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 Advanced Technology Program (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 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 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.

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.
• Improve quality of life.

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.

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 ^(15-18). 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.

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.

Technical Contacts

Mrunal Chapekar, Ph.D., Program Manager
E-mail: mrunal.chapekar@nist.gov
Phone: 301-975-2587
Fax: 301-926-9524

Andrew Klein, Business Manager
E-mail: andrew.klein@nist.gov
Phone: 301-975-4292
Fax: 301-926-9524

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: February 1997
Last updated: April 12, 2005