Technology update Advances in tissue-engineered skin substitutes


Existing tests cannot provide absolute assurance that such products will not transmit unknown diseases. Similarly, tissue obtained from animal sources also carries the theoretical risk of transmitting infection, particularly prion-related diseases such as Creutzfeldt-Jakob disease.


Further concerns Many TESSs contain bovine, porcine or human constituents and thus may have religious and ethical implications that need to be addressed (such as obtaining informed consent). Furthermore, the cost- effectiveness of their usage has not been well established[24]


.


THE FUTURE Tangible concepts are beginning to emerge from the clinical evaluations carried out on TESSs. Biologically active and appropriate matrices and factors, in combination with automated tissue printing techniques[33] designed to produce a new generation of complex skin substitutes, are paving the way to a new concept known as ‘skingineering’[27]


. Other developments


include: n


The use of metabolically active fibroblasts[34]


n — these are provided


directly to the wound bed to stimulate the healing process


The use of chimeric epithelium — these comprise allogeneic keratinocytes together with 5% autologous keratinocytes[34,35]


xenogeneic keratinocytes[36] n


or autologous and and


can overcome initial problems with immunological rejection


Addition of genetically modified cells — cultured skin substitutes (CSS) contain keratinocytes that are genetically modified to overexpress vascular endothelial growth factor. This results in enhanced vascularisation of the graft (in animal models)[37,38]


n


Cutaneous gene therapy — junctional epidermolysis bullosa, a genetic cutaneous disease, can result from the mutation of genes encoding subunits of the protein laminin 5, which helps to anchor filaments in the basement membrane of skin[39]


. This disease


phenotype can be corrected by gene transfer of LAMB3 using a retroviral gene transfer vector[40,41]


. Similarly, genetically


Original artwork by: Jennifer Khan-Perez, Year 2 Medical Student, University of Manchester, UK


modified cultured skin grafts could potentially act as vehicles for cutaneous gene therapy in specific wound healing disorders


n


Use of genetically modified grafts to treat systemic disorders — genetically modified keratinocyte grafts have been used for systemic delivery of human growth hormone[42,43] factor IX[44-46]


, and human (to treat haemophilia B).


Proteins secreted by keratinocytes have been identified in the serum after grafting[47,48]


.


CONCLUSION The healing of burns and chronic wounds is a multi-step process that requires the intricate harmonisation of many different cell types, such as keratinocytes, fibroblasts, melanocytes and endothelial cells within the wound healing environment. Given the complexity involved, it is unlikely


that replacing or supplementing any one cell type or tissue will be successful in achieving satisfactory healing. Identifying specific patient factors and requirements, and developing a mechanism to supplement the lost tissue in its entirety, should be the goal of further research. Importantly, recent advances and


anticipated future developments should be complemented by adhering to the tenets of good basic wound care such as adequate debridement, skin care and infection control. Management of the patient rather than the ‘wound’ should be the primary goal.


AUTHOR DETAILS Mayura Hanis Damanhuri is a Year 3 Medical Student at the Manchester Royal Infirmary and University of Manchester, UK


Jemma Megan Boyle is a Year 4 Medical Student at the Royal Bolton Hospital and University of Manchester, UK


Stuart Enoch is Programme Director – Education and Research, Doctors Academy and Specialist Registrar in Plastic and Reconstructive Surgery, University Hospital of South Manchester, UK.


References


43. Vogt PM, Thompson S, Andree C, et al. Genetically modified keratinocytes transplanted to wounds reconstitute the epidermis. Proc Natl Acad Sci USA 1994; 91: 9307–11.


44. Jensen UB, Jensen TG, Jensen PK, et al. Gene transfer into cultured human epidermis and its transplantation onto immunodeficient mice: an experimental model for somatic gene therapy. J Invest Dermatol 1994; 103: 391–394.


45.Gerrard AJ, Hudson DL, Brownlee GG, et al. Towards gene therapy for haemophilia B using primary human keratinocytes.Nat Genet 1993; 3: 180–3.


46. Page SM, Brownlee GG. An ex vivo keratinocyte model for gene therapy of hemophilia B. J Invest Dermatol 1997; 108: 139–45.


47. White SJ, Page SM, Margaritis P, et al. Long-term expression of human clotting factor IX from retrovirally transduced primary human keratinocytes in vivo. Hum Gene Ther 2002 9: 1187–95.


48.Fenjves ES, Gordon DA, Pershing LK, et al. Systematic distribution of apolipoprotein E secreted by grafts of epidermal keratinocytes: implications for epidermal function and gene therapy.Proc Natl Acad Sci USA 1989; 86: 8803–07.


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Technology and product reviews


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