FOR BIOLOGICAL MATERIALS

BACKGROUND OF THE INVENTION

1. Field of the Invention.

[0001] The present invention relates to a portable cryogenic carrying case for biological material.

2. Description of Related Art.

[0002] The FDA recently approved the use of bone grafts, mesenchymal cells, umbilical stem cells, and skin grafts for clinical trials or use in the treatment of many conditions. Transplantation medicine is gaining in popularity as research snowballs and brings the potential advantages of this innovative approach forward. This is the time for development of new and better technologies that streamline the process from production of biomaterials (often consisting of cells to be used in grafting) to their use in treating patients.

[0003] Unfortunately, the technology involved in the production and distribution of the biomaterials has not kept pace with the biotechnical advances. Currently, it is normal practice for biomaterials, such as named above, to be transported on dry ice by a distribution company and then frozen at -80°C or in liquid nitrogen by the purchasing facility, until they are used. The distribution company often supplies these freezers, at great expense to the medical facility. At each stage of transport, the shipment is checked manually, as nurses check boxes on a form, and sometimes even by computer. Full knowledge of what is happening to the biomaterials is woefully deficient. The transport container is only for transport and does nothing to facilitate the use of the biomaterial.

[0004] There are difficulties with every stage in the transport and use of biomaterials. For example, shipping biomaterials on dry ice (-78°C) by FedEx is costly and requires one-time use containers. Although there is a record of where the biomaterials were and for how long, there is no way to know whether they were kept at the required temperature. Suboptimal temperatures are harmful to biologicals. Once the biomaterial arrives at its destination, medical personnel must transfer the biomaterial from the dry ice to a -80°C freezer or liquid nitrogen tank without delay. More often than not, this vital step can be overlooked in a busy hospital. Moreover, since the freezer will contain other specimens, it is likely that an older shipment becomes confused with a newer one. Cells have a limited shelf life, which reduces the viability of a biomaterial graft and the chances that it will "take." It is even possible that inadequate labeling may result in biomaterials from one patient being transferred into another, potentially causing a catastrophic immune reaction. Surgery or implantation of the biomaterial is often less than straightforward. The medical facility must have the requisite sterile instruments and working surfaces on hand. The biomaterial, which has been removed from the freezer to be ready for use, could become too warm due to delays, causing loss of cell viability and denaturation of growth factors. For this reason, some distributors have personnel wait in the room ready for the surgery to be performed until the biomaterial is developed. This is a very expensive and highly inconvenient.

[0005] Even under this labor intensive procedure, graft failure is common. Some of the leading causes of failure are hematoma formation, which can be avoided by meshing of the graft, infection, which can be reduced by meticulous preparation of the area, and surgeon error in placing the grafts upside down.

[0006] These are factors that the current systems of transport and delivery cannot address. The present invention, on the other hand, does. The reusable cryogenic carrying case of the present invention reduces many risk factors that cause biomaterial failure in skin grafts.

SUMMARY OF THE INVENTION

[0007] A mobile, compact, reusable carrier that is able to regulate its internal low temperature using an internal microcontroUed multicore pressure system, simplifies transportation and storage of biomaterials.

[0008] An inbuilt sterile instrument case with a work area, provides a surgeon with a useful tool that increases ease of care during a graft procedure. Grafts can fail due to hematoma, inadequate wound preparation and infection. The carrying case has a set of sterile surgical tools for fenestrating the grafts and reducing the likelihood of hematoma. The surgeon has everything needed in the case to thoroughly prepare a wound site.

[0009] The risks inherently associated with inadequate preparation of surgical trays due to operator error or even malfunctioning sterilization equipment is prevented. The inevitable infection risk associated with having an extra person scrub in (the person from the graft manufacturer) will be avoided. The carrying case has a pouch adjacent to the surgical tools where the graft is placed right side up, making correct placement obvious to the surgeon.

[0010] A microcontroller combined with sensors, a communication board, a radiofrequency identification (RFID) module, a display, and other peripherals in the carrying case enable it to interact with its environment. It collects real time data such as the temperature of the biomaterial, the contents of the case, its location, a log of how long the material has been in transit and where it has been. The data gathered is available to the user, the transport company, the biomaterial manufacturer, or any other interested party.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The exact nature of this invention, as well as the objects and advantages thereof, will become readily apparent from consideration of the following specification in conjunction with the accompanying drawings in which like reference numerals designate like parts throughout the figures thereof and wherein:

[0012] Figure 1 is a front prospective of the outside of the carrying case;

[0013] Figure 2 is a back perspective of the carrying case;

[0014] Figure 3 is an enlarged perspective illustration of three ports located at the back of the carrying case;

[0015] Figure 4 is a cross-section of the case, showing the multilayer structure of the case;

[0016] Figure 5 is a front perspective of the case with the top opened, showing the bottom part with an exploded view of a graft packet;

[0017] Figure 6 is a back perspective of an open carrying case showing inner working surfaces or plates and the graft packet;

[0018] Figure 7 illustrates the seals located around the perimeter in the top and bottom of the carrier case;

[0019] Figure 8 is a cross-section of the top and bottom seal showing how they interconnect;

[0020] Figure 9 is a perspective of an open carrying case showing contents of the top as having a working surface, a plate, a clean area, and an instrument compartment; [0021] Figure 10 is a perspective of an open carrying case showing the multicore cooling system in the bottom of the case;

[0022] Figure 11 is an exploded view of the components of the cooling system in the carrying case, in the bottom part of the case;

[0023] Figure 12 is a perspective of the bottom of the carrying case showing movement of nitrogen in the cooling system as the system is filled;

[0024] Figure 13 is a schematic illustration of a pipe used in the carrying case showing the multilayered construction;

[0025] Figure 14 is a perspective of the open case with the plates removed from the top, showing internal electrical components;

[0026] Figure 15 is a schematic representation of a microcontroller system with a power source and multiple inputs and outputs, with the outputs coupled to multiple peripheral components;

[0027] Figure 16 is a perspective of the bottom of the carrying case showing activation of the emergency pressure release system when there is an unacceptable amount of pressure in the inner and outer cores of the system;

[0028] Figure 17 is a perspective of the bottom of the carrying case showing the next stage in the emergency pressure release system, allowing the excess nitrogen gas to pass into an overflow chamber;

[0029] Figure 18 is a perspective of the bottom of the carrying case showing how the build-up of nitrogen pressure causes failure of the inner and then outer core break caps, followed by nitrogen leakage into the vacuum core of the case.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] A preferred embodiment of the outside of the cryogenic carrying case, is shown in Figure 1. A screen of multiple LEDs 30 that can be programmed to display information about the contents of the case is located on the top. This screen has a non-thermoconductive protecting layer on the inside in order to allow it to function at low temperatures, as well as to prevent heat exchange between the external environment and the inside of the case. The logo 31 on the surface of the case is made of a temperature-sensitive material, so that it can act as a warning that the case is being exposed to excessive heat.

[0031 ] The top and bottom of the case close at the front and are held together by permanent magnets 32 at all four corners 34. A wedge-shaped indentation 33 on the bottom part of the case allows easy opening of the case. One of the magnets in one of the corners of the case is paired with a magnetic switch sensor (not shown) that sends a signal to a microcontroller (described hereinafter), registering if the case is open or closed. The corners of the case 34 are semitransparent to allow light produced by LEDs 35 on the top of the case to propagate to the bottom. A strip 36 of high brightness LEDs is located on the top at the latch area 33, to illuminate the latch area. [0032] The semitransparent corners 34 of the case have built in reflectors. The corners are interconnected by a fiberoptic strip 37. The bottom right corner of the case contains multiple diodes such as infrared receivers, IR transmitters, and triple color high power LEDs 38. These diodes are surface mounted on a printed circuit board (PCB). The light signals from these diodes are transmitted to the other corners via the fiberoptic strip 37 and reflected by the reflectors 39 in each corner. This light signal is transmitted between the top and bottom of the case by way of two pieces of fiberoptics enclosed in small transparent areas at each corner of the case that meet when the case is closed. A GPS and Wifi antenna is located in the bottom right reflector 40. A USB slot 41 is provided to allow added communication capabilities.

[0033] Referring now to Figures 2 and 3, there are three conical openings in the back of the case (Figure 3). An inlet 42 with a one way valve 43 enables charging the refrigeration system of the case with coolant such as liquid nitrogen, for example. An outlet 44 with a one way outlet valve 45 to enable continuous recirculation of nitrogen when long-term storage is desired. An exhaust 46 with an adjustable flow-limited pressure valve 47 enables release of excess nitrogen from the case. For safety, the exhaust tip of the exhaust 46 points towards the floor (not shown). The function of these one way valves will be discussed more fully hereinafter. [0034] The top and bottom of the case is constructed from a multiple layer material, an example of which is shown in Figure 4. An infrared-blocking molded thermal film 48 is used as an outside layer. A non-thermoconductive inner layer 49, such as zirconium, for example, is sandwiched by an inside reflective layer 50. This multilayer structure enables the carrier enclosure to act as a non-thermoconductive barrier between the outside and the inside of the case.

[0035] Figure 5 shows an open carrying case, revealing the inside surface of the bottom 55. A graft pouch 51 is shown in exploded view. A skin graft or other biomaterial frozen in its transport media, is enclosed within the reusable pouch 51 which has tabs 52 on either side. A non-thermoconductive removable film 53 covers the top of the pouch. A thin thermoconductive silver-based silicone/graphite gel (not shown) is on the bottom of the pouch. The graft pouch 51 rests on a base plate 54 in the bottom of the case. It is centered over an opening in the base plate 54 that is directly over the cooling inner core 56 below the base plate. The pouch is in direct contact with the cooling core when inside the case. The core will be described hereinafter.

[0036] Figure 6 shows an open cryogenic carrying case showing the working surfaces contained inside. The graft pouch 51 is held in place on the base plate 54 in the bottom half of the case by two spring-loaded shafts 57 attached to the base plate, for easy release. The base plate contains a basin 53 for washing the graft. A gutter system 59 encircles the entire base plate for collecting and returning spilled liquid to the basin 53. When the case is closed, the gutter 59 is enclosed in the case by a silicone seal 60. A spring ball-loaded magnetic connector 61 located near the hinges 62 allows a microcontroller in the top of the case to communicate with peripheral devices in the bottom (as described hereinafter).

[0037] A plate 63 in the top of the case contains all that a physician requires for accurate, effective, and sterile placement of the graft. An indentation in the top plate 64 contains a drum graft mesher 65, which is used to fenestrate the graft. The graft mesher 65 has a roller wheel 66 attached. This allows physical rotation of the drums. The mesher is held in place by spring-loaded clips at the end of shafts 67, for easy removal and cleaning. The fenestrated graft feeds into a collecting basin 68 that is usually filled with fluid to avoid drying and tearing of the fragile tissue.

[0038] Figures 7 and 8 illustrate the gas and fluid impervious seal used in the cryogenic carrying case. The seal traverses the perimeters of the top and bottom, of the case. The seal has two parts. One part 60 is in the top of the case. The other part 159 is in the bottom of the case. The top seal 60 slides into the bottom seal 159 as shown in Figure 8.

[0039] Referring now to Figure 8, an instrument cover 69 and plate is laser-engraved with a grid that acts as a measuring tool, for use when cutting a graft to size. This also provides an additional sterile working surface. When the instrument cover 69 is closed, as shown in Figure 6, the surgeon has a large clean area on which to manipulate the graft. When the working surface slides back (as shown in Figure 9) access is provided to sterile instruments 70 underneath, nestled on a soft silicone cone-shaped mat (71) held in place by an embedded magnetic strip 72.

[0040] Referring now to Figure 10, the case is cooled by a multicore system, an inner core 56 and an outer core 73. Movement of coolant (liquid nitrogen) is through the inner core 56 and outer core 73, to an overflow pressure tank 74 and out the exhaust 46. An exploded view of the cooling system is shown in Figure 11.

[0041] The inner core 56, located in the case to be under the graft-containing pouch, is constructed of a thermoconductive material. The inner core is overlaid with a widely spread reinforcing Kevlar fiber net that has been soaked in thermoconductive materials such as, for example, resin or silicone gel (not shown). The inner core surface is in direct contact with the thermoconductive bottom part of the graft pouch, as shown in Figures 5 and 9, for maximum heat exchange.

[0042] The multi core cooling system is filled with liquid nitrogen through the inlet port 42 with the one-way valve 43 (Figures 2 and 3). The valve opens during charging from mechanical pressure excited by the fill pipe. [0043] The filling process is illustrated in Figure 12. As the nitrogen (arrow) enters the room temperature inner core 56, it boils and is vaporized. As a result, the pressure in the inner core increases, causing the nitrogen gas to pass through tiny flow rate-limited pressure equalizer microports 74 (Figure 11, 75) into the outer core 73. The outer core 73 is a ring-like structure surrounding the inner core. This release of the warmer vapor into the outer core aids in cooling the inner core 56 as nitrogen gas fills the outer core 73. But, the rate-limited flow through the microport 75 keeps the nitrogen in the inner core under pressure and in liquid form.

[0044] The nitrogen gas then passes from the outer core into a pipe 76, through a double function thermo-insulated solenoid 77, into an overflow tank 74. The nitrogen gas builds up in the overflow tank 74 and an outlet serpentine pipe 78. The flow out the pipe 78 is limited by the adjustable pressure regulation exhaust valve 47 (Figure 10). This exhaust valve 47 determines the amount of residual pressure permitted in the post-solenoid part of the system.

[0045] An important part of the function of the cryogenic carrying case is a microcontrolled solenoid 77. Because the resistance and the amount of power required to open the solenoid 77 is determined by the gas pressure on either side of the solenoid valve 77, this valve can also act as a pressure sensor, giving information back to the microcontroller. The microcontroller ensures that cooling system of the case, while the cooling system of the case is charging and nitrogen gas escapes into the overflow tank, the same amount is added to the inner core 56 until the inner core is full of liquid nitrogen. Because the solenoid operates electromagnetically, there is no direct connection between the moving components and the internal environment of the bottom of the case. Freezing or ice buildup, preventing effective function, is thus unlikely.

[0046] Once the cooling system is charged, the microcontroller stops energizing the solenoid 77, which causes it to close. The liquid state of the nitrogen in the inner core 56 is then maintained by pressure.

[0047] In order to cool down the case for use, and maintain a user-set temperature, a temperature sensor 79 (Figure 10) is located on the pipe near the solenoid 77. The temperature sensor transmits data to a microcontroller, which compares it to a set value. If the temperature is out of range, the microcontroller energizes the solenoid so that it opens and some of the nitrogen is allowed to flow into the overflow tank 74. As the pressure in the inner core decreases, the liquid nitrogen boils, absorbs heat from its surroundings, and the inner and outer core cool. The escaping nitrogen leaves the overflow tank by the serpentine pipe 78, absorbing maximum heat from the case, to the adjustable one-way mechanical valve 47 and exhausts at outlet 46. Since the valve 47 controls the pressure in the overflow tank 74, it can be adjusted for differently-sized devices or other modifications of the system. [0048] For strength and insulation purposes, multilayer pipes (Figure 13) are used in the cooling system. The pipes contain a braided Kevlar outer layer 80 for strength. A thermo-insulation layer 81, made of graphite is used under the outer layer. A low-conducting, non-corroding ceramic or doped non-thermoconductive zirconium layer 82 is used as the inner layer.

[0049] Non-thermoconductive bushings 83 (Figures 10, 11) that support the sides of the outer core 73 and the base of the inner core 56, the vacuum core 84 that provides additional thermoinsulation, and the outer thermal insulation foam zone 85, is an important safety feature of the case, as will be described hereinafter.

[0050] The majority of the electronic components of the cryogenic carrying case are located directly under the outer surface of the top of the case, as shown in Figure 14. The main component is a printed circuit board (PCB) assembly (not shown), which is located below the screen 30 (Figure 1) in the top. This includes a microcontroller with various analog and digital inputs and outputs. The microcontroller receives information from peripherals located throughout the case. The microcontroller outputs are assigned to regulate the function of the case and interact with the peripherals. A schematic of the microcontroller and its various inputs and outputs is illustrated in Figure 15 and is described hereinafter. [0051] The PCB with microcontroller supports USB 41 so that various modules such as Blue Tooth®, Wifi® and GPS®, can be added. The Wifi, similarly, allows the case to transmit information and receive commands. The infrared (IR) transmitting and receiving diodes establish connections with IR capable devices and with other cases in the vicinity. Blue Tooth® establishes connection with Blue Tooth® enabled devices such as Android® phones, iPads® and some laptops. This compatibility with the Android® system is deliberate since the software is open source. However, the microprocessor in the case has internal memory so it can be preprogrammed and perform all the required functions without an external device.

[0052] The cryogenic carrying case gathers information about its contents and surroundings through a system of sensors. First, the radio frequency identification tag (RFID), located as part of the double coil 86 (Figure 14) and motherboard, allows the user and/or cargo to scan in/be scanned in so that the case displays appropriate settings. As mentioned above, a magnetic switch 32 on the front right of the case coupled with corresponding permanent magnets on the top and bottom of the case determines whether it is open or closed. The case has two temperature sensors. One is on the pipe next to the solenoid 79 and monitors the temperature of the inner core 56. The other 87 is close to the outer surface of the case and monitors ambient temperature (Figure 1). [0053] The cryogenic carrying case contains a triple color high power LED surface mounted diode 38 (Figure 1) at one corner of the top that enables it to display colors on the four corners of the case via the fiberoptic strip 37 and reflectors 39 at the other three corners of the case. This allows the case to visually interact with the user about whether it contains an unused graft (green), the graft is expired (yellow) or the case is experiencing unusual pressure (red). Additional information, such as the temperature of the core, the date, the cargo, and the time left, is available via the LED display 30, which is constructed of multiple LEDs and a thermo-insulating backing. The LED display has a Piezo speaker 88 (Figure 14) fixed to the back that allows for audio communication by producing different frequency noises to alert a user or emit a warning, if necessary.

[0054] The cryogenic carrying case uses a charging coil that is connected to a lithium ion battery with charger 89 (Figure 14). The battery can

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also be charged through the USB converter 41. The top of the case contains a double coil 86 (Figure 14) that allows communication between the top and bottom of the case.

[0055] The microcontrolled double function solenoid 77 opens and closes based on readings from the temperature sensors in combination with software that allows the user to vary the range within which the microcontroller will activate the solenoid to open, allowing some high pressure coolant to escape. The solenoid 77 also acts as a pressure sensor because the amount of pressure in the inner core is proportional to the amount of power needed by the solenoid 77 to open it. The microcontroller can sense this change in terms of current and resistance and integrate this information with the information received from peripherals, such as the temperature sensors. This enables the microcontroller to estimate the amount of nitrogen remaining in the case and the number of hours the case has left.

[0056] Because of the risks inherent in using highly-pressurized gases, a system of safety measures has been integrated into the cryogenic carrying case. First, if the core system of the case is exposed to extreme heat, the liquid nitrogen will boil and, as a result, the solenoid valve 77 will sense increased pressure, as shown in Figure 16. When this pressure reaches a predetermined range, the microprocessor will cause the solenoid to be energized into a continuously open position, allowing gas to evacuate and pressure to build up in the overflow chamber, as shown in Figure 17. Excess pressure sensed by the solenoid 77 will trigger audio and visual alarms so the user is warned. The gas escapes into the serpentine pipe where it encounters the flow limited pressure regulated one way exhaust valve and is vented at a low fixed rate through the exhaust vent.

[0057] If the flow rate exceeds the maximum permitted by this valve, the gas will back up via the solenoid 77 and into the outer and inner core. When the pressure reaches the pre-set fail point of the cores, the case is compromised so that it is no longer useable. At ultrahigh pressures (Figure 18), the inner core 56 and outer core 73 break caps 90, 91 that will give way. The vacuum core 84 will absorb some of the escaping gas, redistributing the excess pressure throughout the interior of the core. Next, the vacuum core break cap 92 will fail and the remaining nitrogen will enter the thermal insulation foam, which will act as a crumble foam area to absorb the initial force (Figure 18). Finally, the gas may escape at the junction between the plates and the shells and the nitrogen will harmlessly dissipate into the atmosphere.

[0058] In summary, the invention is a portable reusable cryogenic carrying case for the transport, storage and use of temperature-sensitive materials. The case is capable of maintaining very low temperatures for extended periods of time while continuously monitoring and regulating the temperature of the biomaterial. It also gathers data such as a real time record of how old the biomaterial is, preventing use of cells with age-related diminished viability. Of course, it is entirely possible that the main benefit of biomaterial grafts consists in the secretion of growth factors, cytokines, and angiogenic factors. Again, the controlled environment provided by the case will guarantee that these biological agents remain active until the implant is placed and that the cells continue making them for as long as possible. The invention allows real time close monitoring of a biomaterial. It is possible to track immunologically distinct lines. These can be matched with the MHC profiles of individual patients, much as blood typing is today, thereby increasing the length of time that the cells will be viable, increasing the likelihood of success of graft procedures. From the moment the biomaterial is produced and placed in the device until the time it is sited on or in a patient, this invention will ensure that it is in a sealed, sterile container, kept at a constant temperature, monitored for temperature, location, and who performed the task, and the data are transmitted and made available to the distributor and end-user upon demand. The case benefits the patient, the medical facility, and the biomaterial producers. It is even environmentally friendly, being entirely re-usable.

[0059] In addition, the case can easily be modified for transport and storage of other temperature sensitive biologies, including blood, vaccines, viruses, sperm, and more. It can also be modified for nonbiologics. The case is also seen as having value for wound care in military zones, especially because it is easily transported and tracked.