Research Proposals the science case for Clinical Research Director and Non-clinical Chair of Burns Research
Phase I: Components of Proposed Programme
This integrated research proposal encompasses acute care, wound healing and rehabilitation and aims to bring the laboratory to the bedside to improve care for burn patients.
Clinical Research Network
The National Centre for Integrated and Multidisciplinary Research in Burn Care (NCIMRBC) would be located within the University of London in facilities provided by Barts and the London School of Medicine and Dentistry, Queen Mary University of London. It would be housed within the new research laboratories provided by the Institute of Cell and Molecular Science (ICMS) as a new team within the Centre for Cutaneous Research, led by nomination to the position of the Healing Foundation Clinical Research Director, by Mr Simon Myers, an experienced burn surgeon, who has recently been recruited to the CCR as a Clinical Senior Lecturer. However the clinical burns research would require a satellite clinical research centre and use of the existing satellite laboratory within the Partner NHS Trust, St Andrew’s Unit, Broomfield Hospital and dedicated research staff on site together with a strategy to maintain the links between the two sites. The research at Broomfield would however be directed by the Clinical Research Director in collaboration with the current consultant staff who have been nominated for honorary Clinical Senior Lecturerships, and executed by Clinical Research Fellows and Research Nurses.Clinical Research Programme directed by Simon MyersThe scope of the clinical studies that could be produced over a 10 year period from the clinical team (Clinical Director, Senior lecturers/consultants, clinical research fellows and research nurses) are so extensive that they are described in brief, and suitable first studies detailed in the Appendix. The studies will have collaborations with work going on in the CCR already. They fall into three categories:
Mechanisms of burn wound healing
There is a need for a more complete understanding of the mechanisms of burn wound extension & burn wound healing, particularly the cellular interactions and signalling pathways activated in wound healing following burn injury. These studies can be performed in surgical specimens removed as part of patient care following suitable LREC approval and informed consent - for example:
- The expression of growth factors and cytokines in the burn wound: a spatiotemporal study using micro-array and proteomics approaches
A detailed study of the cytokine and growth factor expression will be undertaken with biopsies from burn wound base and edge at different time points following injury. Studies by immunochemistry and ISH will be extended from the suction blister model to include modern investigative techniques: expression arrays and proteomics using high density 2D gel maps and mass spectrometry. All these facilities are available as core facilities in the ICMS.
- Analysis of the mechanisms of burn wound extension
Following burn injury a zone of stasis appears around the edge with progressive microvascular deterioration, mediated in part by the local inflammatory response, release of prostaglandins/thromboxanes, free radical production by histamine activation of the xanthine oxidase pathway, hypernatraemic effects on neutrophil function and thrombomodulin shedding. Cell signalling pathways involved in wound extension will be studied in human burn wound material, and animal models will be established.
- How are stem cells replaced in burn wounds?
The identification of stem cells in vivo has been assisted by the identification of novel stem cell markers which will be applied to burn edges including the patent protected MCSP marker. In addition, generative potential will be assessed by colony forming assays and the development of holoclones, meroclones and paraclones from isolated keratinocyes in the wound edge.
The complications of burn injury
These include both local and systemic effects
- The role of fibroblast senescence in the development of hypertrophic scarring
Studies have shown that abnormalities in hypertrophic scarring affect epidermal-mesenchymal interactions. The lack of a suitable animal model means that many studies have been performed in vitro. Normal fibroblasts undergo senescence and we hypothesise that the hypercellularity of the hypertrophic scar could result from failure of these mechanisms. Understanding the regulation of this process could lead to therapeutic interventions.
- The response of the bone marrow to major cutaneous injury
Thermal injury quantitatively and qualitatively alters hematopoiesis. Granulocyte and macrophage production after burn injury or burn wound infection is significantly reduced, and further compromised by endotoxin. Hematopoietic stem cells normally proliferate and mature into lymphoid, erythroid, and myeloid precursor cells, but the balance of these cell populations is modulated by major thermal injury, with or without sepsis favouring the monocyte/macrophage lineage. Granulocyte colony-stimulating factor-treated animals exhibit significantly less bone marrow suppression although, G-CSF levels in burn injury are elevated, and neutropenia and myeloid maturation arrest correlate with reduction in bone marrow G-CSF receptor expression. Prostaglandin PGE2 can, in part, also restore the balance in bone marrow granulocyte and monocyte production. Understanding the dynamics of the different precursor pools could be used to identify patients at greater risk for systemic inflammatory sequelae following major thermal injury.
- Metabolic consequencies of major cutaneous loss, burn sepsis, and multi-organ failure: modulation of the cytokine storm
The metabolic response to large burn injury is complex, including skeletal muscle proteolysis, lipolysis, gluconeogenesis, increased metabolic rate, and a severe systemic inflammatory response induced by the injury, infections, and surgical procedures. Hypermetabolism is mediated by hormones – catecholamines, glucagon, and cortisol – and by cytokine and lipid mediators – inlerleukin-1, interleukin-6, tumour necrosis factor. These responses are interlinked, since cytokines activate the hypothalamo-adrenal axis. The systemic “cytokine storm” and inflammation may develop into shock and multiple organ failure if the primary insult is overwhelming or a second inflammatory insult such as sepsis triggers exaggerated inflammation – the two-hit phenomenon.
Pharmacological modulation of the exaggerated inflammatory response in burn primed patients may prevent organ dysfunction. Corticosteroid treatment and administration of cytokine synthesis inhibitors are potential approaches.
Therapeutic interventions in burn injury
Opportunities will arise not only as a direct effect of the research in CCR but also from advances in the medical and surgical management of burns including:
- Skin Engineering – developments involving Integra and Recell
Integra dermal regeneration template has become an accepted reconstructive option in burn care providing wound closure post-early near-total wound excision with the potential to limit late scar morbidity. The Recell technique provides a suspension of autograft keratinocytes without the delay of cell culture and by, for example, applying keratinocytes suspended in fibrin glue beneath Integra an improved autologous permanent wound closure for massive burn injuries may be achieved.
- Embryonic signalling pathways and the stem cell niche
Whilst the environmental stimuli and the specific cues that direct keratinocyte stem cell lineage and commitment are not well understood, a number of important developmental, molecular signalling pathways appear to play a major role in directing epidermal stem cell fate6,7. Wnt/ß-catenin/Lef-1 constitutes one such pathway, and activation of this pathway appears to direct keratinocyte stem cells to follow hair follicle differentiation pathways8-11. The Sonic Hedgehog (Shh) signalling pathway regulates proliferation of cells that undergo differentiation into hair follicle epithelium12-13. However, de-regulation of the Shh pathway also leads to tumour development demonstrating the importance of tightly controlled pathways.
- Antimicrobial peptides in the treatment of burn wounds
Human defensins have specific spectrums, but synergistic effects are achieved by various combinations. The induction of human defensins could provide a completely new strategy for the treatment of infections, perhaps avoiding the problems of acquired resistance seen with current antibiotics particularly in burn care. The production of human defensins via genetic engineering is the preferred method, either by cell-based or cell-free protein expression systems. Understanding the post-translational modification of these, and other, antimicrobial peptides may allow their incorporation and active release from biological dressing systems, dermal regeneration templates, and cultured cell delivery systems. It will also be important to understand the in vivo consequencies of upregulation, or modification of expression profiles.
- Hepatocyte Growth Factor Expression in Burns: the Effect of Exogenous Application
This study is detailed in the Appendix as it is currently able to be pursued as soon as a clinical fellow in recruited.
- Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D, Lim KC, Dai X, Alegre ML, Fuchs E. GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev 2003; 17: 2108-22
- Jamora C, DasGupta R, Kocieniewski P, Fuchs E. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 2003; 422: 317-22
- Zhou P, Byrne C, Jacobs J, Fuchs E. Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate. Genes Dev 1995; 9: 700-13
- Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001; 105: 533-45
- Merrill BJ, Gat U, DasGupta R, Fuchs E. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev 2001; 15: 1688-705
- DasGupta R, Rhee H, Fuchs E. A developmental conundrum: a stabilized form of beta-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells. J Cell Biol 2002; 158: 331-44
- St-Jacques B, Dassule HR, Karavanova I, Botchkarev VA, Li J, Danielian PS, McMahon JA, Lewis PM, Paus R, McMahon AP. Sonic hedgehog signaling is essential for hair development. Curr Biol 1998; 8: 1058-68
- Wang LC, Liu ZY, Gambardella L, Delacour A, Shapiro R, Yang J, Sizing I, Rayhorn P, Garber EA, Benjamin CD, Williams KP, Taylor FR, Barrandon Y, Ling L, Burkly LC. Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration. J Invest Dermatol 2000; 114: 901-8
The Non-Clinical Professor of Burn Injury Study: Potential research themes
The major funding component of phase I will consist of a Non-Clinical Professor (1a) and support package (1b) to investigate specific areas of infection and/or immunity in burns patients.
- Burn Infection (Collaboration with M Curtis, D Wareham, Centre for Infectious Disease, ICMS)
Under normal circumstances, a highly effective panel of integrated mechanical, chemical and biological systems protect the host from infections through the skin. The breakdown of this barrier function following major thermal injury coupled with the physical environment of abundant moisture, nutrients and gaseous supply provide the perfect setting for bacterial growth and rapid proliferation. Secondary infection of burn wound thus still constitutes one of the greatest threats to burns patients, who have survived the acute episode.Current standard care involves systemic antibiotics (ß-lactams and aminoglycosides) or topical antimicrobial agents such as silver sulfadiazine. Whilst this approach has limitations in terms of penetration of partial and full thickness burns, limited efficacy against both Gram-negatives and Gram-positives and potential toxicity to human cells, the major obstacle to overcome in the management of burns wounds is treatment of infection by multiply antibiotic resistant bacteria: the most common pathogens now isolated from burn wounds are methicillin resistant Staphylococcus aureus (MRSA), multiply drug resistant Pseudomonas aeruginosa and Acinetobacter sp and increasingly vancomycin resistant enterococci (VRE). The problem of ongoing outbreaks with such resistant organisms has attracted considerable public and professional concern and in 2005 a working party under the auspices of the Health Protection Agency was set up to address the problem of multi-drug resistant Acinetobacters (Health Protection Agency, 2005).
The key target of preventing bacteraemia and sepsis due to bacterial infections of burn wounds remains a fundamental issue in burns care. Hence a major goal of the research lead by the Non Clinical Professor of burns injury will involve analysis of the bacterial determinants of pathogenesis in burns infections and, in the context of the wider interdisciplinary team, the identification of novel, candidate therapeutic strategies based on an improved understanding of the patho-physiology of the infected wound.
Background to bacterial research in Epithelial Pathogens Group, ICMS Bacterial research in the ICMS is focused on the molecular basis of pathogenicity of Gram-negative bacteria at epithelial surfaces. The Centre of Infectious Disease has considerable expertise in the characterisation of bacterial virulence factors through both reverse genetic and directed mutagenesis strategies. This approach combines in-silico analyses of the genomes of diverse strains with the genes required for full virulence in model systems. This provides the perfect partnership through the ICMS for the development of microbial research in burns patients.
The identification and characterisation of the major virulence determinants of Gram-negative organisms and from this the development of novel targeted therapeutic approaches is a major theme. A breach in the normal defensive barriers of the host, through for example thermal injury or co-infection by another organism, can dramatically influence the virulence of a given organism. Two examples of microbial virulence research currently underway are given below
Extracellular and cell associated hydrolytic enzymes are considered to play an important role in the infection process not only by the generation of nutrients for bacterial growth but also by inactivation/degradation of host macromolecules involved in tissue homeostasis and host defence. Hence these enzymes represent potential targets for the development of novel treatment approaches. Proof of principle studies in P. gingivalis, led to a larger applied genomics programme in the identification and validation of protease targets in other Gram negative bacteria including P. aeruginosa. Less information is available with regard to the degradative capabilities of Acinetobacter sp. However, we have hypothesized that a protease of A. baumanii is able to degrade insulin leading to the development of glucose intolerance in burns patients14, and an extracellular lipase produced by clinical isolates of this organism may cause extensive damage to fat deposits seen in infected burns patients.
Type III secretion systems
Type III secretion systems (TTSS) are devices used by many Gram-negative pathogens to subvert the function of epithelial and immune cells and/or to facilitate invasion. A “molecular syringe” protrudes from the bacterial cell surface and inserts into the plasma membrane of the target cell transporting TTSS effector proteins into the cytoplasm where they interact with specific components. P. aeruginosa possesses a type III secretion system which enables delivery of at least four effector (Exo) proteins (ExoS, T, U and Y) directly into the cytoplasm of epithelial cells. Inactivation of Rho and Rac by the Rho-GAP activity of ExoS and ExoT leads to inhibition of both wound healing and tissue regeneration. Active or passive immunisation with recombinant PcrV, a component of the TTSS apparatus essential for secretion, was found to be entirely protective in a mouse burn model of P. aeruginosa infection. Similarly, administration of anti-PcrV monoclonal antibodies reduced mortality, inflammation and injury in an acute lung infection model15. Further characterisation of the role and nature of the TTSS in burn wound isolates may enable similar approaches to be implemented in patients with infected burns.
Serological identification of novel virulence determinants
Analysis of the human serum antibody response developed during an episode of infection provides a well established means of identifying gene products likely to have a role in the infection process. In-vivo induced antigen technology (IVIAT) uses sera from infected patients to probe an expression library for genes specifically expressed in-vivo. Using sera from patients who have recovered from A. baumannii infection, and comparing them with the sera of those who have simply been colonised with the organism, it would be possible to define those antigens that are expressed in-vivo during the establishment and progression of A. baumannii infection.
Regulation of virulence
Pseudomonas aeruginosa can switch between a free-living (planktonic) or biofilm lifestyle, a versatility that enables it to thrive in many different environments contributing to its success as a human pathogen. The production of many bacterial virulence factors relies on a cell density dependent signalling system known as quorum sensing (QS) whereby bacteria secrete LMW molecules into the environment which are detected by the surrounding bacteria. The signalling molecules are often homoserine lactone substances, which act as autoinducers driving transcriptional regulation of QS responsive genes. Disruption of the P. aeruginosa QS system has been shown to influence both local and systemic spread of P. aeruginosa in thermally injured skin. A number of interrelated systems have been identified in P. aeruginosa and S. aureus and may also be present in A. baumannii. Characterisation of these systems may therefore help elucidate common mechanisms of pathogenesis, which could be open to modification with novel inhibitors of QS systems.
Proposed areas of study
Genomic analysis of burn pathogens
Molecular analysis of the interaction of a bacterial pathogen with the human host using modern technologies is now fundamentally dependent on the complete genome sequence of that pathogen. This information enables rapid identification of genes from protein analyses, transcriptome analyses using microarrays, proteomic analysis via 2D gels and related separation techniques and description of co-ordinatedly regulated networks of genes involved in pathogenesis. The genome sequences of representatives of the predominant isolates from burns infections are already available but there are still significant gaps in our knowledge base. In particular, the genome sequence of Acinetobacter sp is not yet publicly available. As part of the broader initiative in burns microbiology, consideration will therefore be given to develop funding applications to work with the Sanger Centre to fully sequence a clinically relevant multi-drug resistant form of this species and other unsequenced pathogens relevant to burns microbiology.
Epidemiology and infection outcome
Although genomic analyses of sequenced strains may give important information on the bacterial determinants involved in burn wound infection, clinical isolates often differ markedly from those chosen for sequencing. Acquisition of foreign DNA in the form of plasmids, transposons and integrons may lead to increased virulence as well as additional antimicrobial resistance. In order to develop better infection control and treatment strategies there is a need to understand where and why virulent and resistant strains evolve and the dynamics of transmission. Multi-locus sequence typing (MLST) which relies on DNA sequence comparison of fragments of protein encoding housekeeping genes has become the gold standard typing technique and is being applied to multi drug resistant isolates of A. baumannii. Correlation of the molecular epidemiology of burn wound pathogens with the type and severity of human infection may help to identify virulent clones, distinguish between colonisation and infection and target or rationalise antimicrobial therapy.
Model system development for the analysis of pathogen/epithelium interactions
More sophisticated models, employing higher organisms, attempt to reproduce the complex interaction of bacterial virulence factors with the host immune defence. Such an approach has been used by us to identify the importance of P. aeruginosa virulence factors in-vivo using the nematode C. elegans. This model has additional advantages enabling gene expression in-vivo to be studied using green fluorescent protein (GFP) or RT-PCR reporter assays. A collection of C. elegans innate immunity mutants are also available enabling bacterial pathogenicity to be studied in an immunocompromised background. As C. elegans is susceptible to most burn wound pathogens such as P. aeruginosa, S. aureus and more recently A. baumannii16 it could be used for high throughput screening of clinical isolates to identify virulent strains.
- D. Furniss, S. Gore, B. Azadian, SR Myers. JBCR. 2005:26(5):405-408
- Sawa T, Yahr TL, Ohara M, Kurahashi K, Gropper MA, Wiener-Kronish JP, Frank DW. Nat Med.1999 Apr;5(4):378-9
- Smith MG, Des Etages SG, Snyder M. Mol Cell Biol. 2004 May;24(9):3874-84
- Burn Care and Immunity (Collaboration with Dan Pennington, Immunology, ICMS)
Innate Immune Response
Human immunological defences consist of two immunological subsystems - innate and adaptive. The innate immune response is a collection of host defences from barrier function to highly selective recognition of pathogens; which give together a rapid and blunt response to infection and tissue destruction. The adaptive immune system, in contrast uses antigen receptor genes encoding receptors to any antigen, but is slower to respond and requires instruction from the innate immune response.
It is recognized that extensively burned patients have an increased susceptibility to infection and often succumb to multiple organ failure related to sepsis. Numerous investigations performed over many years have demonstrated immunologic abnormalities in burn patients many of them in the innate responses eg. involving opsonin levels , the complement system , phagocyte and neutrophil function . More recently it has become clear that the innate immune system of the skin (dendritic as well as epithelial cell mediated) recognises pathogen associated molecular patterns (PAMP) using pathogen recognition receptors (PRP). The toll-like receptors (TLR) have 10 family members specific for microbial ligands, which direct pathogen killing and the release of proinflammatory cytokines and antimicrobial peptides or host defence peptides. Amongst the functions of these peptides are: activation and attraction of antigen presenting cells and lymphocytes, endotoxin neutralisation, promotion of healing and angiogenesis, modulation of the adaptive immune responses, inactivation of microbes through multiple effects at their membranes, and simultaneous attack of both internal and external targets in some groups. There are hundreds of receptors involved in innate immune recognition of PAMPs such as: bacterial lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acids (LTA), etc. PAMPs have in common that they are produced by the pathogen not host, they are necessary for pathogen survival and pathogenicity, and they are shared by the pathogen class – so that all gram negative bacteria will be recognised by a PRP to LPS. The TLRs are an important group of PRPs, and link the innate with adaptive immune systems via activation of the NF- kB pathway.
In the skin, Langherhan’s cells, monocytes and macrophages respond to bacterial LPS via TLR4 to produce IL-1, which in turn stimulates beta defensin-2 (HBD-2) synthesis in neighbouring keratinocytes17. Burn injury primes the innate immune system for enhanced TLR2- and TLR4-mediated responses. Augmented TLR reactivity might contribute to the development of heightened systemic inflammation following severe injury18. A previously unsuspected role for CD4(+)CD25(+) T regulatory cells in controlling host inflammatory responses via TLR after injury has been suggested19.
Defensins are effector molecules of the innate host defense system with antimicrobial activity against a variety of pathogens, including microorganisms commonly found in burn units. beta-Defensins are variably expressed in the epithelia of skin and other organs.
Syndecan 1 is a major heparan sulfate proteoglycan present on many host cells involved in thermal injury. Syndecan 1 cleavage results in the release of intact, soluble proteoglycan ectodomains that have diverse roles in innate immunity. Here we show for the first time that thermal injury results in shedding of syndecan 1 from host tissue and preliminary data suggest that shed syndecan 1 plays an important role in the pathogenesis of P. aeruginosa infection of thermal injury and that syndecan 1-neutralizing agents may be effective supplements to current P. aeruginosa treatments20.
Following release of antimicrobial peptides and the initial response to mechanical injury of the skin. An inflammatory response occurs with influx of phagocytes and serum factors, such as complement and mannose-binding lectin (MBL), which is a broad-spectrum pattern recognition molecule that plays a key role in innate immunity. A growing consensus from studies in humans and mice suggests that lack of MBL together with other comorbid factors predisposes the host to infection in burn victims21.
Adaptive Immune Response
Burn injury is associated with an adaptive Th2 or type 2 T-helper lymphocyte response, and impaired IL-12 production. Th2 cytokines, IL-4, IL-10, inhibit the generation of Th1 cells essential to host resistance to infection. T cell function in burn injury has been extensively explored in a model of susceptibility to herpes simplex viral infection in mice. Exogenous administration of rhGH caused an improvement in the resistance of burned mice to HSV-1 infection. IFN-gamma, a typical antiviral cytokine induced by rhGH through the regulation of the suppressor macrophage generation, may therefore play a role in the protection of burned mice infected with a lethal amount of HSV-122. Therapy has been attempted with IL-12 and soluble IL-4 receptor23 and IL-12 and BEN24. Interleukin-12 (IL-12), a cytokine that induces expression of the T-helper-1 lymphocyte phenotype, had been shown to increase survival after a septic challenge in an animal model of burn injury25. IL-12 is the most effective therapy so far tested in this burn plus CLP model. It acts at least in part through IFN-gamma. However, IFN-gamma therapy was not as effective as IL-12.
The ability of a host to produce Th1 cytokines, such as gamma interferon (IFN-gamma) and interleukin-12 (IL-12), upon infectious challenge is impaired after burn injury. Stimulation of hematopoiesis, to regenerate new immune cells, may be an effective strategy for improving resistance to infections after severe burn trauma. Fms-like tyrosine kinase 3 ligand (Flt3L) is a hematopoietic cytokine that stimulates the expansion and differentiation of NK cells and DC. We hypothesis that Flt3L treatments after burn injury may stimulate the production of functional effector cells of innate immunity and restore appropriate Th1 cytokine responses to Pseudomonas aeruginosa, as shown in burned mice in vivo amd in splenic cultures. Flt3L may also have potential for restoring NK cell and DC functions and improving immunity after burn injury26.
Severe injury induces detrimental changes in immune function, often leaving the host highly susceptible to developing life-threatening opportunistic infections. Advances in our understanding of how injury influences host immune responses suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2-type immune responses. Using a TCR transgenic CD4(+) T cell adoptive transfer approach, injury skews T cell responses toward increased Th2-type reactivity in vivo without substantially limiting Ag-driven CD4(+) T cell expansion27.
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- Murphy TJ, Choileain NN, Zang Y, Mannick JA, Lederer JA. J. Immunol. 2005 Mar 1;174(5):2957-63
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- Moller-Kristensen M, Ip WK, Shi L, Gowda LD, Hamblin MR, Thiel S, Jensenius JC, Ezekowitz RA, Takahashi K. J Immunol. 2006 Feb 1;176(3):1769-75.Takeda et al, 2003
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- Kobayashi M, Takahashi H, Herndon DN, Pollard RB, Suzuki F. Can J Microbiol. 2002 Oct;48(10):886-94
- Kobyashi M, Takahashi H, Herndon DN, Pollard RB, Suzuki F. Burns. 2003 Feb;29(1):37-42
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Phase II: Injury Rehabilitation Model
Rehabilitation after burn injury remains problematic both in terms of maximising function and providing psychosocial adaptation. Medical and surgical advances over the past 25 years have dramatically decreased the mortality of severely burned patients but patients may require protracted surgical, medical, psychological, and rehabilitation interventions over many years. Little is known about the effects on quality of life, access to care and rehabilitation, and the cost and effectiveness of various treatment strategies. Key concepts to address these issues include financing and delivery of burn care, quality and effectiveness of burn treatment and interventions, and psychosocial factors of the burn patient and family. At present population based data on incidence, prevalence and cost ofburn injury is limited to hospital based datasets, which need to be expanded into the community and home setting.
It is commonly believed that injury size is the principal determinant of outcome, but injury location, socio-economic background, and psychological adaptation be important in recovery following burn injuries. What is known about the psychosocial adaptation of burn victims is very limited, Key factors influencing rehabilitation of burn survivors need to be identified following initial care during the acute care hospitalisation such as compliance with aftercare, family function, posttraumatic stress disorder and pre-morbid conditions. Complex methods of data acquisition and data management will be necessary to identify, measure and influence this process of adaptation.
In order to provide a model of outcome measurement, quality control, and quality improvement and to develop a viable model of integral rehabilitation, general research efforts are necessary to:
- Define the scope, incidence, prevalence, and costs of burn injuries
- Determine the variability in practice and detect any evidence-based practices
- Define all diagnostic tools of compliance with aftercare and impact on social adaptation
Research priorities for the rehabilitation project, will
- Develop population-based data on the incidence, prevalence, and scope of the burn problem, including outpatient and in-patient facilities
- Determine major factors that increase costs of care
- Determine whether the treatment in burn centres improves outcomes
- Identify barriers to access to rehabilitation
- Determine the ideal volume of patient referral to burn centres
- Determine the effect of different topical and surgical techniques in the quality of outcomes
- Develop outcome measurements of the integration of burn victims in the mainstay of society, with a significant focus in population at risk (children, adolescents, elderly)
- Identify determinants of non-compliance
- Develop tools to impact in patients with non-compliance and improve sub-optimal outcomes
- Evaluate all factors in the psychosocial background of the patients and determine outcome measurement algorithms
There are existing training programmes for burns education for surgeons, nurses and allied health professionals at Broomfield. Simon Myers has already contributed a course module in burns to the Cardiff Critical Care MSc course. There is a rapidly developing expertise in the CCR in distance learning by WebCT, which is being applied to three diploma courses. Therefore the development of e learning for an MSc in plastic surgery and burns care is timely and short and long teaching courses can be integrated into these programmes as modules. The development of these programmes requires allocation of dedicated teaching and administrative resource.
M: Curricula Vitae
Name: Irene May Leigh
Present Position: (Barts and the London SMD, QMUL)
- Professor of Cellular and Molecular Medicine
- Centre Lead, Centre Cutaneous Research
- Director Cancer Research UK Skin Tumour Laboratory
- Dean for Research (1997-2002)
- Joint Director of Research and Development, (2002-2005)
- Warden’s Team: E Learning
- Honorary Consultant Dermatologist, Barts/London NHS Trust (1983 - present)
BSc 1968 1st Class Honours in Anatomy, University of London, MBBS 1971 University of London, MRCP 1975, FRCP 1989, MD 1991 University of London, F Med Sci 1999 Academy of Medical Sciences, DSc (Med) 1999 University of London
- Established biomedical researcher of international reputation
- Developed a world class Cellular and Molecular Research Centre
- Extensive research management experience in HEI and NHS
- Developed research strategy, infrastructure, institutional bids and managed significant research budgets
- On senior management team of HEI for over 8 years
- Annual grant income: CR UK (PI) £984,000, Non-CR UK >£1.5 m
- Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin26 mutations in hereditary non- syndromic sensorineural deafness. Nature 1997;387:80-83
- Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM,Matlashewski G, Banks L. Role of p53 polymorphism in the development of human papillomaviru associated cancer. Nature 1998;393:229-234
- Popp S, Waltering S, Holtgreve-Grez H, Jauch A, Proby C, Leigh IM, Boukamp P. Genetic characterisation of a human skin carcinoma progression model: from primary tumor to metastasis. JID 2000;115:1095-1103
- Huen AC, Park JK, Godsel LM, Chen X, Bannon LJ, Amargo EV, Hudson TY,Mongiu AK Leigh IM, Kelsell DP, Gumbiner BM, Green KJ. Intermediate filament-membrane attachments function synergistically with actin dependent contacts to regulate intercellular adhesive strength. J Cell Biol.2002;159: 1005-17
- Kelsell DP, Norgett EE,…Leigh IM et al Mutations in ABCA12 Underlie the Severe Congenital Skin Disease Harlequin Ichthyosis. Am J Hum Genet. 2005 May;76(5):794-803. Epub 2005 Mar 8
Name: Simon Richard Myers
Present Position: (Barts and the London SMD, QMUL)
- Clinical Senior Lecturer in Burns & Wound Healing
- Honorary Consultant in Plastic Surgery, Barts & The London NHS Trust
MBBS 1988, FRCS England 1992, PhD (Lon.) 1999: Keratinocyte growth and differentiation in cutaneous wound healing and cultured keratinocyte grafting, FRCS [Plast] 2001
- Experienced burn surgeon – directed service for 4 years
- Clinical and laboratory based burn teaching and research experience
- Experience directing skin bank
- Maintained and developed paperless burn EPR
- Involved in International humanitarian collaborations in burn care
- Largest grant :European Commission Research & Technological Development Grant No. BE3524, 1996: 2,127,000 €
- Award of Merit, NHS Champions, 2004 [Evening Standard/King’s Fund/London Tonight]
- The Development of Novel Dermal Matrices for Cutaneous Wound Repair. Edwin T Anthony, Mobin Syed, Simon Myers, Graeme Moir, Harshad Navsaria. Drug Discovery Today: Therapeutic Strategies. In press 3/2006
- Acinetobacter Infection is Associated with Acquired Glucose Intolerance in Burn Patients. D. Furniss, S. Gore, B. Azadian, SR Myers. JBCR. 2005:26(5):405-408
- Case-Controlled Study of Patients with Self-Inflicted Burns. Horner BM, Ahmadi H, Mulholland R, Myers SR, Catalan J. Burns. 2005 Jun;31(4):471-5
- Estimation of breast burn size. Hidvegi N., Nduka C., Myers S., Dziewulski P. PRS. 2004 May;113(6):1591-7
- Development of HRGs for Adult Critical Care: A National Pilot Study. University of Sheffield School of Health & Related Research [MREC/02/04/088], 2003
Name: Harshad Navsaria
Present Position: (Barts and the London SMD, QMUL)
- Professor of Cell and Tissue Engineering
- Member of Tissue Engineering Advisory Board, Purdue University, USA (2001 - 2003)
- Section Editor for Drug Discovery Today. 2005
- Academic Dean 2005
- Chairman of the School Board 2005
- Teaching Lead 2003-2006
BSc Physiology & Biochemistry 1984, MSc Biochemical Immunology 1988, PhD Keratinocyte Biology 1998
- Integral in development of CCR
- International reputation for in vitro keratinocyte culture systems and clinical application
- Decades of experience in supervision of Plastic/Burn Surgeons in burn research
- Involved in International humanitarian collaborations in burn care
- Selected to exhibit on "Skin: A birthday suit for life" at The Royal Society, 1999
- Exhibit on "Tissue Engineering of Skin" in the British pavilion, Expo 2000, Hannover, 2000
- Annual grant income: >£200,000 pa from councils, charities and industry
- Ojeh NO, Frame JD, Navsaria HA. In vitro characterisation of an artificial dermal scaffold. 2001. Tissue Engineering, vol 8(4), 457-472
- Navsaria HA, Rugg EL. Telomere shortening: significant for keratinocyte grafting? 2003. Lancet,vol 361, 1316-1317
- Navsaria H, Ojeh N, Moiemen N, Griffiths M, Frame J. Re-epithelialisation of full thickness burn from stem cells of hair follicles micrografted into tissue engineered skin. 2004. PRS ;113(3):978-81
- Price RD, Das-Gupta V, Harris PA, Leigh IM, Navsaria HA. The role of allogenic fibroblasts in an acute wound healing model. Plast Reconstr Surg. 2004 May;113(6):1719
- Griffiths M, Ojeh N, Livingstone R, Price R, Navsaria H. The length of survival and pathological features of an allogeneic living skin substitute, ApligrafÒ, in an acute human wound model. 2004. Tissue Engineering. Jul-Aug;10(7):1180-95
Name: Peter Dziewulski
Present Position: (St Andrews Centre for Plastic Surgery & Burns, Broomfield Hospital)
- Consultant Plastic & Reconstructive Surgeon
- Director of Burn Unit
FRCS, FRCS [Plast]
- Chairman British Burn Association and Member Executive Committee British Burn Association
- Has organised and runs only U.K. level III Burn Fellow Training Post. 7 Fellows trained are all practising Consultant Burns Surgeons in UK and abroad
- Board of Trustees Healing Foundation
- Chairman, Rehabilitation Committee International Society for Burn Injuries
- Editorial Committee Burns Journal International Society for Burn Injuries
- Court of Examiners MRCS, Royal College of Surgeons of England
- Reviewer British Journal Plastic Surgery
- BAPS Overseas Committee British Association of Plastic Surgeons
- Key Instructor and Senate April 2003 Emergency Management of Severe Burns Course
- Convenor BBA Educational Lecture Courses Royal College of Surgeons of England
- Undergraduate Tutor St Andrews Centre
- Lim EH, Sood MK, Dziewulski P. Unilateral palmar and axillary hyperhidrosis post electrical flash burn. Burns. 2006 May;32(3):389-90
- Langlois NE, Tarran S, Dziewulski P. A study of burns for wound ageing reveals changes in unburnt skin with implications for future research. Med Sci Law. 2005 Jul;45(3):205-10
- Leon-Villapalos J, Kaniorou-Larai M, Dziewulski P. Full thickness abdominal burn following magnetic resonance guided focused ultrasound therapy. Burns. 2005 Dec;31(8):1054-5
- Tarran S, Dziewulski P, Sztynda T, Langlois NE. A study of p53 expression in thermal burns of human skin for determination of wound age. Med Sci Law. 2004 Jul;44(3):222-6
- Hettiaratchy S, Dziewulski P. ABC of burns: pathophysiology and types of burns. BMJ. 2004 Jun 12;328(7453):1427-9