EUROPEAN TISSUE REPAIR SOCIETY

TISSUE ENGINEERING III

BIOTECHNOLOGY – DEVICE INDUSTRY PERSPECTIVE

HEALTHCARE continues to be viewed as high priority in almost every country and globally represents expenditure of the order of $2.5 trillion.¹ The Medical Devices and Pharmaceutical sectors represent about 20% ($500 billion) of the expenditure, the balance being associated with provision of services infrastructure, which is the underlying driver of product demand. The Device Industry, valued at $160 billion, is an extremely diverse sector (Table 1) and provides the tools medical professionals require to address clinical problems at every phase within the recovery process.

The medical market, dominated by the United States (48%), Europe (26%) and Japan (11%), continues to experience a growth rate close to 10% p.a. This growth is driven by:

• positive impact of demographics (for example, the over-65 age group in USA is predicted to grow from 12% to 20% of population by 2030),
• increased patient awareness of available treatments and greater involvement in the decision making process,
• significant advances in medical technology, in particular the emergence of biotechnology-based solutions and associated advances in diagnostic technology.

These changes are occurring within an industry whose primary source of revenue is built on products based on excellence in materials and design. Technological advances in these areas will continue to impact positively on the industry and the future need for the associated expertise as a source of new and exciting product opportunities is not in doubt. However, in this article the potential impact of discoveries in imaging technologies, medical robotics and numerous other enablers of clinical practice will not be addressed. The focus will be on emergence of technology- based products derived from the growth in understanding of the biology of tissue repair and regeneration.

It is believed that biotechnology will have a significant impact² on the evolution of the industry as a whole over the coming twenty years. Advances in molecular biology and genetics in particular are likely to have the greatest impact because they will offer the industry an opportunity to 1) enhance understanding as to how existing products work in the clinic, and 2) provide numerous opportunities to build totally new biological solutions.

An excellent example of the former is the recent emergence of low intensity ultrasound as a scientifically and clinically recognised approach to treating fracture repair.3 Although the potential for this technology was first indicated clinically in the early 1950s, approval and acceptance as something more than a ‘black box’ therapy through FDA approval, only emerged in the late 1990s with considerable help from emerging technologies in molecular biology. Clearly there will be other technologies languishing on the sideline that can, through more thorough investigation with the application of these emerging techniques, be refined and rediscovered.

Tissue engineering represents an excellent example of an emerging sector for the industry offering new biologybased solutions.4 This sector is built around a growing understanding of basic cellular biology as well as the cells’ ability to respond to changes in their environment, for example, application of micro-mechanical force. The multi-discipline nature of this new field presents a real challenge to the scientific community with success being very dependent on the merging of the sciences associated with engineering, biology and material. This convergence of the disciplines is being effectively addressed within many of the newly formed Tissue Engineering Centres across the globe.

Within its broadest definition Tissue Engineering is seen by many to encompass implantable devices formed from

• donor replacement tissue (allograft)
• natural and synthetic biopolymer scaffolds
• growth factors (autologous and recombinant proteins)
• living cells (alone or within viable tissue).

Allograft-based material has been used extensively over the last century and, next to autograft, remains the ‘gold standard’ against which the performance of the next generation of tissue-engineered treatments for skin, bone, cartilage and vascular diseases will be measured. Much progress has been made in sourcing of cadaveric material with the emergence of suppliers with FDA approved processes that maximise safety. However, many problems remain, real or perceived, regarding infection, disease transmission and long-term availability of material in a market where demand for organ/tissue implants is ever growing. There is a quest, therefore, for technologies that are not reliant on supply of allograft tissue. Zenograft-based material has been proposed as a possible alternative source, however in the foreseeable future this is unlikely to emerge as a viable alternative given the significant immunological and disease transmission issues likely to be encountered.

The use of biopolymers, either natural or synthetic, in the form of a scaffold to promote tissue repair and regeneration is a viable safer alternative to allogeneic tissue.5 Such materials have been with us for decades and the majority of existing commercial products applied to tissue engineering are built around collagen, polylactic and polyglycolic acids, and processed coral. Although effective, these first generation products fall short of meeting the range of clinical challenges associated with achieving effective tissue repair. Many more design variations for scaffolds using these and newer ‘bespoke’ biomaterials^6,7 are currently at various stages of pre-clinical and clinical evaluation. Expectations are high that through surface modification, greater control of porosity and incorporation of cell adhesion proteins, much can be achieved. The principal goal is to have a matrix that 1) mimics the function of natural tissue from the outset, 2) has an optimised rate of degradation so as to be comparable with rate of tissue ingrowth, and 3) exhibits improved rate of cellular migration into and tissue growth within the scaffold. All of these are challenging goals that require much improvement in materials and design before they are realised.

Growth factors and recombinant proteins represent a dimension of tissue engineering that has received considerable attention and investment during the 1980/90s.^8,9 These are viewed by many regulatory authorities as pharmaceutical products requiring extensive clinical trials. Despite this, a number have been approved for marketing in various countries; OP-1, a bone morphogenic protein that stimulates bone growth has been approved in Europe, rhBMP-2, a recombinant bone morphogenic protein approved for spinal fusion applications in USA, and a possible alternative to allograft; rhPDGF, platelet derived growth factor approved for treatment of chronic wounds in USA and Europe; AGF, autologous growth factor derived from blood used principally in USA for fracture repair in combination with a bone graft substitute.

Although many of these products are recent to the market only one (rhPDGF: Regranex®, Johnson & Johnson) has achieved sales in excess of $50 million. This is disappointing considering the pharmaceutical-like investment required to bring the products to market. It may be that the current range of growth factors and mechanisms adopted for delivery are inadequate to achieve the desired step-change in clinical performance over conventional therapy. A new generation2 of recombinant molecules/proteins are in development, but progress in achieving approval to market will be slow given the significant regulatory hurdles. Within the scientific community there also remains the concern that a single molecule (magic bullet) approach to promoting the complex cascade process associated with tissue repair may well not be the answer. The delivery of a range of factors at different stages in the repair process may be desirable to effectively regenerate fully functional natural tissue.

Tissue engineering, defined by devices that combine cells and biomaterials may well be the approach that ultimately provides the complete answer. To many the area of cell manipulation alone or in combination with biomaterials to generate a bioengineered cellular matrix outside the body is seen as core tissue engineering and the field most likely to have the greatest impact in the long-term on the ever growing crisis in cadaveric tissue supply.^4,10

The earliest market approaches to cell-based tissue engineering utilise cultured 1) autologous epithelial cells from skin (Epicel®) as a treatment for life threatening burns, 2) autologous chondrocytes from articular cartilage (Carticel®) as treatment for focal defects in articular cartilage of the knee. This autologous cell expansion service was pioneered by Genzyme Biosurgery and today a number of other providers have entered the market. The disadvantages associated with this service-based approach are the significant turnaround time (weeks) in providing products for treatment, the high cost when compared to conventional treatments and inadequate level of clinical benefit to justify the cost and use in anything but life-threatening situations (severe burns). However, a number of companies are continuing to develop more cost-effective ‘service-based’ approaches and these may result in greater acceptance with the marketplace.

Few bioengineered live tissue products have emerged onto the market11,12 despite two decades of activity. Apligraf® (Organogenesis/Novartis) is a product composed of two layers, an upper epidermis and a lower dermis with a limited shelf life as it needs to be maintained above freezing prior to use. Dermagraft® (Advanced Tissue Sciences/ Smith & Nephew) is a product composed of a single layer dermal replacement, which is cryopreserved at –70°C and has a shelf life of nine months. Both products are bioengineered from cells derived from neonatal foreskin and recommended in the treatment of chronic wounds. The ability to extensively expand the sourced allogeneic cells means that a large quantity of tissue can be engineered from a single cell source. TranCyte®, a decelluralised bioengineered extracellular matrix (version of Dermagraft®) is also available as a temporary extracellular matrix dressing for treatment of severe burns.

Despite the early introduction of bioengineered tissue products the market has been very slow to develop and certainly not lived up to the earlier expectation of being worth $2 billion by 2002.^10,13 This early market promise has been forestalled in part by numerous technical issues that still remain to be resolved before the full potential of bioengineered tissue can be realised in the treatment of skin, bone, cartilage and vascular disorders. The essential requirements for success in tissue engineering are improved means of reproducibly sourcing viable cells; understanding of mechanisms controlling cell function; optimisation of 3D structures so as to mimic natural tissue architecture and function; greater understanding of scale-up issues associated with manufacturing and preservation of tissue to achieve a cost effective ‘off the shelf’ product. These unresolved challenges present considerable barriers to progress and availability of a range of ‘off the shelf’ bioengineered tissue replacement/organs as a cost-effective clinical option is unlikely to be with us for a decade or more. In addition to the technical challenges, a range of business related issues face the industry in its effort to build tissue engineering as a platform from which high value products can be developed.¹⁴ These are:

• Increasing development cost, driven principally by the need to generate compelling clinical evidence to meet the ever more stringent requirements to prove cost effectiveness,
• The ever-changing regulatory environment for approval of tissue-based products and devices, combined with active agents such as growth factors. The move to pharmaceutical type regulations presents a problem for an industry not built around pharmaceutical level of R&D investment. The need for industry to collaborate and lobby in addressing these issues is clear, to ensure it is not disadvantaged by inappropriate regulatory demands that delay time to market,
• Introduction of new tissue-engineered products often requires the physician/surgeon to abandon his long-tried and tested procedure in favour of something new at higher cost. As the surgeon population is inherently cautious (rightly so) achieving adoption of a new technology that involves fundamental changes in procedure can and does slow market acceptance of new platform technologies such as tissue engineering.
• Achieving reimbursement status with Health Authorities, Insurance Plans, Medicare (USA) etc, has emerged as a requirement in most markets. This post-regulatory hurdle, which varies between and within markets, affects pharmaceutical and device industries alike. However, given that the device industry is built around introduction of a large number of medium value products ($100m per product) compared to pharmaceuticals (target >$1bn per product) the impact of these barriers on growth is more acutely felt. It is important, therefore, that reimbursement and cost-effectiveness issues are addressed early within the product development programme.

The Device industry, not unlike many others, relies heavily on innovation in product development emerging from within start-ups and small and medium-sized enterprises (SME) to grow their businesses. The existence and future health of entrepreneurship in this sector is of importance to the major industry players. Recent developments in the marketplace in relation to two of the pioneers in Tissue Engineering (Advanced Tissue Sciences and Organogenesis moving into Chapter 11 in the USA) are a cause of concern to the industry. It is hoped that the products Dermagraft® and Apligraf®, developed by these pioneers, will remain within a competitive marketplace as both represent significant milestones in the evolution of tissue engineering. It is reassuring to see that investment in companies building new bioengineered tissue products10 continues to grow and the emergence of a large number of European start-up companies may result in earlier market entry of some next generation products. Larger organisations that invest heavily in late stage R&D and marketing need to continue to maintain and increase their awareness of developments within emerging companies and take steps to establish early alliances.

Based on everything that has been said about the healthcare market, one can conclude that demand for more effective products will continue unabated. How much of a role tissue engineering, particularly bio-engineered tissue, will play in this growing market remains unclear. The potential, given resolution of the technical problems, remains enormous. It is clear, however, that the product gap that has emerged between where we are today and achieving a broad range of bioengineered tissue-based products (2015 and beyond) will have to be filled through further refinement of existing tissue and cell-based products and introduction of products based on novel biomaterials and design.

References

1. Extrapolated from Frost & Sullivan report ‘The United States Healthcare Industry’; 2002.
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5. Ansell, C., ‘Polymeric Biomaterials from Lab. Bench to Hospital Bed’. In: Arshady, R., ed. Vol. 1; Introduction to Polymeric Biomaterials. Citrus Books, 2003; 345–369.
6. Tateishi, T., Ushida, T., Chen, G., Murata, T., Mizuno, S., ‘Biodegradable Hybrid Porous Biomaterials for Tissue Engineering’. In: Lewandrowski, K., ed. Tissue Engineering and Biodegradable Equivalents, Scientific and Clinical Applications. Marcel Dekker In., 2002; 99–110.
7. Pearson, R.G., Bhandari, R., Quirk, R.A., Shakesheff, K.M. Recent Advances in Tissue Engineering: An Invited Review. J. Long-term Effects of Medical Implants 2002; 12: 1–33.
8. Lieberman, J.R., Dacuiski, A., Einhorn, T.A. The role of growth factors in the repair of bone: Biology and clinical applications. J. Bone Joint Surg Am 2002; 84-A: 1032–44.
9. Limova, M. New therapeutic options for chronic wounds, Dermatol Clin 2002; 20: 357–63.
10. Lysaght, M.J., Reyes, J. The Growth in Tissue Engineering. Tissue Engineering 2001; 7: 485–93.
11. Lee, K.H., Tissue-engineering human living skin substitutes: development and clinical application. Yonsei Med J 2000; 41: 744–49.
12. Harding, K.G., Morris, H.L., Patel, G.K. Science, medicine and the future: healing chronic wounds. BMJ 2002; 324: 160–3.
13. Lysaght, K.J., Nguy, J., Sullivan, K. An economic survey of the emerging tissue engineering industry. Tissue Eng. 1998; 4, 231–9.
14. Goodman, C.S., Gelijins, A.C. The changing environment for technological innovation in healthcare. Baxter Health Policy Rev. 1996; 2: 267–315.

Corresponding author:
Gareth Lloyd-Jones
Medical Industry Consultant
Smith & Nephew plc
York Science Park
York, YO10 5DF, UK
E-mail: gareth_lloyd_jones@hotmail.com