Feedback Controlled Syringe Pump

Abstract

Provided is an automated syringe pump that includes a syringe plunger controller and an elastic member, such as a spring, positioned between a rigid member and a syringe plunger retainer. The controller may include a transducer, such as a linear potentiometer, for generating a signal representative of force applied to a syringe plunger present in the syringe plunger retainer. In addition, the controller may include a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on the syringe plunger and constant flow rate of fluid out of a syringe operated by the automated syringe pump. Also provided are methods, systems and kits using the automated syringe pumps.

Description

CROSS-REFERENCE TO RELATED APPLICATION

Pursuant to 35 U.S.C. §119(e), this application claims priority to the filing date of U.S. Provisional Patent Application Ser. No. 61/250,155, filed Oct. 9, 2009, which application is incorporated herein by reference in its entirety.

INTRODUCTION

Automated syringe pumps are used throughout research institutions, medical facilities, and industry for infusion and withdrawal of a wide variety of fluids at flow rates ranging from nL/hr to mL/sec, a range of more than nine orders of magnitude. A variety of automated syringe pumps have been developed, including those described in U.S. Pat. Nos. 7,361,157; 7,311,879; 7,135,290; 6,932,242; 5,896,804; 5,295,967; 5,242,408; 5,219,099; 5,176,646 and 5,176,502.

Traditional approaches to automated syringe pump design have focused on reduction or elimination of dynamic behavior. Specifically, dynamic behavior in the syringe is either designed out by using high stiffness materials (e.g. glass, stainless steel), or by operating syringes in steady-state configurations only (e.g. as in medical applications for drug delivery).

However, these dynamic effects, while negligible in traditional syringe pump applications, become more significant in microfluidic applications where compliant syringes are used to drive dynamic operation of high resistance flows. Microfluidics, fluidic systems where the pipe dimensions are on the order of microns, gives rise to additional syringe pump requirements. The small channel dimensions of the microfluidic channels require high pressures to develop small fluid flows. Therefore, when a traditional syringe pump is used to drive a microfluidic chip with a disposable polymeric syringe, the dynamics of the system become dominant, as the barrel of the syringe expands, acting as a fluidic capacitor.

SUMMARY

The present invention provides a unique solution to problems currently encountered in the automated syringe pump art. Contrary to the prevalent approach of the art to eliminate all possible dynamic behavior, the present invention incorporates a dynamic behavior, e.g., in the form of an elastic member, such as a spring, into the syringe pump controller of an automated syringe pump. By intentionally incorporating this dynamic behavior of known quantity into the system and then providing a feedback control loop around this element, the invention achieved unprecedented ability to control pressure in the syringe and/or flow of fluid out of the syringe. Embodiments of the invention provide these advantages without the use of wetted components and/or with inexpensive off the shelf components.

Aspects of the invention include an automated syringe pump that includes a syringe plunger controller and an elastic member, such as a spring, positioned between a rigid member and a syringe plunger retainer. The controller may include a transducer, such as a linear potentiometer, for generating a signal representative of force applied to a syringe plunger present in the syringe plunger retainer. In addition, the controller may include a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on the syringe plunger and constant flow rate of fluid out of a syringe operated by the automated syringe pump. Also provided are methods, systems and kits using the automated syringe pumps.

Accordingly, automated syringe pumps are provided that include a syringe plunger controller configured to move a syringe plunger relative to a syringe barrel, where the syringe plunger controller includes an elastic member positioned between a rigid member and a plunger retainer.

In certain embodiments, the elastic member includes a spring, such as a compression spring and a tension spring. In some cases, the rigid member includes a slide, where in particular instances the slide is operatively coupled to a motor.

In some embodiments, the plunger controller further includes a transducer for generating a signal representative of force applied to a plunger present in the plunger retainer. The transducer may be a position sensor, such as a linear potentiometer, coupled to the plunger retainer and the rigid member. In particular cases, the controller further includes a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on a plunger and constant flow rate of fluid out of a syringe operated by the automated syringe pump.

In additional embodiments of the present disclosure, an automated syringe pump is provided that includes: (a) a syringe holder; (b) a syringe plunger retainer; and (c) a syringe plunger controller configured to move a syringe plunger held in the syringe plunger retainer relative to a syringe barrel held in the syringe holder. In these embodiments, the syringe plunger controller includes: (i) an elastic component; and (ii) a proportional-integral-derivative (PID) controller, where the elastic component and the PID controller together provide for at least one of constant pressure on a plunger and constant flow rate of fluid out of a syringe held in the syringe holder.

In some cases, the plunger controller includes a motor and slide and the elastic component may include a compression spring and a tension spring. In certain instances, the compression spring and tension spring are coaxial. In addition, in particular embodiments, the controller includes a transducer for generating an electrical signal representative of force applied to the syringe plunger held in the syringe plunger retainer. The transducer may be a linear potentiometer.

Other aspects of the current disclosure include a method of forcing fluid out of a fluid loaded syringe using an automated syringe pump of the present disclosure.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic of a feedback controlled syringe pump of the present disclosure.

FIG. 2 shows a schematic of the syringe and the flow conditions.

FIG. 3 shows a schematic of a fluidic circuit of a single compliant syringe in a syringe pump of the present disclosure.

FIG. 4 shows a graph of characteristic depressurization time constants for four syringes when connected to one meter long capillaries with diameters between 10 and 250 microns.

FIG. 5 shows a schematic of the syringe system model.

FIG. 6 shows a graph of the percent deflection observed in the plunger and barrel for 1 mL, 3 mL, 5 mL, and 10 mL plastic syringes.

FIG. 7, top, shows a graph of the velocity calibration performed for infusion and withdrawal of pump #0 while unloaded and loaded with 45 N. FIG. 7, bottom, shows a graph of the velocity calibration curve fit from all data points for pump #0.

FIG. 8, top, shows a graph of the velocity calibration performed for infusion and withdrawal of pump #1 while unloaded and loaded with 45 N. FIG. 8, bottom, shows a graph of the velocity Calibration curve fit from all data points for pump #1

FIG. 9 shows a graph of dynamic responses to a step change in input for syringe pump #1. The average time constant was 9.5 ms.

FIG. 10 shows a graph of the real time response of a pressure controlled syringe pump of the present disclosure.

FIG. 11 shows a graph of the first calibration using a syringe pump of the present disclosure.

FIG. 12 shows a graph of the second calibration using a syringe pump of the present disclosure with the linear positioner secured with glue.

FIG. 13 shows a graph of the third calibration using a syringe pump of the present disclosure with an alternative excitation voltage (HP DC Power Supply V_sup=20V).

FIG. 14 shows a graph of the final calibration using a syringe pump of the present disclosure with the sensor lubricated, reassembled and linear potentiometer secured with cyanoacrylate gel.

FIG. 15 shows a graph of the final force calibration line fit. Data points in the range of 15 N to 100 N or 1.5 V to 5.5 V are shown.

FIG. 16 shows a graph of average actuation flow rate, actual flow rate, and measured pressure versus time. The graph shows a response time of about 38 seconds.

FIG. 17 shows a graph of pressure step response times. Response times were between 2 and 18 seconds for an increasing pressure step and between 2 and 8 seconds for a stopping step.

FIG. 18 shows a pressure calibration verification chart. Predicted pressure values were within 5-8% using standard values and without calibration or correction for syringe friction.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As used herein, the following terms have the following meanings unless otherwise indicated.

As used herein, the terms “commercial, off-the-shelf” or “COTS” refer to products that are ready-made and available for sale, lease, or license to the general public.

As used herein, the terms “proportional-integral-derivative controller” or “PID controller” refer to a control loop feedback mechanism used in control systems. A PID controller attempts to correct the error between a measured process variable and a desired setpoint by calculating and then outputting a corrective action that can adjust the process accordingly. The Proportional value determines the reaction to the current error, the Integral value determines the reaction based on the sum of recent errors, and the Derivative value determines the reaction to the rate at which the error has been changing. The weighted sum of these three actions is used to adjust the process via a control element.

The terms “operatively connected”, “operatively linked” and “operatively coupled”, as used herein, are used interchangeably and mean that the elements are connected to each other either directly or indirectly.

The terms “optional” or “optionally” as used herein mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Aspects of the invention include an automated syringe pump that includes a syringe plunger controller and an elastic member, such as a spring, positioned between a rigid member and a syringe plunger retainer. The controller may include a transducer, such as a linear potentiometer, for generating a signal representative of force applied to a syringe plunger present in the syringe plunger retainer. In addition, the controller may include a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on the syringe plunger and constant flow rate of fluid out of a syringe operated by the automated syringe pump. Also provided are methods, systems and kits using the automated syringe pumps.

Below, the subject automated syringe pumps are described first in greater detail, followed by a review of the various methods in which that the automated syringe pumps may find use, as well as a discussion of various representative applications in which the subject automated syringe pumps and methods find use.

Feedback Controlled Syringe Pumps

Provided are feedback controlled syringe pumps for control of applied pressure or volumetric flow. Enhanced volumetric control facilitates faster, more reliable dynamic control for micro-fluidic applications, especially for improving the dynamic response of microfluidic systems where polymeric syringes and high resistance flows are driven with commercial off-the-shelf (COTS) syringe pumps. In certain embodiments, the disclosed syringe pumps are configured to measure the flow as well as pressure without wetted components.

As summarized above, syringe pumps of the invention deviate from the conventional wisdom in the art by including a known, predetermined dynamic behavior into the syringe pump controller and then building a feedback control loop around this known, predetermined dynamic behavior. In certain embodiments, the known, predetermined amount of dynamic behavior is provided by the presence of an elastic member positioned between a rigid member of the syringe pump controller and the syringe. In certain embodiments, the elastic member is a spring element, e.g., an element made up of one or more springs, such as helical springs. Of interest in certain embodiments is an elastic member made up of both a compression spring and a tension spring, e.g., where these springs are coaxially aligned. In embodiments where the elastic member comprises a compression spring and a tension spring, the combined spring rate of the springs may vary, ranging from 20 lb/in to 80 lb/in, such as 30 lb/in to 70 lb/in and including 40 lb/in to 60 lb/in, with a force range of −15 lbs to 35 lbs, such as −10 lbs to 30 lbs, including -5 lbs to 25 lbs. In particular embodiments, the combined spring rate of the springs is 48.2 lb/in with a force range of −5 lbs to 25 lbs.

Automated syringe pumps of the invention may be configured to operate syringes of a variety of different sizes, including microfluidic syringes. Embodiments of the syringe pumps are configured to operate syringes ranging in size from 0.3 mL to 1 L, such as 0.5 mL to 250 mL and including 1 mL to 100 mL. Microfluidic syringes are syringes that range in size from 0.5 μL to 1 mL, such as 2.5 μL to 500 μL, and including 5 μL to 250 μL.

An exemplary feedback controlled syringe pump of the present disclosure is depicted in FIG. 1. Aspects of the syringe pump 100 depicted in FIG. 1 include a motor, a transducer and an elastic member. The motor may be any type of motor known to one of skill in the art, such as but not limited to a linear stepper motor 110 with a linear actuator, linear screw drive actuator, and the like. In certain embodiments, the transducer is a position sensor, such as but not limited to a linear potentiometer 115. The linear position sensor detects the displacement and thus enables an estimate of the pressure within the syringe from the applied force.

In some cases, the elastic member includes one or more springs, such as a compression spring 117 and a tension spring 119. In particular instances, the compression spring 117 and the tension spring 119 are coaxial. In certain embodiments, the elastic member is positioned between the rigid member and the plunger retainer 120. In some cases, this provides a constant amount of system compliance which enhances pressure to position sensitivity. In particular embodiments, the syringe pump also includes a zero point adjustment screw 125, which is configured to provide for adjustment of the pressure zero point of the system.

Additional aspects of the syringe pump 100 depicted in FIG. 1 include a rigid member and mounting hardware for the syringe. In some cases, the rigid member is a slider 130, which may be operatively coupled to the motor, such that operation of the motor moves the slide linearly. In certain embodiments, the rigid member is guided along a linear path by precision rods 135, such that the rigid member slides along the precision rods. In some cases, the motor includes a screw 140 which engages the slide, such that operation of the motor turns the screw which causes the slide to move.

In some cases, the mounting hardware for the syringe includes a syringe plunger retainer 120 and a syringe barrel retainer 140. The syringe plunger retainer is configured to couple the syringe plunger, for example the end of the syringe plunger, to the elastic member. In some embodiments, the syringe pump further includes a guide 150 which is configured to align the plunger retainer with the elastic member. The syringe barrel retainer is configured to hold the syringe barrel in a fixed position relative to movement of the slide and the plunger retainer when the motor is engaged. Thus, operation of the motor moves the slide linearly. The movement of the slide is transmitted through the elastic member to the plunger retainer, causing the plunger retainer to move the syringe plunger present in the plunger retainer. Movement of the syringe plunger into the barrel of the syringe forces fluid out of the opposite end of the syringe 160.

In particular embodiments, the transducer (e.g. position sensor or linear potentiometer) is coupled to the plunger retainer and the rigid member. In certain embodiments, the transducer is coupled to the rigid member using an adhesive, such as but not limited to glue, adhesive, cyanoacrylate gel, and the like. In some cases, the transducer is configured to generate a signal representative of force applied to the syringe plunger present in the plunger retainer. The force applied to the rigid member (e.g. the slide) is transduced using the linear potentiometer and a known calibration for the compliance of the elastic member (i.e., the known spring constant of the springs). In particular cases, the spring facilitates application-to-application repeatability where the compliance of the syringe and the fluidic resistance of the system depend on the application. Thus, the spring when coupled with a linear potentiometer and Hooke's Law, will provide a measure of the force applied to the plunger of the syringe. Consequently, the syringe pump can be controlled to deliver a constant force/pressure or a constant velocity/flow rate by using a proportional-integral-derivative (PID) controller.

In certain embodiments, the transducer is a spring loaded linear potentiometer. In these embodiments, the spring loaded linear potentiometer includes a spring that has a spring constant ranging from 0.001 N/m to 10 N/m, such as from 0.01 N/m to 5 N/m, including from 0.1 N/m to 1 N/m. In other embodiments, the transducer is coupled to the plunger retainer by a threaded connection. In these embodiments, the threaded connection has a screw thread size ranging from #0-80 to #10-24, or larger. One of skill in the art will recognize that metric sized screw threads may also be used in embodiments where the transducer is coupled to the plunger retainer by a threaded connection.

In certain embodiments, the linear potentiometer has a total displacement ranging from about 0.1 in. to about 10 in., such as from about 0.1 in. to about 5 in., including from about 0.1 in. to about 1 in. In particular instances, the linear potentiometer has a total displacement of about 0.5 in.

In certain embodiments, the syringe pump is configured to deliver a force ranging from about 1 N to about 200 N, such as from about 5 N to about 150 N, including from about 15 N to about 100 N. In particular embodiments, the syringe pump is configured to respond quickly to step changes in input. For instance, in some cases, the syringe pump has a response time of about 60 seconds or less, such as about 40 seconds or less, including about 20 seconds or less, for example about 10 seconds or less, such as about 1 second or less, including about 0.5 seconds or less, for instance about 100 milliseconds or less, such as about 10 milliseconds or less.

In certain embodiments, the automated syringe pumps of the present disclosure also include one or more digital inputs and/or one or more digital outputs. The digital inputs and/or digital outputs can be used to trigger internal programming and provide analog-to-digital (A/D) as well as digital-to-analog (D/A) conversion for ease of integration into existing systems. In certain embodiments, the resolution of the A/D convertor is at least 10 bit, such as at least 16 bit, including at least 18 bit. In certain embodiments, the resolution of the D/A convertor is at least 10 bit, such as at least 16 bit, including at least 18 bit. In certain embodiments, the automated syringe pumps also include a capacitor, where the capacitor facilitates the reduction of high-frequency noise in the linear potentiometer.

In some cases, the syringe pumps also include a means for communicating with other devices, such as but not limited to a USB interface, a serial interface, and the like. In some cases, the automated syringe pumps further include a display for outputting data and/or results to a user in a human-readable format.

The following sections provide exemplary embodiments and additional disclosure allowing one of skill in the art to make and use the claimed invention. A detailed description of systems of the disclosure is provided. Methods for using the systems are also discussed.

Systems

Systems of the present disclosure include one or more feedback controlled syringe pumps described herein. For instance, systems of the present disclosure may include one, two, three, four, five, six, seven, eight, nine, ten, or more syringe pumps. In some cases, the syringe pumps may be operated in parallel, such that the mixing ratios of the syringes can be monitored and controlled individually. In certain embodiments, the one or more syringe pumps are controlled by a single syringe plunger controller. In other cases, each of the one or more syringe pumps is controlled by individual syringe plunger controllers.

In other exemplary embodiments, a syringe pump of the present disclosure may be configured to accept one or more syringes. For instance, the syringe pump may be configured to use one, two, three, four, five, six, seven, eight, nine, ten, or more syringes. In these embodiments, the syringe plunger retainer is configured to retain one or more syringe plungers, such as two, three, four, five, six, seven, eight, nine, ten, or more syringe plungers. Thus, in these embodiments, the syringe plunger retainer engaged the plungers of the one or more syringes in parallel. Similarly, in these embodiments, the syringe barrel retainer is configured to retain one or more corresponding syringe barrels, such as two, three, four, five, six, seven, eight, nine, ten, or more syringe barrels.

Methods

Provided are methods for forcing fluid out of a fluid loaded syringe. In certain embodiments, the method uses an automated syringe pump of the present disclosure. The method includes positioning a syringe loaded with said fluid into an automated syringe pump including a syringe plunger controller configured to move a syringe plunger of the syringe relative to a syringe barrel of the syringe, where the syringe plunger controller includes an elastic member positioned between a rigid member and a syringe plunger retainer. The method further includes causing the syringe plunger controller to move the syringe plunger relative to the syringe barrel to force fluid out of the syringe.

In some embodiments, the syringe plunger controller can further include a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on the syringe plunger and constant flow rate of fluid out of the syringe operated by the automated syringe pump.

In some cases, the elastic component includes a compression spring and a tension spring. In certain embodiments, the controller includes a transducer for generating an electrical signal representative of force applied to the syringe plunger held in the syringe plunger retainer. The transducer may, in particular embodiments, be a linear potentiometer.

Kits

Also provided are kits that find use in practicing the subject methods, as described above. For example, kits for practicing the subject methods may include one or more automated syringe pumps of the present disclosure. As such, in certain embodiments the kits may include one or more syringes for use in the presently disclosed syringe pumps. The syringes may be provided in separate pieces, such that the syringe barrel and the syringe plunger are assembled together by the user. In other embodiments, the syringes may be provided as pre-assembled syringes.

In addition to the above components, the subject kits may further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc. Another means would be a computer readable medium, e.g., diskette, CD, DVD, computer-readable memory, etc., on which the information has been recorded or stored. Yet another means that may be present is a website address which may be used via the Internet to access the information at a removed site. Any convenient means may be present in the kits.

Utility

As can be seen, the automated syringe pumps of the present disclosure find use in a variety of different applications where it is desirable to use an automated syringe pump that provides for at least one of constant pressure on a plunger and constant flow rate of fluid out of a syringe operated by the automated syringe pump. In certain embodiments, the methods are directed to automated syringe pumps that find use in applications such as, but not limited to laboratory applications (i.e., for syringe volumes less than about 200 mL), industrial applications (i.e., for syringe volumes of about 200 mL or greater), embedded applications for biotechnology, and medical infusion pumps (e.g. for delivering an active agent to a subject at a constant pressure or constant flow rate). The subject automated syringe pumps also find use in microfluidic applications, and the like.

As can be appreciated from the disclosure provided above, the present disclosure has a wide variety of applications. Accordingly, the following examples are offered for illustration purposes and are not intended to be construed as a limitation on the invention in any way. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Thus, the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

EXAMPLES

Materials and Methods

Fluid-Circuit Analogy

Complex fluidic systems can be analyzed in a simplified fashion by creating an analogy between a fluid flow network and an electrical network. Table 1 indicates the analogies between potential, current, resistance, capacitance, and inductance. The fluid-circuit analogy holds only for creeping flow systems, where the Reynolds number is less than unity. It is also a reasonable approximation in laminar flow systems where fluid momentum effects are negligible.

TABLE 1
Fluid-Circuit Analogy
Electrical
Property	Fluid Analog	Units	Notes
Voltage	Pressure, ΔP	F	Driving force
		L2
Current	Flow Rate, Q	L3	Volumetric flow rate of fluid
		T
Resistance	Fluidic	FT	Resistance to flow
	Resistance, Rf	L5
Capacitance	Fluidic	L5	Plastic expansion of tubing,
	Capacitance, Cf	F	syringes, or bladders
Inductance	Fluidic	—	Fluid momentum, not relevant for
	Inductance, Lf		creeping flow regimes where the
			fluid-circuit analogy holds.

Applying these concepts to Ohm's law, gives equation [1]:

ΔP=R_fQ  [1]

Fluidic Resistance

The fluidic resistance of a circular channel can be derived by using equation [1]. Based on a steady state solution of the Navier-Stokes Equations, the flow rate through a pipe with a circular cross section under laminar flow conditions is given by equation [2]:

$\begin{array}{cc}Q=\frac{\mathrm{\pi \Delta }Pa^4}{8\mu L}& \left[2\right]\end{array}$

Equation [2] can be rearranged to obtain an expression for fluidic resistance, R_f, as shown in equation [3]:

$\begin{array}{cc}{R}_f=\frac{8\mu L}{\pi a^4}& \left[3\right]\end{array}$

Fluidic Capacitance

In situations where a compliant syringe is coupled to a capillary with a high fluidic resistance, the syringe, when pressurized deforms laterally and longitudinally until the pressure in the syringe balances the output flow through the capillary. FIG. 2 shows a schematic of a single-compliant syringe with a large fluidic resistance, R_f, at the output.

Fluidic capacitance is defined by equation [4]:

$\begin{array}{cc}{C}_f=\frac{\Delta V}{\Delta P}& \left[4\right]\end{array}$

Equation [4] becomes the following equation [5] when strains due to the pressure are considered in the calculation of the volume:

$\begin{array}{cc}{C}_f=\frac{1}{P}\left(V_f-V_i\right)=\frac{1}{P}\left(\frac{\pi D_o^2h_o}{4}{\left({\varepsilon }_D+1\right)}^2\left({\varepsilon }_h+1\right)-\frac{\pi D_o^2h_o}{4}\right)& \left[5\right]\end{array}$

Equation [5] can be simplified and second order terms in strain (ε^⇑2<<ε) can be dropped, as shown in equation [6]:

$\begin{array}{cc}{C}_f=\frac{\pi D_o^2h_o}{4P\left({\varepsilon }_h+2{\varepsilon }_D\right)}& \left[6\right]\end{array}$

The strains, ε_h and ε_D, are obtained from using the model for a thin-walled pressure vessel, as shown in equations [7]:

$\begin{array}{cc}{\varepsilon }_h=\frac{{\mathrm{PD}}_o}{4\mathrm{tE}}{\varepsilon }_D=\frac{{\mathrm{PD}}_o}{2\mathrm{tE}}& \left[7\right]\end{array}$

The strains in equations [7] can be combined with equation [6] to give equation [8]:

$\begin{array}{cc}{C}_f=\frac{5\pi D_o^2h_o}{16\mathrm{tE}}& \left[8\right]\end{array}$

Fluidic System Time Constant

The time constant of a single compliant syringe in a syringe pump to changes in set point can be modeled by the simple fluidic circuit shown in FIG. 3. The time constant of this RC fluidic circuit is obtained by combining equations [3] and [8], giving equation [9] as shown below:

$\begin{array}{cc}\tau =\frac{80D_o^2h_o\mu L}{{\mathrm{tED}}_c^4}& \left[9\right]\end{array}$

In equation [9], D_c is the diameter of the capillary. FIG. 4 provides a chart of time constants for four polymeric syringes (1 mL, 3 mL, 5 mL and 10 mL) with capillaries ranging in diameter from 10 and 250 microns. The capillary was one meter long for all of these cases and the fluid was water at 15° C.

Derivation of Governing Equations

As described in detail above, the system includes an electrical motor with a gear box, a linear screw, a spring, a syringe, and an output fluidic circuit. The relationship between the input voltage, or input duty cycle, and the velocity of the motor is considered linear with a negligible transient. Thus, the syringe pump can be modeled as follows in equation [10]:

$\begin{array}{cc}\frac{x}{t}=f\left(U\right)& \left[10\right]\end{array}$

In equation [10], U is the duty cycle and dx/dt is the linear velocity of the linear stage. The remainder of the system can be represented as shown in FIG. 5, which depicts a schematic of the syringe system model.

Two differential equations are required, one for each input parameter: Linear stage position, x; and Pressure, P, or Deflection, δ. Equation [10] is one differential equation and a second representing pressure or deflection is needed. Starting with the kinematic constraint on x, δ, and x_f; and its derivative:

x_fx+δ {dot over (x)}_f={dot over (x)}+{dot over (δ)}  [11]

The fluid circuit analogy can be substituted in for {dot over (x)}_f and Hooke's law can be used to obtain for δ:

$\begin{array}{cc}\frac{Q}{A}=f\left(U\right)+\frac{A}{k}\stackrel{.}{P}& \left[12\right]\end{array}$

Equation [1] can be substituted in for Q, giving equation [13]:

$\begin{array}{cc}\frac{P}{{\mathrm{AR}}_f}=f\left(U\right)+\frac{A}{k}\stackrel{.}{P}& \left[13\right]\end{array}$

The expression can be rearranged to solve for dP/dt, as shown in equation [14]:

$\begin{array}{cc}\frac{P}{t}=\frac{k}{A}\left(\frac{P}{{\mathrm{AR}}_f}-f\left(U\right)\right)& \left[14\right]\end{array}$

Thus, the control system can be modeled with the following equations [10] and [14], repeated below:

$\begin{array}{cc}\frac{x}{t}=f\left(U\right)& \left[10\right]\\ \frac{P}{t}=\frac{k}{A}\left(\frac{P}{{\mathrm{AR}}_f}-f\left(U\right)\right)& \left[14\right]\end{array}$

In these equations, f(U) is obtained experimentally, A is the area of the syringe, R_f is the fluidic resistance of the output fluidic circuit, and k is the spring constant.

Maximum Flow Rate

The system may be used for high flow resistance applications; thus, the system can be flow limited in the case of low flow resistance systems. The maximum flow rate for the system can be calculated using equation [15]:

Q_max=V_{max ARf}  [15]

In equation [15], V_max is the maximum velocity of the linear stage, A is the area of the syringe, and R_f is the fluidic resistance of the output fluidic circuit.

Approximate Response Time

The response time for a step change in input is approximately equal to:

$\begin{array}{cc}{t}_{\mathrm{approximate}}=\frac{\Delta \mathrm{PA}}{kV_{\max \square }}& \left[16\right]\end{array}$

In equation [16], k is the spring constant, ΔP is the change in pressure, A is the area of the syringe, and V_max is the maximum linear velocity of the stage. This equation can be used to select an appropriate spring stiffness for the desired applications.

Model Validation

The equations of the syringe presented above assume that the deflections in the plunger and the syringe barrel are small when compared to the deflection of the spring. FIG. 6 shows a graph of the percent deflection observed in the plunger and barrel for 1 mL, 3 mL, 5 mL, and 10 mL plastic syringes (see Table 2 below for syringe geometries). Spring constants from 10 lb/in to 80 lb/in are included.

Software Architecture

The software architecture of the syringe pump was divided into three sections: Embedded Software, Communication and Data Interface, and User written software in LabView (National Instruments, Austin, Tex.).

Embedded Software

The embedded software was written in TranRunC with a PID task and a supervisory task for each syringe pump. The supervisory task was responsible for proving set points, volume tracking, flow rate calculation, and monitoring for an overpressure condition. Commands sent from LabView through network variables were translated into tasks for the supervisory tasks. The goal of this level of software was simplicity with more complex fluidic assays being controlled by the user using software such as, but not limited to LabView.

Communication and Data Interface

The communication between LabView and the Embedded System was chosen to approximate communication of a serial control line. The network variables CMD, CMDData, CMDPumpID, and newCMD were used to transmit commands from the client to the real time ETS computer. The serial communication system's response provided the output data. For the LabView implementation, network variables were used to transmit data back to the computer.

User Written Lab View Software

A User Interface in LabView enabled the user to provide setpoints based on flow rate or pressure. The user provided the system's fluidic resistance to obtain flow rates. Fluidic resistance can be determined through calculation or by calibrating the system with a known pressure for a long period of time.

Results

Syringe Friction

The syringes used were disposable polymeric syringes manufactured by BD Biosciences (San Jose, Calif.). Table 2 below provides the geometric characteristics of these syringes.

TABLE 2
BD Polymeric Syringe Geometries
	ID	hmax	twall	Lplunger	Aplunger	Asyringe	Asyringe
Syringe	in	in	in	in	in2	in2	m2
1 mL	0.1825	2.22	0.0935	3.4325	0.017203361	0.02615867	1.68765E−05
3 mL	0.3385	2	0.033	3	0.0156128	0.08999269	5.80597E−05
5 mL	0.473	1.75	0.033	2.82	0.03446525	0.17571635	0.000113365
10 mL	0.566	2.4	0.0345	3.6735	0.039444	0.25160701	0.000162327

The 10 mL syringe had the most syringe friction, and was the syringe used in all experiments. The friction present in this syringe was 2.319+/−0.217 (95% confidence). Table 3 below summarizes the measurement of the syringe friction.

TABLE 3
10 mL Syringe Friction Measurement
Measurement                Frictional Force (N)
1                          2.3481627
2                          2.2607892
3                          2.3481627
Average                    2.319
Standard Deviation         0.0504
95% Confidence             0.217
Equivalent Pressure (N/m2) 14286 Pa (2.073 psi)

Syringe Pump Calibration

The position and velocity of the syringe pump was calibrated to the number of the counts of the encoder. A function in C accounts for encoder roll over. The calibration equation, was F(N)=19.9060 V−18.2119 with a R² value of 0.98 and limited hysteresis. This equation was used for forces in the range of about 15 to about 100 N. The spring constant of the spring compliance device was 5.56 N/mm (42.291 lb/in). Table 4 below shows the position calibrations for each syringe pump.

TABLE 4
Position Calibrations for Syringe Pumps
		Standard
	Calibration	Deviation	95% Confidence
Pump #	mm/count	mm/count	mm/count
0	3.91963E−06	2.62459E−08	5.8479E−08
1	3.87862E−06	3.87862E−06	6.2657E−08

Velocity calibrations were obtained using a test which iterates from a duty cycle of 5% to 100%. Velocities were computed as 5 second averages. FIGS. 7 and 8 show the calibrations for pumps 0 and 1, respectively.

Dynamic Response

The dynamic response of pump #1 was measured. The step response was measured twice, once at a duty cycle of 42.2% and another at 100%. These responses are shown in FIG. 9. The resulting average time constant was 9.5 ms. Thus, the system reached steady state almost instantly and no derivative control was required.

Real Time Syringe Control Results

Reliable pressure control of the syringe pump was accomplished using the spring compliance device when attached to a 1 m length of capillary tubing. The slope of the eluted volume plot was very stable and the flow rate, to first order, was stable. A plot of the pressure set point versus measured pressure is shown in FIG. 10. The pressure was filtered by averaging the three most recent points, taken at a frequency of 1 kHz.

It is to be understood that this invention is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.

Claims

1. An automated syringe pump comprising a syringe plunger controller configured to move a syringe plunger relative to a syringe barrel, wherein said syringe plunger controller comprises an elastic member positioned between a rigid member and a plunger retainer.

2. The automated syringe pump according to claim 1, wherein said elastic member comprises a spring.

3. The automated syringe pump according to claim 2, wherein said elastic member comprises a compression spring and a tension spring.

4. The automated syringe pump according to claim 1, wherein said rigid member comprises a slide.

5. The automated syringe pump according to claim 4, wherein said slide is operatively coupled to a motor.

6. The automated syringe pump according to claim 1, wherein said plunger controller further comprises a transducer for generating a signal representative of force applied to a plunger present in said plunger retainer.

7. The automated syringe pump according to claim 6, wherein said transducer is a position sensor coupled to said plunger retainer and said rigid member.

8. The automated syringe pump according to claim 7, wherein said position sensor is a linear potentiometer.

9. The automated syringe pump according to claim 1, wherein said controller further comprises a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on a plunger and constant flow rate of fluid out of a syringe operated by said automated syringe pump.

10. An automated syringe pump comprising:

(a) a syringe holder;

(b) a syringe plunger retainer;

(c) a syringe plunger controller configured to move a syringe plunger held in said syringe plunger retainer relative to a syringe barrel held in said syringe holder, wherein said syringe plunger controller comprises: (i) an elastic component; and (ii) a proportional-integral-derivative (PID) controller;

wherein said elastic component and said PID controller together provide for at least one of constant pressure on a plunger and constant flow rate of fluid out of a syringe held in said syringe holder.

11. The automated syringe pump according to claim 10, wherein said plunger controller comprises a motor and slide.

12. The automated syringe pump according to claim 11, wherein said elastic component comprises a compression spring and a tension spring.

13. The automated syringe pump according to claim 12, wherein said compression spring and tension spring are coaxial.

14. The automated syringe pump according to claim 13, wherein said controller comprises a transducer for generating an electrical signal representative of force applied to said syringe plunger held in said syringe plunger retainer.

15. The automated syringe pump according to claim 14, wherein said transducer is a linear potentiometer.

16. A method of forcing fluid out of a fluid loaded syringe, said method comprising:

(a) positioning a syringe loaded with said fluid into an automated syringe pump comprising a syringe plunger controller configured to move a syringe plunger of said syringe relative to a syringe barrel of said syringe, wherein said syringe plunger controller comprises an elastic member positioned between a rigid member and a syringe plunger retainer; and

(b) causing said syringe plunger controller to move said syringe plunger relative to said syringe barrel to force fluid out of said syringe.

17. The method of claim 16, wherein said syringe plunger controller further comprises a proportional-integral-derivative (PID) controller that provides for at least one of constant pressure on said syringe plunger and constant flow rate of fluid out of said syringe operated by said automated syringe pump.

18. The method of claim 16, wherein said elastic component comprises a compression spring and a tension spring.

19. The method of claim 16, wherein said controller comprises a transducer for generating an electrical signal representative of force applied to said syringe plunger held in said syringe plunger retainer.

20. The method of claim 19, wherein said transducer is a linear potentiometer.