The robots are coming; lab automation is moving a step further as robots develop the sophistication to take over traditional benchtop tasks Essay

The work station robot, already hard at work in industrial and
pharmaceutical laboratories, has begun to appear in clinical
laboratories. This herald of a new phase in automated medical
technology provides a host of advantages in routine analysis. During the
coming decade, it will profoundly change the way we perform tests.



Over the past 20 years, laboratory medicine has moved toward
progressively greater levels of automation. Today, practically every
clinical chemistry technologist uses at least one instrument requiring
only placement of specimens in a sample tray and a push of the start
button. From that point, the instrument calibrates itself with
appropriate standards, analyzes the specimens, and prints a report that
can often be appended directly onto the patient’s chart.

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Many instrument also provide accuracy and precision estimates and
reports that indicate whether the result is within normal range. In
highly computerized hospitals, analyzers interface with hospital
information systems to generate and forward reports electronically. Some
systems can combine reports from various work stations.



Specimen collection and preparation, in fact, are the only steps in
the entire process from requisition to billing that are still unassisted
by automation. It isn’t yet feasible to automate the collection of
patient specimens, but a new breed of robot work stations can largely
take over preparation of specimens for analysis, thus extending
laboratory automation one crucial step further.


In this article, we will examine the many benefits of robotics in
the clinical laboratory, the basic technical elements involved, and the
actual process of putting robots to work in a variety of
applications–including our own experience with a mechanical helper at
the bench.



The idea of robot work stations isn’t new. Back in 1971, Dr.
Raymond Gambino predicted, “As wage rates continue to rise and
skilled help becomes scarcer, the robot’s utility will become more
attractive.” Robotic technology is built into most of the
high-throughput instruments we use today, and even the earliest
automated analyzers included basic robotic components.



Laboratory robotics evolved from the manually operated manipulation
devices developed to handle hazardous–and particularly,
radioactive–materials. These early robots were just pivoted gripper
hands enclosed in an isolated area and operated by a technologist from
without. Ultimately, the development of electronic and sensor controls
allowed walkaway operation, and the stand-alone robot was born.



The heart of a prototype robot work station is the arm/hand
assembly, an electromechanical device mounted in the center of a work
bench. The arm, a horizontal bar attached to a vertical column, is
placed on a turntable attached to a base unit. The robot’s
computer controller rotates the turntable through 360 degrees and moves
the arm assembly up and down the column and in and out from the center.



A mechanical hand attachment performs the actual tasks. This hand
has three types of motion, or degrees of freedom, to position itself
anywhere within a defined reach of the base unit. Visualize a cylinder;
within it coordinate system, the hand can rotate, move up or down, and
move in and out.



In the most versatile arrangement, the hand itself can rotate about
the arm in a wristlike motion. Interchangeable hands can be attached to
perform a variety of functions. For example, a unit with two clamp-like
finger devices can open or close upon electronic command to grasp vials,
test tubes, and other items. Another hand can be fitted with a syringe
whose plunger is operated by the computer controller, adding a finger
motion or fifth type of movement to the robot’s repertoire. For
maximum flexibility, the arm should be able to change hands under
computer control during the course of operation.



Other lab equipment is permanently fastened to the work surface
surrounding the arm unit–standard accessories including test tube racks
and reagent bottles, along with other familiar devices modified for
remote control operation (electronic balances, vortex mixing stations,
automatic liquid dispensers, heating baths, centrifuges, and sample
shakers). Finally, the work station incorporates some devices unique to
robotics, such as stands in which to park idle robot hands, racks for
pipet tips and other robot supplies, stations to uncap bottles or
specimen containers, and mechanical or optical sensors enabling the
robot to verify its operations.


This verification process is critical because the robot cannot
“see” what it is doing. It depends on knowing the precise
location of its supporting equipment and specimens. To that end, when
it picks up a sample tube from a rack it can be programmed to touch the
tube against a switch sensor, producing a signal that tells the computer
a tube was indeed lifted from that location.



Programming the robot through a computer control unit calls for
ingenuity and patience. First, it must be taught the location of all
supporting apparatus and its movement coordinates. The software
controlling this process must provide a convenient way to identify these
points within the robot’s cylinder-shaped range of motion. In the
system we use, the programmer steps the arm and hand to the desired
position by push button. Each position is assigned a name that is
stored in a dictionary in the computer’s memory.



Next, the programmer defines a series of unit activities that can
be performed anywhere in the work space. A typical routine–say, for a
pouring action–would consist of a wrist rotation with the robot hand
holding an open test tube. Routines and locations can then be combined
to form procedures. In an “empty to waste” procedure, for
example, the hand would move over a waste beaker and execute the pour
routine.



Using this programming method, we can develop unit operations to
perform the functions of weighing, pipetting, centrifuging, decanting,
mixing, heating, performing column chromatography, extracting,
filtering, and other ordinary laboratory tasks. In the final step, the
programmer combines locations, routines, and procedures to create a
“method” for the complete process of specimen preparation.



The process control software also permits other typical computer
functions like the ability to loop, or go back and perform the same task
repeatedly; to branch into different program segments depending on
certain variables; to index to different test tube rack positions; to
perform calculations; to control peripheral devices; and to read and
write to a disk and communicate with other computers.



Our familiarity with manual methods of specimen preparation may
make this process seem like more trouble than it’s worth, but
remember that initial programming is a one-time chore. Once the robot
has been taught its tasks, it offers a number of key advantages over
manual performance–especially to financially constrained laboratories
of the future:



* Accuracy. Test results are only as accurate as the preparation
of specimens and standards. Once the rest of the test process is
automated, specimen preparation often becomes the chief source of error.



It’s part of human nature for people to make mistakes. A step
may be skipped, a reagent may be delivered incorrectly, a specimen may
be accidentally contaminated by an unwashed apparatus, or a balance may
be misread. Day and night shift personnel may vary slightly in habits
or practices, such as reading the miniscus of a pipet differently,
leading to small but systematic differences in test results.



By performing tasks identically every time without procedural
mistakes, robots can improve method accuracy. Once a procedure has been
successfully adapted to the robot and programming glitches have been
eliminated, the robot only makes mistakes when a component is worn or
fails. And these errors are almost always obvious immediately, usually
bringing the procedure to a halt. Subtle and easily overlooked robot
errors are rare.



* Precision. A robot processes each specimen with much lower
variance than a person does. A technologist may have to answer the
telephone or be distracted by a co-worker at a critical moment and leave
some samples in an incubator bath a few minutes too long. Robots, which
always follow the exact same program, eliminate many of these random
deviations.



* Reliability. If the results of a complex procedure are needed at
any time of the day or night, as with certain toxicology procedures, a
robot is always on duty. Technologists who are most skilled and
experienced in a particular procedure will not be at the bench round the
clock.



* Documentation. Specimen preparation may take different paths
depending on the situation. If the initial result is too high, the
sample may have to be diluted and run again. Or the supplied volume may
be too small for standard treatment. The robot computer, working in
concert with the instrument’s computer, can be programmed to handle
these variations and document the exact method of preparation for each
specimen. A technologist needn’t be present to make the decision
and record the results.



* Cost. The typical robot work station currently costs about the
same as 1-1/2 to 2 years of an experienced technologist’s salary
and benefits. The system we use cost approximately $47,000, which
includes a base price of $25,000 and an additional $22,000 in needed
accessories, such as shakers, centrifuges, vortexes, and capping
stations. Depending on the procedures the robot will perform,
accessories can run from $20,000 to $40,000 over the basic arm/hand unit
cost.



Obviously, the robot represents a significant investment, but one
with the potential to pay for itself in a reasonably short period. It
enhances productivity by allowing more tests to be run at existing staff
levels and frees personnel for more challenging activities requiring
human hudgment.



Particular work stations may be especially appropriate for robot
specimen preparation. High-volume work stations are good candidates,
even if the specimen treatment process is simple, since such repetitive
tasks are boring and tiring. Unpopular tasks, such as fecal analysis,
are also likely targets. So are complex procedures with a high margin
for error or dangerous procedures involving radioactive or other toxic
reagents.



To evaluate the feasibility of using routine robotics in laboratory
medicine, our biochemistry department at The Cleveland Clinic Foundation
recently installed a Zymark Robotic System, manufactured by Zymark
Corp., Hopkinton, Mass. The robot’s first task was a complex one:
sample preparation for therapeutic drug monitoring. We trained it to
perform all steps in the liquid-solid extraction of tricyclic
antidepressant drugs from plasma prior to their analysis by
high-performance liquid chromatography (HPLC). Here is how we
incorporated the robot into routine use for the analysis of tricyclic
antidepressants.



Before teaching the robot any task, you must define every operation
involved, down to the smallest step. Figure I presents a dual flow
diagram for our manual and robotic tricyclic procedures.



Each movement involved in extracting the specimen must be
programmed as an absolute or relative position where the robot will
perform a specific step. The most efficient way is to program the
system “from the top down”–that is, by delineating the major
steps necessary to reach the goal, and then writing subroutines to reach
the end point of each major step.



The robot performs the entire procedure by combining and
integrating these subroutines. Figure II shows the string of robotic
commands necessary to perform a tricyclic antidepressant assay from the
time of specimen delivery to the robot until the specimen is ready for
injection on the HPLC. This program may look quite simple, but keep in
mind that each step involves numerous subroutines composed of many
individual steps.



The Zymark robot system and its auxiliary equipment for drug
extraction are shown as a schematic diagram in Figure III. The robot
computer controller, a separate component that functions as the robotic
brain, is programmed in a language called Easy-Lab that uses English to
communicate with the programmer.



First, we program each step in a routine. Using a manual
controller, the operator moves the robot arm, with appropriate hand
attached, with appropriate hand attached, to a desired position and
assigns each location a name that is stored, along with the hand’s
exact coordinates, in the computer dictionary. From this point on, the
hand will travel only to that position when instructed to do so. Each
location can have only one name; if the same location is used in a
different subroutine, it cannot be renamed.



This initial process is somewhat time-consuming. It usually takes
three to five minutes to define one position. We estimate that it took
about 72 hours to program the entire tricyclic assay. A complete
printout of the program requires 1,436 lines, one line for each command
the robot is given to complete the process. Once the initial subroutine
positions have been named, we don’t have to reprogram their
locations coordinates for use in other procedures. For example, the
position programs for adding internal standards to plasma or loading an
HPLC injection vial are the same for all assays.



After the robot has learned the various subroutines, they must be
edited so that the total program is integrated to provide a continuous
flow of movement from one subroutine to the next.



Programming is really quite straightforward, as long as yo remember
that the robot moves in three dimensions and always travels between two
points by the shortest possible route. When integrating subroutines
some distance apart, the robot may choose an unanticipated path–and
crash into any obstruction along the way. These mishaps occur quickly.
By the time you realize a crash is imminent, it will already have
happened.



Naturally, these crashes can damage robot hands. Avoid them by
establishing safe positions for the robot to reach during a subroutine.
It may take the arm/hand assembly a few seconds longer to go from point
A to point B via a safe route, but it will arrive at Point B without
crashing.



The hardest part of teaching a robot, in fact, is recognizing the
fact that it is a slavishly cooperative helper. It does exactly what
it’s told, and wrong moves usually result from programming errors.
Once you discover the flaw in its instructions, the problem can
generally be corrected.



When the robot has been successfully taught to carry one specimen
through the entire procedure without error, it can process any number of
specimens identically. At this point, the program is ready for
verification, to make sure it produces the same results as manual
preparation.



We verified our tricyclic antidepressant assay in the usual manner,
by comparing results obtained manually for standards, controls, and
patient specimens with the same specimens processed by the robot. The
data, excerpted in Figures IV and V, have clearly demonstrated that
reproducibility of the robot assay compares well with that of the manual
method. We are now in the process of adapting ELISA-type immunoassays
and the determination of antiepileptic drugs, various drug metabolites,
and porphyrins to robotic analysis.



Our experience has confirmed our belief that robotics are indeed
the wave of the future, with a wide variety of potential applications.
It’s a common misconception that only high-volume laboratories can
use robotics efficiently. In reality, mid-size or even some small
hospital labs can use robots effectively which careful planning.



Versatility is one key benefit to consider. Similar assays can be
easily performed at the same work station. A robot performing
liquid-solid extractions of one drug can conduct the same procedure on
many different drugs using the same basic ssytem and operating
principles. Switching assays, once the robot is programmed, usually
takes no more time than is needed to change reagent bottles, rack in the
new set of specimens, and tell the robot to perform the new assay. This
usually takes less than 15 minutes.



The main limit on a robot’s repertoire is the space available
at the bench. The arm moves within a full circle and has access to any
point within its diameter. The number of pieces of equipment and
support racks this area will hold determines how many procedures can be
performed.



Our robot performs both liquid-liquid and liquid-solid extractions
in its work area. The platform shaker and centrifuge are designated
only for liquid-liquid extractions and are not used during the
liquid-solid extraction phase. Conversely, the column extracting
station is unused during the liquid-liquid extractions.



The robot can function overnight without supervision, so it’s
possible to start a day’s workload the night before by having the
night technologist rack the specimens, place them by the robot, tell it
the number of specimens to be processed, and push the start button.
Robotic procedures aren’t necessarily faster than manual methods,
as Figure IV also shows; their value lies in the employee time saved by
walkaway operation.



So far, we haven’t focused on the one most important part of
robot operations: people. Robots will work for anyone who can perform
the setups, but they each need a special caretaker–one person
responsible for their care, preventive maintenance, and troubleshooting.
In our lab, two technologists have been trained to program and
troubleshoot the robot.



Since we put our robot into practice last May, it has been down
only twice, both times within the first 60 days of implementation.
Preventive maintenance consists of oiling the arm once a month. We
don’t think that’s a bad track record for a workhorse that’s willing to run day and night.



Unfortunately, the very idea of robots often triggers a response of
mistrust and anxiety from medical technologists, who picture their jobs
being eliminated. We have found, however, that attitudes quickly change
once the staff understands both the advantages and limitations of
robotics. It doesn’t take long to recognize that the robot
actually provides technologists with a new level of freedom.



Rather than eliminating jobs, robots provide a new resource that
allows the expansion of laboratory services with no significant increase
in personnel costs. Released from repetitive, routine procedures,
technologists can pursue tasks that demand more of their skills and
intellectual ability, such as improving communication between the
laboratory and clinical services, developing new analytical techniques,
and pursuing clinically relevant research projects. Robotics are just
another avenue toward better patient care.



In years to come, we will see robots used extensively in clinical
pharmacology labs as well as routine clinical chemistry sections. How
will widespread implementation of robotics change the clinical chemistry
laboratory of the future? It will provide a cost-effective way to
deliver many services without a significant rise in labor and operating
costs. More important, it will free more professional time and talent
for tasks that require human intervention.



After working with our robot for nine months, we share the growing
conviction that robots will be a major part of laboratory medicine in
the next few years, and not just in large institutions. Their
versatility, cost-effectiveness potential, and ease of operation
guarantee an important role. Getting to know them now, and implementing
them as soon as it’s feasible to do so, will improve our efficiency
and the quality of our patient care.

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