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New materials to treat cutaneous wounds

 
 
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Hyaluronic acid, a molecule which plays an essential part in the constitution of artificial skins, is degradable by the organism and may be modified chemically without losing its biological properties..

Severe burn victims, individuals suffering from chronic venous ulcers or diabetes, skin diseases and reconstructive surgery ... The needs for artificial skin are numerous and truly satisfactory solutions are still to be found. Researchers in four European countries (Italy, Belgium, Germany and the United Kingdom) have joined forces to devise a biodegradable matrix to act as a support for dermal and epidermal cells destined for skin grafts. This system makes it possible to effectively reconstitute tissue.

     

Treating skin wounds and lesions in a way which is both effective and aesthetic remains an outstanding medical problem. While the first thing that springs to mind is healing the wounds of severe burn victims - almost 20 000 in Europe every year - this problem concerns many other patients, too. Approximately 1% of the world population is affected by chronic venous ulcers due to heart diseases which reduce their healing capacity; the skin lesions, which primarily affect the legs, can take more than nine months to heal. Diabetics, of whom there are more than 10 million in Europe, are also vulnerable and frequently suffer from wounds to the feet; these lesions lead 60 000 of them every year to undergo amputation, which could be avoided if efficient skin reconstruction procedures existed. Finally, the need for artificial skin also affects individuals suffering from serious hereditary skin diseases, such as bullous epidermolysis, which require reconstructive surgery.

At the present time, skin grafts are also used to this end. Epidermal cells are cultivated in the laboratory in order to obtain a fine layer of cells which may be grafted onto the wound. This reconstituted skin is nevertheless delicate to handle on account of its fragility and has the disadvantage of retracting too greatly during the healing process. What is more, the high cost of this process reduces the extent to which it can be used.

A polysaccharide matrix

It was in this context that Fidia Advanced Biopolymers (Italy) conceived the creation of an artificial skin combining biomaterials with living cells. This company proposed to manufacture a fabric which would permit the multiplication of epidermal cells (keratinocytes) on one side and dermal cells (fibroblasts) on the other. Holes arranged at regular intervals would make it possible to form links between the two tissues and thus would guarantee the solidity of the newly formed skin.

The first difficulty with a project of this kind is the choice of an adequate support, namely one which is accepted by the human body, which is biodegradable and which permits skin cell seeding and harmonious development. The company opted for a molecule which is naturally present in intercellular spaces: hyaluronic acid. This polysaccharide has the advantage of being recognised by the molecular receptors, of being degradable by the organism and of being capable of being modified chemically without losing its biological properties. So researchers studied the physical properties and surface of hyaluronic acid derivatives and tested their pace of decomposition so that they would correspond to that of the skin reconstitution.

A second difficulty was that of preserving the desired organisation of tissues when several types of cells co-exist on the same support. This question initially led the researchers to study the dermal and epidermal parts separately. They developed derivatives of hyaluronic acid which could be used to make a scaffold consisting of a fine membrane destined to receive the epidermal cells and a thicker structure, which was three-dimensional and spongy, destined to receive the dermal cells. Within the framework of the project Development of a biodegradable scaffold for dermo-epidermal skin grafts under the Brite-Euram programme on biomaterials, European cooperation made it possible to bring together people with very different skills and to achieve the critical mass needed to develop a product of this kind. "One of our partners, for example, works in the textile industry. He proved to be indispensable for adapting the technology of non-woven products, used in the manufacture of materials such as Kleenex, to the production of the matrix," explains Alessandra Pavesio, researcher at Fidia and coordinator of the project.

Reconstruction in two stages

Two first-generation systems, one for each of the two types of cell, have been produced and are now being commercialised in Italy. The patient's fibroblasts and keratinocytes are separated after biopsy and cultivated separately. The dermal matrix is then applied to the wound and the vascularisation of this tissue is awaited before the epidermal layer is positioned. The whole procedure lasts about a month.

The next stage consists of applying to the same support - which is smooth on one side and spongy on the other - the keratinocytes and the fibroblasts. "The main advantage of a single-stage system will be to simplify and shorten the procedure. This new matrix ought to be ready for clinical trials within a year and a half, but we will still have to wait another two or three years before we can hope to commercialise it", specifies Alessandra Pavesio.

Only one competitive product based on the same principle currently exists: a matrix in collagen of bovine origin developed by the firm Organogenesis, the licence for which has been ceded to Novartis. "Apart from the fact that it is unlikely to be widely accepted in Europe on account of its animal origin, the use of a protein in this system may provoke autoimmune reactions. What is more, this process uses donor cells, which does not facilitate their integration into the reconstructed skin", pursues the project coordinator.

The immunological neutrality of hyalonuric acid and the autologous grafting of skin cells thus constitute the major advantages of the Italian product. These specific qualities are helping to place Europe in a good position in a highly competitive field which, up to the present time, has included very few industries from the old continent. Fidia Advanced Biopolymers is now envisaging extending this research to create matrices adapted to other soft tissues, such as adipose tissues, for the reconstruction of breasts after therapeutic ablation.

 
Project
Development of a Biodegradable Scaffold for Dermo-Epidermal Skin Grafts

Reference
BRPR 960227

Programme
Brite EuRam III

Contact
Alessandra Pavesio
Fidia Advanced Biopolymers
Fax : +39 0 49 82 32 752
E-mail : apavesio.fab@protec.it
apavesio@fidiapharma.it


Partners
- Fidia Advanced Polymers, Abano Terme, Italy
- Centro Nazionale per la Ricerca e lo Sviluppo dei Materiali Sepa (PASTIS), Brindisi, Italy
- Rheinisch-Westfälische Technische Hochshule (RWTH), Aix-la-Chapelle, Germany
- Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
- Queen Mary & Westfield College, London, United Kingdom
- Houget Duesberg Bosson (HDB), Ensival (Verviersl), Belgium.

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Image obtained with an electronic microscope showing human skin fibroblasts growing and multiplying by adhering to the structure in biocompatible Laserskin® material developed by the FAB company.

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