title: Acute cutaneous wounds treated with human decellularised dermis show enhanced angiogenesis during healing.
abstract: BACKGROUND
  The influence of skin substitutes upon angiogenesis during wound healing is unclear.
  
  
  OBJECTIVE
  To compare the angiogenic response in acute cutaneous human wounds treated with autogenic, allogenic and xenogenic skin substitutes to those left to heal by secondary intention.
  
  
  METHODS
  On day 0, four 5mm full-thickness punch biopsies were harvested from fifty healthy volunteers (sites 1-4). In all cases, site 1 healed by secondary intention (control), site 2 was treated with collagen-GAG scaffold (CG), cadaveric decellularised dermis (DCD) was applied to site 3, whilst excised tissue was re-inserted into site 4 (autograft). Depending on study group allocation, healing tissue from sites 1-4 was excised on day 7, 14, 21 or 28. All specimens were bisected, with half used in histological and immunohistochemical evaluation whilst extracted RNA from the remainder enabled whole genome microarrays and qRT-PCR of highlighted angiogenesis-related genes. All wounds were serially imaged over 6 weeks using laser-doppler imaging and spectrophotometric intracutaneous analysis.
  
  
  RESULTS
  Inherent structural differences between skin substitutes influenced the distribution and organisation of capillary networks within regenerating dermis. Haemoglobin flux (p = 0.0035), oxyhaemoglobin concentration (p = 0.0005), and vessel number derived from CD31-based immunohistochemistry (p = 0.046) were significantly greater in DCD wounds at later time points. This correlated with time-matched increases in mRNA expression of membrane-type 6 matrix metalloproteinase (MT6-MMP) (p = 0.021) and prokineticin 2 (PROK2) (p = 0.004).
  
  
  CONCLUSIONS
  Corroborating evidence from invasive and non-invasive modalities demonstrated that treatment with DCD resulted in increased angiogenesis after wounding. Significantly elevated mRNA expression of pro-angiogenic PROK2 and extracellular matrix protease MT6-MMP seen only in the DCD group may contribute to observed responses.
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester, Lancashire, United Kingdom; University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, Lancashire, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Greaves
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester, Lancashire, United Kingdom; University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, Lancashire, United Kingdom.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Lqbal
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, Lancashire, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Morris
authors.affiliation: Department of Histopatholgy, Pennine Acute Hospitals NHS Trust, Royal Oldham Hospital, Rochdale Road, Oldham, Lancashire, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Benatar
authors.affiliation: School of Materials, University of Manchester, Manchester, Lancashire, United Kingdom.
authors.forename: Teresa
authors.initials: T
authors.lastname: Alonso-Rasgado
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, Lancashire, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Baguneid
authors.affiliation: Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology (MIB), The University of Manchester, Manchester, Lancashire, United Kingdom; Centre for Dermatology, Institute of Inflammation and Repair, Faculty of Medicine and Human Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Bayat
mesh_terms: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000098:blood supply / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D018919:Neovascularization, Physiologic / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D017768:Skin, Artificial; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C116973:HIF3A protein, human; C423608:PROK2 protein, human