ATP Focused
Program: Tissue Engineering
PROGRAM OVERVIEW
Tissue engineering
integrates discoveries from biochemistry, cell and molecular biology,
genetics, material science and biomedical engineering to produce innovative
three dimensional composites having structure/function properties that
can be used either to replace or correct poorly functioning components
in humans or animals or to introduce better functioning components into
these living systems. The material components may be processed from naturally-derived
or synthetic substances or combinations of these. The cellular components
may be of human or animal origin. Proposed methodologies will be required
to comply with all applicable Federal and State guidelines.
The largest market
for this technology is to replace structurally or physiologically deficient
or diseased tissues and organs in humans. Scientists, physicians and surgeons
have played major roles in discoveries that serve as the basis for the
design of tissue engineered products. The availability of tissue engineered
products will change the way that medicine will be practiced in the future
by providing more efficient lower cost alternatives to tissue restoration.
When used in vitro, tissue engineered composites will be useful
for required safety and efficacy tests of potential new drugs and also
may contribute to an understanding of genetic or environmental factors
which may be responsible for the onset of diseases.
Systematic transplantation
of living organs or implantation of organ and tissue replacements began
about 40 years ago. Although providing previously unavailable benefits,
many unsolved problems remain associated with these procedures. There
is a significant shortage of donor organs. More than 10,000 persons have
died during the past five years while waiting for an organ transplant.
Transmissions of infective agents such as the AIDS or hepatitis C virus
are of concern and transplant recipients must remain on costly immunosuppressive
agents for the remainder of their lives. Outcome studies have shown that
survival rates are poor despite the high cost of these procedures.
A multitude of applications
for engineered tissues and organs exist in the human health arena. Examples
include whole organ replacements for life-threatening situations associated
with liver, pancreas, heart or kidney failure, and replacement of lost
skin covering due to massive burns or chronic ulcers. Other applications
include repair of defective or missing supportive structures such as long
bones, cartilage, connective tissue and intervertebral discs; replacement
of worn and poorly functioning tissues as exemplified by aged muscle or
cornea; replacement of damaged blood vessels; and restoration of cells
to produce necessary enzymes, hormones, and other metabolites. Preliminary
data suggest that tissue engineered composites can be designed to cross
the blood-brain barrier and thus have the potential to correct deficits
associated with brain tissues such as found in Alzheimer's and Parkinson's
disease.
The overall economic
goal of this program is to reduce the greater than $1+ trillion annual
U.S. health care costs. This outcome will result from increased efficacy
and reduced costs in the diagnosis, treatment and clinical management
of targeted health conditions.
Industry interest
in this technology sector is evidenced by (1) the large numbers of white
papers they sent to the ATP outlining their ideas for potential advances,
(2) winning proposals in areas of tissue engineering submitted by industry
in ATP's General Competitions, and (3) large attendance by industry of
a workshop held in November 1994 at the National Institute of Standards
and Technology (NIST). This workshop, co-sponsored by NIST, the Food and
Drug Administration (FDA), the National Institutes of Health (NIH), and
the National Science Foundation (NSF) was attended by approximately 250
scientists representing industry, government and academia
(1) Abstracts of some of the program idea
white papers that represent diversified sectors are provided at the end
of this paper. Copies of submitted white papers may be requested from
ATP.
The Advanced Technology
Program (ATP) believes that it can make a real difference in this
still emerging field by conducting a focused program competition
in tissue engineering at this time to accelerate the development
of a suite of highly beneficial and synergistic platform technologies.
The benefits will be widespread as people from many walks of life
receive better and less expensive treatments that extend and improve
the quality of their lives. The sharing of knowledge and ideas
developed through collaborative, peer-reviewed research stimulated
by the ATP will in turn foster further technological advances.
The tissue engineering community is composed primarily of small
businesses with particular specialties. Progress is being made,
but in bits and pieces. To make a substantial advance towards
realizing the rich potential offered by tissue engineering requires
a concerted interdisciplinary effort. It also requires alliances,
joint ventures and cooperation among scientists, developers, manufacturers,
engineers, and clinicians. Funding from the ATP will focus attention,
will unify, intensify, and expand the fragmented efforts of small
firms in the industry by sharing part of the financial burdens
linked with significantly high technical risks, and will encourage
collaborations and sharing of ideas across disciplines and organizations.
TECHNICAL
GOALS AND PROGRAM SCOPE
Technical plans must
address one or more aspects of the design and development of tissue engineered
devices for diagnostic and/or therapeutic use including:
A) biomaterials,
B) cellular
components,
C) manufacturing
processes, and
D) implantation/transplantation
technologies.
Targets may include,
but are not limited to, endocrine, musculoskeletal, cardiovascular, neurological
and vascular systems. Non-biological replacements, made of metals, plastics
or combinations of these including heart valves, heart pacemakers, maxillofacial
implants and total joint replacements are in clinical use at this time.
Therefore, proposals for the development of non-biological implants
such as these which are made from materials designed not to interact with
the host tissue are out of the scope of this program.
Tissue Engineering
seeks to replace damaged or non-functioning tissues and organs with human
and animal equivalents. This would supplant existing treatment modalities
which depend either on the use of therapeutics and drugs or artificial
replacements. Whereas the former may have limited benefit and serious
side effects, the latter may have the disadvantage of poor integration
and adverse reactions with surrounding tissues. Although records of human
part replacements have been known for more than a century (e.g. the replacement
of a confederate soldier's shattered tibia with a tree limb), it is only
in recent years that vital biocompatibility issues are beginning to be
understood and therefore can be addressed to ensure successful long-term
outcomes.
The ultimate success
in the transplantation of engineered tissues or organs resides in the
immunological acceptance of the product by the host as "non-foreign".
An individual's own cells are not foreign, of course, and if used would
not evoke rejection. Differentiated donor cells from another individual,
on the other hand, would likely have one or more surface markers that
would be incompatible to the host. Since the availability of an individual's
own cells at the time of need is unlikely, cost-effective universal donor
cell lines that are non-immunogenic are needed.
A)
In the area of biomaterials, proposals are sought that
address innovations with respect to:
Development and
design of naturally-derived, synthetic or hybrid scaffolding
materials upon which cell growth can occur or which, when implanted,
will evoke specific cellular responses in the host. In order
to achieve the desired physical and chemical features, these
materials may be used individually or in composites but, in
either case, need to have evidence
of biocompatibility.
Development of
biocompatible polymer materials that coat implantable structures.
For coating purposes, biomaterials that prevent adhesion of
circulating proteins that lead to malfunction of the implanted
structures are needed. These biomaterials may be complexed with
active agents such as peptides or other novel molecules.
Biocompatible
materials that encapsulate living cells or groups of cells for
transplantation. These materials require diffusion characteristics
as necessary, for example, in the encapsulation of beta islets
cells for the treatment of diabetes. In this case, the encapsulation
material should be permeable to small molecules like glucose
and insulin but
restrictive to larger molecules that are associated with adverse
immune responses.
Technologies that
would provide more cost effective structure/function design
of novel biomaterials from novel sites such as genetically altered
plants or animals also would fit within the biomaterials scope,
provided that there is evidence of biocompatibility.
B)
In the realm of cellular components, proposals are solicited
that describe technological advances for:
Large-scale culturing
of human and animal cells including skin, muscle, cartilage, bone, marrow,
endothelial and stem cells for use either in replacement therapies for
humans or for targeted differentiation.
Development of
transgenic animals as a source of cells, tissues and organs for use
as xenografts.
Proposed technologies
that would lead to optimization of target-determined biological and
physical properties of cells either through genetic or environmental
manipulation are within scope of this program.
To achieve acceptance,
donor cells need to be used that will not have surface markers to evoke
an antibody response by the host which, in turn, could lead to rejection.
Primitive stem cells satisfy this criterion since they do not yet express
major surface antigens such as the histocompatibility MHC I and MHC II
loci. (2) Another
possibility is exemplified by a treatment modality called myoblast transfer
therapy. When grown in in vitro, myoblasts (immature muscle cells)
divide, migrate, form myofibers and, in the process, hide the antigenic
determinants. In this scenario, implantation of cultured myoblasts from
a normal donor would fuse with defective myoblasts in the patient's body
and thereby contribute the missing functions.
(3) (4)
Two additional cell associated parameters with application to tissue engineering
have been identified recently and are being studied by many investigators.
In the first instance,
it has been demonstrated in vitro that applied external physical
forces on progenitor cells can direct their differentiation.
(5) (6)
Thus, for example, appropriate tension applied to cells of mesenchymal
origin will result in tendon cell formation. Such findings suggest that
engineered cell transplants can be increasingly fine tuned by application
of external physical forces. Transplantation of tissue engineered tendon
or tendon progenitor cells under the proper physical conditions may eliminate
the major hurdle to excellent surgical results by inhibiting adhesion
formation.
The second finding
relates to apoptosis or programmed cell death.
(7) It appears that our body's constituent
cells have inherent biological clocks that are programmed to carry out
their function for given periods of time before the nuclear DNA breaks
apart "spontaneously". This mechanism explains many previous observations
that described loss of cellular structure or function. It is common knowledge,
for example, that decreased muscle strength and decreased memory retention
accompany aging. Transplantation of active myoblasts to restore normal
muscle strength or active neuronal cells to increase retentive powers
could result in 30+ million people gaining physical and mental independence.
This is particularly important as the population in the United States
is growing older
C)
In the area of manufacturing processes, technology advances
that would enable tissue engineered products to be available to large
patient populations at reasonable costs are sought:
Innovative methods
to enhance automation and scale-up of bioreactors for cell growth without
compromising cellular integrity are sought. The retention of the desired
genotypic and phenotypic expressions through many passages is of particular
importance.
To ensure uniformity
of products and retention of functionality through multiple in vitro
manipulations, proposed technologies may address manufacturing processes
for use of biomaterials as encapsulating agents for biologically active
cells or for use as scaffolds.
New designs and
improved methods for sterilization, storage and transport of tissue
engineered products, including 3-dimensional composites of cells and
biomaterials for safety and efficacy measurements.
D)
Creative solutions are sought to advance transplantation/implantation
technologies, and ensure that tissue engineered devices can be
diffused broadly into a multitude of different environments. Technologies
are needed that will broadly enable the design of easily available devices,
and tests to monitor the transplantation/implantation procedures and subsequent
functional/structural integration for ultimate use in humans.
Exclusions
from technical scope include the following:
1) materials that
do not support cell growth or evoke a favorable biological response
2) materials that
do not have evidence of biocompatibility
3) unbounded searches
for totally new biologically active materials
4) development of
transgenic animal systems for non-tissue engineering related purposes
5) development of
devices or diagnostic kits that do not contain tissue engineered components
ECONOMIC GOALS
AND SCOPE
The overall goal of
the Tissue Engineering Focused Program is to promote U.S. economic
growth by focusing on the development of a tissue engineering industry
that would have global preeminence. Significant societal benefits in terms
of extended and improved life years are expected to emerge. The acute
and chronic shortage of donor tissues and organs, will make these devices
life-saving in many instances. Furthermore, development of readily accessible
and transportable tissue engineered devices will make new treatment modalities
available worldwide and thus result in high market revenues and in high-value
jobs for the U.S. To be in scope, business plans of proposals
must contribute to the overall goal of reducing direct hospital and medical
costs, as well as those costs associated with the long-term care of the
ill or disabled. Therefore, it will be necessary to estimate
to what extent, the proposed project is expected to contribute to lower
direct health costs by one or more of the following:
- Creating biocompatible
replacements for diseased, missing or non-functioning tissues and organs.
- Engineering cells,
tissues, and organs in transgenic animals for use as xenotransplants.
- Designing and testing
new technologies for making biologically active extracorporeal devices
to manage organ failure until donor organs become available.
- Finding methodologies
to develop reliable tools that will result in "off-the-shelf" tissue
engineered products for in vitro and in vivo use.
- Isolating or synthesizing,
purifying, and testing new biocompatible materials.
Indirect health
care cost reductions that may be addressed include discussion of how the
proposed technology will:
- Prevent health-dependent
early retirement.
- Remove people from
disability rolls.
- Increase exports
of tissue engineered products.
- Increase family-member
productivity by eliminating the need for "stay at home" care.
- Create jobs in
biomedical and biotechnology industries.
With the support of
this program, the tissue engineering companies dedicated to the health
care field will develop the necessary tools and knowledge to design and
fabricate extracellular matrices for prostheses and for cell growth. Ultimately,
this will provide replacement structures which will have functional equivalence
to the original tissues for which they serve as substitutes. Applications
include a large number of diseases and injuries including those associated
with bone, cartilage, tendons, connective and brain tissues and blood
vessels. Furthermore, functional 3-dimensional devices made from transplantable
biologically active materials will be able to serve as artificial organs
such as pancreas, liver, heart and kidney. Associated with these advances,
3-dimensional composites have the potential for in vitro applications.
POTENTIAL
FOR U.S. ECONOMIC BENEFITS
The total spending
for health care in 1994 was $991 billion. (8)
This included spending by consumers, private insurance companies and federal,
state and local governments including Medicaid and Medicare. Nearly seventy
percent of this spending was for costs associated with hospital care ($393.6
billion), physicians' services ($208 billion) and nursing home care ($84.7
billion). The remaining $305 billion were expended for other professional
medical and dental health services, government public health activities,
private health insurance, drug and medical sundries, research and construction
and additional personal health care costs. It is estimated that tissue
engineering may address diseases and disorders that account for about
one-half of the existing total health care costs
(9) (10)
(11) which,
by 1995 already had climbed to about $1+ trillion.
(12) Data from the Office of the Actuary
of the Health Care financing Administration indicate that even though
there was a 4.6% increase in Gross Domestic Product, the average increase
in national health expenditures increased by 5.5% between 1994-1995.
(13)
The diseases that
potentially can be treated with tissue engineered products have large
direct and indirect costs. For example, the cost per patient for a liver
transplant is $256,000 over five years, with $215,000 for the first year.
Of the 4,166 liver transplants that were performed between 1987 and 1989,
2,279 recipients survived five years. The total medical costs for this
five year period for these survivors and the 1,887 who died before the
end of the five year period were $960 million.
(14)
An extracorporeal
tissue engineered device that can serve as an artificial liver is close
to receiving FDA approval. In the short term, this device will be life
saving for patients waiting for a donor organ replacement. Ultimately,
functional implantable 3-dimensional devices have the potential to obviate
the need for donor organs entirely. For example, if the cost of such a
device plus the cost of associated surgical procedures were to be $50,000
and if the follow-up costs were to be $2,000 per year for five years,
then approximately a four-fold reduction in cost over a five-year period
could be predicted. Not only would this be a reduction in costs from present-day
therapy, but survival rates would be expected to be improved and the quality
of life for the patients would be better. It is estimated that the development
of such a device would be accelerated at least five years with ATP funding.(1-14)
(15)
(16)
(17) (18)
Other organ transplants including heart, kidney, and lung are equally
costly. The total five year costs per kidney transplant performed between
1987 - 1989 was greater than $ 70,000. (19)
Comparable savings will be attainable with tissue engineered replacement
devices for these disorders.
The annual direct
and indirect costs of diabetes mellitus is $120 billion which represents
11.6 percent of the total personal health care expenditures in the United
States. At this time, insulin injections or pump-delivery of insulin are
the accepted treatment protocols for diabetes. Although effective in preventing
near-term complications, recent studies have demonstrated that the wide
swings in blood glucose levels associated with these therapeutic modalities
are the bases of the costly and life-threatening secondary complications
associated with the disease. These secondary complications include blindness,
kidney disease, limb amputations and heart disease. A great need exists
to find a therapeutic mechanism that reproduces the instantaneous response
of the normal pancreas to changing glucose levels. Successful transplantation
of an effective artificial pancreas manufactured with the use of encapsulation
technologies of isolated beta islet cells would produce such desired results
in diabetic patients. These benefits have been demonstrated at a research
level in large animal models, including dogs.
As mentioned, diabetes
and its associated secondary illnesses including circulatory, retinal,
and renal complications consume over ten percent of the total health care
cost of the United States. Expenditures to treat diabetics could be significantly
reduced by creating an artificial pancreas which is equivalent to a normally
functioning organ. A prototype of such a device has been implanted in
two patients who were in critical condition.
(20) Research and development are needed
to upscale cell production, chemically modify and mass produce the biomaterial
used for encapsulation, and design and implement manufacturing conditions
to produce devices for the millions of patients who need to be treated.
If the cost of the artificial pancreas were to be put at $20,000 per device,
then the anticipated market could be $1 billion per year for the more
than 14 million Americans with diabetes. (21)
The total annual expenditure to treat diabetes and its secondary effects
could be reduced ten to twenty-fold.
Other disorders, including
Parkinson's Disease, epilepsy, hemophilia, and Alzheimer's Disease, could
be treated with the use of tissue engineering technologies by encapsulation
and implantation of the appropriate cells. By replacing damaged or non
functioning tissues and organs with functionally equivalent composites,
important gains will be achieved both in improving the quality of life
and reducing the total health care costs. In Parkinson's disease, successful
transplantation of dopamine secreting cells is projected to reduce the
total costs (lost income + direct medical cost + long term care) associated
with the disease in the year 2010 from $11 billion to $8 billion (14).
Present-day tissue
replacements with non-biological products such as metals and plastic
already have provided benefits to the U.S. economy. In the United
States, for example, more than 250,000 total hip replacements
are performed annually on patients ranging from 30 to 90 plus
years of age.
(22) In nearly all cases, post-surgical
success as measured by elimination of pain and suffering and restoration
of functional mobility is good to excellent. Most patients can resume
a lifestyle similar to that practiced before hip disease became an issue.
When average lifetime earnings of patients were coupled to the number
of hip replacements performed up to 1988, it was found that the added
earnings to the U.S. economy from the return to work by successful hip
replacement recipients was greater than $10 billion (22).
Although surgical successes continue, hip implants do wear out and
need revisions or replacements. This is particularly evident in the
younger patients who have returned to an active lifestyle. There were
2.7% and 12.9% increases in hip and knee revisions, respectively, from
1993 to 1994 .
(23) Revisions or replacements are costly,
do not appear to function as well as the initial implant and also lead
to lost earnings. (24)
Therefore, successful development of permanent tissue engineered joint
replacements would be of even greater economic benefit.
INDUSTRY COMMITMENT
AND NEED FOR ATP
More than 50 white
papers in support of a tissue engineering program were received from companies
engaged in varying aspects of tissue engineering research and development.
Typically, results of early research licensed from university-based institutions
funded by grants from NIH, NSF and private entities such as the Pugh foundation,
American Red Cross, and Howard Hughes Foundation, serve as the basis for
development of tissue engineered methodologies. Newly discovered technologies,
licensed to "start-up" companies, often will continue to be developed
under the guidance of the scientific inventor or discoverer and with limited
funding from private placements, other investors, and state-supported
seed money. Although initial feasibility studies are positive, many technical
challenges and areas of high risk remain to make these technologies be
of benefit for humanity. These include:
- Design and implementation
of cost effective scale-up for cell growth in a manner whereby there
is no change in genotypic and phenotypic expression and no adventitious
agents are introduced during in vitro manipulations
- Defining and designing
conditions for long-term tissue and cell storage that will make products
globally available in varying environmental conditions
- Developing technologies
for the efficient manufacture of biocompatible materials derived from
transgenic plants and animals or chemical synthesis that ensure product
homogeneity and retention of chemical structure and biological activity
- Increasing duration
of functionality for tissue engineered devices by including chemical
and physical properties that inhibit potentially adverse reactions in
the host
- Engineering universal
donor cell lines that are multi-potential and non-immunogenic in human
recipients
The demand for these
products are clearly present. The quality of health care available in
the United States is unmatched. Indeed, as the media including television
brings the United States' technical achievements to the world stage, the
clamor for these features are heard globally. Therefore, long-term business
strategies should aim at maximizing investments into final products for
national and global markets.
Many of the companies
involved in Tissue Engineering are small and the research is high
risk. ATP funds are needed to reduce the major research risks
to advance this technology to the point where it becomes a core
investment for this industry sector. Furthermore, ATP's support
of a National Platform in Tissue Engineering can promote and support
working alliances between and amongst companies with complimentary
ideas and technical abilities. ATP's support is needed to help
bring this emerging technology over the initial technical barriers
toward commercialization and thus assure that the resulting multi-billion
dollar benefits become part of the United States economy.
REFERENECES
1. Presentations were published in: Tissue Engineering (1995) 1: 147-228
2. Business Week, December 6, 1993
3. Fang Q, Chen M, Li HJ et.al. "MHC-I Antigens on Cultured Human Myoblasts"
Transplant Proc (1994) 26: 3467-3471
4. Law P, Goodwin T, Fang Q et. al. "Whole Body Myoblast Transfer" Transplant
Proc (1994) 26:
3381-3383
5. Berthiaume F, Toner M, Tompkins R., Yarmush M, "Tissue Engineering"
in Implantation Biology: The Host Response and Biomedical Devices, ed.
RS Greco, CRC Press, 1994
6. McNamee HP, Liley HG, Ingber DE "Integrin Control of Inositol Lipid
Synthesis in Vascular Endothelial Cells and Smooth Muscle Cells" Exp Cell
Res (1996) 224: 116-122
7. Strater J, Wedding U, Barth TF et. al. "Rapid onset of apoptosis in
vitro follows disruption of beta 1-integrin/matrix interactions in human
colonic crypt cells", Gastroenterology (1996) 110: 1776-1784.
8. Healthcare Financing Administration, Division of National Cost Estimates,
Department of Health and Human Services 1995
9. Langer R, Vacanti, JP, Tissue Engineering, (1993) Science 260: 920-926
10. Nerem RM, Sambanis A, Tissue Engineering: From Biology to Biological
Substitutes (1995) Tissue Engineering 1: 3-12
11. Wilkerson Group, Inc. , Research on Market Potential for Tissue Engineering,
February 1992
12. The Washington Post, September 1996
13. Office of the Actuary, Health Care Financing Administration, Department
of Health and Human Services
14. Calculations based on data in "The Market for Artificial Organs and
Tissues in the U.S.., Theta Corporation, 1995
15. Lysaght, MJ, Division of Medicine and Biology, Brown University, Rhode
Island Center for Cellular Medicine, April 1996
16. Rozga J, Morsiani E, LePage E, Moscioni AD, Giorgio T, Demetriou AA,
Isolated Hepatocytes in a Bioartificial Liver: A Single Group View and
Experience (1994) Biotechnology & Bioengineering 43: 645-653
17. Poynard T, Barthelemy P, Fratte S, et al.
Evaluation of efficacy of liver transplantation in alcoholic cirrhosis
by a case control study and simulated controls, (1994) The Lancet 344:
502-507
18. American Liver Foundation, Vital Statistics of the United States,
Vol 2, part A, 1988
19. Companies with Research and Development efforts in Tissue Engineering,
Institute for Biotechnology, November 1994
20. Soon-Shiong P, Heintz RE et.al.
Insulin Independence in a Type I diabetic Patient after Encapsulated Islet
Transplantation, (1994) Lancet 343: 950-951
21. The New York Times, May 1993
22. Praemer A, Furner S, Rice DP, Musculoskeletal Conditions in the United
States, (1993) American Academy of Orthopaedic Surgeons
23. "Clinical Aspects" in Implant Wear: The future of Total Joint Replacement,
ed. TM Wright and SB Goodman, pp 3-5, American Academy of Orthopaedic
Surgeons (1996)
24. BierbaumBF, Engh CA, Harris WH, Rosenberg AG "Revision Total Hip Arthroplasty:
Controversies in Fixation of the Stem", (1996) American Academy of Orthopaedic
Surgeons, #242
Date created: August
3, 1997
Last updated:
April 11, 2005
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