Tissue engineering is an interdisciplinary field that applies the principles of engineering (materials science and biomedical engineering) and the life sciences (biochemistry, genetics, cell and molecular biology) to the development of biological substitutes that can restore, maintain, or improve tissue functions. In its broader definition, tissue engineering includes isolated cells, tissue-inducing substances, and cells placed on or within matrices. However, in this instance the discussion of tissue engineering is limited to the development, design, and implantation of devices consisting of matrices in association with cells, which can migrate, differentiate, and perform normal cell/tissue functions. The matrices can be fashioned from natural materials such as collagen or from synthetic polymers. The cellular components may be of human or animal origin, with or without genetic modification. The purpose of this chapter is to present some of the key commercialization issues which exist in the new field of tissue engineering and consider how to utilize these as potential business opportunities.
The largest market for tissue engineered products is replacement of structurally or physiologically deficient or diseased tissues and organs in humans. The potential markets for tissue engineered products vary extremely both in size and degree of market development. For example,a recent report1 indicated that the heart valve replacement and skin repair product markets have maximum potential market sizes of $225 and $5,945 million, respectively. Because the heart valve market is well developed, new products must compete with existing products for market share. In contrast, the skin market is virtually untapped, with room for many new products for a variety of clinical indications. Revenues in the total market are anticipated to grow at double-digit rates for the next five years,1 making this a potentially rewarding field for investment. Tissue engineering may eventually address diseases and disorders which account for approximately half of current annual U.S. health care costs, which are estimated to be approximately one trillion dollars at this time.2–5
Tissue engineering companies are developing new generations of medical products not easily accommodated within traditional Food and Drug Administration classifications and definitions. Hybrid matrix/live cell-containing devices, which may have attributes of drugs or biologicals, are seemingly subject to multiple regulatory definitions and classifications. Historically, the FDA has responded to the scientific and medical challenges presented by new technology by involving two or more FDA centers in product review with one FDA agency taking the primary responsibility. However, at the present time, products composed of or intended to contain intact cells fall within the jurisdiction of the Center for Biologics Evaluation and Research (CBER). It is extremely clear that hybrid products (in which the primary mechanism of action is that of the somatic cell therapy component) will be regulated as biological products. It is not as clear whether products in which the matrix of the hybrid product is the major mechanism of action (such as in skin, heart valve, or ligament constructs) will be devices or biologics. Both of the allogeneic hybrid skin graft products of Organogenesis, Inc., and Advanced Tissue Sciences, Inc., are being regulated as devices. The FDA and other concerned parties are working to formulate regulations and documents (such as points to consider and guidance documents) to clarify these issues. A list of some of the important historical regulatory milestones and more recent documents of relevance for tissue-engineered products are listed in Table 7.1.
The first FDA approval of an engineered tissue product, without a living cellular component, occurred with the PreMarket Application (PMA) approval for IntegraTM Artificial skin on March 1, 1996. More recently on May 22, 1998 Organogenesis received the first PMA approval for a hybrid product (ApligrafTM) with living keratinocytes and fibroblasts for treatment of venous leg ulcers. Subsequently, on June 20, 2000, ApligrafTM was approved by the FDA for a second major application in the treatment of diabetic foot ulcers.
Systematic transplantation of living tissues and organs has become an every-day event. Although there are significant benefits, there are also many problems associated with transplantation procedures. First, there is a significant shortage of donor organs. More than 10,000 people have died during the past 5 years while waiting for an organ transplant. Many patients must undergo expensive procedures, such as kidney dialysis, while on the transplant waiting list. Secondly, transmission of infectious agents, such as acquired immunodeficiency syndrome (AIDS) or hepatitis C, from donors to the transplant recipients are of concern. Furthermore, transplant recipients must remain on costly immunosuppressive agents for the remainder of their lives. The ultimate potential annual U.S. market size for organ and tissue transplants projected by Drs. Vacanti and Langer,2 assuming an unlimited supply of transplants for all potential applications, is indicated Table 7.2. However, many scientific advances in the fields of tissue engineering and xenotransplantation must be made for this potential to materialize. The numbers are also predicated on transplantation being such a safe procedure that it would be considered appropriate therapy for a wide range of organ and tissue diseases for which transplantation would not presently be considered an option. 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 current tissue restoration and organ transplantation techniques.
Development of the full potential of tissue engineering is dependent upon major technological innovation. The National Institute of Standards recently identified some research areas in which substantial technical innovation is required (Table 7.3).9 Discussion of all these opportunities for technical innovation and commercialization is beyond the intent of this chapter. The discussion is limited to two to illustrate the decision process used to determine whether or not a technical opportunity is also a wise business venture.
Footnote. Life Science Holdings, Inc., the parent company of Organ Recovery Systems, Inc., identified development of effective transport solutions and devices to enable product distribution and methods to increase product shelf life as commercial opportunities. Life Science Holdings had acquired rights to several technical innovations in the field of low temperature biology and following extensive due diligence, established Organ Recovery Systems to develop storage and transportation products. From a corporate perspective, considerable care must be taken prior to launching an all-out product research and development effort.
Involvement in projects based on prior investment or an emotional attachment, “invented here” syndrome, is not adequate justification for further research and development. The product concepts considered were subjected to a series of tests, which are listed in Table 7.4, before committing to long-term research and development programs.
Case Studies: Development of Effective Transport Solutions and Devices to Enable Product Distribution
The first anticipated products being developed by the Company are temperature-controlled shipping units with data-logging capabilities. These devices will be used for refrigerated transportation of highly perishable medical products such as stem cells, organs for transplantation, and tissue engineered living replacement parts. The first organ transportation device has kidney perfusion capabilities. This organ transport device, in combination with effective organ preservation solutions, should result in more human organs (kidneys, livers, and hearts) being available for transplantation by expansion of the acceptable postmortem organ ischemia time for organ acceptance. This device will also be effective for transport of xenogeneic organs when they are approved for human use. These devices are being developed to meet the following design criteria:
- Compact, light weight, and strong
- High technology insulation, which reduces coolant requirements
- Simple, reliable, and not requiring continuous attention
- Monitoring, documentation, and feedback control capabilities
Current model devices for organ transport can maintain temperatures for 2 days. Future devices will maintain temperature for longer periods and enable organs and tissue engineered products to be distributed world wide. At the present time, a kidney transport device (Fig. 7.1) and a chemically defined solution (UnisolTM) designed to maintain cell viability and tissue functions during refrigerated transportation are in preclinical trials.
How do these products hold up by our general criteria for product development (Table 7.4)? According to our internal confidential review, these products demonstrated a strong likelihood of technical feasibility, efficacy and cost effectiveness. They are also expected to be unique to the market or first in the market and are protected by a very strong proprietary position due to the Company's aggressive pursuit of patents and technology licensing. The time to market should be less than five years because regulatory hurdles are relatively low and much of the hardware is available off the shelf. These products not only prospectively fulfill an unmet need in potentially large markets (namely the entire field of tissue engineered biological products and xenogeneic organs), but also have more immediate markets for shipment of highly perishable biomedical materials such as stem cells and organ transplants. Finally, the Company determined that these projects were within current financial means and identified strategies for future funding based upon achievement of specific project milestones.
Development of Methods to Increase Product Shelf-life
The product development criteria (Table 7.4.) for product shelf life methods were also reviewed at great length by Organ Recovery Systems. There was no question regarding the opportunity to fill unmet needs in potentially large markets. Such methods were considered to be technically feasible and could be designed to be both efficacious and relatively cost effective. The technology would be both unique to the market and probably first in the market with a very strong proprietary position based upon multiple patent families and trade secrets. The only methods currently used for unlimited storage and stabilization of cells and tissues involve the application of cryobiology.6–8 These methods are generally limited in application to single cells and simple cell aggregates. The technical barriers associated with ice formation and cryoprotectant toxicity have blocked progress in the extension of cryobiology methods to larger biological structures. The first barrier (ice formation) is significant; however, the later is largely an engineering issue. Ice may form and cause problems for cell and tissue stabilization and storage intracellularly and extracellularly, both within the tissue matrix and around the biological materials. The Company has two innovative approaches to defeating the technical barrier presented by ice.
The first approach is to control ice formation in such a manner that the ice which forms does not have opportunities to grow in forms which cause either cellular or matrix damage. Ice control will be achieved by combining proprietary synthetic ice blockers with traditional cryoprotectants. Synthetic ice blocking molecules are being designed to bond with ice crystals. Some of these compounds have turned out to be available “off-the-shelf,” but have not been identified previously as having antifreeze potential; others are presently being synthesized.
The second approach is complete avoidance of ice formation by vitrification. Using this approach, a noncrystalline solid structure (glass) is achieved by replacing at least 50% of the water with cryoprotective chemicals. The major barrier to development of vitrification solution formulations is screening the vast quantity of potential cryoprotective chemicals, combinations and concentrations that are possible. The technical barriers are achievable engineering issues relating to addition and removal of a high concentration of cryoprotective agents in such a manner that toxicity is avoided and effective warming techniques are perfected. These technical barriers should be easier to overcome for tissue engineered structures once optimal vitrification solutions have been developed.9,10
Unfortunately, continuing our review of criteria from Table 7.4, the time to market for most applications in tissue engineering for new storage technology is probably greater than five years and the cost to market was not considered to be without undue financial risk by the Company and its partners. This resulted in the development of new storage methods for tissue engineered products being given a low priority. This decision was subsequently reversed when funding was obtained in response to a request for proposals from the National Institute of Standards & Technology (NIST).11 The funding obtained from NIST reduced the financial risks of this research program for the Company. At this time the development of molecular approaches to ice control for engineered tissue storage has the highest corporate priority.
Ultimately, the success of tissue engineered products, in common with any highly perishable product, depends upon the availability of practical product storage and transportation methods. The customers for the Company's storage and transportation products will be tissue engineering organizations, organ procurement organizations, hospitals, tissue processing and banking organizations and companies which supply reagents and biological materials to research organizations pursuing tissue engineering programs (A partial list of potential corporate customers is given in Table 7.5).
In conclusion, the field of tissue engineering presents both challenges and opportunities for the development of new medical products but great care should be taken in review of potential opportunities before committing to product development.
- U.S. Organ Transplant and Related Product Markets. Frost & Sullivan. 1996
- Langer R, Vacanti JP. Tissue Engineering. Science. 1993;260:920. [PubMed: 8493529]
- Nerem RM, Sambaris A. Tissue Engineering. 1995. p. 3. [PubMed: 19877911]
- Wilkerson Group, Inc., Research on Market Potential for Tissue Engineering 1992.
- Heart and Stroke Facts-1996 Statistical Supplement. American Heart Association.
- Mazur P. Freezing of living cells: Mechanisms and implications. Am J Physiol. 1984;247:C125–C142. [PubMed: 6383068]
- Karow AM. Biophysical and chemical considerations in cryopreservation In:Organ preservation for transplantation Karow AM, Pegg DE, eds, New York: Decker1981. 113.
- Brockbank KGM. Essentials of Cryobiology In:Principles of Autologous, Allogeneic, and Cryopreserved Venous Transplantation KGM Brockbank, ed. Austin, TX: RG Landes Company, (Medical Intelligence Unit Series) and Springer-Verlag,1995 .
- Song YC, Khirabadi BS, Lightfoor FG. Avoidance of ice by vitreous cryopreservation dramatically improves the function of vascular grafts. Nat Biotechnol. 2000;18:296–299. [PubMed: 10700144]
- Brockbank KGM, Lightfoot FG, Song YC. et al. Interstitial ice formation in cryopreserved homografts: A possible cause of tissue deterioration and calcification in vivo. J Heart Valve Dis. 2000;9:200–206. [PubMed: 10772037]
- Request for Proposals for the ATP Focused Program Competition 97-07 National Institute of Standards and Technology, February1997.
Kelvin G.M. Brockbank.
Landes Bioscience, Austin (TX)
Brockbank KGM. Tissue Engineering Constructs and Commercialization. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.