U.S. patent application number 12/901408 was filed with the patent office on 2011-04-28 for feedback controlled syringe pump.
Invention is credited to Thomas Henry Cauley III, Albert P. Pisano.
Application Number | 20110097229 12/901408 |
Document ID | / |
Family ID | 43898599 |
Filed Date | 2011-04-28 |
United States Patent
Application |
20110097229 |
Kind Code |
A1 |
Cauley III; Thomas Henry ;
et al. |
April 28, 2011 |
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.
Inventors: |
Cauley III; Thomas Henry;
(Berkeley, CA) ; Pisano; Albert P.; (Danville,
CA) |
Family ID: |
43898599 |
Appl. No.: |
12/901408 |
Filed: |
October 8, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61250155 |
Oct 9, 2009 |
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Current U.S.
Class: |
417/518 |
Current CPC
Class: |
A61M 2205/332 20130101;
A61M 5/1456 20130101; A61M 5/1454 20130101 |
Class at
Publication: |
417/518 |
International
Class: |
F04B 7/00 20060101
F04B007/00 |
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.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] Pursuant to 35 U.S.C. .sctn.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
[0002] 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.
[0003] 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).
[0004] 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
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] 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.
[0012] 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
[0013] FIG. 1 shows a schematic of a feedback controlled syringe
pump of the present disclosure.
[0014] FIG. 2 shows a schematic of the syringe and the flow
conditions.
[0015] FIG. 3 shows a schematic of a fluidic circuit of a single
compliant syringe in a syringe pump of the present disclosure.
[0016] 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.
[0017] FIG. 5 shows a schematic of the syringe system model.
[0018] 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.
[0019] 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.
[0020] 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
[0021] 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.
[0022] FIG. 10 shows a graph of the real time response of a
pressure controlled syringe pump of the present disclosure.
[0023] FIG. 11 shows a graph of the first calibration using a
syringe pump of the present disclosure.
[0024] FIG. 12 shows a graph of the second calibration using a
syringe pump of the present disclosure with the linear positioner
secured with glue.
[0025] 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.sub.sup=20V).
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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
[0036] 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.
[0037] 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
[0038] 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.
[0039] 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.
[0040] 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 .mu.L to 1 mL,
such as 2.5 .mu.L to 500 .mu.L, and including 5 .mu.L to 250
.mu.L.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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
[0052] 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.
[0053] 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
[0054] 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.
[0055] 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.
[0056] 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
[0057] 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.
[0058] 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
[0059] 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.
[0060] 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
[0061] Fluid-Circuit Analogy
[0062] 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-US-00001 TABLE 1 Fluid-Circuit Analogy Electrical Property
Fluid Analog Units Notes Voltage Pressure, .DELTA.P F Driving force
L.sup.2 Current Flow Rate, Q L.sup.3 Volumetric flow rate of fluid
T Resistance Fluidic FT Resistance to flow Resistance, R.sub.f
L.sup.5 Capacitance Fluidic L.sup.5 Plastic expansion of tubing,
Capacitance, C.sub.f F syringes, or bladders Inductance Fluidic --
Fluid momentum, not relevant for Inductance, L.sub.f creeping flow
regimes where the fluid-circuit analogy holds.
[0063] Applying these concepts to Ohm's law, gives equation
[1]:
.DELTA.P=R.sub.fQ [1]
[0064] Fluidic Resistance
[0065] 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]:
Q = .pi..DELTA. P a 4 8 .mu. L [ 2 ] ##EQU00001##
[0066] Equation [2] can be rearranged to obtain an expression for
fluidic resistance, R.sub.f, as shown in equation [3]:
R f = 8 .mu. L .pi. a 4 [ 3 ] ##EQU00002##
[0067] Fluidic Capacitance
[0068] 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.sub.f, at the output.
[0069] Fluidic capacitance is defined by equation [4]:
C f = .DELTA. V .DELTA. P [ 4 ] ##EQU00003##
[0070] Equation [4] becomes the following equation [5] when strains
due to the pressure are considered in the calculation of the
volume:
C f = 1 P ( V f - V i ) = 1 P ( .pi. D o 2 h o 4 ( D + 1 ) 2 ( h +
1 ) - .pi. D o 2 h o 4 ) [ 5 ] ##EQU00004##
[0071] Equation [5] can be simplified and second order terms in
strain (.epsilon..sup. 2<<.epsilon.) can be dropped, as shown
in equation [6]:
C f = .pi. D o 2 h o 4 P ( h + 2 D ) [ 6 ] ##EQU00005##
[0072] The strains, .epsilon..sub.h and .epsilon..sub.D, are
obtained from using the model for a thin-walled pressure vessel, as
shown in equations [7]:
h = PD o 4 tE D = PD o 2 tE [ 7 ] ##EQU00006##
[0073] The strains in equations [7] can be combined with equation
[6] to give equation [8]:
C f = 5 .pi. D o 2 h o 16 tE [ 8 ] ##EQU00007##
[0074] Fluidic System Time Constant
[0075] 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:
.tau. = 80 D o 2 h o .mu. L tED c 4 [ 9 ] ##EQU00008##
[0076] In equation [9], D.sub.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.degree. C.
[0077] Derivation of Governing Equations
[0078] 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]:
x t = f ( U ) [ 10 ] ##EQU00009##
[0079] 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.
[0080] Two differential equations are required, one for each input
parameter: Linear stage position, x; and Pressure, P, or
Deflection, .delta.. Equation [10] is one differential equation and
a second representing pressure or deflection is needed. Starting
with the kinematic constraint on x, .delta., and x.sub.f; and its
derivative:
x.sub.fx+.delta. {dot over (x)}.sub.f={dot over (x)}+{dot over
(.delta.)} [11]
[0081] The fluid circuit analogy can be substituted in for {dot
over (x)}.sub.f and Hooke's law can be used to obtain for
.delta.:
Q A = f ( U ) + A k P . [ 12 ] ##EQU00010##
[0082] Equation [1] can be substituted in for Q, giving equation
[13]:
P AR f = f ( U ) + A k P . [ 13 ] ##EQU00011##
[0083] The expression can be rearranged to solve for dP/dt, as
shown in equation [14]:
P t = k A ( P AR f - f ( U ) ) [ 14 ] ##EQU00012##
[0084] Thus, the control system can be modeled with the following
equations [10] and [14], repeated below:
x t = f ( U ) [ 10 ] P t = k A ( P AR f - f ( U ) ) [ 14 ]
##EQU00013##
[0085] In these equations, f(U) is obtained experimentally, A is
the area of the syringe, R.sub.f is the fluidic resistance of the
output fluidic circuit, and k is the spring constant.
[0086] Maximum Flow Rate
[0087] 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.sub.max=V.sub.max AR.sub.f [15]
[0088] In equation [15], V.sub.max is the maximum velocity of the
linear stage, A is the area of the syringe, and R.sub.f is the
fluidic resistance of the output fluidic circuit.
[0089] Approximate Response Time
[0090] The response time for a step change in input is
approximately equal to:
t approximate = .DELTA. PA k V max .quadrature. [ 16 ]
##EQU00014##
[0091] In equation [16], k is the spring constant, .DELTA.P is the
change in pressure, A is the area of the syringe, and V.sub.max is
the maximum linear velocity of the stage. This equation can be used
to select an appropriate spring stiffness for the desired
applications.
[0092] Model Validation
[0093] 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.
[0094] Software Architecture
[0095] 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.).
[0096] Embedded Software
[0097] 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.
[0098] Communication and Data Interface
[0099] 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.
[0100] User Written Lab View Software
[0101] 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
[0102] Syringe Friction
[0103] 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-US-00002 TABLE 2 BD Polymeric Syringe Geometries ID h.sub.max
t.sub.wall L.sub.plunger A.sub.plunger A.sub.syringe A.sub.syringe
Syringe in in in in in.sup.2 in.sup.2 m.sup.2 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
[0104] 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-US-00003 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/m.sup.2) 14286 Pa (2.073 psi)
[0105] Syringe Pump Calibration
[0106] 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 R.sup.2 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-US-00004 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
[0107] 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.
[0108] Dynamic Response
[0109] 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.
[0110] Real Time Syringe Control Results
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
* * * * *