Tissue Engineering Designing for Health

Tissue engineering Designing for health

The tissue engineering that is now emerging in biomedical research will ensure health and safety and the by Tim groups is concerned with living tissues and how we can harness monitoring and documenting of all Hardingham biological processes to achieve healing and repair, where it is stages of the process. (UK Centre for Tissue otherwise failing. It aims to develop our scientific understanding of This requires the co-ordination Engineering, Liverpool how living cells function, so that we can gain control and direct their of a broad range of different disci- and Manchester) Downloaded from http://portlandpress.com/biochemist/article-pdf/25/5/19/3747/bio025050019.pdf by guest on 26 September 2021 activity to the promote the repair of damaged and diseased tissue1. plines. The future development of tissue engineering thus depends very much on bringing together broadly The potential for medical interven- living cells with particular tissue based research teams to form inter- tion with a tissue-engineering solu- functions and a material support disciplinary collaborations, as we tion is seen nowhere better than that forms a structure for culturing have at the UK Centre for Tissue with the chronic, persistent leg the cells in the laboratory and for Engineering in Manchester and ulcer, which provides a diabetic delivering the tissue equivalent Liverpool, with input from cell biol- patients with a constant source of to the damaged or diseased site in ogists, molecular biologists, bio- discomfort and incapacity. the patient at surgery (Figure 1). material scientists, bioengineers and The patient does not lack the It can be in the form of skin, a healthcare clinicians1. inherent capacity to heal a skin blood vessel or in a more complex wound; however, at the site of the organ structure, depending on the Advances in cell biology ulcer, this fails to occur naturally. clinical application. What is lacking are the biological The ‘package’ therefore contains A key to new developments in tissue signals, the chemical messengers and several important and quite different engineering lies in the current physical cues, that initiate the events material components, and its progress in research in cell biology. of cell migration, blood-vessel for- assembly involves a manufacturing Sequencing of the human mation and tissue assembly that process that extends from the culture genome is leading to a rapid characterize normal wound-healing. of living cells, to the fabrication increase in the understanding of If we can provide those biologi- techniques for three-dimensional the biological signals and cellular cal signals in a ‘tissue-engineered’ structures, to engineering and bio- interactions that govern natural package, we can kick-start a repair reactor design (Figure 1). It is carried repair processes. The theme that process, which the patients own out in a regulatory framework that also underlines the approach is that tissues can then complete. It sounds easy, but how can this really be achieved? Cells Cell expansion Biomaterial support

What forms the tissue- engineered package? Bioreactor culture

The precise form will vary with the Tissue-engineering medical application for which it is process designed, but the typical elements Tissue construct are as follows: one or more types of Integration with Figure 1. Schematic patient tissues Key words: cartilage formation, collagen, matrix Implantation representation of the biology, stem cells, tissue engineering tissue-engineering process.

Figure 2. Retroviral primary chondrocytes from adult

transduction of passaged 1. Chrondocyte in 2. Chrondocyte in 4. Transduced chrondocyte human articular cartilage to reform human articular cartilage monolayer culture in alginate culture cartilage in culture (Figure 2)3. chondrocytes with SOX9. In common with many other dif- The stages involved are as ferentiated cells, chondrocytes lose follows: (1) isolation of their differentiated characteristics cells from cartilage culture when isolated and grown in culture. in monolayer; (2) They become progressively fibro- 3. Retroviral expansion of cell number blastic and stop producing cartilage Endogenous SOX9 transduction Matrix (1000-fold), with the expression of SOX9 assembly matrix gene products, such as colla- associated loss of SOX9 gen II and aggrecan. They recover

expression3; (3) retroviral some chondrogenic potential if Downloaded from http://portlandpress.com/biochemist/article-pdf/25/5/19/3747/bio025050019.pdf by guest on 26 September 2021 transduction with SOX9 in many clinical applications, the It has long been known that cultured in agarose or alginate, (~90% efficient)4; and (4) planned long-term solution will these cells can be found in bone rather than as a monolayer, but this re-formation of the engage the patient’s own cells and marrow (stromal stem cells), but recovery is slow and inefficient. chondrogenic matrix in tissues to complete a biological more recent evidence has suggested We have found that by using alginate culture. repair. This is where it differs from that they can be found in other sites retroviral transduction4 of an essen- the established use of medical in the body and can even, for exam- tial chondrocyte transcription fac- devices, such as joint replacements, ple, be harvested from the fat tor, SOX9, into these cells, they which have been very successful in removed at liposuction! There is become more chondrogenic, even some applications, but in which the great interest in these sources of after many passages in culture. damaged tissues are replaced with cells for tissue-engineering applica- The transduced cells respond more inert non-biological materials. tions, although much research is strongly to alginate culture and The applications of tissue needed before their full potential to growth factors such as insulin- engineering will be more diverse (and limitations) will be known2. like growth factor I and transform- than has been possible with non- ing growth factor 1 or 3, which biological devices. These will range Matrix biology and have an anabolic effect and greatly from small-blood-vessel replace- cartilage formation increase matrix production. ment, bone, tendon, ligament and The experiments are important in cartilage repair, healing of skin Extracellular matrices provide the demonstrating that, given appropri- wounds, nerve regeneration and shape and form of all tissues. In ate signals, the recovery of cartilage the repair of problems that cause those applications where some matrix formation is feasible in incontinence. There is also likely immediate mechanical properties extensively cultured primary human to be a range of applications in are required, such as in cartilage, chondrocytes. It also raises the reconstructive surgery and in cell- skin, blood vessel or bone, there is a prospect that if natural mechanisms based therapies for degenerative need for a structural matrix. are found to enhance SOX9 gene problems in muscle, heart and brain. Although natural or artificial bio- expression, the response may be materials may be used to provide achieved without viral transduction. Stem cells temporary support, the ability to Similar principles may be applied to drive the assembly of an organized other matrix-producing cells and To help fuel these aspirations, there extracellular matrix by cells in cul- lead to more efficient matrix assem- are remarkable new developments in ture is a very important issue in gen- bly for applications in tissues such stem-cell research. erating a tissue with properties as cartilage, intervertebral disc, ten- In addition to embryonic stem suitable for engraftment in a patient. don, ligament and blood vessel. cells, which in the early embryo have At present, there is much the potential to divide and form all research and discovery in matrix Products for healthcare the tissues of the body, it is now biology that is leading to a better recognized that, even as adults, we understanding of extracellular When will tissue-engineering prod- all contain some cells that retain the matrix assembly. We have been ucts be available in the National ability to form different tissues. investigating the potential of Health Service? Progress so far has

been slow. The first products for to development in biotechnology, and radical solutions to some impor- treating chronic skin wounds have which will complement the strong tant medical problems. been effective, but not great com- base of pharmaceutical and health- mercial successes. However, several care companies in the UK. It remains References countries, including the UK, have a challenge for tissue engineering 1. http://www.ukcte.org recognized that, with a potential for that the products need to meet real 2. Alison, M.R., Poulsom, R., Otto,W.R. et al. (2003) rapid advance, this area justifies medical needs. Furthermore, for J. Cell Sci. 116, 599–603 greater research investment. them to be funded from healthcare 3. Hardingham, T., Tew, S. and Murdoch, A. (2002) Arthritis Res. 4 (suppl. 3), 63–68 There is an expanding worldwide resources, they need to be cost- 4. Li,Y., Tew, S.R., Russell, A.M., Gonzalez, K.R., need for better treatments for many effective, and this will be achieved Hardingham, T.E. and Hawkins, R.E. (2003) Tissue Eng., in the press chronic clinical problems, particu- more easily in some applications larly those that are common in the than others. Downloaded from http://portlandpress.com/biochemist/article-pdf/25/5/19/3747/bio025050019.pdf by guest on 26 September 2021 elderly. Progress is dependent on the However, despite these many Tim Hardingham is research base skills in molecular and hurdles, the potential advantages are Professor at the School of Biological Sciences, cellular biosciences, in which the large, and it seems clear, that over the Manchester University. His main research is on UK has great strength. It is therefore next 5–15 years, there will be a cell adhesion and the extracellular matrix. a field in which the UK can be com- steady introduction of tissue-engi- e-mail: [email protected] petitive, and research here will lead neered products that will offer novel