NOTE: From 1994-1998, the bulk of ATP funding was applied to specific focused program areas—multi-year efforts aimed at achieving specific technology and business goals as defined by industry. ATP revised its competition model in 1999 and opened Competitions to all areas of technology. For more information on previously funded ATP Focused Programs, visit our website at http://www.atp.nist.gov/atp/focusprg.htm.

Bioengineering of Cellular Signal Transduction.

Jerome S. Schultz, Center for Biotechnology and Bioengineering, University of Pittsburgh.

950066

This paper focuses on the development of implantable biosensors that use living cells as the transduction element. This approach represents a merging of biosensor and tissue engineering technologies. The technology is applicable particularly, although certainly not exclusively, to the aging population which, in this manner, could be monitored continuously in a "non-medical" environment. The cost of healthcare will be reduced and the quality of life will be greatly enhanced.

Tissue Engineered Cardiovascular Implants

Robert M. Nerem, Ph.D., Institute Professor and Parker H. Petit Chair, Georgia Institute of Technology, Atlanta, GA.

950028

This paper focuses on the development of the next generation of cardiovascular implants. It is anticipated that implants of both blood vessel substitutes and cardiac valves , engineered from living cells and biomaterials, will not only have extensively longer lifetimes but also will eliminate the need for costly lifelong antithrombotic and antibiotic therapy as well as for periodic replacement devices. It is anticipated that these tissue replacements will allow for self-repair and physiologic adaptation to their environment.

Autologous Tissue Engineering Applications

James R. McNab, Jr., Chairman, Reprogenesis Inc., Dallas, TX

950031

This paper focuses on the need of government investment to help industry bring the proven core technology of tissue engineering to the market place by supporting studies that will result in manufacturing processes which are efficient and cost-effective for the production of safe and effective tissue-engineered devices. Research & Development in Tissue engineering is driven by market size which is exemplified by companies working on diabetes and orthopaedic treatments. Reprogenesis is addressing the niche markets of urological disorders and breast reconstruction and augmentation where sizable markets have been identified. Three products which use autologous tissues for: (1) treatment of vesicoureteral reflux which affects one in ten newborns, (2) treatment of Type III stress incontinence for which over $10 billion is spent annually (NIH report) and (3) breast implants of which 250,000 procedures are conducted in the U.S. annually, are in development. The need for ATP support is to expedite the development of needed tissue engineered products for which the competitive edge presently is held by the U.S. because of its advanced research but which will become an endangered species as foreign investments come in for development and marketing opportunities.

Support for a focused program in Tissue Engineering

Steven A. Shaya, Ph..D., Corporate Director, Johnson & Johnson, New Brunswick, NJ

950100

This document brings support from the J&J Family of Companies ($15 billion annual sales and $5 billion in medical device sales) for tissue engineering. J&J has an internal tissue engineering program and also sponsors research at academic institutions. The company is particularly interested in the development of new manufacturing techniques for three dimensional structures with applications to medical devices and tissue constructs in the areas of cardiovascular, dermatological, orthopaedic, neurological, musculoskeletal and diagnostic areas.

Support for a focused program in Tissue Engineering

John M. McPherson, Ph.D., Vice President, Genzyme Corporation, Cambridge, MA

950099

This document comments on the draft of the White Paper from November 1994 and suggests that naturally derived or synthetic scaffolds should also be considered as a matrix for cell differentiation as well as proliferation. Recent evidence suggests that the extracellular matrix can play an inductive role in cell differentiation. Furthermore, Dr. McPherson suggests that the role of cytokines in the area of tissue engineering should be considered (this actually had been mentioned in the White Paper).

The paper stresses the Company's belief that support in tissue engineering will lead to significant patient benefit and ultimately reduce the cost of health care. Genzyme already markets "EPICEL" , an autologous keratinocyte graft to treat serious burn victims. The product has been credited with life-saving procedures. The Company is developing autologous chondrocytes for treating focal defects in cartilage of knees. A recent Publication in "The New England Journal of Medicine" demonstrated long term good results of such defects in several patients. Much remains to be done in the area of development.

Anastomosis and Regeneration of Severed Blood Vessels

John R. Castle, NuFlo Corporation, Bellevue, WA

In collaboration with:

Biosupport Inc.
Davis & Geck Co.
Mold Rite Corporation
Batelle Northwest Laboratory
Seattle V.A. Hospital
Loyola University Medical Center
University of Pittsburgh Medical Center
University of Washington Medical Center

This paper describes how regenerating tissue on bioabsorbable templates, either ex-vivo or directly at the site of injury, will permit damaged or missing tissue to regrow in a properly organized manner. In particular, NuFlo is developing bioabsorbable endoluminal connectors which will allow rapid anastomosis of severed blood vessels without suturing. The proposed devices are designed to provide support without thrombus formation during healing and then be reabsorbed by the body after healing to avoid term damage.

It is estimated that a savings of $280 to $1680 per operation that involves end-to-end vessel anastomoses will be realized by the use of this new device. It is estimated that there are close to three million procedures annually where this may occur.

Industry commitment is reflected in the teaming relationships that NuFlo has established to help develop the technology into a product which can then be brought to market.

Program Idea for Focused Program in Tissue Engineering

Ben Bronstein, M.D., President and Daniel S. Cutter, Ph.D., Nephros Therapeutics Inc., Waltham, MA and W.R. Grace Company, Boca Raton, FL

950086

This paper addresses the obstacles that must be overcometo move the promising "Tissue Engineering" technology - the brink of a new era in the healing arts - from the incubator of the experimental laboratory into the rough and tumble world of commerce. American science has produced the significant insights and new technologies and American companies are poised to speed the new products into the world marketplace. However, European and Japanese corporations are tapping US laboratories, eagerly seeking opportunities to participate. The authors discuss the costs and risks of necessary core technologies that would provide the infrastructure necessary to move these technologies to market. The healing technology must be reproducible and cost effective. The Grace-Nephros collaboration is concerned with developing bioartificial replacements for solid organs within the abdomen. ATP funding is necessary to provide the crucial bridge that cerries tissue engineering technology to the point where it becomes a commercial-grade risk.

Support of a Program Proposal for Tissue Engineering

Peter C. Johnson, M.D., Director, Pittsburgh Tissue Engineering Initiative and Reed E. McManigle, JD/MBA,, Pittsburgh Tissue Engineering Initiative, Pittsburgh, PA

950019

This submission describes The Pittsburgh Tissue Engineering Initiative (PTEI) which is designed to foster the growth of a tissue engineering industry in the Pittsburgh region. It will facilitate interdisciplinary collaboration, promote and market related research activities, aid in commercializing viable technologies and bring together managerial and financial resources to support commercial ventures. The PTEI believes that Tissue Engineering has reached the stage of intellectual development such that it is becoming commerically viable and that commercial exploitation of tissue engineering technology will create market opportunieites of significant proportions. The PTEI will rely on discoveries and early development in Genetics, Transplantation Immunology, Cancer, Thrombosis, Biomaterials, Bioengineering and Rehabilitation Science from the Univervsity of Pittsburgh and in Computing, Robotics, Entrepreneurialism, Engineering Design, Bioengineering and Imaging Technology from Carnegie-Mellon University

Tissue Engineering

David L. Clapper, Ph.D., Director of Cell Biology, BSI Corporation, Eden Prairie, MN

950018

This submission emphasizes the development of bioactive implant devices that are to be implanted in patients and that subsequently engineer a desirable response from the patients' own tissues. In addition, this paper emphasizes the important goal of "..providing cultured tissues or biologically - active prostheses to replace diseased or non-functioning tissues." The replacement devices/tissues (new and improved) that would result from a successful tissue engineering program would expand the U.S. economy by several times the $5 billion that are spent at this time worldwide per year solely on orthopaedic and cardiovascular prostheses. BSI has broad patent coverage on the use of photochemistry to modify device surfaces with appropriate proteins in order to produce desirable "in vivo" tissue responses This technology has been applied to vacular grafts, model breast implants, artificial corneal lenses, hip and dental implants, and catheters. A specific example where ATP would make a difference is cited with respect to the development of a small diameter (<6 mm) vascular graft that could be used in coronary bypass surgery. It is estimated that it will take about 5 years to demonstrate safety and efficacy in animals for this project. If success is indicated by year three, for example, it is thought that many cardiovascular device companies would step in to commercialize the technonology at this time.

Tissue Engineering Using Tissue-Specific Cells

Joseph P. Vacanti, Associate Professor of Surgery, Harvard Medical School, Boston, MA

950023

This paper addresses a core technology in tissue engineering using tissue specific cells on temporary synthetic degradable scaffolds to produce devices which, when implanted, will turn into a totally natural new tissue to act as a substitute tissue for replacement therapy. In every subspecialty of surgery, the fundamental rate limiting problem has to do with tissue and organ scarcity. Reconstructive coronary artery surgery is limited by the availability of blood vessels suitable for bypass. Transplantation surgery, whether it be liver, kidner, lung, or heart is limited by the ever increasing donor scarcity. In the economic domain, surgical reconstruction has enormous impact on the U.S. healthcare system. The United States spends $526 million per year for 3,500 liver transplant operations and over $400 billion dollars per year on loss of tissue or end stage organ failure. Tissue engineering offers the hope of delivering the replacement function in a much more cost-effective and beneficial way. Tissue engineering, although in its infancy, has the potential to change the way medicine and surgery are currently practiced. It can provide needed tissue to not only alleviate suffering but actually prevent death in those situations where the tissue is necessary for life-sustaining function.

Tissue Engineered Cardiovascular Device and Beyond...A vision for the Future

Toad Campbell, Manager, Bioscience, St. Jude Medical Inc., St Paul, MN

950051

This paper addresses a Technology Platform of human tissue engineering that will generate tissue engineered human heart valves, peripheral and coronary vessels and cardiac muscles that will revolutionize the treatment of CVD in the United States and the World.

The initial focus is on the development of a tissue engineered heart valve that will have the potential of integrating, growing and repairing as if the patient's own tissues. This will be a "living" device platform and should replace the current forms of heart valve replacements which all are passive devices.

Tissue Engineering

Teresa M. Grillot, M.S., Director Health Economics and Reimbursement and Gail K. Naughton, Ph.D. Executive Vice President. and COO, Advanced Tissue Sciences, La Jolla, CA.

950087

This paper addresses the tissue engineering technologies that Advanced Tissue Sciences is using to provide solutions to the existing shortage of organs for transplantation. Advanced Tissue Sciences (ATS) has replicated a variety of human tissues including skin, cartilage, liver, bone, cardiovascular and other tissues. Skin replacements could benefit 600,000 patients with diabetic foot ulcers and over 13,000 severely burned patients. Cartilage tissue could be used to repair defects in about 500,000 orthopaedic cases. Tissue replacement also could be used in over 500,000 patients subjected to cardiovascular procedures involving heart valves or vessels. Although only 3500 patients received a liver transplant in 1993, over 30,000 died from chronic liver disease.

Tissue engineering offers the possibility of tissue replacements that could be readily available and have long shelf life. ATS is commited to apply advances in tissue engineering to improve patient care.

As part of the program, ATS has made advances in the scale-up of living systems, bioreactor technology, and new methods of cryopreservation necessary to efficiently transport living human tissue to physicians and patients for optimal use.

ATS technology allows the creation of three-dimensional completely human tissues by providing a growth environment for cells that closely mimic those found in the body. The cells attach, divide and secrete the same extracellular matrix proteins and array of growth factors that occur in the body. ATS is developing systems to be shipped stored and available "off the shelf" for physicians use.

The technical challenges include large-scale cell culture systems, nutrient transport, sterilization, and cryopreservation of the transplants, as well as cell sourcing, design of the polymer devices and signals to direct cell growth and maintenance of differentiated function.

Applications for ATS products include partial or full-thickness burns treatment with "Dermagraft-TC" which is in clinical trials. This treatment reduces the number of needed surgical procedures per patient, fewer reconstructive surgeries, less lengthy rehabilitation. Similar accelerated healing and decreased need for follow-up surgeries has been shown in a clinical trial that measures healing of diabetic, venous and pressur ulcers with the use of "Dermagraft".

Working with St. Jude Medical, ATS is developing a heart valve that consists of human cells grown on acellular porcine matrices. Implantation of these heart valves should reduce calcification and improve durability of these replacement devices (now needed with porcine heart valves) and therefore decrease the need to be on anti-coagulants to reduce risk of thrombosis. Ultimately, a fully human, tissue engineered heart valve should be able to allow normal growth at any age.

Another application for tissue engineering technology is to repair or replace segments of blood vessels that are weakened , damaged or obstructed. Presently available grafts constructed from PTFE or Dacron suffer from platelet aggregation, leakage, minimal tissue infiltration and lack of elasticity.

Acute liver failure affects about 30,000 person per year. Few functioning healthy livers are available for transplantation. Furthermore, liver transplantation is costly and failure rates are high. Long-term solutions to this problem are being addressed by making liver tissues for transplantation from liver cells grown "ex vivo" on biodegradable biopolymers. Since liver has more than one cell type, this is a complex problem. In the interim, a short-term, life-saving rescue device is being developed that is an external liver assist device (similar to dialysis) which is being engineered in a small enough enclosure to be portable.

Over 500,000 orthopaedic patients per year in the United States could be candidates for cartilage replacement. At this time, serious cartilage defects in the hip and knee are handled by replacements of these joints with artificial prostheses. ATS with Smith-Nephew is developing a cartilage replacement tissue that will be constructed from human chondrocytes grown "ex vivo" on a biodegradable polymer that can be administered by arthroscopic surgery.

Whatever the device, a multi-disciplinary approach in the research, development, optimization, testing and manufacturing of tissue-engineered products is needed to bring these products to market. ATP will force novel liaisons that will accelerate and leverage industry's investment in higher risk research and development that harbors greater payoffs in the form of unlimited tissue and organ availability and sustained competitiveness in a worldwide market that will never see a fulfillment of organ and itssue needs without tissue engineering.

Review of Draft Proposal in Tissue Engineering

Roy D. Crowningshield, Ph.D.,Senior Vice President Science and Technology, Zimmer Warsaw, IN

950071

This paper reviews the NIST draft on Tissue Engineering prepared in October 1995 and comments that in the area of Orthopaedics the most likely successfully engineered orthopaedic tissue will be articular cartilage for isolated defect repair.

Review of Draft Proposal in Tissue Engineering

Henry S. Kingdom, M.D.,Ph.D., Vice President, Clinical and Regulatory Affairs, Baxter, Round Lakes, IL

950072

This paper indicates that of the Tissue Engineered areas addressed in the 1994 NIST Draft, former BAXTER executives head companies in the field of skin and cartilage and that Baxter, itself, has initiatives in the areas of kidney and pancreas transplants and an active inhouse program in hemophilia and heart valve and blood vessel replacement. Thus Baxter is actively involved in 4 of the 5 areas identified in the NIST draft.

Synthetic bilayer collagen saphenous vein analogue; an application of tissue engineering

Paul Termin, D.V.M., Ph.D., Vice President, Organogenesis, Inc. Canton, MA

950073

This paper addresses the design and fabrication of collagen-based small diameter arterial vascular prostheses to replace the transplantation and re-implantation of autogenous saphenous veins or synthetic materials that are presently used as replacement arteries in surgical procedures. Replacement arteries are needed to restore normal blood flow in heart disease patients with arterial plaques and to restore circulation in distal limbs of patients with collapsed arteries. Atherosclerotic heart disease (ASHD) can affect the function of most organs of the body and often require either an interventional radiologic or cardiology (angioplasty) procedure or a surgical procedure (bypass graft). These procedures, in turn, use replacement parts for damaged blood vessels. Replacement materials used at this time, such as the synthetic Teflon (PTFE) or Dacron (PET) conduits, often evoke an adverse reaction in the host and therefore need to be replaced. Transplantation of the saphenous vein from the thigh region to the heart not only requires two surgical procedures but also the vein's ability to tolerate arterial pressures is limited. Therefore, the need for a substitute that will both be biocompatible and serve well under high arterial pressures. At this time, there are about one million procedures conducted annually that require blood vessel replacements.