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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.
Tissue engineering potentially offers dramatic improvements in medical care for hundreds of thousands of patients annually, and equally dramatic reductions in medical costs. Organ transplants alone present many opportunities because of the significant shortage of donor organs. More than 10,000 people have died during the past five years while waiting for an organ transplant. Infectious agents such as hepatitis C and HIV further complicate the organ transplants, and recipients generally must remain on costly immunosuppressive drugs for the balance of their lives. Outcome studies have shown that the survival rates for major organ transplants are poor despite their high cost. "Engineered" replacement organs could sidestep many of the hazards and problems associated with donor organs, and at lower cost. For example, 4,166 liver transplants were performed in the United States between 1987 and 1989. At the end of five years, the total medical costs for the survivors and the 1,887 patients who died within the five-year period came to $960 million. Estimates place the cost of an implantable artificial liver, plus attendant surgical procedures, at $50,000, with follow-up costs of $2,000 per year for five years. If so, 4,166 liver patients could be treated for five years at a total cost of $250 million-a savings of $710 million-and with a higher survival rate and better quality of life for the patients.
Other equally promising applications include replacement of lost skin due to severe burns or chronic ulcers; replacement or repair of defective or damaged bones, cartilage, connective tissue, or intervertebral discs; replacement of worn and poorly functioning tissues such as aged muscles or corneas; replacement of damaged blood vessels; and restoration of cells that produce critical enzymes, hormones, and other metabolites.
However, there are a number of significant barriers to the emergence of Tissue engineering/regenerative medicine in the UK. The industry does not yet have a clear identity and visibility, as there are no exemplars of the conversion of emerging regenerative medicine businesses into major public companies. The complex nature of the science and engineering involved, combined with a weak venture finance climate, means it is difficult for new companies to attract investment and to develop the manufacturing capability required to bring regenerative medicine products to the market. Finally, the regulatory environment is still evolving, and reimbursement and investment models have yet to emerge.
Tissue engineering companies
Genzyme Biosurgeryhave Carticel, a suspension product for cartilage repair and Epicel, autologous kerinocyte sheets for the treatment of severe burns, on the market in the USA.
Clinical Cell Culture (C3) have ReCell, an innovative single-use medical device for harvesting autologous skin cells. Developed as an 'off the shelf'kit, ReCell enables a thin split thickness biopsy to be processed into an immediate cell population for delivery onto the wound surface. This lab in a box allows clinicians to create a skin suspension 30 minutes after biopsy taken from patient. C3 also have CellSpray, which is a cultured epithelial autograft suspension that is sprayed onto injured skin in order to provide a rapid epidermal cover, promote healing and optimise scar quality. C3 has recently merged with VisioMed, to create Avita Medical.
Axordia is one of the UK's leading human embryonic stem cell companies, and has two novel therapies in development: a next generation cardiovascular stent, which will prevent restenosis and a cell therapy to treat age related macular degeneration, in collaboration with University College London and the Institute of Opthalmology (The London Project). Axordia was acquired by Intercytex in December 2008, for £1.68M.
Intercytex has four products in development; Cyzact, a chronic wound healing product, VAVELTA, a facial rejuvenating product, ICX-TRC, a hair regenerating product, and ICX-SKN, a skin graft replacement product. Intercytex's acquisition of Axordia offers access to embryonic stem cell therapies, and broaden's the company's portfolio. In February 2009, Intercytex was placed in an 'offer period' for merger or acquisition following the cessation of clinical trials for Cyzact. Results showed that the product failed to meet its primary endpoint of a statistically significant increased in wound closure compared to the current gold-standard treatment of compression bandages, over a 12 week timeframe.
Orthomimeticsproduce biological scaffolds to be used in orthopaedic tissue regeneration in relation to cartilage, ligament and tendon repair. Four scaffolds are currently in development: ChondroMimetic, LigaMimetic, TenoMimetic and VitroMimetic. ChondroMimetic - an off-the-shelf implant that helps to support the repair of defects involving both articular cartilage and bone - received a CE mark in January 2009, meaning that it can now be marketed in the EU.
Smith and Nephewpreviously marketed Dermagraft and Transcyte in the UK. However, the products were removed from sale and the rights sold to US-based company Advanced Biohealing (2006/07).
Bioceramic Therapeutics produce smart materials that help the body to repair itself. Clinical focus includes bone tissue growth, and tissue healing.
Organogenesis refer to themselves as the world's leading regenerative medicine company. Although not currently available in the UK, they offer bioactive wound healing product Apligraf (for non-healing wounds), and have VCT01 in development. In the bio-aesthetics area, they offer Revitix, for skin rejuvenation. Lastly, in the biosurgery area, they offer CuffPatch (a collagen biomaterial to be used in rotary cuff tendon repair surgeries), FortaGen (a tissue repair product), FortaPerm (used in the surgical treatment of bladder incontinence), and BioSTAR (a collaboration with MNT medical Inc, that has resulted in Fortaflex being applied to a device that can be implanted to treat cardiac sources of migraine, stroke and other neurological attacks).
Stem Cell Sciencesis an international R&D company specialising in stem cells and stem cell technologies for research. R&D work on potential therapeutic areas include treatments for central nervous system disorders, including acute spinal cord injury, Parkinson's disease, epilepsy and for key orphan indications. Stem Cell Sciences was acquired by US-based StemCells Inc in March 2009 for $4.8 million.
Products on or nearing the market are considered to be 'early' examples of regenerative medicine. Such products were perceived as being based on relatively simple science, and raised few safety issues. The majority of these products were reported as being skin, soft tissue and cartilage therapies. However, while available, these products incur extremely high manufacturing costs that do not compare with the reimbursable costs of alternative, existing gold-standard treatments. The margin on these products is often not high enough to justify the substantial cost of development and clinical trials. Respondents considered that a product has a chance of commercial success if:
There is a large market and the product is relatively easy to produce.
There is a small, customised market of high-value goods for life-threatening disorders.
The products that are currently on the market mostly fall into the first category: there is a large potential market, and the product is relatively easy to produce. The initial focus of regenerative medicine has been on autologous therapies, but it is acknowledged that these are difficult to commercialise, and certainly do not enable scale-up and standardisation of products, or provide large financial reward. Some of the limitations of current products on the market are;
Issues with storage and the short shelf-life of autologous therapies.
Long lead time for clinicians to receive products, from ordering to delivery.
Lack of long-term clinical results, leading to problems with product adoption and reimbursement.
Cost, value for money.
Potential U.S. Organ and Tissue Markets
Although the UK's regenerative medicine science is first rank, the industry has fallen behind the USA when it comes to translating and commercialising the science. In some areas, such as human embryonic stem cells, the UK even has a scientific lead of several months over the USA. Scientific leads like this may, however, quickly disappear if the translation and commercialisation of therapies is hindered. This is seen as being influenced by:
The struggle to raise enough funds for translation - a typical funding gap. Private equity investors are unwilling to fund high risk, early stage regenerative medicine ventures. This is especially true when stem cells are involved.
Venture capitalists require more data before they are willing to invest.
The NHS structure and NICE are felt to be a huge burden for reimbursement, mostly due to the extent of clinical evidence required. Respondents frequently reported their fears that such evidence demands were set at often unrealistic levels (i.e. the same data/large scale trials are required for regenerative medicine products as for pharmaceuticals).
Reimbursement is easier in countries that have more of a private health care structure.
Competitiveness has been hindered by a lack of regulatory clarity (i.e. what are the rules, definitions, expected clinical trials and how will this be measured?)
Fostering effective collaboration between academia, industry and clinicians.
Multidisciplinary collaboration between key stakeholders is a necessity in driving the field towards utilisation. The translation of regenerative medicine could be enhanced with the appointment of 'knowledge translators'. These new roles would span academic-industrial-clinical boundaries, and would assist in the diffusion of information and understanding, which would lead to the acquisition and sharing of credible knowledge. This in turn would improve the utility and thus the adoption of regenerative medicine.
Improving the management of university intellectual property.
Partnerships and the management of intellectual property are vital components to knowledge acquisition and sharing in relation to driving regenerative medicine forward. However, there were competing tensions: universities were perceived to be making bigger requests for payment in relation to IP rights, while others saw academic collaborations as a means of acquiring cheap knowledge.
Bridging the development funding gap.
The majority of respondents reported difficulties in gaining adequate funding in order to progress their work in regenerative medicine into clinical development.
Creating an evidence base.
Despite the UK's leading scientific position, it is acknowledged that more work is needed to establish the mode of action, efficacy and safety of different regenerative medicine therapies.
Reducing regulatory uncertainty.
One significant barrier to the commercialisation of regenerative medicine and the lack of products on the market is the uncertain regulatory environment that has been charged with sanctioning products as efficacious and safe for use.
Improving reimbursement procedures.
The structure of the NHS and, in particular, its purchasing system is considered to be a major barrier obstructing the entry of tissue engineering products into the UK healthcare market. This included the higher up-front cost of products to the healthcare service in comparison with existing therapies, and the impact that this will have on service delivery when the financial structure of the NHS leads to 'siloed' budgeting.
Establishing clinical utility
For tissue engineering to progress and develop into commercially-viable and widely-used products, the outcomes of the innovation process - the therapies - must have clinical utility.
Creating a new system of distribution
Consideration needs to be given to the distinct characteristics that regenerative medicine products have that fundamentally influence their distribution, storage and shelf-life. For regenerative medicine is to be utilised in any volume, some respondents felt that a nationalised distribution system will be needed.
Bringing about cultural change in the health service
To assist in the greater translation of regenerative medicine science, and to create a therapeutic product with clinical utility, widespread cultural, institutional and behavioural change is needed. All members of the regenerative medicine community must acknowledge and understand the difficulties of bringing a novel product to market. The utilisation of regenerative medicine products is likely to demand a conceptual shift in the working practices of clinicians, as therapies are anticipated to offer a step-change in care. This will be a very difficult barrier to overcome, with clinicians known to favour particular techniques that they have had success with. Training and education will need to be provided by the manufacturer, and should be targeted at the appropriate level for all staff that will come into contact with the product.
In summary, when bringing a product to market the following barriers are perceived:
Access to capital, finance.
Distribution channels, logistics.
Access to skilled human capital.
Scientific barrier, products that work.
Cost, cost effectiveness proof.
Regulatory requirements, lack of clarity.
Clinical validation, evidence, data.
Clinicians' acceptance, adoption despite absence of long-term data.