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CCR and Broomfield

Collaborations in burns research between CCR and St Andrew’s

Collaborative research between St Andrew’s Billericay and CCR started soon after the inception of the laboratory with the personal support of Mr Mike Hackett who saw the potential of such collaboration and funded both the laboratory development and many of the first Clinical Research Fellows who worked in the laboratory until his early death. Additionally, close research relationships were developed with Prof Roy Sanders in the development of RAFT at Mount Vernon Hospital, and for animal work with Prof Colin Green at Northwick Park. A research collaboration was also established with Robin Martin and the Blond-McIndoe Centre, East Grinstead. One of the earliest appointments to the group was a keratinocyte biologist, Harshad Navsaria, who provided support for early collaborations and has developed an independent programme of tissue engineering (see publication list). The collaboration has been particularly successful in sponsoring research fellows in plastic surgery training, many of whom are now established consultants in the UK including Bruce Philp and Simon Myers himself. Tissue engineering research is currently jointly providing a producer unit for cultured keratinocytes to Broomfield Hospital and research activity in tissue engineering.

Existing research programmes

Externally funded programmes each led by a senior academic and employing over 80 researchers (details in supplementary papers: also see website www.smd.qmul.ac.uk

These research teams are:

  1. Cell immortalisation and senescence (David Beach)
  2. Barrier function (Carolyn Byrne)
  3. Genetically inherited skin disease (David Kelsell)
  4. Epidermal Stem Cells (Ian Mackenzie)
  5. Tissue engineering (Harshad Navsaria)
  6. Keratinocyte migration and invasion (Edel O’Toole)
  7. Hair biology (Mike Philpott)
  8. Clinical cancer programme (Charlotte Proby)
  9. Prostate cancer (David Prowse)
  10. Epidermolysis Bullosa (Andy South)
  11. HPV and cancer (Alan Storey)

Existing clinical research projects in wound healing and tissue engineering

1. Wound Healing (Simon Myers) (Lon.), PhD 19991

Wound healing is a complex biological process involving the coordinated response of multiple cell types: keratinocytes, fibroblasts, endothelial cells and immune cells in the processes of cell proliferation, migration, angiogenesis and scar matrix remodelling. The unique nature of burn injury causes deregulation of many of these processes with resultant delay in healing, hypertrophic scarring and poor function and cosmesis. Studies in progress:

  1. Growth factor profiles have been established in a suction blister model – a controlled human model of superficial partial-thickness cutaneous insult, and are being extended to follow gene expression longitudinally in wounds of different depths in porcine models and human wounds This work forms a sound base for specific investigation of factors, and assessment of their therapeutic benefit (see proposal in supplementary papers)

  2. Antimicrobial peptides Using RT-PCR and in situ hybridization (ISH), human beta defensin-1 and -2 transcripts have been localised to keratinocytes within interfollicular skin and the hair follicle This work was extended to gastric mucosa where HBD-2 was markedly upregulated in a dose and time dependent manner following H pylori and proinflammatory stimuli2-4

  3. Hypertrophic scarring and keloids Hypertrophic scarring most commonly occurs when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds, and is considered a dermal pathology in which the epidermis has only a passive role. However, in a previous study we showed activation of the epidermis of hypertrophic wounds and keloids with expression of hyperproliferative keratins K6, K16 and K17 by immunochemistry, and ISH5. These studies are being pursued in a dedicated nurse-led keloid clinic with a clinical research fellow (E Anthony)

  4. Psychotherapy & Counselling Research (Nancy Cohen) Under the supervision of a Consultant Psychotherapist, body image, mood and quality of life have been investigated in young people burned in childhood in a doctorate thesis. The experiences of senior medical staff of different professional groups have been explored in an MSc

2. Tissue Engineering/Somatic Stem Cell Therapy & Ex Vivo Gene Therapy (Harshad Navsaria)

Over the last twenty years, our work has focused on the biology of cultured keratinocytes using complex three-dimensional organo-typical cultures, preclinical animal models in rodents and pigs, and their clinical application to acute and chronic wounds in humans.  Investigations into the use of delivery systems, dermal matrices, hair follicle transplantation, and the biology of transplantation of allogeneic grafts have led to further clinical refinement.

The CCR is a thus  provider unit for cultured keratinocytes to patients with large burn injuries at The Chelsea & Westminster burn service, and Broomfield burn service, usinga variety of delivery systems. Thisprogramme currently involves three ClinicalResearch Fellows who are Plastic Surgeons: Mobin Syed [PhD student],Edwin Anthony [MD student], and Partha Vaiude. Ongoing research projects in this area include studies to improve graft structure, identify derived therapeutic agents, and investigate both somatic and embryonic stem cell grafts. Ex vivo gene therapy to treat patients with RDEB is also under way.

i. Development and application of new dermal templates

New dermal templates are currently being evaluated in acute burns at Broomfield. The application of cultured epidermal autografts and allografts is improved by the use of dermal templates including Alloderm and Integra. However results are still suboptimal and new dermal agents are needed, which requires a fundamental understanding of matrix expression and organisation during normal wound healing, and of epidermal-mesenchymal interactions in vitro and in vivo.

ii. Improved cultured epidermal autografting (CEA)

Research on CEA has been a traditional line of collaborative investigation between Broomfield and CCR and is currently addressing the synthesis of dermo-epidermal junction proteins and the long-term viability of the grafts. The development of composite dermo-epidermal grafts in the laboratory to create more sophisticated skin replacements are being evaluated including the inclusion of skin adenexae and melanocytes.

iii. Allogenic transplantation

Adequate autologous skin is often not available in major burns, so the use of allogeneic materials and tissue banking has been intimately linked with burn care. The advent of new anti-rejection therapies raises the possibility of allogenic skin and composite graft transplantation. Reports of hand transplantation have shown that full thickness skin transplantation is possible with immunosuppression.

iv. Ex vivo gene therapy

In autosomal recessive skin diseases marked by absence of type VII collagen and laminin 5 (RDEB and JEB), keratinocytes have been transduced in vitro to express the missing proteins both in vitro and in transplants onto SCID mice. Clinical trials of ex vivo gene therapy using corrected keratinocytes are therefore in preparation and require the technologies developed for burns patients in CEA grafting.

v. Bronchial epithelium

Human bronchial epithelial cells have been cultured from bronchial brushings, which retain their in vivo phenotype, and immortal cell lines using HPV constructs are being developed to model inhalational injury and to study in-vitro toxicology on bronchial epithelium and for tissue engineering.

References

  1. Keratinocyte growth and differentiation in cutaneous wound healing and cultured keratinocyte grafting
  2. Ali RS et al J Invest Dermatol 2001;117; 106-11
  3. Bajaj-Elliot M, et al. Gut 2002 51:356-61
  4. Chronnell CM, et al J Invest Dermatol. 2001 Nov;117(5):1120-5
  5. Machesney M, et al Am J Pathol. 1998 May;152(5):1133-41
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