EUROPEAN  TISSUE  REPAIR  SOCIETY

SMITH & NEPHEW

Smith & Nephew is a focused high-technology Medical Devices business, with leading global market positions in Orthopaedics, Wound Management and Endoscopy.

However, its founding origins are very much in the manufacture of Wound Healing products and we have continually striven to provide the best solutions to our customers' problems, and to identify the most appropriate advanced technologies. With this in mind, Smith & Nephew has worked with its partner, Advanced Tissue Sciences, for over seven years to develop a unique solution to the problem of Diabetic Foot Ulcers (DFUs).

In late 2001, Smith & Nephew gained FDA approval for Dermagraft - a metabolically active Human fibroblast -derived Dermal Replacement for the treatment of Diabetic foot ulcers. This pioneering product is currently one of only a small number of Tissue Engineered products available and approved for medical use. Whilst not commercially available across Europe, it is available in the USA, Canada, Finland, Australia and South Africa.

Overview

Each year disease, accident, congenital abnormalities and defects cause millions of people in the United States to experience tissue loss or end-stage organ failure.1 The economic expense of these conditions is staggering, more than $400 billion per year,2,3 but it may not come close to the immeasurable, permanent impact that these conditions have on patients' quality of life.

The goal of tissue engineering, a dynamic interdisciplinary field that combines the principles of the life sciences and engineering, is to develop biological substitutes for damaged tissues and organs. Using living cells, bio-chemicals (this was always an odd word to me), and synthetic materials, Tissue Engineers (an eclectic group that include chemical engineers, chemists, material scientists, cell biologists and surgeons) have already begun to develop tissues as varied as skin, cartilage, blood vessels, bone and liver. Begun in earnest in 1987, the science of tissue engineering, which spans both the medical device and biotechnology industries, is now moving rapidly from the lab to implantation into patients in both physicians' offices and operating rooms around the globe.

The Need for Tissue Engineering

Standard treatments for organ or tissue loss include transplants from healthy donors, surgical reconstruction (involving synthetic implants in many cases), and the use of mechanical devices such as kidney dialyzers.1 While these treatments can save lives and/or decrease morbidity, each has significant drawbacks and most are associated with substantially decreased quality of patient life.

Several of the problems associated with standard treatments for organ and tissue loss include the severely limited number of donor organs, the need to replace malfunctioning or rejected donor tissue, the safety of donor organs (with regard to transmission of communicable diseases from the donor to the recipient), the inability of mechanical or artificial organs to perform all of the biological functions of natural organs, and otherwise less-than-optimal outcomes.

In addition, in the case of tissue loss associated with chronic wounds such as pressure, venous and diabetic foot ulcers, there are limited therapies currently available; medical professionals work to induce natural wound healing, but this healing process is often thwarted by unresolved disease and other factors. For example, diabetic foot ulcers, which occur in people with diabetes, are often slow to heal. One result of these non-healing ulcers is nearly 86,000 lower extremity amputations every year.4

Advantages of Engineered Tissue

By using the body's own cells to produce bioengineered tissues and organs that function like their natural counterparts, tissue engineering may offer a better solution for the repair and reconstruction of damaged tissue and organs. There are numerous potential advantages to tissues and organs developed through tissue engineering, including:

Availability:

A distinct advantage is that tissue engineered products can be manufactured, so physicians and their patients may no longer have to depend on the limited supply of donor organs and tissue. As a result, physicians may be able to intervene before their patients become critically ill, thereby avoiding additional medical intervention and hospital stays. Availability also means that patients and their families can be spared the often agonizing search for obtainable, suitable organs or tissue.

Specific indications and optimal outcome:

Tissue engineering allows for the development of products that are uniquely suited for their intended use and, accordingly, provide a better outcome for patients. For example, tissue engineering helps provide better patient outcomes in the treatment of severe burns.

Cadaver skin, the current standard for temporary coverage of large, third-degree (full-thickness) burns, may be rejected within one to three weeks of its placement, increasing the risk of bacterial infection, potentially necessitating reapplication. Initial rejection may result in more rapid rejection of subsequent allografts, and repeated allograft applications increase the cost of care and the potential risk for life-threatening infections. Tissue engineered skin does not share the same risks of rejection, potentially improving outcomes for burn victims.

Lower total health care costs:

Tissue engineered products are expected to ultimately lower total health care costs. By replacing a diseased tissue or organ with a fully functioning, healthy substitute, the need for ongoing or repeat medical care, as well as all related health expenses, could be greatly diminished.

Reduced risk of disease transmission:

Tissue engineered products substantially reduce the risk of disease transmission from donor to recipient, which can be significant and life-threatening. For example, cytomegalovirus (CMV) affects approximately 50% of the U.S. adult population and can be transmitted from donor to recipient through the transplantation of organs and tissue.5 This virus has already been identified as a significant cause of disease and mortality among organ transplant recipients; approximately 20 to 22% of those organ recipients who had not previously been exposed to CMV developed CMV-related disease after receiving a CMV positive organ.6 Recent studies among burn victims who received cadaver skin show that CMV is equally as communicable through skin. Tissue engineering allows for extensive safety testing beyond the worldwide testing standards currently in place for donor tissues.

The Technology of Tissue Engineering

There are currently three general strategies for the development of tissue engineered products.1 In the first strategy, tissue engineers culture cells in vitro on or within matrices before implanting the tissue or organ into human recipients. The matrices are designed from synthetic polymers or from 'biomaterials' such as collagen. The second approach involves implanting biomaterials into the patient to elicit the desired biological response. The third method is cell therapy, in which cells that perform a specific needed function are implanted into the patient; cell therapy is based on principles similar to those of organ transplantation, but avoids the complications of surgery.

Key issues in tissue engineering include cell source, cell preservation, and the choice of matrix material. Cells may be selected from patients themselves, other human donors, or animal sources. When cells do not come directly from the patient, extensive testing is necessary to ensure the absence of pathogens, including CMV, the human immunodeficiency virus (HIV) and hepatitis B virus and hepatitis C virus. Cell preservation is accomplished through methods such as cryopreservation (frozen storage). Cell preservation is required to maintain cell banks for many different tissues and to help ensure uninterrupted availability of products.

The matrix material used in tissue engineering products should allow cells to assemble into tissues that closely resemble (in shape, density and vascular make-up) their in vivo counterparts. Tissue engineers have focused on biodegradable polymers (substances of high molecular weight) which will be compatible with cells in the long-term. Once cells are seeded onto polymer scaffolds and begin to multiply, they secrete growth factors and human proteins. These substances foster reproduction on the scaffold by enhancing growth and nourishing cells.

Tissue Engineered Products

Among the first tissue engineered products to move to medical and commercial applications are those used to treat patients who have damaged or destroyed skin (e.g., burn victims, patients with chronic ulcers). The first commercial therapeutic product, TransCyte®, a temporary biological covering of second and third-degree burns, was approved for marketing in the U.S. in 1997. It is now being manufactured and distributed by Smith & Nephew, along with DERMAGRAFT® for the treatment of diabetic foot ulcers. Other indications where tissue engineered products have shown clinical benefit include the treatment of venous ulcers, epidermolysis bullosa, and defects following MOH's Surgery.

Other Potential and Future Applications

Smith and Nephew is applying the same or related tissue engineering technology to develop more advanced products for addressing deficiencies in repair across a wide range of both chronic and acute wounds, and restoring articular surfaces and meniscus in knee joints. In the future, tissue engineered products are expected to include, not only bioengineered skin, cartilage and cardiovascular applications, but also tendon, ligament, bone, pancreas and liver.

Tissue engineering is predicted to have a tremendous impact on medicine in coming decades. The potential of this technology to positively affect the quality and length of life for those people who need it is significant. Smith and Nephew are proud to be pioneering the commercial application of this technology in addressing deficient repair processes in wound healing.

Mark Richardson PhD, R&D Director,
Smith and Nephew Wound Management
Chris Roberts PhD, Clinical Research Director,
Smith and Nephew Wound Management

References

1. Langer, Robert and Vacanti, Joseph, P. 'Tissue Engineering', Science, May 1993; 260: 920-926.
2. Data derived from American Heart Association, American Diabetes Association, American Liver Foundation, American Lung Foundation, American Kidney Foundation, Muscular Dystrophy Association, Industry sources, National Institute of Neurological Disorders and Stroke, and American Academy of Orthopedic Surgeons.
2. Procedure number: National Inpatient Profile 1991 Data, Hospital Discharge Survey; length of stay: 1991 Diagnostic Related Groupings, Federal Register, Department of Health and Human Services (Medicare-based information).
4. American Diabetes Association.
5. Kealey, G., et al. 'Cadaver Skin Allografts and Transmission of Human Cytomegalovirus To Burn Patients', Journal of the American College of Surgeons, March 1996.
6. Drew, W. Lawrence. 'Cytomegalovirus Infection in Patients with AIDS', Journal of Infectious Diseases, August 1988.
7. Langer, Robert and Vacanti, Joseph P. 'Artificial Organs', Scientific American, September 1995; 273, 3: 130-133.

DERMAGRAFT® is manufactured and distributed exclusively by Smith & Nephew, Inc.
DERMAGRAFT and TRANSCYTE® are registered trademarks of Smith & Nephew.
Smith & Nephew, Inc. 11775 Starkey Road, P.O. Box 1970, Largo, Florida 33779, USA.
Caution: Federal (U.S.) law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).