In Vivo Stimulation of De Novo Collagen Production Caused by Cross-linked Hyaluronic Acid Dermal Filler Injections in Photodamaged Human Skin | Dermatology | JAMA Dermatology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.239.150.57. Please contact the publisher to request reinstatement.
1.
Matarasso  SLCarruthers  JDJewell  ML Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane).  Plast Reconstr Surg 2006;1173S- 34SPubMedGoogle ScholarCrossref
2.
Sakai  SYasuda  RSayo  TIshikawa  OInoue  S Hyaluronan exists in the normal stratum corneum.  J Invest Dermatol 2000;1141184- 1187PubMedGoogle ScholarCrossref
3.
Weindl  GSchaller  MSchafer-Korting  MKorting  HC Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects.  Skin Pharmacol Physiol 2004;17207- 213PubMedGoogle ScholarCrossref
4.
Tammi  MIDay  AJTurley  EA Hyaluronan and homeostasis: a balancing act.  J Biol Chem 2002;2774581- 4584PubMedGoogle ScholarCrossref
5.
Duranti  FSalti  GBovani  BCalandra  MRosati  ML Injectable hyaluronic acid gel for soft tissue augmentation. A clinical and histological study.  Dermatol Surg 1998;241317- 1325PubMedGoogle Scholar
6.
Biesman  B Soft tissue augmentation using Restylane.  Facial Plast Surg 2004;20171- 177PubMedGoogle ScholarCrossref
7.
Andre  P Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA–Q-Medical, Sweden) in European countries: a retrospective study from 1997 to 2001.  J Eur Acad Dermatol Venereol 2004;18422- 425PubMedGoogle ScholarCrossref
8.
Lemperle  GMorhenn  VCharrier  U Human histology and persistence of various injectable filler substances for soft tissue augmentation.  Aesthetic Plast Surg 2003;27354- 366PubMedGoogle ScholarCrossref
9.
Narins  RSBrandt  FLeyden  JLorenc  ZPRubin  MSmith  S A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds.  Dermatol Surg 2003;29588- 595PubMedGoogle Scholar
10.
Olenius  M The first clinical study using a new biodegradable implant for the treatment of lips, wrinkles, and folds.  Aesthetic Plast Surg 1998;2297- 101PubMedGoogle ScholarCrossref
11.
Yoon  ESHan  SKKim  WK Advantages of the presence of living dermal fibroblasts within Restylane for soft tissue augmentation.  Ann Plast Surg 2003;51587- 592PubMedGoogle ScholarCrossref
12.
Fisher  GJDatta  SCTalwar  HS  et al.  Molecular basis of sun-induced premature skin ageing and retinoid antagonism.  Nature 1996;379335- 339PubMedGoogle ScholarCrossref
13.
Griffiths  CERussman  ANMajmudar  GSinger  RSHamilton  TAVoorhees  JJ Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid).  N Engl J Med 1993;329530- 535PubMedGoogle ScholarCrossref
14.
Talwar  HSGriffiths  CEFisher  GJHamilton  TAVoorhees  JJ Reduced type I and type III procollagens in photodamaged adult human skin.  J Invest Dermatol 1995;105285- 290PubMedGoogle ScholarCrossref
15.
Kang  SCho  SChung  JHHammerberg  CFisher  GJVoorhees  JJ Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo.  Am J Pathol 2005;1661691- 1699PubMedGoogle ScholarCrossref
16.
Quan  THe  TKang  SVoorhees  JJFisher  GJ Ultraviolet irradiation alters transforming growth factor-β/smad pathway in human skin in vivo.  J Invest Dermatol 2002;119499- 506PubMedGoogle ScholarCrossref
17.
Lin  WShuster  SMaibach  HIStern  R Patterns of hyaluronan staining are modified by fixation techniques.  J Histochem Cytochem 1997;451157- 1163PubMedGoogle ScholarCrossref
18.
Tammi  RMacCallum  DHascall  VCPienimaki  JP M. H, Tammi M. Hyaluronan bound to CD44 on keratinocytes is displaced by hyaluronan decasaccharides and not hexasaccharides.  J Biol Chem 1998;27328878- 28888PubMedGoogle ScholarCrossref
19.
Varani  JSchuger  LDame  MK  et al.  Reduced fibroblast interaction with intact collagen as a mechanism for depressed collagen synthesis in photodamaged skin.  J Invest Dermatol 2004;1221471- 1479PubMedGoogle ScholarCrossref
20.
Olsen  BRBerg  RAKishida  YProckop  DJ Collagen synthesis: localization of prolyl hydroxylase in tendon cells detected with ferritin-labeled antibodies.  Science 1973;182825- 827PubMedGoogle ScholarCrossref
21.
Lambert  CAColige  ACLapiere  CMNusgens  BV Coordinated regulation of procollagens I and III and their post-translational enzymes by dissipation of mechanical tension in human dermal fibroblasts.  Eur J Cell Biol 2001;80479- 485PubMedGoogle ScholarCrossref
22.
Orringer  JSVoorhees  JJHamilton  T  et al.  Dermal matrix remodeling after nonablative laser therapy.  J Am Acad Dermatol 2005;53775- 782PubMedGoogle ScholarCrossref
23.
Ignotz  RAMassague  J Transforming growth factor β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix.  J Biol Chem 1986;2614337- 4345PubMedGoogle Scholar
24.
Fisher  GJWang  ZQDatta  SCVarani  JKang  SVoorhees  JJ Pathophysiology of premature skin aging induced by ultraviolet light.  N Engl J Med 1997;3371419- 1428PubMedGoogle ScholarCrossref
25.
Varani  JPerone  PFligiel  SEFisher  GJVoorhees  JJ Inhibition of type I procollagen production in photodamage: correlation between presence of high molecular weight collagen fragments and reduced procollagen synthesis.  J Invest Dermatol 2002;119122- 129PubMedGoogle ScholarCrossref
26.
Kessler  DDethlefsen  SHaase  I  et al.  Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype.  J Biol Chem 2001;27636575- 36585PubMedGoogle ScholarCrossref
27.
Silver  FHSiperko  LMSeehra  GP Mechanobiology of force transduction in dermal tissue.  Skin Res Technol 2003;93- 23PubMedGoogle ScholarCrossref
28.
Nagata  K Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum.  Matrix Biol 1998;16379- 386PubMedGoogle ScholarCrossref
29.
Orringer  JSKang  SJohnson  TM  et al.  Connective tissue remodeling induced by carbon dioxide laser resurfacing of photodamaged human skin.  Arch Dermatol 2004;1401326- 1332PubMedGoogle Scholar
30.
Day  AJPrestwich  GD Hyaluronan-binding proteins: tying up the giant.  J Biol Chem 2002;2774585- 4588PubMedGoogle ScholarCrossref
31.
Delvoye  PWiliquet  PLeveque  JLNusgens  BVLapiere  CM Measurement of mechanical forces generated by skin fibroblasts embedded in a three-dimensional collagen gel.  J Invest Dermatol 1991;97898- 902PubMedGoogle ScholarCrossref
32.
Fisher  GJChoi  HCBata-Csorgo  Z  et al.  Ultraviolet irradiation increases matrix metalloproteinase-8 protein in human skin in vivo.  J Invest Dermatol 2001;117219- 226PubMedGoogle ScholarCrossref
33.
Grinnell  F Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading.  Trends Cell Biol 2000;10362- 365PubMedGoogle ScholarCrossref
34.
Grinnell  F Fibroblast biology in three-dimensional collagen matrices.  Trends Cell Biol 2003;13264- 269PubMedGoogle ScholarCrossref
35.
Lambert  CAColige  ACMunaut  CLapiere  CMNusgens  BV Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension.  Matrix Biol 2001;20397- 408PubMedGoogle ScholarCrossref
36.
Lambert  CASoudant  EPNusgens  BVLapiere  CM Pretranslational regulation of extracellular matrix macromolecules and collagenase expression in fibroblasts by mechanical forces.  Lab Invest 1992;66444- 451PubMedGoogle Scholar
37.
Quan  THe  TKang  SVoorhees  JJFisher  GJ Connective tissue growth factor: expression in human skin in vivo and inhibition by ultraviolet irradiation.  J Invest Dermatol 2002;118402- 408PubMedGoogle ScholarCrossref
38.
Takehara  K Growth regulation of skin fibroblasts.  J Dermatol Sci 2000;24 ((suppl)) S70- S77PubMedGoogle ScholarCrossref
39.
Massague  J How cells read TGF-β signals.  Nat Rev Mol Cell Biol 2000;1169- 178PubMedGoogle ScholarCrossref
40.
Karimipour  DJKang  SJohnson  TM  et al.  Microdermabrasion: a molecular analysis following a single treatment.  J Am Acad Dermatol 2005;52215- 223PubMedGoogle ScholarCrossref
41.
Verzijl  NDeGroot  JThorpe  SR  et al.  Effect of collagen turnover on the accumulation of advanced glycation end products.  J Biol Chem 2000;27539027- 39031PubMedGoogle ScholarCrossref
Study
February 2007

In Vivo Stimulation of De Novo Collagen Production Caused by Cross-linked Hyaluronic Acid Dermal Filler Injections in Photodamaged Human Skin

Author Affiliations

Author Affiliations: Departments of Dermatology (Drs Wang, Garza, Kang, Orringer, Fisher, and Voorhees) and Pathology (Dr Varani), University of Michigan Medical School, Ann Arbor. Dr Garza is now with the Department of Dermatology, University of Pennsylvania, Philadelphia.

Arch Dermatol. 2007;143(2):155-163. doi:10.1001/archderm.143.2.155
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.

Design  In vivo biochemical analyses after filler injections.

Setting  Academic referral center.

Participants  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.

Main Outcome Measures  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.

×