for monitoring the integrity of a container is provided, the method comprising: determining whether the measured power consumption of the container's heat engine exceeds the expected power consumption; and if the measured power consumption exceeds the expected power consumption, outputting a report on the integrity of the container in response to the determination.

[0056] Embodiments of this technology also provide a non-transitory data carrier carrying code that, when implemented on a processor, causes the processor to execute the methods described herein.

[0057] The technology further provides processor control code to implement the methods described above, for example, on a general-purpose computer system or on a digital signal processor (DSP). The technology also provides a carrier carrying the processor control code to implement any of the methods described above at runtime, particularly on a non-transitory data carrier or on a non-transitory computer-readable medium (such as a disk, microprocessor, CD-ROM, DVD-ROM, programmable memory (such as read-only memory (firmware))) or data carrier (such as an optical or electrical signal carrier). The code can be provided on a (non-transitory) carrier such as a disk, microprocessor, CD-ROM, or DVD-ROM, on a programmable memory such as non-volatile memory (e.g., flash memory), or on read-only memory (firmware). The code (and / or data) used to implement embodiments of the technology can include source code, object code, or executable code in a conventional programming language (interpreted or compiled) such as C, or assembly code, code for setting up or controlling an ASIC (Application-Specific Integrated Circuit) or FPGA (Field-Programmable Gate Array), or code for using a language such as Verilog. TMThe code may be in a hardware description language such as VFIDL (Very High Speed ​​Integrated Circuit Hardware Description Language). As those skilled in the art will understand, such code and / or data may be distributed among multiple coupled components that communicate with each other. The technology may include a controller comprising a microprocessor, working memory, and program memory coupled to one or more components of the system.

[0058] Computer program code for performing operations using the techniques described above can be written in any combination of one or more programming languages, including object-oriented programming languages ​​and conventional procedural programming languages. Code components can be embodied as procedures, methods, etc., and can include sub-components, which can take the form of instructions or sequences of instructions at any level of abstraction, ranging from direct machine instructions of the native instruction set to high-level compiled or interpreted language constructs.

[0059] Those skilled in the art will also appreciate that all or part of the logical methods according to preferred embodiments of the present technology can be suitably embodied in a logic device comprising logic elements for performing the steps of the described methods, and such logic elements may include components such as logic gates in, for example, programmable logic arrays or application-specific integrated circuits. Such a logical arrangement can be further embodied in enabling elements for temporarily or permanently establishing logical structures in such arrays or circuits using, for example, a virtual hardware descriptor language, which can be stored and transmitted using a fixed or transmissible carrier medium.

[0060] In an embodiment, this technology can be implemented in the form of a data carrier having functional data thereon, the functional data including functional computer data structures, so that when loaded into and operated on a computer system or network, the computer system can perform all the steps of the above method.

[0061] Those skilled in the art will understand that, although the best mode of performing this technology has been described above, as well as other modes of performing this technology where appropriate, this technology should not be limited to the specific configurations and methods disclosed in this description of the preferred embodiments. Those skilled in the art will recognize that this technology has a wide range of applications, and that embodiments can be modified extensively without departing from any inventive concept as defined in the appended claims.

Claims

1. A container for cryogenic storage of biological samples, the container comprising: An insulating housing comprising a cavity for containing at least one cryogenically stored biological sample; And its characteristics are: A sealed reservoir, at least partially surrounding the cavity of the housing, the sealed reservoir comprising a liquefied gas, and the sealed reservoir further comprising an inlet valve for filling the sealed reservoir with a gas or liquefied gas. The container further includes a heat transfer motor for condensing the gas in the sealed reservoir to provide liquefied gas, or cooling the liquefied gas in the sealed reservoir. An airflow mechanism, wherein the valve is coupled to the airflow mechanism to allow gas to flow into the sealed reservoir and to allow evaporated gas to flow out of the sealed reservoir, and wherein the airflow mechanism includes a chamber containing an oxygen scavenger and / or a chamber containing a desiccant, the chambers being located between a gas inlet and the inlet valve; and wherein the inlet valve also functions as a pressure reducing valve.

2. The container according to claim 1, wherein, The chamber is removably provided in the airflow mechanism.

3. The container according to claim 1 or 2, wherein, The airflow mechanism further includes a conduit coupled to the inlet valve, wherein the conduit includes a first branch and a second branch, wherein the gas inlet is provided on the first branch of the conduit and a one-way valve provided along the first branch, the one-way valve being used to prevent evaporated gas from within the sealed reservoir from flowing along the first branch, and the airflow mechanism further includes an outlet provided on the second branch of the conduit and a one-way valve provided along the second branch of the conduit, the one-way valve being used to prevent gas from outside the container from flowing through the second branch and into the sealed reservoir.

4. The container according to any of the preceding claims, wherein, A flow sensor is provided to detect fluid flowing into and / or out of the sealed reservoir.

5. The container according to any one of the preceding claims, further comprising a heat exchanger coupled to the heat transfer engine, wherein the heat exchanger extends into the sealed reservoir to achieve cooling of the liquefied gas.

6. The container according to any one of the preceding claims, wherein, The heat transfer engine is any one of the following: a refrigeration machine, a Kleemenco cycle refrigeration machine, a pulse tube refrigeration machine, an acoustic Stirling refrigeration machine, a Joule Thompson refrigeration machine, and a Stirling refrigeration machine.

7. The container according to any of the preceding claims, further comprising at least one sensor in the sealed reservoir for sensing the volume of liquefied gas within the sealed reservoir.

8. The container of claim 7, further comprising a controller coupled to the at least one sensor, wherein the controller is configured to: Determine whether the at least one sensor indicates that the volume of the liquefied gas is lower than the required volume; and A control signal is sent to the heat engine to start it, so as to condense any evaporated liquefied gas in the sealed reservoir.

9. The container according to any one of the preceding claims, further comprising a power meter for measuring the power consumption of the heat engine when it is turned on.

10. The container according to any of the preceding claims, further comprising a communication module for communicating information to any one or more of: a user of the container; a remote server; a manufacturer or supplier of the container; an electronic display; or an electronic device.

11. The container according to any of the preceding claims, further comprising a vacuum insulator and / or a removable insulating cover, wherein the housing and the cavity are sealable by the removable cover.

12. A method for monitoring the volume of a liquefied gas within a container according to any one of claims 1 to 11, the method comprising: Determine whether at least one sensor indicates that the volume of the liquefied gas is below the required volume and / or that evaporating liquefied gas is flowing out of the sealed reservoir; as well as A control signal is sent to start the heat engine to condense any evaporated liquefied gas in the sealed reservoir of the container.

13. A method for monitoring the integrity of a container according to any one of claims 1 to 11, the method comprising: Determine whether the measured power consumption of the heat engine in the container exceeds the expected power consumption; as well as If the measured power consumption exceeds the expected power consumption, a report on the integrity of the container is output in response to the determination.

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