NATICK, MA--Like ancient alchemists who tried to turn lead into gold,
engineers at ZymeQuest hope to turn Type A, B, and AB blood into the universal
Type O that can be given to anyone. Unlike the alchemists, ZymeQuest appears to
The medical implications of this innovation are staggering. Each year,
health-care professionals perform four million blood transfusions. Nearly 500
times per hour someone needs a blood transfusion. Hospitals spend an estimated
$2 to $3 billion a year to test and retest this blood. And these same hospitals
throw out about 6% of the blood they receive because it spoils before the
hospitals get patients whose blood type matches the donor blood they have on
ZymeQuest's Universal Blood Machine not only increases the safety of blood
transfusions, but the process it enables costs less to carry out than repeated
blood-type testing, saving hundreds of millions of dollars annually for
hospitals and other health-care centers.
The engineering implications are also far-reaching in the lessons they hold
for designers of other medical and non-medical devices. That's because many of
the design challenges themselves were universal, among them the need to:
Achieve high tolerances.
Software--including Pro/ENGINEER from Parametric Technology Corp., Mastercam
from CNC Software, and PartAdvisor from Moldflow--enabled engineers to design
the machine's complex components.
Use of off-the-shelf plastics from a variety of vendors enabled engineers to
make critical components--cassette, seal assembly, and bags--disposable, says
Glen Jorgensen, director of ZymeQuest's systems development laboratory and
project leader. Since there are only a few hundred blood centers in the U.S.,
Europe, and Japan who would be customers, making those components disposable so
users will have to re-stock them regularly is key to profitability of the
In the beginning. The system had its origins some 14 years
or more ago as the dream of Jack Goldstein of the Kimball Research Institute at
the New York Blood Center. Goldstein's research into a way to alter the
chemistry of the blood's red cell surface to convert all types of blood to type
O seemed doable (see sidebar). What was needed was a working system to turn the
dream into reality.
ZymeQuest, with headquarters in North Andover, MA, also had enough faith in
the conversion process to license it from Goldstein in 1991 and arrange to
continue the research using the New York facility as a scientific base.
Enter Jorgensen, who at the time was an independent consultant, and his
business partner Don Barry. Wanting to get the conversion process developed as
quickly as possible, ZymeQuest contracted with Jorgensen to build a prototype of
the system. Working out of Jorgensen's basement, Jorgensen and Barry,
ZymeQuest's manager of electronic systems, had a working model of the Universal
Blood Machine ready for Phase I testing in eight months. Pleased with the
results, ZymeQuest took the design team under its wings and set up a design and
development laboratory in Natick, MA, to develop the next-generation conversion
Putting plastics to work. Key system components include a
disposable cassette and a rotating seal assembly. The importance of this aspect
of the design cannot be understated.†Each component in the disposable
system had its challenges when it came to the selection of the right material
for the job. First, engineers decided to use FDA-approved Class VI implantable
plastics across the board. Other criteria included: moldability, structural
integrity, and ability to withstand gamma sterilization.
Design of the critical cassette and rotating seal assembly proved far from
easy, Jorgensen notes. Tolerance and performance requirements of the components
were especially demanding.
"The business depended on us to develop devices that not only met the
performance challenge and were reliable--but they had to be inexpensive,"
Jorgensen recalls. "Since the components had to be made of plastic, this made
dimensional stability and strength essential, particularly in the highly
stressed, thin sections that support the seal faces of the rotating seal and the
valve seats in the cassette."
Maximizing molding. Initially, engineers machined the
plastic components to quickly put a working system together. However, the parts
were far from ideal. Jeremy Fennelly, plastics engineer and consultant, joined
the team to design the final configuration and optimize the injection-molding
tool design and the materials used, starting with the design of the cassette.
Simulation through the use of molding software helped make this practical.
The software employed, Part AdviserTM from Moldflow Corp. (Lexington,
MA), gave Fennelly the power to predict how a part would fill, offered a picture
of the optimized gate location in the mold, and optimized injection-molding
conditions. The material selected for the cassette: Makrolon 2458 polycarbonate
(PC) from Bayer Polymers Div. (Pittsburgh).
ZymeQuest designers used the Moldflow software to model various gate
configurations. With each iteration, they could look at flow-front temperatures
and pressures, weld lines, air entrapment, fill time, and pressure drop.
"This analysis gave us the confidence to move forward with an expensive
production tool," says Jorgensen. "We gave the software's recommendations to
moldmaker GW Plastics Inc. (Bethel, VT) to set up the molding conditions. The
initial parts came out of the mold usable. It's the first time we have seen this
type of success with such a complex part. The savings in time-to-market proved
Success of this cassette design prompted the engineers to use Part Adviser in
the design of the even more complex rotating seal assembly. Plastic components
(one fixed part and a component that moves at 3,000 rpm) form the heart of the
centrifuge equipment. Flatness and tolerance had to be exact to ensure that
liquids wouldn't leak. Molded-in stresses had to be minimized to ensure the
parts would have a robust snap-fit.
For the top and lower halves of the rotating seal assembly that come in
contact with blood, Fennelly again called on Makrolon PC. The material, he
found, gave the components the needed dimensional stability and tensile
strength, yet kept the two flat-face seals in place during the 3,000 rpm speeds
achieved during centrifuge operation.
The other three components that shield the seal, since they don't come in
contact with blood, were designed using a less expensive material. This time
Fennelly turned to K-Resin KRO3, a styrene butadiene copolymer supplied by
Phillips Chemical (Bartlesville, OK).
The bags used to hold the blood and chemical reagents presented a different
problem when it came to the selection of a material. The material had to
withstand autoclaving and heat sealing, resist extreme pH chemicals, and be
plasticizer-free to avoid introducing any contaminants to the reagents. A
three-layer polyester/polypropylene film met the requirements. The material:
Cryovac M-312 film from Cryovac Sealed Air Corp. (Duncan, SC). "It's really a
superior film," Glen enthuses.
Tying it all together. What made the design process a
success, says Jorgensen, was the integration of state-of-the-art software into a
"virtual" corporation. "It's the same logic that allows software tools to do the
technical part of the job," he adds. "We created a seamless communications
network throughout our three facilities, using modern electronic equipment to
move data (high-speed modems, the Internet) around internally and externally
(among the many suppliers) at a minimal cost. It's nearly a paperless process."
Since the ZymeQuest endeavor was small and brand new, the team was not tied
to one system as is often the case in a large corporate setting. That fact
enabled the electronic network to be shared with everyone. "We used
off-the-shelf software to do the job," Barry explains, "but integrated it so
that information flows effortlessly." This includes the firm's extensive design
history file, all design changes, inventory management, vendor communications,
and even training records. In fact, ZymeQuest often selects vendors because they
have the electronic tools to make the process seamless.
From design to market. Currently, ZymeQuest has Phase II
clinical trials of the system underway at two leading hospitals to determine
whether converted B Cells have the same medical utility as unconverted O cells.
So far, studies have shown that the converted cells behave like normal O
cells--and they don't trigger an immune reaction.
The first FDA-approved system should hit the marketplace early in the first
decade of the new millennium.
How the ZymeQuest blood conversion system operates
A unit of packed red blood cells (A, B, or AB) is sterile-connected to the
ZymeQuest disposable set using a Terumo SCDTM sterile connection
device produced by Terumo Medical Inc. (Somerset, NJ). Sterile reagents supplied
by ZymeQuest also are plugged into the disposable set.
Technicians activate the appropriate pair of valves, located in the
disposable cassette, to allow the cells to drain into the centrifugal processing
A typical process cycle includes the addition of a liquid reagent, mixing,
centrifugal sedimentation of the cellular material, and the discharge of the
non-cellular liquid to waste. This last step involves pumping a specially
formulated hydraulic fluid into the lower of two cavities located within the
centrifugal processing chamber and which are separated by a flexible membrane.
The cells are contained in a bag centrally positioned in the upper cavity.
The expanding membrane discharges the sedimented fluid from the bag in the
second cavity. This fluid stream is directed by the valving set within the
cassette to a waste container. The washed cell mass remains in the processing
bag ready for the next wash cycle.
Several washing cycles and reagents are required to convert a unit of red
blood cells. A specified amount of each reagent is metered into the cells as a
function of the starting mass. This sequential washing continuously reduces the
pH in preparation for the enzymatic conversion, restoration of the pH back to
physiologic levels, and the complete removal of the washing reagent to prepare
the cells for long-term storage and subsequent transfusion.
In the middle of these cycles, technicians add a genetically engineered
enzyme to the cells. The incubation temperature of the cells is directly
measured with an infrared temperature sensor. Temperature adjustments are made
by controlling the temperature and the circulation rate of the hydraulic fluid
flowing through the lower cavity of the centrifugal chamber, which remains in
thermal contact with the cells. After the last cycle, technicians move the cells
to a collection bag. They meter a measured amount of storage solution to
preserve the cells throughout the cells' shelf life.
Software streamlines design
To design the complex shapes envisioned for the Universal Blood Machine,
ZymeQuest engineers used several software packages.
For 3D solid modeling, the design team used Parametric Technology Corp.'s
(Waltham, MA) Pro/ENGINEER. To test the concept, the team e-mailed the files to
one of its machining partners. The machine shop used CNC Software's (Tolland,
CT) MastercamTM program to directly convert the digital model into
machining instructions for one of its high-end milling centers. Directly,
prototype parts were in the design team's hands. Following a testing period,
engineers began design refinements to meet the performance and cost criteria.
Some components, like the long, thin, multi-port connector that snaps into
the cassette, required sophisticated stress analysis to insure that the
deflection of the plastic fell within the tolerance absorbed by the soft O-rings
required to form a leakproof seal. Parametric's integrated
Pro/MECHANICATM stress analysis package accomplished this task.
Engineers incorporated modifications on every component into the next generation
of detailed design efforts.
To find the best gate locations for injection molding, engineers used Part
Adviser from Moldflow Corp. (Lexington, MA). "We had a seamless connection
between the Pro/ENGINEER solid model and Part Adviser," says Plastics Engineer
Jeremy Fennelly. "This link enabled us to transfer data back and forth to the
molder on various models and analyses."
Not only did the Moldflow software identify some ultra-thin sections
engineers did not see with the solid model, but it enabled them to test three or
four gate locations using several resins to come up with the optimum gate
locations and materials for each of the five parts, Fennelly notes. "The entire
process took just five weeks. And the parts fit perfectly," he says.
Banking on blood conversion
Blood donors ready to give the gift of life must sit down with a pen and take
a test. The questionnaire--along with biochemical tests of the blood--is part of
a rigorous screen process that has made the U.S. blood supply one of the safest
in the world.
Once that blood reaches the hospital, however, even the most careful initial
screen efforts can't protect a patient from getting a fatal transfusion of the
wrong blood type. Also, as much as 6% of the donor blood goes to waste because
hospitals can't use those units within their 42-day shelf life. The solution:
use type O blood!
How do hospitals get enough of the life-saving type O blood? That's the
question Jack Goldstein of the Kimball Research Institute at the New York Blood
Center asked. Conversion of all blood to type O would address supply and
shipping imbalances, he envisioned.
With this in mind, Goldstein and other researchers set out to use an enzyme
to alter the chemistry of the blood's red cell surface. Chains of sugars, which
cover the cell surfaces of the four human blood types--A, B, AB, and O--all have
the same basic sequence, with fucose at the end and galactose next in line.
A and B cells cannot be transfused into people with O blood. The extra sugar
branch stimulates the immune system's antibodies to attack the foreign cells.
Clipping off that added sugar branch from A and B cells transforms them into
type O, averting the immune response.
The large number of sugar chains and their different orientations on cell
surfaces made finding the right conditions for conversion a real challenge for
Goldstein. Type B cells have over half a million sugar chains on their surface,
while type A cells have twice that amount. Some are perpendicular to the
surface; others lie parallel.
"This is what fascinated me," Goldstein reports, "to get enzymes and
conditions where the enzymes would work." For instance, the enzyme for B
conversion works best at a high acidity, but blood cells do their job of
carrying oxygen in neutral conditions. Goldstein had to strike a balance that
allowed the enzyme to clip off the extra galactose, without destroying the red
cell's function. Eventually, he determined that the reaction could take place at
26C, rather than the higher temperature the blood cells are accustomed to, and
at a slightly acidic pH of 5.5 or 5.6.
"When I started this work, no one had really treated red cells at such a low
pH," Goldstein continues. "It was thought that they would just become
nonviable." That turned out not to be the case. In Goldstein's process, not
every sugar chain on every cell gets changed, he notes, but as long as enough
are clipped, the body accepts the cells. It was at this juncture that ZymeQuest
entered the scene to make Goldstein's system a reality.
Partners in design
Lab Engineering and Manufacturing, Inc.
Precision machining and
Precision Sheet metal
Ams Machine, Inc.
Precision Machining and assembly
Design Resources, Inc.
PCB layout and fab
Bodine Electric Co.
Carroll Touch, Inc.
Touch screen panels
Round Rock, TX
Technology 80, Inc.
Imbedded Logic Motor Controllers
Injection Molding, Assembly
Alps South Corp.
St. Petersburg, FL
Apple Pattern, Inc.
Structural molded parts
CryoVac Sealed Air Corp
Specialty plastic film
Industrial Design and Artwork
Carroll Design Inc.
Jack Carroll and Lars Fischer
What this means to you
Enzyme conversion system will transform A, B, and AB type blood into type O
blood, the universal blood type that can be used by anyone needing a blood
Design and molding software played key roles in the system's design.
Use of various plastic components made the system workable and affordable.
An electronics network built around off-the-shelf devices enabled designs
and communications to flow seamlessly between all parties involved in the
Timeline for design
Dr. Goldstein and staff conduct Phase I clinical trials of B-to-O
conversion using existing laboratory cell washers
Design & Fabricate 3 add-on controllers, called, "Zeke 1," for Phase II
Design"next generation" prototype
Strategic change: Redesign and rename to "Zeke 2"
Design modifications: performance enhancements "Zeke 2.1"
Design and prototype a multi-unit scale-up system for high thru-put; rename
to "Zeke 3"