Patent Grant
11384751
The invention relates generally to microfluidic systems, and more particularly to multichannel pumps and applications of the same.
The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention.
Bioreactors offer the unprecedented opportunity to maintain tissue explants in a close-to-physiological environment. Typically, a two-chambered bioreactor, such as the Puck neurovascular unit (NVU), is perfused by two single-channel rotary planar peristaltic micropumps (RPPM), with one for each side of the blood-brain barrier (BBB). For multiple NVU bioreactors, there will be the twice the number of motor cartridges as the bioreactors. Since the physical volume occupied by a motor cartridge and their motor control electronics can be substantially greater than that of a Puck bioreactor, it would be advantageous to have a single motor provide perfusion control to both sides of a two chambered bioreactor, and also multiple such bioreactors so as to thereby increase the parallelism and throughput of an organ-on-chip bioassay. Were the bioreactors only single chamber, one single-channel pump would be required for perfusion, and a multichannel pump would be able to perfuse the same number of single-sided bioreactors.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.
In one aspect, the invention relates to a peristaltic micropump. In one embodiment, the peristaltic micropump includes a plurality of channels, wherein each channel is flexible, has a middle channel portion, and is operably in fluidic communications with a first port and a second port, and wherein the middle channel portions of the plurality of channels are arranged in one or more concentric circles; and an actuator comprising a bearing assembly driven by a motor, wherein the bearing assembly comprises a plurality of rolling members and a bearing accommodating member for accommodating the plurality of rolling members, wherein the actuator is positioned in relation to the plurality of channels such that when the bearing accommodating member rotates, the plurality of rolling members rolls along the one or more concentric circles of the middle channel portions of the plurality of channels to cause individually fluids to transfer between the first port and the second port of each of the plurality of channels simultaneously at different flowrates.
In one embodiment, each channel is in fluidic communications with a respective fluid, wherein one of the first and second ports of each channel is an input port for inputting the respective fluid, and the other is an output port for outputting the respective fluid at a predetermined flowrate with a predetermined volume.
In one embodiment, the plurality of channels is formed in a layer of a flexible material.
In one embodiment, the flexible material comprises a polymer of polydimethylsiloxane (PDMS), or its derivatives.
In one embodiment, the actuator is configured such that when the actuator is activated, during a full rotation of the bearing accommodating member, each channel is being compressed by at least one rolling member.
In one embodiment, when the actuator is deactivated, each channel is compressed by one or more rolling members as so to prevent passive forward or reverse flows through the channels of the peristaltic micropump.
In one embodiment, each channel has a cross-section area that determines a flowrate of a fluid flowing through said channel, and wherein the cross-section area is in any one of geometric shapes.
In one embodiment, when the bearing accommodating member rotates at a central axis, each rolling member operably rolls about a respective axis that is not parallel to the central axis.
In one embodiment, the bearing accommodating member comprises a bearing cage defining a plurality of spaced-apart openings thereon, and the plurality of rolling members is accommodated in the plurality of spaced-apart openings.
In one embodiment, the plurality of spaced-apart openings defines one or more concentric circles that are operably coincident with the one or more concentric circles of the middle channel portions of the plurality of channels.
In one embodiment, each of the plurality of rolling members comprises a ball, or a roller.
In one embodiment, the bearing accommodating member comprises a hub having a plurality of shafts radially protruded from the hub, and the plurality of rolling members is rotatably attached to the plurality of shafts, respectively.
In one embodiment, each of the plurality of rolling members comprises a can follower, a cylindrical roller, or conical roller.
In one embodiment, the peristaltic micropump is a rotary planar peristaltic micropump (RPPM).
In one embodiment, the peristaltic micropump further comprises a microcontroller being in wired or wireless commutations with the actuator for controlling operations of the actuator.
In another aspect of the inventions, a peristaltic micropump has a plurality of channels configured to transfer one or more fluids; and an actuator configured to engage the plurality of channels, and rotate about a central axis, wherein the actuator comprises a plurality of rolling members and a driving member configured such that when the driving member rotates, the plurality of rolling members rolls along the plurality of channels to cause individually the one or more fluids to transfer through each of the plurality of channels simultaneously at different flowrates, wherein during a full rotation of the driving member, each channel is being compressed by at least one rolling member.
In one embodiment, the plurality of channels is formed in a layer of a flexible material.
In one embodiment, the flexible material comprises a polymer of polydimethylsiloxane (PDMS), or its derivatives.
In one embodiment, each channel has a cross-section area that determines a flowrate of a fluid flowing through said channel, and wherein the cross-section area is in any one of geometric shapes.
In one embodiment, the plurality of rolling members is disposed between the plurality of channels and the driving member.
In one embodiment, each channel has a middle channel portion, and wherein the middle channel portions of the plurality of channels are arranged in one or more concentric circles.
In one embodiment, when the driving member rotates at a central axis, each rolling member operably rolls about a respective axis that is not parallel to the central axis.
In one embodiment, the driving member comprises a bearing accommodating member configured to accommodate the plurality of rolling members.
In one embodiment, the bearing accommodating member comprises a bearing cage defining a plurality of spaced-apart openings thereon, and the plurality of rolling members is accommodated in the plurality of spaced-apart openings.
In one embodiment, the plurality of spaced-apart openings defines one or more concentric circles that are operably coincident with the one or more concentric circles of the middle channel portions of the plurality of channels.
In one embodiment, each of the plurality of rolling members comprises a ball, or a roller.
In one embodiment, the bearing accommodating member comprises a hub having a plurality of shafts radially protruded from the hub, and the plurality of rolling members is rotatably attached to the plurality of shafts, respectively.
In one embodiment, each of the plurality of rolling members comprises a can follower, a cylindrical roller, or conical roller.
In one embodiment, the peristaltic micropump is a rotary planar peristaltic micropump (RPPM).
In one embodiment, the driving member is driven by a motor.
In one embodiment, the peristaltic micropump further comprises a microcontroller being in wired or wireless commutations with the actuator for controlling operations of the actuator.
In yet another aspect, the invention relates to a pump array includes a plurality of peristaltic micropumps disclosed above, arranged in a baseplate; and a microcontroller being in wired or wireless commutations with the actuator of each of the plurality of peristaltic micropumps for individually controlling operations of the plurality of peristaltic micropumps.
In one aspect of the invention, a push-pull micropump includes one or more pairs of channels configured to transfer one or more fluids, each channel pair having an aspiration channel and an injection channel; and an actuator configured to engage the one or more pairs of channels, wherein the actuator comprises a plurality of rolling members and a driving member configured such that when the driving member rotates, the plurality of rolling members rolls along the one or more pairs of channels to cause individually the one or more fluids to transfer through each channel pair simultaneously at different flowrates or the same flowrate, depending upon actuated lengths of the aspiration and injection channels of each channel pair, wherein an actuated length of a channel is defined by a length of the channel along which the plurality of rolling members rolls during a full rotation of the driving member.
In one embodiment, each channel pair is configured such that the actuated length of the aspiration channel is longer than that of the injection channel, whereby the aspiration and injection channels of each channel pair have different flowrates.
In one embodiment, each channel pair is configured such that the actuated length of the aspiration channel is same as that of the injection channel, whereby the aspiration and injection channels of each channel pair have the same flowrate.
In one embodiment, the aspiration and injection channels of each channel pair have different cross-sectional areas.
In one embodiment, each channel has a middle channel portion, and wherein the middle channel portions of the aspiration and injection channels of each channel pair are arranged as segments of two concentric circles with different radii.
In one embodiment, when the driving member rotates at a central axis, each rolling member operably rolls about a respective axis that is not parallel to the central axis.
In one embodiment, the driving member comprises a bearing accommodating member configured to accommodate the plurality of rolling members.
In one embodiment, the bearing accommodating member comprises a bearing cage defining a plurality of spaced-apart openings thereon, and the plurality of rolling members is accommodated in the plurality of spaced-apart openings.
In one embodiment, the plurality of spaced-apart openings defines one or more concentric circles that are operably coincident with the one or more concentric circles of the middle channel portions of the one or more pairs of channels.
In one embodiment, each of the plurality of rolling members comprises a ball, or a roller.
In one embodiment, the bearing accommodating member comprises a hub having a plurality of shafts radially protruded from the hub, and the plurality of rolling members is rotatably attached to the plurality of shafts, respectively.
In one embodiment, each of the plurality of rolling members comprises a can follower, a cylindrical roller, or conical roller.
In another aspect, the invention relates to a pump array comprising a plurality of push-pull micropumps as disclosed above, arranged in a baseplate; and a microcontroller being in wired or wireless commutations with the actuator of each of the plurality of push-pull micropumps for individually controlling operations of the plurality of push-pull micropumps.
These and other aspects of the invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
The accompanying drawings illustrate one or more embodiments of the invention and, together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. The invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting and/or capital letters has no influence on the scope and meaning of a term; the scope and meaning of a term are the same, in the same context, whether or not it is highlighted and/or in capital letters. It will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any terms discussed herein, is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.
It will be understood that when an element is referred to as being “on” another element, it can be directly on the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being “directly on” another element, there are no intervening elements present. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below can be termed a second element, component, region, layer or section without departing from the teachings of the invention.
It will be understood that when an element is referred to as being “on,” “attached” to, “connected” to, “coupled” with, “contacting,” etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on,” “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” to another feature may have portions that overlap or underlie the adjacent feature.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” or “includes” and/or “including” or “has” and/or “having” when used in this specification specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element's relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation shown in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on the “upper” sides of the other elements. The exemplary term “lower” can, therefore, encompass both an orientation of lower and upper, depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
As used herein, “around,” “about,” “substantially” or “approximately” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the terms “around,” “about,” “substantially” or “approximately” can be inferred if not expressly stated.
As used herein, the terms “comprise” or “comprising,” “include” or “including,” “carry” or “carrying,” “has/have” or “having,” “contain” or “containing,” “involve” or “involving” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.
As used herein, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.
The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention.
It has been demonstrated by co-inventors of this invention in U.S. patent application Ser. Nos. 14/651,174, 14/646,300, 15/820,506 and 16/049,025, which are incorporated herein by reference in their entireties, that the exemplary embodiments of rotary planar peristaltic micropumps (RPPM) are capable of pumping a wide range of flows that are appropriate for microfluidic experiments. An RPPM can also be readily incorporated directly into a microfluidic chip, and its functionality when integrated with microfluidic networks is enhanced by a proximal and reliable means of switching fluidic inputs upstream or fluidic outputs downstream from the pump body.
In certain aspects, the invention relates to single-motor-driven multichannel micropumps in which fluids are individually transferred through each of the multichannels simultaneously at controllable flowrates. The multichannel micropumps are advantageous to have a single motor provide perfusion control to multiple bioreactors and thereby increase the parallelism and throughput of an organ-on-chip bioassay.
In one embodiment, when the bearing cage 210 rotates at a central axis, each ball 215 operably rolls about a respective axis that is not parallel to the central axis.
In one embodiment shown in
Each channel has a cross-section area that determines a flowrate of a fluid flowing through said channel, and wherein the cross-section area is in any one of geometric shapes.
In one embodiment, the channels 221-228 are formed in a layer of a flexible material. The flexible material can be a polymer of polydimethylsiloxane (PDMS), its derivatives, or other polymer compounds.
It should be noted that
In one embodiment, the multichannel pump has a microcontroller that is in wired or wireless commutations with the motor and hence actuator for controlling operations of the actuator.
This approach enables even more sophisticated pumping systems, for example where the pumping channels are not all identical. Some of the channels could have larger cross-sectional areas to pump faster than other channels. In one embodiment, four of the channels with smaller cross-sectional areas could deliver fluid via a long needle to the bottom of four wells in a standard well plate, as indicated by the two tubes 603 and 604 illustrated for a single well in
By aligning nine of the 6-channel pumps 355 in the baseplate 330, as shown in
In addition, the pump array also includes a microcontroller (not shown) being in wired or wireless commutations with the actuator of each of the nine peristaltic micropumps 355 for individually controlling operations of the plurality of peristaltic micropumps 355.
In one embodiment, alignment pockets accept pins/dowels or similar features, which can be used to align chip to actuator.
In one embodiment, the number of individual circuits may be adjusted to suit operational needs.
In one embodiment, chip features markings to identify individual circuits for ease of use.
In one embodiment, chip designed for use with 12-ball actuator.
In one embodiment, channel shape/length/spacing designed such that at least one actuating ball is always pinching each channel closed (positive flow).
The differences in the flow rates of each pump arose either from non-planarity of the molded fluidic chip, or manufacturing tolerances in the motor cartridge components. To test whether the flow rate differences was due to fluidic planarity or to hardware of the pump motor frame, the pump was rotated 180°, and it was determined that one side of the fluidic chip exhibited less compression of the channels than the other.
When using pumps to fill or empty a small volume, such as a well in a 96-well plate, the amount of fluid delivered and fluid removed must be carefully controlled, lest the well be either inadvertently over-filled or emptied.
Three eight-channel pumps as shown in
As shown in
In one embodiment, the inner channels 731 have direct access to the outside of the pump fluidic chip. The reduction from eight to six channels provides the space required for the inner channels 731 to cross to the outside. Traces coming from the inside race 732 past the outside ball track 715 and may need to be deeper or wider as they cross the outside ball track 716 so as to not have their flow blocked when the outer balls 715 of the actuator 710 cross the channels to the inside. Depending upon the spacing's and compression forces, it might be possible to use a single race of larger balls that blocks both channels at the same time.
Using the through-plate circular chip design, the inner channels could be accessed from the inside of the ball races, and the outer channels from the outside. This would obviate the need to compensate for the outer actuating balls crossing over the fluidics from the inner channel.
In this embodiment of a multichannel pumps, it would be possible to adjust the length of the pumping regions so that all channels on the multichannel pump in
In certain embodiments, the different type actuators can be also used, which the numbers of actuating members, such as cam followers and rollers, are mounted on shafts (sockets) around a single hub.
For example,
For such multichannel pumps as disclosed above, when the actuator rotates, the rolling members are also rotating relative to the rolling bearing cage and middle, circumferential channel portions of the multiple channels. During operation, rolling members, such as 815, 915, 1015, 1115 or 1115′, engage and compress the middle, circumferential channel portions of the multiple channels and pump fluids through the multiple channels simultaneously at different flowrates. When the pump is not in operation, one or more rolling members placed on the circumferential channel portions of the multiple channels prevent passive forward or reverse flow through the pumps.
The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the invention pertains without departing from its spirit and scope. Accordingly, the scope of the invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.
This application is a divisional application of U.S. patent application Ser. No. 17/269,329, filed Feb. 18, 2021, which is a national stage entry of PCT Patent Application Serial No. PCT/US2019/047190 (hereinafter “the '190 application”), filed Aug. 20, 2019, which itself claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 62/719,868, filed Aug. 20, 2018, and 62/868,303, Jun. 28, 2019. The '190 application is also a continuation-in-part application of U.S. patent application Ser. No. 15/820,506, filed Nov. 22, 2017, now allowed, which is a divisional application of U.S. patent application Ser. No. 13/877,925, filed Jul. 16, 2013, now abandoned, which is a national stage entry of PCT Application Serial No. PCT/US2011/055432, filed Oct. 7, 2011, which claims priority to and the benefit of, U.S. Provisional Patent Application Ser. No. 61/390,982, filed Oct. 7, 2010. The '190 application is also a continuation-in-part application of U.S. patent application Ser. No. 16/049,025, filed Jul. 30, 2018, which is a continuation application of U.S. patent application Ser. No. 14/363,074, filed Jun. 5, 2014, now U.S. Pat. No. 10,078,075, is a national stage entry of PCT Application Serial No. PCT/US2012/068771, filed Dec. 10, 2012, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 61/569,145, 61/697,204 and 61/717,441, filed Dec. 9, 2011, Sep. 5, 2012 and Oct. 23, 2012, respectively. The '190 application is also a continuation-in-part application of U.S. patent application Ser. No. 16/012,900, filed Jun. 20, 2018, which is a divisional application of U.S. patent application Ser. No. 15/191,092 (the '092 application), filed Jun. 23, 2016, now U.S. Pat. No. 10,023,832, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 62/183,571, 62/193,029, 62/276,047 and 62/295,306, filed Jun. 23, 2015, Jul. 15, 2015, Jan. 7, 2016 and Feb. 15, 2016, respectively. The '092 application is also a continuation-in-part application of U.S. patent application Ser. Nos. 13/877,925, 14/363,074, 14/646,300 (the '300 application) and Ser. No. 14/651,174 (the '174 application), filed Jul. 16, 2013, Jun. 5, 2014, May 20, 2015 and Jun. 10, 2015, respectively. The '300 application, now U.S. Pat. No. 9,874,285, is a national stage entry of PCT Application Serial No. PCT/US2013/071026, filed Nov. 20, 2013, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 61/729,149, 61/808,455, and 61/822,081, filed Nov. 21, 2012, Apr. 4, 2013 and May 10, 2013, respectively. The '174 application, now U.S. Pat. No. 9,618,129, is a national stage entry of PCT Application Serial No. PCT/US2013/071324, filed Nov. 21, 2013, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. Nos. 61/808,455 and 61/822,081, filed Apr. 4, 2013 and May 10, 2013, respectively. The '190 application is also a continuation-in-part application of U.S. patent application Ser. No. 16/511,379, filed Jul. 15, 2019, which is a divisional application of U.S. patent application Ser. No. 15/776,524, filed May 16, 2018, now allowed, which is a national stage entry of PCT Application Serial No. PCT/US2016/063586 (the '586 application), filed Nov. 23, 2016, which claims priority to and the benefit of, U.S. Provisional Patent Application Ser. No. 62/259,327, filed Nov. 24, 2015. The '586 application is also a continuation-in-part application of U.S. patent application Ser. Nos. 13/877,925, 14/363,074, 14/646,300, 14/651,174 and 15/191,092, filed Jul. 16, 2013, Jun. 5, 2014, May 20, 2015, Jun. 10, 2015 and Jun. 23, 2016, respectively. The '190 application is also a continuation-in-part application of PCT Patent Application Serial No. PCT/US2019/034285 (the '285 application), filed May 29, 2019, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/677,468, filed May 29, 2018. The '285 application is also a continuation-in-part application of U.S. patent application Ser. Nos. 15/776,524 and 16/012,900, filed May 16, 2018 and Jun. 20, 2018, respectively. Each of the above-identified applications is incorporated herein by reference in its entirety. Some references, which may include patents, patent applications, and various publications, are cited and discussed in the description of the invention. The citation and/or discussion of such references is provided merely to clarify the description of the invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.
This invention was made with government support under Grant Nos. 5UG3TR002097-02, U01CA202229 and HHSN271201700044C awarded by the National Institutes of Health, Grant No. 83573601 awarded by the U. S. Environmental Protection Agency, Grant No. 2017-17081500003 awarded by the Intelligence Advanced Research Projects Activity, and Grant No. CBMXCEL-XL1-2-001 awarded by the Defense Threat Reduction Agency through Subcontract 468746 by Los Alamos National Laboratory (LANL). The government has certain rights in the invention.
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| 992205 | Still | May 1911 | A |
| 3684408 | Maclin | Aug 1972 | A |
| 11135582 | Schaffer | Oct 2021 | B2 |
| 20020062105 | Tanner | May 2002 | A1 |
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