Microfluidic peristaltic pump assembly

Abstract

A fluidic pump including at least three fluid-filled chambers, at least one fluidic path that crosses the at least three fluid-filled chambers, and at least one dedicated pressure controller. Each of the three fluid-filled chambers is separated into two parts by a flexible membrane, wherein fluid pumping is conducted through a peristaltic motion of the flexible membrane. The at least one dedicated pressure controller deflects the flexible membrane from a side opposite to the at least one fluidic path. At least one of the at least three fluid-filled chambers pumps fluid by the deflected flexible membrane (deflected by the at least one dedicated pressure controller) and has a profile matching the deflection of the membrane. The fluidic pump further includes a means to provide an electric current to the dedicated pressure controller.

Description

MICROFLUIDIC PERISTALTIC PUMP ASSEMBLYCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 662,031 filed on June 20, 2024, the contents of which provisional application are hereby incorporated by reference for all purposes.FIELD

[0002] The present disclosure relates to the transport of fluids in microfluidic devices and, in particular, to microfluidic pumps and methods of delivering accurate dosage with such pumps.BACKGROUND

[0003] Peristaltic pumps are widely used because of their robust and well-characterized performance as well as straightforward operation. Various approaches to designing systems that set the motion of fluid along the fluidic channel in a peristaltic pump have been attempted. Most of these techniques are based on a principle of squeezing microchannels filled with fluids and typically employ a device with rolling cams or bearings [see, e.g., S. Pennathur, Lab Chip 8(3), 383-387 (2008)]. Earlier designs of bearing-based peristaltic pumps included linear micropumps with continuous outflow, although they often suffered from backflow and strokes. Various improved designs were proposed over time, such as a round micropump (see, e.g., X. Zhang, Z. Chen, and Y. Huang “A valve-less microfluidic peristaltic pumping method,” Biomicrofluidics 9, 014118 (2015)), in which circular micro-channels embedded in polydimethylsiloxane (PDMS)are squeezed by bearings, enabling continuous, steady, and precise fluidic perfusion with optimized channel layout.

[0004] Alternative to cams and bearings approaches to move liquids along the channel in the peristaltic pump using the technique of channel pressurization by several diaphragm valves placed in-series have been introduced to solve the problem of accurate delivery of nanoliter volumes of liquids to certain micro-vials fabricated in microfluidic chips. Microfluidic peristaltic pumps containing pneumatically controlled diaphragm microvalves built with PDMS membranes [see, e.g., Marc A. Unger, Hou-Pu Chou, Todd Thorsen, Axel Scherer, and Stephen Quake, "Monolithic Microfabricated Valves and Pumps by Multilayer Soft Lithography," Science, vol. 288, no. 7, pp. 113-116, April 2000.] are extremely precise.

[0005] A basic peristaltic pump described by Unger et al includes two elastomer layers. One layer contains channels for moving liquids (liquid flow layer), and the other layer (control pneumatic layer) contains a multitude of channels / conduits that can be filled with pressurized gas. The control layer is separated from the liquid flow layer by thin diaphragms. When the pneumatic pressure in the conduits of the control pneumatic layer increases to a sufficiently high level, diaphragms are deflected toward the nearby liquid flow channel and block it. The choice of technique of blocking the channel in the diaphragm microvalve by the flexible diaphragm separates the designs of diaphragm valves into Quake, doormat, and plunger microvalves. The Quake microvalve is the most commonly-used pneumatic microvalve. It involves a bilayer PDMS microfluidic chip. Liquid flows inside the bottom layer while the upper layer integrates a manifold of air channels. When activated, the elevated air pressure in the air manifold selectivelypushes the thin membrane down thus blocking the fluidic channel, enabling fluid motion control.

[0006] Like Quake microvalves, “doormat” -style microvalves involve a bilayer structure with a liquid network and an air network (see, e.g., Kazuo Hosokawa, Ryutaro Maeda. "A pneumatically-actuated three-way microvalve fabricated with polydimethylsiloxane using the membrane transfer technique", J. Micromech. Microeng. 10, 2000, 415-420). But unlike the Quake microvalves, the “doormat” -style valves are normally-closed valves, i.e. in a rest state, the liquid channel is blocked by a barrier. In order to open the valve, a pressure lower than the pressure in the liquid channel (e.g., sub-atmospheric pressure) must be applied in the air network. That lower pressure deforms the wall between the two networks, enabling the fluid to overpass the barrier. Plunger microvalves (see, e.g., A. K. Au, H. Lai, B. R. Utela, A. Folch. "Microvalves and Micropumps for BioMEMS", Micromachines 2011 , 2(2), 179-220) involve a multilayer design where the fluidic inlet and outlet are on different layers and separated by a holed layer. A fourth pneumatic layer enables the control of PDMS membrane deformation, hence enabling or disabling fluid flow through the holed layer. Plunger microvalves are more complex systems requiring many microfabrication steps. Nevertheless, that complexity enables one to tune the valve features (e.g., tuning the maximum of operating pressure).

[0007] In summary, in most modern mechanical peristaltic pumps, several pneumatically driven diaphragm valves of any type are placed in series along the same channel, and these valves open and close in a specific sequence, pushing the liquid along the channel of the peristaltic pump. There are alternatives to the mechanical action, mostpopular being pumps based on the electroosmotic effect, stimulated by externally applied electric fields see, e.g., A. Bandopadhyay, D. Tripathi, and S. Chakraborty, "Electroosmosis-modulated peristaltic transport in microfluidic channels," Physics of Fluids 28, 052002 (2016)). In these pumps, the electric field controls peristaltic motion of an aqueous electrolyte through three consecutive fluid reservoirs connected by a through channel.

[0008] All currently used microfluidic peristaltic pumps suffer from at least one of the following technological problems:

[0009] 1 . Accuracy: there are large variations in the amount of liquid delivered in a single peristaltic cycle. While pumps work well when the amount of delivered liquid is averaged over many cycles, the errors in a single cycle often exceed 100%.

[0010] 2. Delivery threshold: most, if not all pumps, cannot deliver single or tens of nanoliters of fluid per second, or per peristaltic cycle.

[0011] 3. Backflow: in many cases, the transported fluid may, due to vibrations or other mechanical or thermal effects, move in the direction opposite to the direction of the peristaltic action.

[0012] 4. Size limitations: the miniaturization of many existing peristaltic pumps is constrained by modern mechanical manufacturing capabilities and requirements imposed on accuracy of the delivery.

[0013] 5. Power consumption: peristaltic action often requires significant pressures to be applied, which limits energy efficiency of peristaltic pumps.

[0014] Thus, there is a need for a technological solution to provide accurate, digitized delivery of liquids, such as therapies, markers, additives, etc., and overcomeshortcomings of the above-discussed conventional devices that currently hamper the development and use of microfluidic peristaltic pumps.SUMMARY

[0015] The present disclosure provides a description of systems and methods associated with peristaltic microfluidic pumps configured to deliver flow rates as low as 1 nL / s, and as high as 0.1 mL / s, with a variance of a single-dose delivery lower than 2%, leak and backflow proof, all in a millimeter sized package. The is achieved by manufacturing a fluidic manifold with at least three fluidic chambers, each separated into two parts by a flexible membrane, with at least one inlet and outlet fluidical ly connected through the pumping chamber, and fluid transport maintained by applying pressure, delivered by dedicated pressure controller(s), to deflect the membrane in the chambers in a peristaltic sequence.

[0016] The present disclosure describes a fluidic pump including at least three fluid- filled chambers, at least one fluidic path that crosses the at least three fluid-filled chambers, and at least one dedicated pressure controller. Each of the three fluid-filled chambers is separated into two parts by a flexible membrane, wherein fluid pumping is conducted through peristaltic motion of the flexible membrane. The at least one dedicated pressure controller deflects the flexible membrane from a side opposite to the at least one fluidic path. At least one of the at least three fluid-filled chambers pumps fluid by the deflected flexible membrane (deflected by the at least one dedicated pressure controller) and has a profile matching the deflection of the membrane. Thefluidic pump further includes a means to provide an electric current to the dedicated pressure controller.

[0017] The present disclosure also describes a method of accurate fluidic delivery in a peristaltic microfluidic pump, fabricating at least one pumping chamber of a fluidic peristaltic pump having a profile that matches a deflection of a flexible membrane.

[0018] The present disclosure additionally describes a method of peristaltic pumping using gas or liquid to activate a membrane using a fluidic pump, the method includes a repeatable sequence of the actions including: deflecting the flexible membrane of an inlet chamber, of the plurality of fluid-filled chambers, thereby opening an inlet; deflecting the flexible membrane of a pumping chamber, of the plurality of fluid-filled chambers, to fill the pumping chamber with a fluid to be pumped; deflecting the flexible membrane of the inlet chamber in an opposite direction, thereby closing the inlet; deflecting the flexible membrane of an outlet chamber, of the plurality of fluid-filled chambers, thereby opening an outlet; deflecting the flexible membrane of the pumping chamber, thereby transferring the fluid into the outlet; and deflecting the flexible membrane of the outlet chamber, thereby closing the outlet.

[0019] The present disclosure further describes a method of reducing gas bubbles in a peristaltic microfluidic pump, including: extracting gasses, via a semi-permeable membrane used in at least one fluid-filled chamber, of a plurality of fluid-filled chambers, from a transported fluid by applying a pressure difference across the semi-permeable membrane.Additionally present disclosure describes a method of preventing flow leaks in a peristaltic microfluidic pump, including stretching and compressing a flexible membrane including circular protrusions and indentations around fluid filled chambers.BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0020] The scope of the present disclosure is best understood from the following detailed description of exemplary embodiments when read in conjunction with the accompanying drawings. Included in the drawings are the following figures:

[0021] FIG. 1 is a schematic illustration of a three-dimensional configuration of a manifold assembly in accordance with exemplary embodiments.

[0022] FIG. 2A is a schematic illustration of a three-dimensional configuration of fluidic components of the manifold assembly of FIG. 1 in accordance with exemplary embodiments.

[0023] FIG. 2B is a schematic illustration of a three-dimensional configuration of the pressure controller components of the manifold assembly of FIG. 1 in accordance with exemplary embodiments.

[0024] FIG. 3A depicts projections of the fluidic components of the manifold assembly of FIG. 1 onto the XZ (top) and XY (bottom) planes, in accordance with exemplary embodiments.

[0025] FIG. 3B depicts projections of the pressure controller components of the manifold assembly of FIG. 1 onto the XZ (top) and XY (bottom) planes, in accordance with exemplary embodiments.

[0026] FIG. 3C depicts a flexible membrane in accordance with exemplary embodiments.

[0027] Fig. 4 depicts projections of the manifold assembly of FIG. 1 onto the XZ (top) and XY (bottom) planes, and onboard dedicated pressure controllers, in accordance with exemplary embodiments.

[0028] Fig. 5 is a schematic illustration of a dedicated pressure controller in accordance with exemplary embodiments.

[0029] Fig. 6 shows a fluidic manifold with an alternative design of fluidic channels, projected onto the XY plane, and fluidic path from an inlet to an outlet in accordance with exemplary embodiments.

[0030] Fig. 7 depicts a focused illustration of a leak-proof membrane pre-stretching design in accordance with exemplary embodiments.

[0031] Fig. 8 illustrates a pumping chamber and membrane deflections in accordance with exemplary embodiments.

[0032] Fig. 9 illustrates a peristaltic sequence of subsequent membrane deflections in accordance with exemplary embodiments.

[0033] Fig. 10 illustrates three and four-chamber configurations of a peristaltic pump in accordance with exemplary embodiments.

[0034] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detaileddescription of exemplary embodiments is intended for illustration purposes only and is, therefore, not intended to necessarily limit the scope of the disclosure.DETAILED DESCRIPTIONPrinciple of Operation

[0035] The principle of operation of the proposed peristaltic pump is based on the displacement of fluid to be transported by a flexible membrane sweeping through a pumping chamber. The flexible membrane may be comprised of a material amenable to stretching. In its neutral state, the flexible membrane separates the pumping chamber in two halves. One half is occupied by the transported fluid. The other half contains a sequentially pressurized and de-pressurized non-solid material, which may be either gas or liquid. The pressure of the non-solid material is modulated by a dedicated onboard or external bi-directional pressure controller, and the pressure difference between the transported fluid and the non-solid material is the mechanism that deflects the membrane, e.g., a plurality of dedicated pressure controllers configured to deflect the flexible membrane from a side opposite of the at least one fluidic path. Hereafter, bi-directional pressure controllers are controllers that are capable of increasing and decreasing pressure of fluid in the volume that they control. The fluid moves to the pumping chamber from an inlet chamber. The inlet chamber contains the non-solid material that is pressure-modulated by a dedicated pressure controller and the flexible membrane separating the material from the narrow inlet channel with the transported fluid. In its neutral state, the flexible membrane seals the inlet channel, either by a pressure gradient or by pre-stretching. It thus acts as (i) an inlet valveoperated by the flexible membrane, and (ii) a dedicated pressure controller. When the fluid needs to be transported from the inlet chamber to the pumping chamber, the flexible membrane is deflected by a dedicated pressure controller. From the pumping chamber, the transported fluid moves to an outlet chamber. In the outlet chamber, similar to the inlet chamber, the flexible membrane, in its neutral state, seals a narrow outlet channel, either by pre-stretching or by applied pressure. It thus acts as (i) an outlet valve operated by the flexible membrane, and (ii) a dedicated pressure controller .When the fluid needs to be transported to the outlet channel, the flexible membrane is deflected from that outlet channel by a dedicated pressure controller.

[0036] FIG. 1 illustrates schematics of an exemplary embodiment of a manifold assembly 100 of a peristaltic pump (herein referred to as “manifold assembly 100”) and depicts a three-dimensional representation, with coordinate axes labeled X-Y-Z. Visible boundaries of different components are shown as solid lines, while some invisible boundaries are shown as dashed lines.

[0037] The manifold assembly 100 includes three separate parts: a fluidic manifold 101 , a pneumatic manifold 102, and a flexible membrane 108.

[0038] The fluidic manifold 101 includes fluidic path (i.e. , a path for the transported fluid). The fluidic manifold 101 represents a solid block with several cavities filled with the liquid to be transported. First, there is an inlet channel 103, which must be fluidically connected with a source of the fluid (e.g., a reservoir, a container, etc.). Second, there is an outlet channel 104, which must be fluidically connected with a destination point for the transported fluid (e.g., a reservoir, a cannula, a needle, etc.). Third, there is a fluidichalf of a pumping chamber 105. Finally, there is (or are, if several) a fluidic channel 107 that connects the inlet channel 103 with the pumping chamber 105 and connects the pumping chamber 105 with the outlet channel 104. As described in more detail below, there may also be three small circular cavities (i.e. , indentations) for a membrane locking mechanism, e.g., leak-preventing circular locks.

[0039] The pneumatic manifold 102 represents a solid block with three cavities 110. Of these three cavities 110, the first cavity 110a (also referred to as inlet chamber or valve 110a), is adjacent to the inlet channel 103. The second cavity 110b represents half of the pumping chamber 105, and the third cavity 110c (also referred to as outlet chamber 110c) is adjacent to the outlet channel 104. Each of the cavities 110 is filled with a nonsolid material. The non-solid material can be any compressible (gas) or incompressible (liquid) substance that yields easily to external pressure. For example, the non-solid material may be air or water. In what follows, and without the loss of generality, the non- solid material that fills the three cavities 110 is referred to as "air" for brevity. However, any other non-solid material (as noted above) may be used. Each of the three air-filled cavities 110 is connected with a dedicated pressure controller 106, such that the air pressure in each cavity (110a, 110b, 110c) is modulated independently of the other two cavities. Each pressure controller may be either (I) bi-directional, so that it is capable of reducing and increasing the air pressure in respective cavity it controls, or (ii) unidirectional, so that it is capable of reducing or increasing the air pressure in respective cavity it controls.

[0040] The flexible membrane 108 is disposed between the fluidic manifold 101 and the pneumatic manifold 102. The flexible membrane 108 is configured to fully separate the fluidic manifold 101 and the pneumatic manifold 102, and the corresponding adjacent fluidic and air cavities. In the inlet chamber (inlet valve) 110a and the outlet chamber (outlet valve)110c, the flexible membrane 108 covers the inlet channel 103 and the outlet channel 104, respectively. In the pumping chamber 105, flexible membrane 108 separates the transported fluid from air. The flexible membrane 108 may be manufactured from any flexible material, such as hyperelastic films, nanometer thin metals, oxide films, or any other material capable of bi-directional deflection. It is noted that the flexible membrane 108 must be thin enough to minimize the pressure required to deflect it, but still thick enough to avoid the diffusion of air through it. In some embodiments, the flexible membrane 108 may be semi-permeable to allow removal of air bubbles traveling from the inlet by applying vacuum by pressure controllers, or partially semi-permeable so that only one of the three chambers 110 is used for air bubble removal. E.g., extracting gasses, via a semi-permeable membrane used in at least one fluid-filled chamber, of a plurality of fluid-filled chambers, from a transported fluid by applying a pressure difference across the semi-permeable membrane. In the inlet chamber 110a or outlet chamber 110c, the flexible membrane 108 is deflected by decreasing air pressure. Such a deflection opens the inlet channel 103 (or outlet channel 104) so that the fluid can be transported. The fluid transport is conducted by the deflection of the flexible membrane 108 in the pumping chamber 105.

[0041] FIGS. 2A and 2B separately depict the three components of the fluidic manifold 101. Specifically, FIG. 2A illustrates a fluidic part of the manifold assembly 100 of FIG. 1 and depicts an inlet opening 203 (i.e. an opening of the inlet channel 103 shown in FIG.1 ), an outlet opening 204 (i.e. an opening of the outlet channel 104 shown in FIG. 1 ), a fluidic half 205a of the pumping chamber 105 (shown in FIG. 1 ), openings 207 of the fluidic channel 107 (herein referred to as “fluidic channel openings 207”), and circular indentations 209a for a membrane pre-stretching (locking) mechanism. In the current embodiment, the inlet opening 203 and outlet opening 204 are circular, and the fluidic channel openings 207 are oval. These shapes, however, are exemplary. Other shapes may be used, generally subject to optimization (such as oval inlet and outlet, and circular fluidic channels).

[0042] The fluidic half 205a of the pumping chamber 105 has circular or oval cross sections in the XZ plane (e.g., prolate spheroid) to accommodate and fit a deflected flexible membrane 108, and the energy to fully deflect the flexible membrane 108 is minimized. While generally any shape of the pumping chamber 105 may be used, pumping chambers with sharp corners are typically considered to be inferior to circular and oval shapes due the difficulty of fitting the deflecting flexible membrane 108 to the chamber walls, aimed at achieving full contact of the flexible membrane 108 and the wall with minimum required energy.

[0043] FIG. 2B illustrates the pneumatic manifold 102 of manifold assembly 100 depicted in FIG. 1 and depicts the inlet chamber 110a, the outlet chamber 110c, an airfilled half 205b of the pumping chamber 105, openings 206 to the channels that connectchambers 110a, 110b, 110c (shown in FIG. 1 ) with dedicated air pressure controllers, and circular protrusions 209b for the membrane pre-stretching (locking) mechanism. The circular shape of the protrusions 209b, as well as the indentations 209a shown in FIG. 2A, is chosen to match the shapes of their corresponding chambers. While the shape is depicted as circular, they are the subject of optimization and, thus, may be any suitable shape. It is noted that the necessary condition for the protrusion shape is to match the indentations.

[0044] FIGS. 3A and 3B illustrate two-dimensional projections of the fluidic manifold 101 and pneumatic manifold 102, respectively, of FIG. 1. The projections are shown in XZ and XY planes (see FIG. 2A, 2B for three-dimensional orientation). The XZ plane projection is in the direction from the flexible membrane 108 to the respective manifold, and the XY plane projection is along the symmetry plane.

[0045] FIG. 3A illustrates the fluidic manifold 101 of FIG. 1 and depicts, in both the XY plane and the XZ plane, the inlet channel 103, the outlet channel 104, the fluidic half 205a of the pumping chamber 105, the circular indentations 209a for the membrane pre-stretching (locking) mechanism, the fluidic channel openings 207 on the XZ plane, and the fluidic channels 107 on the XY plane. The XY projection also depicts the flexible membrane 108.

[0046] FIG. 3B illustrates the pneumatic manifold 102 of FIG. 1 and depicts the inlet chamber 110a (along with the channel connecting the inlet chamber 110a with a dedicated pressure controller), the outlet chamber 110c (with its own channel connecting the outlet chamber 110c with another pressure controller), the air-filled half205b of the pumping chamber 105 (with a channel connector), and circular protrusions 209b for the membrane pre-stretching (locking) mechanism. In some embodiments, such as that depicted, the protrusions 209b are located on the pressure controller portion of the manifold assembly 100, and the indentations 209a, on the fluidic portion. This, however, may also be reversed so that the fluidic portion of the manifold assembly 100 has protrusions 209b, and the pressure controller portion has indentations 209a.

[0047] FIG. 3C shows the flexible membrane 108 (of FIGS. 1 and 3A) along both the XZ and XY planes having a thickness t. The flexible membrane 108 may be a thin membrane with a thickness (Y dimension) being much smaller than a width (X dimension) and a depth (Z dimension). The thickness of the flexible membrane 108 may be uniform or may have varying thickness due to the fabrication process or additional deposited layers, aimed at matching the fluidic and pressure controller channel openings and minimizing the membrane deflection into these openings. While the flexible membrane 108 is shown as rectangular, it may have any suitable shape; the necessary condition for its shape is to be able to cover all three circular indentations 209a and protrusions 209b that encircle the inlet chamber 110a, outlet chamber 110c, and pumping chamber 105.

[0048] FIG. 4 illustrates a planar view of the manifold assembly 100 of FIG. 1 , projected on the XZ and XY planes. For the XZ plane view, shown in the -Y direction, the left concentric circles show, in the order of reducing diameter, the locking mechanism 115(two dashed circles), the inlet chamber 110a (one dashed circle), and inlet channel(solid circle). The right concentric circles show, in the order of reducing diameter, thelocking mechanism 115 (two dashed circles), the outlet chamber 110c (one dashed circle), and the air channel (solid circle). The central concentric circles show the locking mechanism 115 (two dashed circles) and the pumping chamber 105 (one dashed circle). Dashed ovals and the rectangle show the fluidic channel(s) 107.

[0049] The XY plane view is shown along the symmetry plane (i.e. cutting the manifold assembly 100 in half along that plane). Here, the fluidic manifold 101 is above the flexible membrane 108, and the pneumatic manifold 102 is below the flexible membrane 108. The XY plane view further depicts the inlet chamber 110a and the outlet chamber 110c, both filled with air, and the pumping chamber 105 filled with transported fluid above the flexible membrane 108, and with air below the flexible membrane 108.

[0050] FIG. 4 further illustrates onboard air pressure controllers 106 (shown in Fig. 5 and explained below) of the manifold assembly 100 as well as fluidic channels 107.

[0051] There are three independently operated pressure controllers 106, which control pressure in the inlet chamber 110a, pumping chamber 105, and outlet chamber 110c. The pressure controllers 106 are placed sufficiently close to their respective chambers (i.e., the inlet chamber 110a, pumping chamber 105, and outlet chamber 110c) in order to minimize the volume that needs to be pressurized or depressurized. As explained next, decreasing and increasing pressure in each chamber (inlet chamber 110a, pumping chamber 105, and outlet chamber 110c) moves the flexible membrane 108 in the corresponding chamber in the downward and upward direction, respectively. In its neutral (horizontal) position, the flexible membrane 108 closes the inlet chamber 110a and the outlet chamber 110c. When the flexible membrane 108 moves downward in theinlet (outlet) chamber 110a (110c) due to lower-than-atmospheric pressure in that chamber, the inlet chamber 110a (outlet chamber 110c) opens. To close the inlet chamber 110a (outlet chamber 110c), the corresponding pressure controller 106 increases air pressure in the chamber, and the flexible membrane 108 moves back up to its neutral position. Alternatively, the corresponding pressure controller can be turned off to allow the membrane to relax back to its natural position. When the flexible membrane 108 moves downward in the pumping chamber 105, it lets the transported fluid from the inlet chamber 110a, which must be open at that time, into the pumping chamber 105. The outlet chamber 110c must be closed at that time to prevent backflow. When the flexible membrane 108 in the pumping chamber 105 moves upward, the pumping chamber 105 is closed to prevent backflow.

[0052] The fluidic channels 107 connect the inlet chamber 110a with the pumping chamber 105 and connect the pumping chamber 105 with the outlet chamber 110c. The cross section of the fluidic channels 107 in the direction perpendicular to the XY plane is oval in the presented embodiment, as schematically shown on XZ plane of FIG. 4. In other embodiments, however, the fluidic channels 107 may have a circular or other shaped cross-section such as rectangular, selected from the fluid dynamics and manufacturing considerations and optimization. In preferred embodiments, the area of the fluidic channels 107 is small enough, and the fluidic channels 107 are placed off the edges of the inlet chamber 110a, pumping chamber 105, and outlet chamber 110c, to avoid the formation of air bubbles. In the present embodiment, the fluidic channel 107 from the inlet chamber 110a to the pumping chamber 105 is centered on the symmetryaxis (Y direction) of the pumping chamber 105 (i.e. , it is placed in such a manner that the transported fluid enters the pumping chamber 105 from the center (the top edge of the pumping chamber 105 as it is plotted on the embodiment shown in FIG. 4, XY plane). The actual location of the fluidic channel 107 is subject of design optimization, as outlined below.

[0053] Dedicated pressure controllers 106 that deflect the flexible membrane 108 ideally should be bidirectional to be able to deflect the flexible membrane 108 in the upward and downward directions, and sufficiently small to be able to fit onboard and separately control each of the three chambers (inlet chamber 110a, pumping chamber 105, and outlet chamber 110c). An example of such a small pressure controller is a thermal diffusion gas pump, disclosed in U.S. Patent No. 11 ,885,320 (A. Gimelshein, E. Moskovets, and P. Garbuz, Apparatus and method of operating a gas pump), herein incorporated by reference. Having unidirectional pressure controllers is possible, but will increase the time necessary to relax the membrane back to its natural position. An integrated pressure controller 106a based on thermal diffusion is illustrated in FIG. 5, which represents a zoomed-in view of the dashed oval (integrated pressure controller 106a) of FIG. 4. Here, the integrated pressure controller 106a is a thermal diffusion gas compressor, which has air intake 112, and air outlet 113 which feeds directly into inlet chamber 110a. The direction of the air flow, shown with arrows associated with the air intake 112 and air outlet 113, may be switched from the upward to the downward direction by switching the polarity of the electric current that powers the thermal diffusion gas compressor (i.e., integrated pressure controller 106a).

[0054] In the embodiment presented in FIG. 4, the fluidic channel 107 is manufactured in a way that the inlet chamber 110a and outlet chamber 110c are fluidically connected directly through the fluidic channel 107. It may simplify the manufacturing process and will not create backflow because, as discussed in more detailed below, there is no time when the inlet chamber 110a and outlet chamber 110c are open at the same time. It is also possible to separate the inlet chamber 110a -to- pumping chamber 105 and the pumping chamber 105 -to- outlet chamber 110c fluidic channels. An embodiment in which these channels are separate, and the inlet chamber 110a and the outlet chamber 110c are fluidically connected through the pumping chamber 105, is illustrated in FIG. 6.

[0055] As depicted in FIG. 6, fluidic channels 107 are separated, and the inlet chamber 110a and the outlet chamber 110c are fluidically connected through the pumping chamber 105. The actual location of the fluidic channels 107, however, is a subject of design optimization.

[0056] A feature of the current embodiment is the locking mechanisms 115 (depicted in FIG. 4), which prevent leaks of the transported fluid from the inlet chamber 110a, outlet chamber 110c, and pumping chamber 105. Although robust leak prevention may be achieved by other means such as chemical bonding of the flexible membrane 108 or using volcano valves for the inlet chamber 110a and the outlet chamber 110c, fluid leak prevention in the presented embodiment is achieved by the pre-stretching and locking of the flexible membrane 108 using a circular protrusion-indentation pattern. Such a locking mechanism 115 is illustrated in FIG. 7, which represents a zoomed-in view of the dashed circle (locking mechanism 115) of the XY view of FIG. 4. The protrusion 209b inthe pressure controller manifold stretches out the flexible membrane 108, and the fluidic manifold 101 locks it, thus sealing the corresponding fluidic chamber. If necessary, the protrusion 209b - indentation 209a configuration of the locking mechanism 115 on the respective pressure controller 106 and fluidic manifold 101 may be inverted into the indentation 209a - protrusion 209b configuration.

[0057] FIG. 8 is a schematic illustration of the pumping chamber 105 (the fluidic channel and the pressure controller channel and their entrances into the pumping chamber are not shown for better clarity). The shape and operation of the pumping chamber 105 determine the accuracy and efficiency of the entire microfluidic peristaltic pump. In the pumping chamber 105, the flexible membrane 108 may be deflected in the upward and downward directions by a dedicated pressure controller, which respectively increases and decreases air pressure in the adjacent air channel and the air pocket below the flexible membrane 108. The upward or downward deflection of the flexible membrane 108 pushes out or pulls in the transported fluid through the connected fluidic channels. For the fluid delivery to be digitally accurate, the flexible membrane 108 needs to move all the way up and all the way down, to attain full contact with the wall of the pumping chamber 105. The shape of the pumping chamber 105 in the XZ plane is circular or oval, and in the XY plane is close to a spherical cap. The actual shape of the pumping chamber 105 is the subject of design optimization as outlined below, and the initial shape to be optimized may be a spherical or oval cap. The optimum shape is selected from the energy efficiency and delivery accuracy considerations and there is full contact of the deflected flexible membrane 108 with the wall of the pumping chamber towardwhich the flexible membrane 108 is deflected, achieved by a minimum possible pressure difference between the fluid and the air in the pumping chamber 105. The optimum energy efficiency is achieved not only by properly selecting the shape of the wall to fit the flexible membrane 108 deflection, but also by making the heights of the air-filled half of the pressure chamber, / ?i , and of the fluid-filled half of the pumping chamber 105, h2, much smaller than the chamber diameter d. Highly non-linear dependence of the magnitude of the flexible membrane 108 deflection on the pressure difference between the air and the transported fluid promotes small hdd and hdd ratios to minimize the energy that needs to be spent to deflect the flexible membrane 108. hi in general case does not need to be the same as h2. For any combination of / ?i and h , the volume of fluid delivered in a single peristaltic cycle, is equal to the sum of the volume fluid chamber and the volume of the air chamber. The lowest possible value of / ?i is 0. In this case, the volume of the liquid delivered in a single peristaltic cycle is the volume of the air chamber. The lowest possible value of h2 is also 0. In this case, the volume of the liquid delivered in a single peristaltic cycle is the volume of the fluid chamber. The values of hi and h can not be 0 at the same time. The total volume of the pumping chamber 105 swept by the flexible membrane 108, i.e. the sum of the fluid and air chamber volumes, must be selected to match the required single dose of the pump. The thickness t of the flexible membrane 108 also needs to be much smaller than d to minimize the pressure difference between the pressure-modulated air and the transported fluid in the inlet chamber 110a, outlet chamber 110c, and pumping chamber105, necessary to deflect the flexible membrane 108.

[0058] The flexible membrane 108 deflection in these chambers (i.e., inlet chamber110a, outlet chamber 110c, and pumping chamber 105) is conducted in a special peristaltic sequence, organized to prevent the backflow of the transported fluid, and move it from the inlet to the outlet in discrete doses, with the volume of each dose equal to the volume that flexible membrane 108 sweeps from the fully-down to the fully-up position in the pumping chamber 105 as part of the peristaltic motion. One possible peristaltic sequence of flexible membrane 108 deflections is illustrated schematically in FIG. 9. Locking mechanisms are omitted here for clarity; more detail may be found in FIG. 4, XY plane.

[0059] In FIG. 9, the fluidic manifold 101 is above the flexible membrane 108, and the pneumatic manifold 102 is below the flexible membrane 108, which shows a method of peristaltic pumping using gas or liquid to activate a membrane using the fluidic pump, the method includes a repeatable sequence of actions. Position 9a is the initial, fully neutral horizontal position of the flexible membrane 108. In position 9b, a negative pressure is applied by the inlet pressure controller 106 to the air adjacent to the flexible membrane 108 at the inlet channel 103; the result is the deflection of the flexible membrane 108 downward, which opens the inlet channel 103 (and, thus, inlet chamber 110a). The downward dashed arrow indicates the movement of the fluid that follows the flexible membrane 108 deflection. The next position, 9c, shows the downward deflection of the flexible membrane 108 in the pumping chamber 105 caused by reducing the air pressure below the flexible membrane 108 by the corresponding pressure controller 106. This causes the fluid to move from the inlet channel 103 to the pumping chamber105, as shown by arrow. Then, the inlet channel 103 (inlet chamber 110a) closes, in position 9d, and the outlet channel 104 (outlet chamber 110c) opens, in position 9e, again through pressure modulation by the corresponding pressure controllers 106. In position 9f, the air pressure below the flexible membrane 108 in the pumping chamber 105 increases above ambient, and the flexible membrane 108 moves upward, displacing the fluid from the pumping chamber 105 to the outlet channel 104 (outlet chamber 110c). Then the outlet channel 104 (outlet chamber 110c) closes, in position 9g, and the inlet channel 103 (inlet chamber 110a) opens again, 9h. Position 9h concludes the peristaltic loop, and the next loop starts from 9b. Positions 9b-9h deliver a single dose of the transported fluid and are repeated as necessary. The peristaltic operation and motion described here may be adjusted, including inverse optimization adjustments to match the desired temporal profile of the flow rate of the transported fluid.

[0060] The embodiments of a peristaltic microfluidic pump previously described (and depicted) represent a three-chamber configuration (i.e., one inlet chamber 110a, one pumping chamber 105, and one outlet chamber 110c), which is the minimum number of chambers necessary to maintain peristaltic action. Other embodiments may also be used that employ more than one inlet chamber, pumping chamber, and outlet chamber. Examples of such embodiments are shown in FIG. 10, in which the minimum, three- chamber configuration 10a presented earlier is shown side-by-side with other configurations. Configuration 10b, with two pumping chambers, describes a microfluidic peristaltic pump which offers two different, and discrete, doses, in a single peristalticsequence. Configuration 10c, with two inlets, describes a pump that is configured to transport two distinct fluids. Note that more than two inlets, outlets, and pumping chambers, may also be used.Optimization Strategies

[0061] The geometry of the disclosed manifold assembly 100 can be adjusted and finetuned using numerical and / or analytical means and is generally the subject of optimization. The optimization may proceed through iterations and can be represented in the following algorithm:Model Evolution AlgorithmSet C # model constraintsSet P # set of search parametersSet M # initial approximation of the embodimentDo While performance criteria K are not metDo While numerical solution accuracy A is not reachedRun analytical model and / or multiphysics solver using C to obtain S End DoUpdate M using S and PEnd Do

[0062] The optimization should be based on key geometric and flow parameters P, such as the dimensions of structural components such as chambers and channels, flexible membrane materials, pressure controller properties, gas and fluid properties, etc. It may be bound by a set of constraints C such as the preferred operating pressure, gas, fluid, input power, costs of materials and process, etc. The constraints may also include the desired single dose, average flow rate, flow rate as a function of time, and compression ratios. The optimization process must target the end-of-optimization criteria K. The two primary optimization criteria K are the energy required to perform a single peristaltic cycle which needs to be minimized (the energy spent on membrane deflections, and onkeeping the inlet and the outlet closed when necessary) and the accuracy and precision of a single-dose delivery which needs to accommodate acceptable error bars (close fitting of the deflected membrane to the walls of the pumping chamber). The other optimization criteria may include (i) timing sequence optimization which includes the increase and decrease of pressure in the pumping chamber as a function of time, aimed at achieving a desired time dependence of the flow rate of the transported fluid, (ii) fluid and air path minimization, (iii) leak prevention, (iv) bubble avoidance and possible removal, (v) material lifetimes and additional parts such as inline filters to filter outside air coming to pressure controllers to maximize the lifetime of the pump, (vi) environmental factors and calibration to changes in temperature, pressure, and humidity of the surrounding air, and other criteria. The optimization may also benefit from various modifications to the membrane, such as varying membrane thickness, caulking, hydrophobic and / or porous membrane for air bubble removal from the transported fluid by applying a negative pressure, etc. It may also consider multiple inlets, outlets, and pumping chambers, which may include multiplexes for multiple fluid and / or multiple dose delivery, and factor in aspects of biocompatibility if necessary. Finally, an additional layer of optimization should include fabrication and usage costs, which may account for standard semiconductor materials and processes, 3D printing, etc. The optimization should start with an initial approximation of the apparatus model M, which may be the examples of a three chamber of four chamber embodiments shown above. After that, the main loop is run until the optimum configuration M is found that satisfies the criteriaK. In that loop, the model M is adjusted using the search parameters P and the output from the performance-evaluating solution block. The latter one may be represented as a“do” loop that runs until some prescribed numerical accuracy is reached and may include stand-alone or unified solvers for the gas flow inside the apparatus and the heat flow inside the solid blocks of the device. While simple analytical estimates are possible for these solver steps, the best accuracy of numerical solution would be provided by multiphysics gas solvers based on finite volume and finite element approaches which include moving boundaries / meshes to account for membrane deflections. The optimization process may also include inverse optimization, with peristaltic sequence and timings adjusted based on the desired profile of the flow rate of the transported fluid. The computational optimization process may be assisted and amended by experimental means.

[0063] Techniques consistent with the present disclosure provide, among other features, microfluidic pumps and methods of delivering accurate dosage with such pumps. While various exemplary embodiments of the disclosed systems, devices, and methods have been described above it should be understood that they have been presented for purposes of example only, not limitations. It is not exhaustive and does not limit the disclosure to the precise form disclosed. Modifications and variations are possible in light of the above teachings or can be acquired from practicing of the disclosure, without departing from the breadth or scope.

Claims

WHAT IS CLAIMED IS:

1. Afluidic pump comprising: a plurality of fluid-filled chambers, wherein each fluid-filled chamber of the plurality of fluid-filled chambers is separated into two parts by a flexible membrane, and fluid pumping is conducted through a peristaltic motion of said flexible membrane; at least one fluidic path that crosses the plurality of fluid-filled chambers; a plurality of dedicated pressure controllers configured to deflect the flexible membrane from a side opposite of the at least one fluidic path; and means to provide an electric current to the plurality of dedicated pressure controllers, wherein at least one fluid-filled chamber, of the plurality of fluid-filled chambers, (i) pumps fluid by the flexible membrane deflected by a respective dedicated pressure controller, and (ii) has a profile matching a deflection of the flexible membrane.

2. Afluidic pump according to claim 1 , wherein the plurality of dedicated pressure controllers includes one dedicated pressure controller for each fluid-filled chamber of the plurality of fluid-filled chambers.

3. Afluidic pump according to claim 1 , wherein one or more dedicated pressure controllers, of the plurality of dedicated pressure controllers, are bi-directional.

4. A fluidic pump according to claim 1 , wherein at least one fluid-filled chamber, of the plurality of fluid-filled chambers, has (i) an inlet valve operated by the flexible membrane, and (ii) a dedicated pressure controller.

5. A fluidic pump according to claim 1 , wherein at least one fluid-filled chamber, of the plurality of fluid-filled chambers, has (i) an outlet valve operated by the flexible membrane, and (ii) a dedicated pressure controller.

6. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes at least one inlet chamber.

7. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes at least one outlet chamber.

8. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes at least one fluid pumping chamber.

9. A fluidic pump according to claim 1 , wherein the flexible membrane is prestretched at an inlet and an outlet.

10. A fluidic pump according to claim 1 , wherein the flexible membrane is comprised of a hyperelastic material.11 . A fluidic pump according to claim 1 , wherein the flexible membrane is comprised of a material amenable to stretching.

12. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes an inlet chamber and a pumping chamber that are connected through narrow channels.

13. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes an outlet chamber and a pumping chamber that are connected through narrow channels.

14. A fluidic pump according to claim 1 , wherein the plurality of fluid-filled chambers includes an inlet chamber and an outlet chamber that include leak-preventing circular locks.

15. A method of accurate fluidic delivery in a peristaltic microfluidic pump, comprising: fabricating at least one pumping chamber of a fluidic peristaltic pump having a profile that matches a deflection of a flexible membrane.

16. A method of peristaltic pumping using gas or liquid to activate a membrane using the fluidic pump of claim 1 , said method includes a repeatable sequence of actions comprising:deflecting the flexible membrane of an inlet chamber, of the plurality of fluid-filled chambers, thereby opening an inlet; deflecting the flexible membrane of a pumping chamber, of the plurality of fluid- filled chambers, to fill the pumping chamber with a fluid to be pumped; deflecting the flexible membrane of the inlet chamber in an opposite direction, thereby closing the inlet; deflecting the flexible membrane of an outlet chamber, of the plurality of fluid- filled chambers, thereby opening an outlet; deflecting the flexible membrane of the pumping chamber, thereby transferring the fluid into the outlet; and deflecting the flexible membrane of the outlet chamber, thereby closing the outlet.

17. A method of reducing gas bubbles in a peristaltic microfluidic pump, comprising: extracting gasses, via a semi-permeable membrane used in at least one fluid- filled chamber, of a plurality of fluid-filled chambers, from a transported fluid by applying a pressure difference across the semi-permeable membrane.

18. A method of preventing flow leaks in a peristaltic microfluidic pump, comprising: stretching and compressing a flexible membrane including circular protrusions and indentations around fluid filled chambers.

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