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Performance
of 50 Completed ATP Projects
Status
Report - Number 2
NIST SP 950-2
Chapter
3 - Biotechnology
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Integra
LifeSciences
A New Bioabsorable Polymer:
An Ideal Material for Medical Implants?
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| For
more than 100 years, orthopedic surgeons have been repairing serious
bone fractures by binding the fractures with screws, pins, and other
fixation-type devices. Early on, these devices were often made from
common metals such as iron or steel. Later on, they were made of highly
sophisticated metal alloys of titanium, zirconium, niobium, and tantalum.
Still the search continued for materials that would be more compatible
with the human body, and that search led researchers to consider bioabsorbable
polymers. |
COMPOSITE
PERFORMANCE SCORE
(Based on a four star rating.)
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Problems with Existing
Materials
While effective in binding the fractured bone, the devices made of common
metal corroded when they were implanted in the body and released toxins
that could cause inflam-mation, infection, and even life-threatening injury
to the patient. The metal alloys offer major improvements because they
do not corrode when exposed to body fluids and therefore can be left inside
the body for long periods of time without releasing harmful toxins. They,
too, however, have serious drawbacks. Metal alloys are much harder and
stiffer than the bone they replace or support, and can interfere with
the regrowth of the bone.
Many patients with
metal alloy implants must under-go follow-up surgery, with its associated
cost, risk, and trauma, to remove the implant once the healing process
has occurred. According to a recent study, the cost of a second surgery
can range from $850 for devices located in the shoulder to $2,200 for
devices located in the knee. More than 34,000 of these follow-up surgeries
are performed in the United States each year, resulting in costs of $30–75
million.(1)
Bioabsorbable Polymers
Offered Promise—and Potentially Dangerous Toxins
Polymers offer great potential as a substitute for alloys for use in orthopedic
implant devices. Polymers can be made to be biocompatible and designed
to exhibit more bone-like properties. Their mechanical properties can
be strong enough to withstand weight-bearing applications, yet they still
retain a degree of elasticity not available with metal alloys. Most important,
polymers can be made to be bioabsorbable, that is, they can be made to
dissolve and slowly be absorbed by the body. Further, the rate of dissolving
can be engineered so that it is consistent with the rate of new bone growth.
Under ideal conditions, a bioabsorbable polymer could encourage bone healing
while the body slowly metabolizes it. This eliminates the need for a second
surgery that may be required when an unyielding metal alloy is implanted.
A serious problem
existed, however, with available bioabsorbable polymers—polylactic
acid, polyglycolic acid, and polydioxanone. When they dissolve or degrade
inside the body, they tend to release acids and other toxins that are
harmful. For sutures and small staple devices this is not a serious problem
because the quantity of harmful substances released is small. But for
larger devices, such as weight-bearing screws, the release of harmful
products can be significant and can cause inflammation problems, similar
to the problems that occurred with the crude metal devices of the past.
Over the past two
decades, scientists have attempted to reengineer these polymers to minimize
the release of harmful substances and reduce the resulting inflammation.
This research has had some success but apprehensions remain over problems
of bio-incompatibility. Market experts suggest that unless a major breakthrough
occurs that solves this problem, the market for bioabsorbable polymer
implants will not fully develop and patients will have to continue to
undergo secondary surgeries with their associated costs and risks.
ATP Funds Research
for an Improved, Toxin-free Bioabsorbable Polymer
In the early 1990s, Dr. Joachim Kohn, a professor of chemistry at Rutgers
University, invented new “pseudo-polyamino acids” based on tyrosine,
a naturally occurring amino acid. The polymer’s physical properties
are similar to existing, FDA-approved bioabsorbable polymers, but because
it is derived from tyrosine, any acids or toxins it releases are done
so at significantly slower rates.
Several implant device
manufacturers showed an early interest in Dr. Kohn’s invention, but
none were willing to make a commitment to develop the material because
the technical risk of doing so was very high. Development of the polymer
required the creation of a manufacturing process that guaranteed the material’s
purity and uniform characteristics on an industrial scale. In addition,
quantities of the new polymer had to undergo a series of rigorous tests
to show that the material was indeed capable of being used safely and
effectively in implant devices. All of this had to be accomplished before
additional funds would be committed to run the additional clinical trials
mandated by the FDA approval process.
Integra LifeSciences
Corporation, a small biomaterials company in New Jersey, approached Dr.
Kohn with a plan to accelerate the development of this new polymer. Integra,
in research led by Dr. George L. Brode (principal investigator for the
ATP project) and Dr. John Kemnitzer, would develop a scaleable manufacturing
process for the tyrosine polycarbonate and then perform tests to assess
the new material’s potential for use in implant devices. Once the
difficult technical problems were overcome and the polymer’s potential
was demonstrated, it was expected that private investors in the new implant
technology could be attracted.
To offset the high
technical risks of this endeavor, Integra submitted a single-company proposal
to the Advanced Technology Program’s 1993 General Competi-tion. Potential
economic benefits looked strong, the research plan solid, and Integra
received a $2 million, three-year award from the ATP that began in January
1994.
Integra Overcomes
Technical Obstacles
The first major task of the project was to design and develop a scaleable
process technology that allows for flexible control of several key physical
properties during manufacturing and ensures that the polymer can be produced
with a high degree of purity. This work led to the development of the
successful “Biphasic Process.” Integra filed a patent on this
process, and showed that it was capable of producing commercial quantities
of the new polymer. Having developed the manufacturing process technology,
Integra’s next task was to assess the physical properties of the
new material and prepare prototype
devices for in vitro and in vivo testing.
Working with Rutgers
University and New York’s Hospital for Joint Diseases, Integra conducted
a series of tests to study how well the new polymer material interacts
with living cells. Toxicity and sensitization studies were performed to
assess such issues as tissue compatibility, inflammatory response, bone
growth, and hard tissue response. The results confirmed that the new polymer
does not emit toxic by-products when it degrades and does not have an
adverse affect on tissue or bone. Other tests evaluated the polymer’s
resorption properties, i.e., how the process of bone re-growth interacts
with the degrading polymer. Although the tests were not yet complete at
the time of this study, early results suggest that the new polymer has
resorption rates similar to existing FDA-approved polymers, but does not
cause the adverse secondary reactions due to release of harmful materials.
The polymer’s
mechanical properties were tested and optimized. The results of these
tests indicate that the new polymer can be used in a number of orthopedic
devices, including weight-bearing devices such as large surgical screws.
Integra is also evaluating various composite materials that could be used
with the new polymer to produce materials with a wide range of physical
and mechanical properties. Additional patent applications in this area
are also planned.
Integra forms alliances
with Bionx and Linvatec
With ATP’s support, Integra and Dr. Kohn successfully accelerated
the development of this new polymer to the point that implant device manufacturers
could evaluate the risk associated with commercialization. Two years after
completion of the project, Integra formed two strategic commercial alliances
committed to the development of new orthopedic implant devices using the
new material.
Integra formed an
alliance with Bionx Corporation to develop surgical screws, plates, pins,
wedges, and nails for the fixation and alignment of fractures and for
other musculoskeletal surgical applications. An alliance with Linvatec,
a subsidiary of CONMED Corporation, will develop smaller screws, tacks,
and other arthroscopic fixation devices that will be used to attach soft
tissue to bone in the knee and shoulder. In each case, Integra’s
new commercial partners have agreed to undertake and fund the studies
necessary for FDA approval, a commitment neither Bionx nor Linvatec would
have made were it not for the accomplishments of the ATP project. Both
partners expressed the expectation that their first products would be
launched soon, but the various filings and approvals through the Food
and Drug Administration take time, and it is difficult to predict timing
with accuracy.
According to Dr. Brode,
“without ATP, I don’t know that we could have proceeded. We
would be at least five years or more behind where we are.”(2)
Active Diffusion of
Knowledge
In addition to signing licensing deals, Integra has actively promoted
the diffusion of knowledge developed from the project’s technical
accomplishments. Company scientists and other personnel have made numerous
industry and academic presentations on the characteristics of the new
polymer and on the tests of its mechanical properties and biocompatibility.
Two scientists from Integra were invited to speak at an International
Symposium on Polymeric Drugs and Drug Delivery Systems in Boston, August
1998, sponsored by the American Chemical Society. Currently, Dr. Kohn
and Integra’s other personnel have published 15 peer-reviewed articles
dealing with this new polymer, including those for the American Chemical
Society and the Materials Research Society.
A Platform Technology
with Multiple Uses
The new bioabsorbable polymer is a platform technology with the potential
to answer many challenging clinical and commercial needs. Integra has
begun to adapt the technology, which recently won the Thomas Alvin Edison
Award, to new applications including cartilage repair, wound care, cardiovascular
repair, and drug delivery.
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Project
Highlights
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PROJECT:
To develop a new polymer material for making implantable surgical
devices such as screws, plates, pins, wedges, and nails for repairing
fractured bones; to design and develop a scaleable process for making
it; and to assess the polymer’s suitability as an effective
implant material.
Duration: 1/1/94 – 12/31/96
ATP Number: 93-01-0085
FUNDING (in
thousands):
| ATP |
$1,999
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81%
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| Company |
467
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19%
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| Total |
$2,466
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ACCOMPLISHMENTS:
Development of a new class of bioabsorbable polymers based on tyrosine,
a naturally occurring amino acid, was greatly accelerated. This
new polymer can be used to create implants for surgical devices,
such as pins and screws for repairing fractured bones. Implants
made from this polymer do not exhibit the problems of brittleness,
release of toxins on absorption, or the need for surgical removal–all
characteristics of implants made with existing materials. The material
and process for making it were brought to the stage where prototype
devices could be produced for testing and demonstration, and commercial
development partners, in collaboration with Integra LifeSciences
Corporation, could file for FDA approval. The project’s accomplishments
include:
- development
of a process to produce commercial quantities of tyrosine-based
polymers, for which Integra filed a patent in 1997;
- synthesis
and characterization of bioabsorbable tyrosine polycarbonates
and creation of a variety of prototype fixation devices;
- evaluation
of the bioabsorbable polymer through studies of toxicity and sensitization,
which indicate that the new polymer is comparable to existing
biopolymers in terms of its mechanical and resorbtion properties,
and superior in terms of its biocompatible properties;
- diffusion
of new technical knowledge through numerous presentations and
15 publications;
- licensing
of the technology to two commercial partners; and
- recognition
of the technology by the New Jersey Research and Development Council
who presented the Thomas Alvin Edison Award to Dr. Kohn of Rutgers
University for project-related research.
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COMMERCIALIZATION
STATUS:
On September 18, 1998, Integra announced that it had formed two
strategic commercial alliances for the commercial development of
its tyrosine-based polymer. An alliance with Bionx Corporation is
pursuing use of the new polymer to develop surgical screws, plates,
pins, wedges, and nails to be used for the fixation or alignment
of musculoskeletal fractures. An alliance with Linvatec, a subsidiary
of CONMED Corporation, is pursuing use of the polymer to develop
arthroscopic fixation devices such as surgical screws, tacks, and
other anchoring devices to attach soft tissue to bone in the knee
and shoulder. The partners have filed with the FDA for approval,
and forecast their first products will be launched shortly after
approval.
OUTLOOK:
The tyrosine-based polymer technology is a platform technology with
broad applications in orthopedics (fracture fixation), cartilage
and ligament repair, wound care, cardiovascular repair, drug delivery,
and other uses. In the near term, economic benefits are expected
to accrue from the development of a wide range of orthopedic fixation
devices by Integra and its established commercial partners. The
outlook for continued development and commercialization of the technology
is excellent.
Composite
Performance Score:
COMPANY:
Integra LifeSciences Corporation
105 Morgan Lane
Plainsboro, New Jersey 08536
Contact: George L. Brode, Ph.D.
Phone: (800) 762-1574
Number of employees: at project start 32; number of employees
at project end: 129
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_________________
1. “A
Framework for Estimating the National Economic Benefits of ATP Funding
of Medical Technologies,” The Research Triangle Institute Center
for Economics Research, Project number 6715-01 FR, NIST GCR 97-737, April
1998, section 3.
2. Telephone interview with Dr. Brode of Integra,
Nov. 27, 2000.
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of Contents or go to next section.
Date created: April
2002
Last updated:
April 12, 2005
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