An apparatus and method for a microfluidic culture of non-adherent pre-implantation cells, tissues, organoids, or embryos under environmentally controlled, highly customizable microenvironments

Abstract

An apparatus and method for controllably moving a containment vessel for mammalian gestation, including to provide continuous intermittent motion and culture of an embryo in the containment vessel. The method includes determining compatibility or biocompatibility of a material or substance for gestational development of an embryo. The apparatus includes a motion system having one or more fasteners configured to attach to the containment vessel, a platform configured to support the motion system and allow the containment vessel to move with respect at least one axis while being imaged by an image pickup device, and a drive system having a controller configured to adjust movement of the containment vessel with respect to the at least one axis, including at least one of an inversion frequency, a direction of rotation, a velocity, a rate of change in the inversion frequency, a rate of change in the direction of rotation, and a rate of change in the velocity of the containment vessel, for mammalian gestation.

Description

AN APPARATUS AND METHOD FOR A MICROFLUIDIC CULTURE OF NONADHERENT PRE-IMPLANT ATION CELLS, TISSUES, ORGANOIDS, OR EMBRYOS UNDER ENVIRONMENTALLY CONTROLLED, HIGHLY CUSTOMIZABLE MICROENVIRONMENTSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of provisional U.S. Patent Application No. 63 / 551,643, filed February 9, 2024, which is hereby incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates generally to methods, systems, and devices for continuous intermittent motion of an embryo, and, more particularly, a method, a system, and a device for motion and monitoring an environmentally controlled customizable microfluidic device. The disclosure includes an apparatus for a microfluid culture of non-adherent preimplantation particles, cells, cell aggregates, tissues, organoids, organisms, or embryos (collectively and individually herein referred to as “embryo”) under environmentally controlled, very low shear force, conditions.BACKGROUND OF THE DISCLOSURE

[0003] State of the art technologies to date have not provided a technology for holding and providing constant motion to satisfy the motion requirements of, for example, biomimetic marsupial gestation or other mammalian gestation, while supplying fresh nutrients and removing waste. The inventors have discovered the need for such a technology.SUMMARY OF THE DISCLOSURE

[0004] The inventors have invented a technology (including a method, system and device) for continuous intermittent motion, and culture, of embryos, including, for example, a technology for holding and providing essentially constant motion (for example, in intermittent intervals) to the embryo to satisfy non-adherence to a surface requirements of, for example, pre-implantation stage mammalian gestation (including, for example, biomimetic and / or non-mimic mammaliangestation), while supplying fresh nutrients and removing waste. In various embodiments, the novel technology includes a microfluidic device having a vessel (or containment vessel) and supporting platform, as well as a drive mechanism that includes a controller for determining and maintaining motion necessary for mammalian gestation, including adjusting velocity, acceleration, or deceleration of the motion. The microfluidic device can include a microfluidic chip made of, for example, polydimethylsiloxane (PDMS) and configured with a plurality of micro-channels connected to together to mix, pump, sort, or control the environment formed within the microfluidic device. The technology includes control and regulation of the conditions in, and surrounding, the microfluidic device, such as, for example, temperature, pressure, humidity, and gas, which can include control and regulation of oxygen, nitrogen, and / or carbon dioxide. The technology includes one or more sensors, including an image pickup device (for example, a camera equipped with a time-lapse optical imaging system), for morphological monitoring, analysis, and assessment of the embryo, including at all stages from initial placement of the embryo in the microfluidic device through development and to developmental maturity, as applicable. The culture medium within microfluidic device can be recirculated, refreshed (for example, partial replacement ratios), and / or replaced. Any removed or expended culture medium can be stored on a microfluidic chip or transferred off the microfluidic device into a storage or a device for analysis.

[0005] According to an aspect of the disclosure, an apparatus is provided for controllably moving the microfluidic device for mammalian gestation, including to provide continuous intermittent motion and culture of an embryo in the microfluidic device. The apparatus includes a controller for controlling all operations of the apparatus and conditions in and surrounding the microfluidic device. The apparatus includes a motion system having one or more fasteners configured to attach to the microfluidic device, a platform configured to support the motion system and allow the microfluidic device to move, for example, with respect a center axis (or multiple axes), and a drive system configured to move and adjust movement of the microfluidic device with respect to the center axis (or multiple axes), including at least one of an inversion frequency, a vessel position, a direction of rotation, a velocity, a rate of change in the inversion frequency, a rate of change in the position of the vessel, a rate of change in the direction of the rotation, and a rate of change in the velocity of the microfluidic device, for testing, measuring, monitoring, and / or assessing the embryo and the conditions in and around the microfluidic device, includingmammalian gestation, any (or all) of which can be performed under operation and control of the controller.

[0006] The apparatus can include a biomimetic manifold configured to supply fluids, via one or more supply conduits, at specific or predetermined controlled times, amounts, and flow rates, to the microfluidic device and extract waste via one or more output (or waste) conduits from the microfluidic chip. The fluids can include liquids, gases, or solids. The fluids can include, for example, nutrients, food, water, medicine, drugs, growth factors, reagents, or other substances for testing, measurement, monitoring, analysis, assessment, and / or gestation of an embryo in the containment vessel. The gases can include, for example, oxygen, nitrogen, and carbon dioxide. The solids can include, for example, particles in a colloidal suspension. The biomimetic manifold can operate for biomimetic and / or non-mimetic applications. The biomimetic manifold can include one or more supply conduits configured to supply fluids from a supply source to the microfluidic device, and the output (or waste) conduits can be configured to supply waste or other output from the microfluidic device to, for example, a receptacle or external conduit where the output and / or waste can be analyzed for purposes of, for example, of testing, measurement, analysis, or assessment of the embryo and the environmental conditions, such as, for example, the conditions in and around the microfluidic device. In at least one embodiment the analysis can include depletion and consumption analysis of glucose.

[0007] The biomimetic manifold can include a supply source configured to supply one or more fluids via the one or more supply conduits to the containment vessel for mammalian gestation, as well as testing, measurement, analysis, and assessment of the embryo and the environmental conditions. The biomimetic manifold can include an output (or waste) reservoir configured to receive and hold the output, including waste, received via the one or more output conduits from the microfluidic device.

[0008] The motion system can include an actuator and one or more fasteners configured to attach to the microfluidic device. The actuator can include, for example, a rotor and a rotary member configured to support the rotor and allow the rotor to rotate about the center axis, and a driven gear configured to be driven and rotate the rotor about the center axis. In certain embodiments two or more actuators can be provided, each being configured to rotate about an axis to provide three-dimensional rotation in space, for example, to turn the microfluidic device in anydirection along the x, y, and z axes. The driven gear can be affixed to the rotor, for example, by fasteners, welding, bonding, adhesive, or other attachment mechanism. Alternatively, the driven gear and rotor can be made as an integrated single structure. The center axis can be the center axis of the rotor.

[0009] The center axis is a rotational co-axis of the rotary member and the rotor. The center axis can be a rotational co-axis of the driven gear. In certain embodiments, the center axis is perpendicular to a plane of a surface of the rotor or a direction of rotation of the rotor. The center axis can be substantially perpendicular to a gravity vector, wherein the gravity vector has a direction component that is entirely in the direction of gravity and a magnitude component that is equal to the force gravity exerts on the apparatus.

[0010] In various embodiments, the rotary member can include a hub, a spindle, an axle, a shaft, a gear, a bearing, a roller bearing, a bearing cup, or other device capable of supporting the rotor, while the rotor rotates about the central axis. In at least one embodiment two or more actuators are provided, each having a rotary member configured for axial rotation such that the rotary members provide three-dimensional or 3D rotation. The multi-axis rotation can be controlled based on, for example, an image signal received by the controller from the image pickup device. The system can be configured to move and maintain the embryo in a quasi-zero gravity space.

[0011] The drive system can include a driver gear configured to engage and drive the driven gear to rotate the rotor about the central axis, or multiaxially within a three-dimensional space.

[0012] The microfluidic device can include a microfluidic chip containing a containment vessel and a plurality of microchannels. The microfluidic device includes a container body having a plurality of microchannels (or conduits), chambers, valves, pumps, fluid control elements, and a vessel with two distal ends having an opening at each distal end. The vessel includes a defined volume, channel cross section, length and surface to volume ratio. The containment vessel can be formed as a fluid channel in the container body. The microfluidic device can include a plurality of conduits extending from a planar surface, or from two opposite planar surfaces, of the container body, which can connect to the biomimetic manifold.

[0013] In an embodiment, the microfluidic device can include the container body that includes the vessel with two ends (and / or the vessel conduits) and an opening at each of the two ends, withone opening configured to connect to the one or more microchannels (or supply conduits) and the other opening configured to connect to another one or more microchannels (or waste conduits). In an embodiment the two vessel ends are configured as the embryo loading channel and the channel output, with the channels being closed during culture. The microfluidic device can include a nutrient input and waste output conduit / channels, including, for example, a further number of channels for medium / nutrient managed flow and expended medium transport. In other embodiments, the container body includes one or more microchannels that connect to one end of the vessel and one or more microchannels that connect to the other end of the vessel.

[0014] The biomimetic manifold can be configured to attach to the motion system and supply fluids to the containment vessel and extract waste from the containment vessel while the microfluidic device moves with respect to the center axis (or multiple axes in certain embodiments).

[0015] In certain embodiments, the drive system can include a motor and a drive shaft, wherein the drive shaft is configured to attach to the driver gear. The controller can include a processor, a memory, and a motor driver, which is configured to send electrical signals to the motor to operate and control the motor. The controller can include a biomimetic monitor configured to monitor, analyze, and assess the embryo and its condition, as well as the environmental conditions, for example, based on sensor signals received from one or more sensors. The monitored conditions can include at least one of a size, shape, temperature, color, texture, sedimentation time, and position of the embryo; a density, pressure, temperature, color, texture, and position of, or the fluid in, the vessel; a direction of rotation (including planar or multiaxial rotation) and a velocity of rotation of the vessel. The biomimetic monitor can be configured for operation in either or both biomimetic and non-mimetic applications.

[0016] The biomimetic driver can be configured to determine and maintain movement of the microfluidic device for testing, measuring, monitoring, and / or assessing the embryo, including mammalian gestation, and the environmental conditions. The biomimetic driver can be configured to determine the inversion frequency, the direction of rotation, the velocity, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the velocity of the containment vessel, as well as the sedimentation rate and acceleration the embryoexperiences during rotation and maintaining a constant acceleration to provide quasi-zero gravity conditions.

[0017] According to another aspect of the disclosure, a method is provided for moving the microfluidic device for mammalian gestation, including providing continuous intermittent motion and culture of the embryo. The method includes providing a microfluidic device containing an embryo, affixing the microfluidic device to the motion system (for example, via one or more fasteners), and determining at least one of an inversion frequency, a position of the vessel, a direction of rotation, a velocity, a rate of change in the inversion frequency, a rate of change in the position of the vessel, a rate of change in the direction of rotation, and a rate of change in the velocity of the microfluidic device. The method further includes driving the motion system with respect to the center axis (or about multiple axes for 3D rotation), the motion system being driven according to the determined at least one of the inversion frequency, the position of the vessel, the direction of rotation, the velocity, the rate of change in the inversion frequency, the rate of change in the position of the vessel, the rate of change in direction of rotation, or the rate of change in the velocity of the microfluidic device.

[0018] The method can include supplying fluids via one or more supply conduits to a vessel and extracting an output (or waste) from the vessel via one or more output (or waste) conduits. The fluids can be supplied from a supply source to the vessel via the one or more supply conduits. The waste can be supplied from the vessel to a receptacle (or reservoir) via one or more output conduits. The waste can include a fluid such as animal excretion or secretion (such as, for example, paracrine factors). The waste can be analyzed to test, measure, and assess the real-time condition of the embryo at any instant in time, as well as the effects of the environmental conditions on the embryo and its gestation in the vessel.

[0019] The method can include attaching a biomimetic manifold to the motion system to supply fluids to the vessel and extract waste from the vessel while the microfluidic devices moves with respect to a central axis, or multiple axes in embodiments configured for three-dimensional rotation.

[0020] The method can include monitoring, analyzing, and / or assessing at least one of a size, a shape, a density, a position, and a sedimentation time of the embryo in the vessel. The methodfurther includes monitoring, analyzing, and assessing the velocity of rotation and direction of rotation of microfluidic device.

[0021] According to a further aspect of the disclosure, a non-transitory computer readable storage medium is provided for storing one or more computer-executable programs for moving a microfluidic device for testing, measuring, monitoring, and / or assessing the embryo and the conditions in and around the microfluidic device, including mammalian gestation. The one or more instructions include providing continuous intermittent motion and culture of an embryo in a vessel. The one or more programs contain instructions, which, when executed by the processor, cause the processor to perform operations of provisioning a microfluidic device containing an embryo, affixing the microfluidic device to a motion system or one or more fasteners on the motion system, determining at least one of an inversion frequency, a direction of rotation, a position of the embryo, a velocity, a rate of change in the inversion frequency, a rate of change in the direction of rotation, a rate of change in the position of the embryo, and a rate of change in the velocity of the containment vessel, and driving the motion system with respect to an axis, or multiple axes in embodiments configured for three-dimensional rotation. The motion system is driven according to the determined at least one of the inversion frequency, the direction of rotation, the position of the embryo, the velocity, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the position of the embryo, or the rate of change in the velocity of the containment vessel.

[0022] The operations can include supplying fluids to the containment vessel and extracting waste from the containment vessel. The operation of supplying fluids can include monitoring and adjusting the molarities of the various fluids that are supplied, as well as the timing and rate of supply.

[0023] The operations can include attaching a biomimetic manifold to the motion system to supply, and / or recirculate, fluids in and / or to the containment vessel and extract waste from the containment vessel, while the microfluidic device moves with respect to the axis, or multiple axes in those embodiments configured for three-dimensional rotation.

[0024] The operations can include sending electrical signals to a motor to operate and control the motor to maintain the movement of the containment vessel for mammalian gestation.

[0025] The operations can include monitoring, analyzing, and assessing at least one of a size, a shape, a density, a position, a sedimentation time, or other characteristics of the embryo. The operations can include monitoring and assessing a position of the vessel, a direction of rotation, and a velocity of rotation the containment vessel.

[0026] The operations can include determining the inversion frequency, the direction of rotation, the position of the embryo, the velocity, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the position of the embryo, or the rate of change in the velocity of the containment vessel based on the at least one of the size, shape, density, sedimentation time, and position of the embryo, as well as the position of the vessel, direction of rotation, and velocity of rotation of the containment vessel.

[0027] Additional features, advantages, and embodiments of the disclosure may be set forth or apparent from consideration of the detailed description and drawings. Moreover, it is to be understood that the foregoing summary of the disclosure and the following detailed description and drawings provide non-limiting examples that are intended to provide further explanation without limiting the scope of the disclosure as claimed.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings, which are included to provide a further understanding of the disclosure, are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the detailed description serve to explain the principles of the disclosure. No attempt is made to show structural details of the disclosure in more detail than may be necessary for a fundamental understanding of the disclosure and the various ways in which it may be practiced.

[0029] FIG. 1 shows an embodiment of a nonlimiting embodiment of a continuous intermittent motion device, constructed according to the principles of the disclosure.

[0030] FIG. 2 shows an embodiment of a biomimetic manifold that can be included in the device of FIG. 1.

[0031] FIG. 3 shows an embodiment of a containment vessel that can be included in the device of FIG. 1.

[0032] FIG. 4 shows an embodiment of a system that includes the continuous intermittent motion device, according to the principles of the disclosure.

[0033] FIG. 5 shows an embodiment of a controller that can be included in the device of FIG. 1.

[0034] FIG. 6 shows an embodiment of a process that can be carried out by the device of FIG. 1

[0035] The present disclosure is further described in the detailed description that follows.DETAILED DESCRIPTION OF THE DISCLOSURE

[0036] The disclosure and its various features and advantageous details are explained more fully with reference to the non-limiting embodiments and examples that are described or illustrated in the accompanying drawings and detailed in the following description. It should be noted that features illustrated in the drawings are not necessarily drawn to scale, and features of one embodiment can be employed with other embodiments as those skilled in the art would recognize, even if not explicitly stated. Descriptions of well-known components and processing techniques may be omitted so as to not unnecessarily obscure the embodiments of the disclosure. The examples are intended merely to facilitate an understanding of ways in which the disclosure can be practiced and to further enable those skilled in the art to practice the embodiments of the disclosure. Accordingly, the examples and embodiments should not be construed as limiting the scope of the disclosure. Moreover, it is noted that like reference numerals represent similar parts throughout the several views of the drawings.

[0037] The present disclosure is a technological solution that includes an apparatus, a system, and a methodology for providing continuous intermittent motion and culture of an embryo. In various embodiments, the apparatus and methodology provide continuous intermittent motion and culture of the embryo, including providing constant motion while supplying fluids to the embryo and removing waste necessary for biomimetics of the embryo, as well as analysis and assessment of the embryo in real time and at any instant in time. The apparatus and method provide precise control over embryo motion and media delivery. The apparatus and method use embryo compatible materials that are sterilizable and do not leach potentially embryo toxic moieties. In at least one embodiment the apparatus includes a microfluidic device made of glass, silicon, orpolymer such as polydimethylsiloxane (PDMS). The microfluidic device and / or biomimetic manifold can be constructed of investigational materials to determine the impact of the material or any leachable components on the function, health and development of the embryo. In a similar manner, investigational constituents may be added to or dissolved within the nutrient media (for example, supplied in the fluid) to determine the impact of constituents on the function, health and development of the embryo. The constituents may include soluble chemicals, pharmaceutical agents, or pharmaceutical delivery agents.

[0038] The apparatus is designed and configured to move a microfluid device having a containment vessel in a plane or multi dimensionally in a space for mammalian gestation, including providing continuous intermittent motion and culture of an embryo in the containment vessel. The device includes a motion system having one or more fasteners configured to attach to the microfluidic device, a platform configured to support the motion system and allow the microfluidic device to rotate about a rotational axis (or around multiple axes for multidimensional rotation), and a drive system having a controller configured to adjust movement of the containment vessel with respect to the axis (or multiple axes), including at least one of an inversion frequency, a direction of rotation, a velocity, a rate of change in the inversion frequency, a rate of change in the direction of rotation, and a rate of change in the velocity of the containment vessel, for mammalian gestation. The containment vessel is configured to hold an embryo from initial placement thru gestation.

[0039] In various embodiments, the apparatus provides continuous intermittent motion and culture of an embryo. In at least one embodiment the motion can be sinusoidal. The apparatus provides constant motion while supplying fluids to the embryo and removing waste necessary to support growth and development of the embryo. The apparatus provides precise control over embryo motion and fluid delivery. The apparatus includes embryo compatible materials that are sterilizable and do not leach potentially embryo toxic moi eties. The apparatus allows for time lapse imaging of embryo morphology. In at least one embodiment, the apparatus includes a microfluidic device made of polydimethylsiloxane (PDMS) and cured from a metal template to ensure high purity molds. In a similar fashion, the microfluidic device can be made from any transparent material, including poly methylmethacrylate (PMMA), polycarbonate (PC) or glass. The apparatus, including the microfluidic device, is designed and configured to control and adjust thefrequency of device inversion, direction of rotation, and velocity based on the sizes, densities, sedimentation times, and positions of the embryos.

[0040] FIG. 1 shows a nonlimiting embodiment of a continuous intermittent motion apparatus 1, constructed according to the principles of the disclosure. The apparatus 1 can include a microfluidic device 10. The apparatus 1 includes a motion system 20, a platform 30, a drive system 40, a biomimetic manifold 50 (shown in FIG. 2), and a controller 100 (shown in FIGS. 4 and 5). The microfluidic device 10 includes a container body 11 and a culture (or containment) vessel 14, which can hold an embryo. The microfluidic device 10 can include, or it can be connected to, one or more fasteners 12.

[0041] In various embodiments, the motion system 20 includes a rotor 21, one or more fasteners 22, a driven gear 23, and an image pickup device 25. The rotor 21 can include the one or more fasteners 22, which are configured to secure the microfluidic device 10 fixedly to the rotor 21 while the rotor 21 rotates about an axis at a center of the rotor 21. The rotary member is configured to support and allow the rotor 21 to rotate about its center axis. The driven gear 23 can be attached to, or formed with, the rotor 21 and configured to be driven and rotate the rotor 21 about its center axis. The rotor 21, the driven gear 23, and / or the image pickup device 25 can be constructed to have the center axis as a common rotational co-axis. In at least one embodiment, the image pickup device 25 includes a time-lapse camera system.

[0042] In various embodiments, an optical system 25 comprising an image pickup device is mounted such that the optical axis is coaxial with the rotational axis of rotor 21. The optical system 25 is positioned such that the focal plane of the image pickup device in the optical system 25 and the culture channel plane of culture vessel 14 are conjugates. The image pickup device 25 can be configured to remain fixed and stationary while the culture vessel 14 rotates.

[0043] The platform 30 includes a support 32 and a base 34, which can be attached to each other or made as a single piece. The support 32 can be configured to have a surface plane that is substantially perpendicular to a surface plane of the base 34, as seen in FIG. 1. The plane of the surface of the support 32 (surface plane of the support) can be substantially parallel to the direction of gravity (gravity vector), and the plane of the surface of the base 34 (surface plane of the base) can be substantially perpendicular to the gravity vector. The platform 30 can be configured tosecure and hold the motion system 20, drive system 40, the biomimetic manifold 50 (shown in FIG. 2), a power supply (not shown), and / or the controller 100 (shown in FIGS. 4 and 5).

[0044] The drive system 40 includes a shaft 41, one or more driver gears 43, and a motor 45. The drive system 40 can be secured to the support 32 and / or base 34 in the platform 30. The drive system 40 can be configured to turn the rotor 21 by means of the shaft 41 and one or more diver gears 43. The driver gear 43 is configured to engage and drive the driven gear 23 in the motion system 20.

[0045] In certain embodiments, the biomimetic manifold 50 (for example, shown in FIG. 2) can be configured to be attachable to the motion system 20, such as, for example, by fasteners 22. The biomimetic manifold 50 can be attached to the rotor 21, or, in certain embodiments, to the rotary member 25.

[0046] In various embodiments, components of the biomimetic manifold 50, such as, for example, fluid supply conduits 51 and return (or waste) conduits 53 (shown in FIG. 2) can be formed as channels (or microchannels) in the biomimetic manifold 50 and attachable to the microfluidic device 10, which can be affixed to the motion system 20. In certain embodiments the biomimetic manifold 50 can include a plurality of supply conduits 51 and a plurality of return conduits 53, each connected to a respective supply conduit or return conduit in the microfluidic device 10.

[0047] FIG. 2 shows a nonlimiting embodiment of the biomimetic manifold 50. In the embodiment depicted in FIG. 2, the biomimetic manifold 50 includes at least one fluid supply conduit 51 and at least one return conduit 53, a fluid supply source 52, and a return receptacle 54. Each of the conduits 51 and 53 can be connected at one end to the biomimetic manifold 50 and at another end to the microfluidic device 10. The ends of the conduits 51, 53 connected to the biomimetic manifold 50 can be connected to respective channels (or microchannels) formed in the biomimetic manifold 50. The supply conduit(s) 51 is constructed and connected to supply a fluid from the fluid supply source 52 to one or more corresponding openings 11-1 at one end of the microfluidic device 10 (containing the vessel 14 in the container body 11). The return conduit(s) 53 is constructed and connected to return waste from a respective one or more openings 11-2 at another end of the microfluidic device 10 to the return receptacle 54. As seen in FIG. 2, thecontainment vessel 14 can have opposite ends, each of which can be connected to one or more microchannels in the container body 11 for fluid supply and return, including waste removal.

[0048] In an embodiment, the fluid supply source 52 includes at least one vessel (not shown) that supplies a fluid, such as, for example, nutrients, food, water, medicine, oxygen, nitrogen, carbon dioxide, reagents, or other substances for testing, analysis, assessment, or gestation of the embryo. The return receptacle 54 includes at least one container (not shown) that is configured to receive and hold fluid (for example, containing waste) output from the vessel 14. The return receptacle 54 can be coupled to one or more sensors (not shown) that are configured to test and analyze the return fluid to assess the conditions, including gestational development, of the embryo.

[0049] When the microfluidic device 10 is attached to the motion system 20, the drive system 40 can operate to turn the vessel 14 about, for example, a center axis, which can be positioned to be substantially perpendicular to the direction of gravity. The drive system 40 can operate under controller of the controller 100 (shown in FIG. 4) to adjust and maintain rotation of the vessel 14 for a particular particle or animal embryo contained in the vessel 14.

[0050] FIG. 3 shows a nonlimiting example of an embryo AE in the vessel 14, as a function of time and position. As its initial position (for example, at time t = 0 seconds), the vessel 14 can be positioned such that its longitudinal axis is substantially parallel to the gravity vector, as seen in FIG. 3. It is understood that, in at least one embodiment, the position of the vessel 14, which is in the container body 11 of the microfluidic device 10, depends on the position of the rotor 21 (shown in FIG. 1) to which the microfluidic device 10 is attached. In this example, the embryo AE is located near the upper end of the vessel 14, proximate to the end having the conduit with the opening 11-1. The vessel 14 can be kept in the position seen in FIG. 3 for a period of time until the embryo AE travels due to gravity to a desired position (for example, just below the center of the vessel 14) at time trip. at which time the vessel 14 can be rotated clockwise (or counterclockwise) under operation of the rotor 21 to cause the embryo AE to travel due to gravity to another desired position or remain situated in a quasi-zero gravity state. As seen in the example of FIG. 3, the embryo (AE) can be caused to travel along a length of the vessel 14 to a predetermined location and remain at the location in a quasi-zero gravity state during gestation. In various embodiments, the vessel 14 formed in the microfluidic device 10 can have a length of, for example, less than 40 mm, or between about 40 mm and about 110 mm, or between about 44 mmor 45 mm and about 74 mm or 75 mm, or greater than 75 mm. Tn certain embodiments, the vessel 14 can include dimensions smaller than 40 mm, or greater than 110mm. In various implementations, the location of the embryo can be limited to an optimal location (for example, in the center of the vessel 14) for gestation of the embryo. For instance, the culture vessel 14 can be controlled such that inversion is performed such that the embryo does fall into the inlet conduit or the outlet conduit.

[0051] FIG. 4 shows an embodiment of a system for controllably moving a microfluid device 10 for mammalian gestation, including providing continuous and / or intermittent motion and culture of an embryo in the containment vessel 14. In at least one embodiment, the apparatus 1 includes a plurality of actuators (not shown) for multidimensional rotation of the microfluidic device. In certain embodiments, the system includes the embodiment of the apparatus 1 depicted in FIG. 1, including the rotor 21 configured to turn about the center axis 9, controller 100, and a plurality of sensors 1 to n (where n is a positive integer, such as, for example, 7 shown in FIG. 4), each of which can be configured to detect and measure a particular condition related to the apparatus 1. The sensor 1 can include the image pickup device 25 (seen in FIG. 1), which is configured to capture real-time, time-lapsed images of the vessel 14, including embryo. In various embodiments, certain of the sensors 2-n are configured to detect and measure an inversion frequency, a temperature, a pressure, a vessel position, a direction of rotation, a velocity of the containment vessel 10 or the rotor 21, a velocity of the motor, a rate of change in the inversion frequency, a rate of change in the temperature, a rate of change in the pressure, a rate of change in the position of the vessel, a rate of change in the direction of the rotation, and a rate of change in the velocity. In various embodiments, certain of the sensors 2 to n are arranged to detect and measure a size, shape, density, temperature, impedance, position, and sedimentation time of the embryo. The image pickup sensor 1 can be configured to provide an image signal to controller, which can determine the real-time position of the embryo at any instant in time based on the image signal. In certain embodiments, at least one of the sensors 2 to n is configured to detect and measure properties of the return fluid, such as, for example, the fluid in the return receptacle 54 (shown in FIG. 2) and analyze and assess certain conditions of the embryo based on the waste in the return fluid. At least one of the sensors 2 to n is configured to detect and measure a position, direction of rotation, and velocity of the microfluidic device 10. In an embodiment, one or moreof the sensors 2 to n are configured to detect and measure a direction of rotation of the rotor 21 or device 10, a velocity of rotation of the rotor 21 or device 10.

[0052] In various embodiments, the sensors 2 to n are configured to detect, measure, or analyze conditions of the embryo, the fluid supplied to and / or fluid returned from the microfluidic device 10, the environmental conditions, and conditions of the microfluidic device 10. In an embodiment, the time, volume, velocity, and rate of the fluid supplied to the device 10 can be measured and, based on the measurements, one or more pneumatic valves in the microfluidic device 10 (or biomimetic manifold 50) controlled to regulate at least one of flow, velocity, or rate of the fluid supplied to the vessel 14 and, thereby, embryo.

[0053] In at least one embodiment, the waste in the return fluid from the microfluidic device 10 can be measured, analyzed, and, based on the analysis, an assessment made regarding the condition of the embryo and / or the environmental conditions. For instance, the waste can be analyzed with respect to toxicity, sugars, lipids, pH, alkalinity, nitrogen, carbon dioxide, proteins, hormones, or other parameters indicative of the health and / or gestational development of the embryo to assess appropriateness or suitability of certain fluids supplied to the embryo, the materials used to make the microfluidic device 10 (including any microchannels or the vessel 14), the conditions in or surrounding the microfluidic device 10, including temperature, pressure, and humidity. Based on the waste analysis and assessments, a determination can be made regarding the suitability of certain materials for an artificial womb for gestation of the embryo, as well as media delivery to support the gestation and predict development of an embryo. In at least one embodiment, the controller includes a machine learning model comprising, for example, a convolutional neural network (CNN), a deep-CNN (DCNN), or other deep neural network that is trained using image data sets to predict development of an embryo based on the particular fluids supplied to the embryo in the device 10, the waste returned from the device 10, the materials used to make the vessel 14 and all microchannels, and the development of the embryo in the vessel 14 as a function of time.

[0054] In at least one embodiment, the microfluidic device 10 includes a plurality of supply microchannels, one or more pneumatic valves, and at least one return microchannel, all of which are integrally formed in the microfluidic device 10. The pneumatic valves can be operated to control the volume, velocity, and rate of fluid flowing in any one or more of the microchannels,thereby controlling at least one of flow, velocity, or rate of the fluid supplied to the vessel 14 and, thereby, embryo, or fluid returned from vessel 14. In various embodiments the microfluidic device 10 can include one or more pneumatic devices, including for example, flow control valves, pressure valves, pressure pumps, vacuum pumps, vacuum valves, fiberoptics, and sensors, including active devices that can perform actions on microenvironment on and / or in the microfluidic device 10, including sensors for impedance measurement.

[0055] FIG. 5 shows a nonlimiting embodiment of the controller 100, according to the principles of the disclosure. The controller 100 includes a processor 110, a memory 120, an inputoutput (IO) interface 130, a network interface 140, a biomimetic monitor 150, a biomimetic driver 160, a motor driver 170, and a bus 105. Any or all of the components 110 to 170 can be connected to the bus 105 and exchange data or instructions over the bus 190 and one or more communication links. The controller 100 can be connected to a network 15 (shown in FIG. 4) and configured to communicate via communication link(s) with one or more communicating devices 20 (shown in FIG. 4), thereby facilitating operations, such as, for example, monitoring, measurement, maintenance, analysis, assessment, or remote control of, or by, the controller 100, including communication with each of the sensors 1 to n (shown in FIG. 4). The controller 100 can be included in the apparatus 1 (as seen in FIG. 4), and configured to monitor, determine, and control positioning and movement of the microfluidic device 10, as well as operation of the biomimetic manifold 50 (shown in FIG. 2), including fluid supply 52 (shown in FIG. 2) and return receptacle 54 to control and regulate the conditions in and surrounding the multifluidic device 10, including vessel 14 containing the embryo.

[0056] The biomimetic monitor 150 and biomimetic driver 160 can be provided as separate computing devices, or integrated into one or more computing devices. The biomimetic monitor 150 and biomimetic driver 160 can each be configured for operation in biomimetic and / or nonmimetic applications. In the embodiment of FIG. 5, the components 150 and 160 are provided as separate computer resource assets and integrated in the controller 100. In various embodiments, the controller 100 can include a computer or a server. The components 150 and 160 can include computer resources executable on the processor 110 as one or more computing resource processes. The components 150 or 160 can include a supervised or unsupervised machine learning platform that includes a machine learning model trained to analyze gestational development of an embryo based on analysis of fluids supplied to, and returned from, the multifluidic device 10 together withanalysis of environmental conditions, and predict gestational development of the embryo at a future time.

[0057] In a non-limiting embodiment, the biomimetic monitor 150 and / or the biomimetic driver 160 can include one or more supervised machine learning systems or one or more unsupervised machine learning systems. The machine learning platform can include, for example, a deep neural network (DNN), a convolutional architecture for fast feature embedding (CAFFE), an artificial neural network (ANN), a convolutional neural network (CNN), a deep convolutional neural network (DCNN), region-based convolutional neural network (R-CNN), you-only-look- once (YOLO), a Mask-RCNN, a deep convolutional encoder-decoder (DCED), a recurrent neural network (RNN), a neural Turing machine (NTM), a differential neural computer (DNC), a support vector machine (SVM), a deep learning neural network (DLNN), Naive Bayes, decision trees, logistic model tree induction (LMT), NBTree classifier, case-based, linear regression, Q-learning, temporal difference (TD), deep adversarial networks, fuzzy logic, K-nearest neighbor, clustering, random forest, rough set, or any other machine intelligence platform capable of supervised or unsupervised learning.

[0058] The processor 110 can include any of various commercially available processors, including for example, a central processing unit (CPU), a graphic processing unit (GPU), a general- purpose GPU (GPGPU), a field programmable gate array (FGPA), an application-specific integrated circuit (ASIC), a system-on-a-chip (SOC), a single-board computer (SBC), a manycore processor, multiple microprocessors, or any other computing device architecture. The processor 110 can be arranged to interact with any of the components 120 to 170 to carry out or facilitate the processes included, described or contemplated by this disclosure. The processor 110 can be arranged to run one or more machine or deep learning systems. The processor 110 can be arranged to communicate and interact with the network 15 (shown in FIG. 4) or the one or more communication devices (not shown) via the IO interface 130 or network interface 140.

[0059] The memory 120 can include a read-only-memory (ROM) 120 A, a random-accessmemory (RAM) 120B, a hard drive (HD) 120C, and a database (DB) 120D. The memory 120 can include a non-transitory computer-readable storage medium that can hold executable or interpretable computer program code or instructions that, when executed by the processor 110, cause the steps, processes or methods described herein (including the process seen in FIG. 6) to becarried out. The computer-readable storage medium can be included in, for example, the ROM 120 A or the HD 120C.

[0060] A basic input-output system (BIOS) can be stored in a non-volatile memory in the memory 120, such as, for example, the ROM 120A, which can include, for example, an erasable programmable read-only memory (EPROM), an electrically erasable programmable read-only memory (EEPROM), or a flash memory. The BIOS can contain the basic routines that help to transfer information between the components in the controller 100, such as during start-up.

[0061] The RAM 1206 can include, for example, a static random access memory (SRAM), a non-volatile random-access memory (NVRAM), or any random access memory device suitable for caching data.

[0062] The HD 120C can include, for example, a solid-state drive (SSD), a hard disk drive (HDD), or an optical disk drive (ODD). The HD 120C can be arranged for external use in a suitable chassis (not shown). The HD 120C can be arranged to connect to the bus 105 via a hard disk drive interface (not shown) or an optical drive interface (not shown). The hard disk drive interface (not shown) can include a Universal Serial Bus (USB) (not shown) or an IEEE 1394 interface (not shown) for external applications.

[0063] The DB 120D can be arranged to store historical data, including queries. The DB 120D can be arranged to be accessed by any one or more of the components in the controller 100, including the processor 110. The DB 120D can be arranged to receive a query and, in response, retrieve specific records or portions of records based on the query. A record can include, for example, a file or a log. The DB 120D can store information about each embryo, including a profile file for each such embryo. The profile file can include information for: nutrients needed for the nourishment, development, and maintenance of the embryo (including, for example, an amount of each nourishment and timing of supply of the nourishment); criteria and parametric values for continuous intermittent motion, and culture, of the embryo, including, for example, for providing constant motion to satisfy the motion requirements of, for example, mammalian gestation, while supplying fresh nutrients and removing waste; an inversion frequency value; a direction of rotation value; position values for the embryo; position values for the containment vessel; a velocity value for the containment vessel; a rate of change value for the inversion frequency; a rate of change value for the direction of rotation; a rate of change value for the positionof the embryo; a rate of change value for the velocity of the containment vessel; and a rate of change value for the position of the containment vessel.

[0064] The memory 120, including computer-readable media, can be arranged to provide nonvolatile storage of data, data structures, and computer-executable instructions. The memory 120 can accommodate the storage of any data in a suitable digital format. The memory 120 can include computing resources that can be used to execute aspects of the architecture included in the controller 100, including, for example, a program module, an application program, an application program interface (API), or program data. In the non-limiting embodiment of the controller 100 wherein the biomimetic monitor 150 and biomimetic driver 160 are computer resources that are executable on the processor 110, the components 150 and 160 can be stored in the memory 120. One or more of the computing resources can be cached in the RAM 120B as executable sections of computer program code or retrievable data.

[0065] The computing resources can include an API such as, for example, a web API, a simple object access protocol (SOAP) API, a remote procedure call (RPC) API, a representation state transfer (REST) API, or any other utility or service API.

[0066] The IO interface 130 can be arranged to receive commands or data from an operator, a peripheral device (not shown), the communicating device 20 (shown in FIG. 4), or the processor 110. The IO interface 130 can be arranged to connect to or communicate with the peripheral device (not shown), such as, for example, one or more input-output devices, which can include, for example, a keyboard, a mouse, a pointer, a stylus, a microphone, a speaker, an interactive voice response (IVR) unit, a graphic user interface (GUI), or a display device. The IO interface 130 can include a transmitter, a receiver or a transceiver. The received commands or data can be forwarded from the IO interface 130 as instruction or data signals via the bus 105 to any component or computer resource in the controller 100.

[0067] The network interface 140 can be arranged to connect to the communicating device 20 (shown in FIG. 4) or the network 15 (shown in FIG. 4). The network interface 140 can be arranged to connect to the Internet or an external network. The network interface 140 can include a modem, transmitter, receiver or transceiver. The network interface 140 can include a wired or a wireless communication network interface. When used in a local area network (LAN), the network interface 140 can be arranged to include a wired or wireless communication network interface thatcan connect to the LAN; and, when used in a wide area network (WAN), the network interface 140 can be arranged to include a modem to connect to the WAN network. The modem can be internal or external and wired or wireless. The modem can be connected to the bus 105 via, for example, a serial port interface.

[0068] The biomimetic monitor 150 can be arranged to communicate with one or more of the sensors 2-7 (shown in FIG. 4) and monitor conditions in the apparatus 1 (shown in FIGS. 1 and 4), including the containment vessel 10, the motion system 20, the drive system 40, and the biomimetic manifold 50 (shown in FIG. 2). The biomimetic monitor 150 can receive sensor signals from the sensors 1 to n, including the image signal from the image pickup device 25 (shown in FIG. 1 ), analyze the sensor signals, and determine or assess properties of the microfluidic device 10, the embryo, and the environmental conditions. In various embodiments, the biomimetic monitor 150 can analyze sensor data and determine an inversion frequency, position, velocity, direction, temperature, pressure, and humidity of the microfluidic device 10, the environmental conditions, and the size, density, shape, position, and settlement time of the embryo. The biomimetic device 150 can also analyze and assess the health and development of the embryo based on the sensor data, including sensor data received from sensors that measure properties of the waste in the return fluid from the microfluidic device 10.

[0069] The biomimetic monitor 150 can be arranged analyze the received sensor signals and historical data (for example, stored in the memory 120) and, based on the received sensor data and / or historical data (for example, data profile files in DB 12D), determine drive signals needed for moving the microfluidic device 10 for mammalian gestation, including providing continuous intermittent motion and culture of the embryo in the containment vessel 14. The biomimetic monitor 150 can be configured to determine at least one of an inversion frequency, a position of the vessel, a direction of rotation, a velocity, a rate of change in the inversion frequency, a rate of change in the position of the vessel, a rate of change in the direction of rotation, and a rate of change in the velocity of the containment vessel 14. The biomimetic monitor 150 can be further configured to generate and communicate the drive signals to the biomimetic driver 160 to operate the motion system 20 (shown in FIG. 1), drive system 40, and / or the biomimetic manifold 50 (shown in FIG. 2). In various embodiments, the biomimetic monitor 150 is configure to analyze sensor data from the sensors 1 to n and determine, for an embryo, the suitability of the material used for the containment vessel 14 and / or container body 11 (including channels), the suitabilityof the nutrients and other substances included in the fluid supplied to the embryo, and predict gestational development of the embryo at a point in time in the future.

[0070] The biomimetic driver 160 can be configured to receive the drive signals from the biomimetic monitor 150 and interact with the biomimetic manifold 50 (shown in FIG. 2) to control or adjust the fluid supply 52 (shown in FIG. 2) or return receptacle 54 (shown in FIG. 2), and, to interact with the drive system 40 and control or adjust movement or a position of the microfluidic device 10, such as, for example, by operating the motor 45 to turn the rotor 21 at, or to, determine inversion frequency, direction of rotation, position of the containment vessel, velocity, rate of change in the inversion frequency, rate of change in the direction of rotation, rate of change in the velocity of the containment vessel, or rate of change in the position of the containment vessel.

[0071] The motor driver 170 is configured to communicate with the biomimetic driver 160 (or biomimetic monitor 150) and, based on received drive signals, generate and transmit motor drive signals to the motor 45 to operate at the determined velocity (including determined direction and determined speed of rotation) and rate of change in the velocity (including rate of change direction and rate of change in speed of rotation).

[0072] FIG. 6 shows a process 200 for moving the microfluidic device 10 with the containment vessel 14 for mammalian gestation, including providing continuous intermittent motion and culture of the embryo in the microfluidic device 10 (shown in FIGS. 1-2 and 4).

[0073] Initially, a device 10 with a containment vessel 14 (shown in FIGS. 1 and 4) containing an embryo is provided (Step 205) and attached to the motion system 20 (Step 210). The device 10 can be attached to the rotor 21, for example, using one or more fasteners 12 and / or one or more fasteners 22.

[0074] After the microfluidic device 10, including containment vessel 14, is attached to the motion system 20 (Step 210), condition parameters can be measured by one or more of the sensors n (shown in FIG. 4), including condition parameters of the microfluidic device 10, containment vessel 14, embryo, motion system 20, drive system 40, and / or the biomimetic manifold 50 (shown in FIG. 2) (Step 215). The condition parameters include measurement data parsed, for example, by the processor 110 (shown in FIG. 5), from the sensor signals received from the one or more sensors n. including condition parameter data such as, for example, an inversion frequency value, position values for the containment vessel 14, position values for the rotor 21, speed and directionvalues for the containment vessel 14, speed and direction values for the rotor 21 , temperature value, pressure value, density value, amount and type of fluid supplied to the containment vessel 14, amount and type of fluid (including waste) returned from the containment vessel 10.

[0075] Based on predetermined condition parameters for mammalian gestation values, including for providing motion and culture of the embryo in the containment vessel 14, the biomimetic monitor 150 (or processor 110, shown in FIG. 5) determines target condition parameters (Step 220), which can include for example, a target inversion frequency value, target position values for the containment vessel 14, target position values for the rotor 21, target speed and target direction values for the containment vessel 14, target speed and target direction values for the rotor 21 , target temperature value, target pressure value, target density value, target amount and target type of fluids supplied to the containment vessel 14, target amount and target type of waste received from the containment vessel 10. Initially, the target condition parameters can be retrieved from the memory 120, such as, for example, a profde file in the DB 120D, or historical data stored in memory 120.

[0076] The biomimetic monitor 150 (or processor 110, shown in FIG. 5) compares each of the measured condition parameters against a corresponding determined condition parameter (Step 225). If it is determined that each measured condition parameter is substantially equal to the corresponding target condition parameter (YES at Step 225), then the process returns to measure the condition parameters (Step 215), otherwise (NO at Step 225) one or more drive signals are generated based on the determination (Step 230). The drive signals are generated to cause the motion system 20, drive system 40, or biomimetic manifold 50 to operate such that each measured condition parameter equals the corresponding target condition parameter.

[0077] In certain embodiments, the biomimetic monitor 150 (or processor, shown in FIG. 5) can determine (at Step 220) the suitability of the material(s) used to make the vessel 14 and / or microchannels in the device 10, and / or the suitability of the media delivered via the fluid supply to the embryo. In this regard, the biomimetic monitor 150 can, using the machine learning model (for example, CNN) compare the embryo in real-time images received from the image pickup device 25 against a predicted developmental state of the embryo and determine the suitability of the vessel 14 and / or fluid supplied to the embryo.

[0078] The drive signals are transmitted to the biomimetic driver 160 and / or motor driver 170 (Step 235). In response to receiving the drive signals, the biomimetic driver 160 and / or motor driver 170 transmit one or more signals (including instructions and data) to the motion system 20, drive system 40, or biomimetic manifold 50 to adjust, maintain, or control at least one of an inversion frequency of the containment vessel 10, the position of the containment vessel 10, the direction of rotation of the containment vessel 10 or rotor 21, the velocity of the containment vessel 10 or rotor 21, the rate of change (for example, accelerate or decelerate) in the inversion frequency, the rate of change in the position of the containment vessel 10, the rate of change in the direction of rotation, and the rate of change in the velocity of the containment vessel.

[0079] The process 100 will continue (NO at Step 240) and repeat, unless a determination is made to end the process (YES at Step 240).

[0080] The terms “a,” “an,” and “the,” as used in this disclosure, means “one or more,” unless expressly specified otherwise.

[0081] The term “backbone,” as used in this disclosure, means a transmission medium or infrastructure that interconnects one or more computing devices or communication devices to provide a path that conveys data packets and instruction signals between the one or more computing devices or communication devices. The backbone can include a network. The backbone can include an ethemet TCP / IP. The backbone can include a distributed backbone, a collapsed backbone, a parallel backbone or a serial backbone.

[0082] The term “bus,” as used in this disclosure, means any of several types of bus structures that can further interconnect to a memory bus (with or without a memory controller), a peripheral bus, or a local bus using any of a variety of commercially available bus architectures. The term “bus” can include a backbone.

[0083] The term “communicating device,” as used in this disclosure, means any computing device, hardware, or computing resource that can transmit or receive data packets, instruction signals or data signals over a communication link. The communicating device can be portable or stationary.

[0084] The term “communication link,” as used in this disclosure, means a wired or wireless medium that conveys data or information between at least two points. The wired or wirelessmedium can include, for example, a metallic conductor link, a radio frequency (RF) communication link, an Infrared (IR) communication link, or an optical communication link. The RF communication link can include, for example, WiFi, WiMAX, IEEE 802.11, DECT, 0G, 1G, 2G, 3G, 4G or 5G cellular standards, or Bluetooth. A communication link can include, for example, an RS-232, RS-422, RS-485, or any other suitable interface.

[0085] The terms “computer,” “computing device,” or “processor,” as used in this disclosure, means any machine, device, circuit, component, or module, or any system of machines, devices, circuits, components, or modules that are capable of manipulating data according to one or more instructions. The terms “computer,” “computing device” or “processor” can include, for example, without limitation, a processor, a microprocessor (pC), a central processing unit (CPU), a graphic processing unit (GPU), a data processing unit (DPU), an application specific integrated circuit (ASIC), a general purpose computer, a super computer, a personal computer, a laptop computer, a palmtop computer, a notebook computer, a desktop computer, a workstation computer, a server, a server farm, a computer cloud, or an array or system of processors, pCs, CPUs, GPUs, ASICs, general purpose computers, super computers, personal computers, laptop computers, palmtop computers, notebook computers, desktop computers, workstation computers, or servers.

[0086] The term “computer-readable medium,” as used in this disclosure, means any non- transitory storage medium that participates in providing data (for example, instructions) that can be read by a computer. Such a medium can take many forms, including non-volatile media and volatile media. Non-volatile media can include, for example, optical or magnetic disks and other persistent memory. Volatile media can include dynamic random-access memory (DRAM). Common forms of computer-readable media include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, any magnetic medium, a CD-ROM, DVD, any other optical medium, any other physical medium with patterns of holes, a RAM, a PROM, an EPROM, a FLASH- EEPROM, any other memory chip or cartridge, a carrier wave as described hereinafter, or any other medium from which a computer can read. The computer-readable medium can include a “cloud,” which can include a distribution of files across multiple (e.g., thousands of) memory caches on multiple (e.g., thousands of) computers.

[0087] Various forms of computer readable media can be involved in carrying sequences of instructions to a computer. For example, sequences of instruction (i) can be delivered from a RAMto a processor, (ii) can be carried over a wireless transmission medium, or (iii) can be formatted according to numerous formats, standards or protocols, including, for example, WiFi, WiMAX, IEEE 802.11, DECT, 0G, 1G, 2G, 3G, 4G, 5G, or 6G cellular standards, or Bluetooth.

[0088] The terms “computer resource” or “computing resource,” as used in this disclosure, mean software, a software application, a web application, a web page, a computer application, a computer program, computer code, machine executable instructions, firmware, or a process that can be arranged to execute on a computing device or a communicating device.

[0089] The term “computing resource process,” as used in this disclosure, means a computing resource that is in execution or in a state of being executed on an operating system of a computing device, such as, for example, the processor 110 (shown in FIG. 5). Every computing resource that is created, opened or executed on or by the operating system can create a corresponding computing resource process. A computing resource process can include one or more threads, as will be understood by those skilled in the art.

[0090] The term “database,” as used in this disclosure, means any combination of software or hardware, including at least one computing resource or at least one computer. The database can include a structured collection of records or data organized according to a database model, such as, for example, but not limited to at least one of a relational model, a hierarchical model, or a network model. The database can include a database management system application (DBMS). The at least one application may include, but is not limited to, a computing resource such as, for example, an application program that can accept connections to service requests from communicating devices by sending back responses to the devices. The database can be configured to run the at least one computing resource, often under heavy workloads, unattended, for extended periods of time with minimal or no human direction.

[0091] The term “embryo,” as used in this disclosure, means any particle, cell, cell aggregate, tissue, organoid, organism, or embryo, or any combination thereof.

[0092] The term “fluid,” as used in this disclosure, means any liquid, gas, or solid, including, for example, any media, nutrient, food, water, medicine, drug, growth factor, reagents, or other substance for testing, measurement, monitoring, analysis, assessment, and / or gestation of an embryo. The gas can include, for example, oxygen, nitrogen, and carbon dioxide. The solid can include, for example, particles in a colloidal suspension.

[0093] The terms “including,” “comprising” and variations thereof, as used in this disclosure, mean “including, but not limited to,” unless expressly specified otherwise.

[0094] The term “network,” as used in this disclosure means, but is not limited to, for example, at least one of a personal area network (PAN), a local area network (LAN), a wireless local area network (WLAN), a campus area network (CAN), a metropolitan area network (MAN), a wide area network (WAN), a metropolitan area network (MAN), a wide area network (WAN), a global area network (GAN), a broadband area network (BAN), a cellular network, a storage-area network (SAN), a system-area network, a passive optical local area network (POLAN), an enterprise private network (EPN), a virtual private network (VPN), the Internet, or the like, or any combination of the foregoing, any of which can be configured to communicate data via a wireless and / or a wired communication medium. These networks can run a variety of protocols, including, but not limited to, for example, Ethernet, IP, IPX, TCP, UDP, SPX, IP, IRC, HTTP, FTP, Telnet, SMTP, DNS, ARP, ICMP.

[0095] The term “server,” as used in this disclosure, means any combination of software or hardware, including at least one computing resource or at least one computer to perform services for connected communicating devices as part of a client-server architecture. The at least one server application can include, but is not limited to, a computing resource such as, for example, an application program that can accept connections to service requests from communicating devices by sending back responses to the devices. The server can be configured to run the at least one computing resource, often under heavy workloads, unattended, for extended periods of time with minimal or no human direction. The server can include a plurality of computers configured, with the at least one computing resource being divided among the computers depending upon the workload. For example, under light loading, the at least one computing resource can run on a single computer. However, under heavy loading, multiple computers can be required to run the at least one computing resource. The server, or any if its computers, can also be used as a workstation.

[0096] The term “transmission” or “transmit,” as used in this disclosure, means the conveyance of data, data packets, computer instructions, or any other digital or analog information via electricity, acoustic waves, light waves or other electromagnetic emissions, such as those generated with communications in the radio frequency (RF) or infrared (IR) spectra. Transmissionmedia for such transmissions can include coaxial cables, copper wire and fiber optics, including the wires that comprise a system bus coupled to the processor.

[0097] Devices that are in communication with each other need not be in continuous communication with each other unless expressly specified otherwise. In addition, devices that are in communication with each other may communicate directly or indirectly through one or more intermediaries.

[0098] Although process steps, method steps, or algorithms may be described in a sequential or a parallel order, such processes, methods and algorithms may be configured to work in alternate orders. In other words, any sequence or order of steps that may be described in a sequential order does not necessarily indicate a requirement that the steps be performed in that order; some steps may be performed simultaneously. Similarly, if a sequence or order of steps is described in a parallel (or simultaneous) order, such steps can be performed in a sequential order. The steps of the processes, methods or algorithms described in this specification may be performed in any order practical.

[0099] When a single device or article is described, it will be readily apparent that more than one device or article may be used in place of a single device or article. Similarly, where more than one device or article is described, it will be readily apparent that a single device or article may be used in place of the more than one device or article. The functionality or the features of a device may be alternatively embodied by one or more other devices which are not explicitly described as having such functionality or features.

[0100] The subject matter described above is provided by way of illustration only and should not be construed as limiting. Various modifications and changes can be made to the subject matter described herein without following the example embodiments and applications illustrated and described, and without departing from the true spirit and scope of the invention encompassed by the present disclosure, which is defined by the set of recitations in the following claims and by structures and functions or steps which are equivalent to these recitations.

Claims

1. An apparatus for controllably moving a containment vessel for mammalian gestation, including to provide motion and culture of an embryo in the containment vessel, the apparatus comprising:a motion system configured to attach to the containment vessel;a platform configured to support the motion system and allow the containment vessel to move with respect to at least one axis; anda drive system having a controller configured to adjust movement of the containment vessel with respect to the at least one axis, including at least one of an inversion frequency, a direction of rotation, a position of an embryo, a position of the containment vessel, a velocity, a rate of change in the inversion frequency, a rate of change in the direction of rotation, a rate of change in the position of the embryo, a rate of change in the position of the containment vessel, and a rate of change in the velocity of the containment vessel, for mammalian gestation,wherein the containment vessel is configured to hold the embryo.

2. The apparatus in claim 1, further comprising:an optical system, comprising:a darkfield illumination source;a bright field illumination source;object imaging optics; andan image recording system,wherein the image recording system includes at least one of a digital camera, to timelapse capture morphological changes, if any, of the embryos or cellular aggregates under culture; and3. The apparatus in claim 1 or claim 2, further comprising:a microfluidic device that includes the containment vessel and a plurality of microchannels, wherein the microfluidic device also includes one or more pumps, valves, or fluid manipulation elements.

4. The apparatus in any of claims 1 to 3, further comprising one or more sensors configured to detect and measure at least one of position, size, shape, density, direction, velocity, temperature, and humidity.

5. The apparatus in claim 4, wherein the one or more sensors include a time-lapse image pickup device configured to capture in situ real-time images of the embryo.

6. The apparatus in any of claims 1 to 5, wherein the embryo includes a biological organism, a cell, a cell aggregate, an organoid, or a tissue.

7. The apparatus in any of claims 1 to 6, wherein the containment vessel is configured to facilitate suspended free fall of the embryo in a fluid, including by a Bernoulli effect, Coanda effect, or by sustained and coordinated inversion of the containment vessel by the drive system.

8. The apparatus in any of claims 1 to 7, wherein the drive system is configured to control or regulate a fluid supplied to the containment vessel, wherein the fluid comprises a gas or a nutrient.

9. The apparatus in claim 3, wherein the microfluidic device includes one or more pneumatic valves that control or regulate flow, volume, velocity, or rate of flow in one or more of the microchannels.

10. The apparatus in claim 1, wherein the controller is configured to:receive sensor data from one or more sensors;analyze the sensor data to determine the condition of a supplied fluid, a returned fluid, the embryo, or the containment vessel;generate one or more control signals based on the condition; andadjust, by one or more control signals, at least one of the supplied fluids, the returned fluid, temperature, or humidity.

11. The apparatus in claim 10, wherein the adjusted supplied fluid comprises: a gas comprising oxygen, nitrogen, or carbon dioxide;a nutrient media formulation including dissolved gas;a nutrient, hormone, or a molecular substance consumed by the embryo;an investigational material to improve growth or development of the embryo; oran investigational material to assess potential harm, toxicity, or mutagenicity the embryo.

12. The apparatus in any of claims 1 to 11, wherein the controller is configured to perform compatibility testing with respect to development of the embryo in the containment vessel.

13. The apparatus in claim 3, wherein the microfluidic device comprises a microfluidic chip having one or more glass layers.

14. The apparatus in claim 5, wherein the image pickup device is configured to provide observation of developmental milestones during embryonic development of the embryo in the containment vessel.

15. The apparatus in any of claims 1 to 14, wherein the containment vessel is made of a transparent biocompatible polymer, a polycarbonate (PC), polymethyl-methacrylate (PMMA), polydimethylsiloxane (PDMS), or glass.

16. The apparatus in any of claims 1 to 15, further comprising a biomimetic manifold, wherein at least one of the containment vessel and the biomimetic manifold is constructed from a material of interest to evaluate any leachable component toxicity or mutagenicity on the embryo.

17. The apparatus in claim 10, wherein the one or more control signals operate, or cause to be operated, one or more pneumatic valves in a microfluidic chip.

18. The apparatus in claim 17, wherein the microfluidic chip includes the containment vessel.

19. The apparatus in any of claims 1 to 15, or 17 or 18, further comprising:a biomimetic manifold configured to supply fluids to the containment vessel and extract waste from the containment vessel,wherein the biomimetic manifold is constructed from a material of interest to evaluate a leachable component toxicity or mutagenicity.

20. The apparatus in claim 19, wherein the biomimetic manifold comprises at least one of a plurality of supply conduits configured to supply a fluid containing a nutrient or a gas to the containment vessel;one or more return conduits configured to receive return fluid that includes waste from the containment vessel;one or more sensors configured to detect or measure a property or characteristic in the supply fluid or the return fluid; andone or more pneumatic elements configured to control flow of a portion of the supply fluid or the return fluid,wherein the one or more pneumatic elements comprise one or more of a valve, a pump, or a sensor configured to control fluid flow, pressure, or detect and measure an electrical property, including impedance, to modulate a future fluid input.

21. The apparatus in claim 20, wherein the biomimetic manifold comprises:a fluid supply source configured to supply the nutrients and the gas, via the plurality of supply conduits, to the containment vessel for mammalian gestation; anda return receptacle configured to receive the return fluid, via the return conduit, from the containment vessel.

22. The apparatus in claim 5, wherein the motion system comprises: a rotor comprising configured to attach to the containment vessel; a rotary member configured to support the rotor and allow the rotor to rotate about said axis; anda driven gear configured to be driven and rotate the rotor about said axis, wherein said axis is a rotational co-axis of the rotary member and the rotor, and wherein the image pickup device is positioned coaxially with respect to the rotational axis.

23. The apparatus in claim 22, wherein the driven gear is affixed to the rotor and said axis is a rotational co-axis of the rotary member and the rotor and the driven gear.

24. The apparatus in any of claims 1 to 21, wherein the motion system comprises a plurality of actuators configured for multidimensional rotation of the containment vessel.

25. The apparatus in claim 24, further comprising an image pickup device configured to move in synchronization with the multidimensional rotation of the containment vessel to maintain a fixed view of the containment vessel.

26. The apparatus in claim 23, wherein the drive system includes a driver gear configured to engage and drive said driven gear to rotate the rotor about said axis, which is substantially perpendicular to a gravity vector.

27. The apparatus in claim 3, wherein the microfluidic device includes a container body comprising the containment vessel, the plurality of microchannels, and one or more valves, wherein the containment vessel has two or more ends and two or more openings at each of said two ends.

28. The apparatus in claim 27, wherein the one or more valves are configured to control fluid flow into the containment vessel.

29. The apparatus in claim 28, wherein the one or more valves include a pneumatic valve.

30. The apparatus in claim 22, wherein the rotary member comprises a shaft, a hub, an axle, agear, a bearing, a roller bearing, or a bearing cup, wherein said axis is a center axis of the rotary member.

31. The apparatus in claim 9, wherein the biomimetic manifold is configured to attach to the motion system and supply fluids to the containment vessel and receive return fluids from thecontainment vessel while the containment vessel moves with respect to the axis or the multiple axes.

32. The apparatus in claim 26, wherein the drive system further includes a motor and a drive shaft, wherein the drive shaft is configured to attach to the driver gear.

33. The apparatus in claim 32, wherein the controller comprises a processor, a memory, and a motor driver, which is configured to send electrical signals to the motor to operate and control the motor.

34. The apparatus in any of claims 1 to 33, wherein the controller comprises a processor, a memory, and a biomimetic monitor, which is configured to monitor at least one of:a size, a shape, a density, a position, or a settlement time of the embryo;a position of the containment vessel, a direction of rotation, and a velocity of rotation of the containment vessel.

35. The apparatus in any of claims 1 to 33, wherein the controller comprises a processor, a memory, and a biomimetic driver, which is configured to determine and maintain the movement of the containment vessel for mammalian gestation.

36. The apparatus in claim 35, wherein the biomimetic driver is configured to determine the inversion frequency, the direction of rotation, the position of the embryo, the position of the containment vessel, the velocity, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the position of the embryo, the rate of change in the velocity of the containment vessel, or the rate of change in the position of the containment vessel.

37. A method of providing quasi-zero gravity for mammalian gestation, including providing intermittent motion and culture of an embryo in a containment vessel, the method comprising: providing a containment vessel containing an embryo;determining at least one of an inversion frequency, a direction of rotation of the containment vessel, a position of the embryo, a position of the containment vessel, a velocity of the containment vessel, a rate of change in the inversion frequency, a rate of change in the direction of rotation, a rate of change in the position of the embryo, a rate of change in the position of the containment vessel, and a rate of change in the velocity of the containment vessel; anddriving the motion system with respect to at least one axis, the motion system being driven according to the determined at least one of the inversion frequency, the direction of rotation of the containment vessel, the position of the embryo, the position of the containment vessel, the velocity of the containment vessel, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the position of the embryo, the rate of change in the position of the containment vessel, and the rate of change in the velocity of the containment vessel.

38. The method in claim 37, further comprising:supplying a fluid to the containment vessel; andreceiving a return fluid comprising waste from the containment vessel.

39. The method in claim 38, wherein the fluid is supplied from a fluid supply source to the containment vessel via at least one supply conduit.

40. The method in claim 38, wherein the return fluid is received from the containment vessel at a return receptacle via at least one return conduit.

41. The method in any of claims 37 to 40, wherein the motion system comprises:a rotor configured to support the containment vessel;a rotary member configured to support the rotor and allow the rotor to rotate about said axis; anda driven gear configured to be driven and rotate the rotor about said axis,wherein said axis is a rotational co-axis of the rotary member and the rotor, andwherein an image pickup device is coaxially positioned with the rotational axis.

42. The method in claim 41, wherein the driven gear is affixed to the rotor and said axis is a rotational co-axis of the rotary member and the rotor and the driven gear.

43. The method in claim 41, wherein the drive system includes a driver gear configured to engage and drive said driven gear to rotate the rotor about said axis, which is substantially perpendicular to a gravity vector.

44. The method in any of claims 37 to 43, wherein the containment vessel is formed in a microfluidic chip comprising a container body having a plurality of microchannels in fluid communication with the containment vessel.

45. The method in claim 44, wherein the container body includes one or more pneumatic valvesin fluid communication with the plurality of microchannels.

46. The method in claim 38, wherein:the fluid is supplied from a fluid supply source to the containment vessel via at least one supply conduit; andthe containment vessel has at least one opening at each of two ends, with at least one opening being configured to connect to the at least one supply conduit and another opening configured to connect to at least one return conduit.

47. The method in claim 41, wherein the rotary member comprises a shaft, a hub, an axle, a gear, a bearing, a roller bearing, or a bearing cup and wherein said axis is a center axis of the rotary member.

48. The method in any of claims 37 to 47, further comprising attaching a biomimetic manifold to the motion system to supply fluid to the containment vessel and return waste from the containment vessel while the containment vessel rotates with respect to at least one axis.

49. The method in claim 43, wherein the drive system further includes a motor and a drive shaft, wherein the drive shaft is configured to attach to the driver gear.

50. The method in claim 49, wherein the controller comprises a processor, a memory, and a motor driver, and wherein the controller is configured to send electrical signals to the motor to operate and control the motor.

51. The method in claim 37, the method further comprising: monitoring by one or more sensors at least one of a fluid supplied to the containment vessel, a size, as shape, a density, a position, or a settling time of the embryo, a position of the containment vessel, a direction of rotation of the containment vessel, a velocity of rotation of the containment vessel, anda waste received from the containment vessel;receiving sensor data from the one or more sensors, including an image pickup device; analyzing the sensor data compared to predetermined targets; and adjusting at least one ofthe fluid supplied to the containment vessel, andthe position of the containment vessel, the direction of rotation of the containment vessel, the velocity of rotation of the containment vessel.

52. The method in claim 49, wherein the controller comprises a processor, a memory, and a biomimetic driver, and wherein the controller is configured to determine and maintain the movement of the containment vessel for mammalian gestation.

53. The method in claim 52, wherein the biomimetic driver is configured to determine the inversion frequency, the direction of rotation, the position of the embryo, the position of the containment vessel, the velocity of rotation, the rate of change in the inversion frequency, the rate of change in the direction, the rate of change in the position of the embryo, the rate of change in the position of the containment vessel, or the rate of change in the velocity of the containment vessel.

54. A non-transitory computer readable storage medium storing one or more programs for moving a containment vessel for mammalian gestation, including to provide continuousintermittent motion and culture of an embryo in the containment vessel, the one or more programs comprising instructions, which, when executed by a processor, cause the processor to perform operations comprising:providing a containment vessel containing an embryo;determining at least one of an inversion frequency, a direction of rotation of the containment vessel, a position of the embryo, a position of the containment vessel, a velocity of the containment vessel, a rate of change in the inversion frequency, a rate of change in the direction of rotation, a rate of change in the position of the embryo, a rate of change in the position of the containment vessel, and a rate of change in the velocity of the containment vessel; anddriving the motion system with respect to at least one axis, the motion system being driven according to the determined at least one of the inversion frequency, the direction of rotation of the containment vessel, the position of the embryo, the position of the containment vessel, the velocity of the containment vessel, the rate of change in the inversion frequency, the rate of change in the direction of rotation, the rate of change in the position of the embryo, the rate of change in the position of the containment vessel, and the rate of change in the velocity of the containment vessel.

55. A non-transitory computer readable storage medium storing one or more programs for moving a containment vessel for mammalian gestation, including to provide intermittent motion and culture of an embryo in the containment vessel, the one or more programs comprising instructions, which, when executed by a processor, cause the processor to perform the method in any of claims 37 to 53.

56. A method for assessing compatibility or biocompatibility of a material for an artificial womb, the method comprising:supplying a fluid via at least one channel to a vessel containing an embryo;sensing, by one or more sensors, a real-time state of the fluid supplied to the vessel, the embryo, or the vessel;moving, by a biomimetic driver, the vessel based on the sensed real-time state of the embryo or the vessel to maintain quasi-zero gravity of the embryo in the vessel; anddetermining suitability of a material in the vessel,wherein the one or more sensors include a time-lapse image pickup device configured to in situ image the embryo in real-time, andwherein the state of the embryo or the vessel includes at least one of a size, a shape, a density, a position, or a settling time of the embryo, a position, a rotational direction, or rotational velocity of the vessel.

57. The method in claim 56, wherein the determining the compatibility or biocompatibility of the material in the vessel comprises:analyzing waste returned from the vessel;assessing a real-time developmental state of the embryo compared to target developmental state for the embryo; anddetermining the material to be incompatible or bioincompatible for gestation of the embryo when the real-time developmental state lags the target developmental state for the embryo.

58. The method in claim 56, further comprising:analyzing the fluid supplied to the vessel;analyzing waste returned from the vessel;assessing a real-time developmental state of the embryo compared to target developmental state for the embryo; anddetermining compatibility or biocompatibility of a substance in the fluid for gestation of the embryo.

59. The method in claim 58, wherein the substance is determined to be incompatible or bioincompatible for gestation of the embryo when the real-time developmental state lags the target developmental state for the embryo.

Images