title: In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin.
abstract: OBJECTIVE
  To determine whether endogenous synthesis of new extracellular matrix may contribute to the degree and duration of clinical benefits derived from cross-linked hyaluronic acid dermal filler injections.
  
  
  METHODS
  In vivo biochemical analyses after filler injections.
  
  
  METHODS
  Academic referral center.
  
  
  METHODS
  Eleven healthy volunteers (mean age, 74 years) with photodamaged forearm skin. Interventions Filler and vehicle (isotonic sodium chloride) injected into forearm skin and skin biopsy specimens taken 4 and 13 weeks later.
  
  
  METHODS
  De novo synthesis of collagen, the major structural protein of dermal extracellular matrix, was assessed using immunohistochemical analysis, quantitative polymerase chain reaction, and electron microscopy.
  
  
  RESULTS
  Compared with controls, immunostaining in skin receiving cross-linked hyaluronic acid injections revealed increased collagen deposition around the filler. Staining for prolyl-4-hydroxylase and the C-terminal and N-terminal epitopes of type I procollagen was enhanced at 4 and 13 weeks after treatment (P<.05). Gene expression for types I and III procollagen as well as several profibrotic growth factors was also up-regulated at 4 and 13 weeks compared with controls (P<.05). Fibroblasts in filler-injected skin demonstrated a mechanically stretched appearance and a biosynthetic phenotype. In vitro, fibroblasts did not bind the filler, suggesting that cross-linked hyaluronic acid is not directly stimulatory.
  
  
  CONCLUSIONS
  Injection of cross-linked hyaluronic acid stimulates collagen synthesis, partially restoring dermal matrix components that are lost in photodamaged skin. We hypothesize that this stimulatory effect may be induced by mechanical stretching of the dermis, which in turn leads to stretching and activation of dermal fibroblasts. These findings imply that cross-linked hyaluronic acid may be useful for stimulating collagen production therapeutically, particularly in the setting of atrophic skin conditions.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. frawang@umich.edu
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Luis A
authors.initials: LA
authors.lastname: Garza
authors.forename: Sewon
authors.initials: S
authors.lastname: Kang
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Orringer
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001132:Arm; D024042:Collagen Type I / Q000187:drug effects* / Q000378:metabolism; D020405:Dermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007271:Injections, Intradermal; D008297:Male; D008875:Middle Aged; D015595:Skin Aging / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015291:Transforming Growth Factors / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D019714:Tissue Inhibitor of Metalloproteinases; D015291:Transforming Growth Factors; D006820:Hyaluronic Acid; C445361:Restylane