Dual growth factor releasing multi-functional nanofibers for wound healing.

The objective of this research is to develop a dual growth factor-releasing nanoparticle-in-nanofiber system for wound healing applications. In order to mimic and promote the natural healing procedure, chitosan and poly(ethylene oxide) were electrospun into nanofibrous meshes as mimics of extracellular matrix. Vascular endothelial growth factor (VEGF) was loaded within nanofibers to promote angiogenesis in the short term. In addition, platelet-derived growth factor-BB (PDGF-BB) encapsulated poly(lactic-co-glycolic acid) nanoparticles were embedded inside nanofibers to generate a sustained release of PDGF-BB for accelerated tissue regeneration and remodeling. In vitro studies revealed that our nanofibrous composites delivered VEGF quickly and PDGF-BB in a relayed manner, supported fibroblast growth and exhibited anti-bacterial activities. A preliminary in vivo study performed on normal full thickness rat skin wound models demonstrated that nanofiber/nanoparticle scaffolds significantly accelerated the wound healing process by promoting angiogenesis, increasing re-epithelialization and controlling granulation tissue formation. For later stages of healing, evidence also showed quicker collagen deposition and earlier remodeling of the injured site to achieve a faster full regeneration of skin compared to the commercial Hydrofera Blue® wound dressing. These results suggest that our nanoparticle-in-nanofiber system could provide a promising treatment for normal and chronic wound healing.

[1]  James J. Yoo,et al.  The effect of controlled release of PDGF-BB from heparin-conjugated electrospun PCL/gelatin scaffolds on cellular bioactivity and infiltration. , 2012, Biomaterials.

[2]  Ping Li,et al.  Ski, a modulator of wound healing and scar formation in the rat skin and rabbit ear , 2011, The Journal of pathology.

[3]  Kam W Leong,et al.  In vivo wound healing of diabetic ulcers using electrospun nanofibers immobilized with human epidermal growth factor (EGF). , 2008, Biomaterials.

[4]  D. Greenhalgh,et al.  PDGF and FGF stimulate wound healing in the genetically diabetic mouse. , 1990, The American journal of pathology.

[5]  A. Wellmann,et al.  Priming with a combination of proangiogenic growth factors improves wound healing in normoglycemic mice. , 2011, International journal of molecular medicine.

[6]  D. M. Lynn,et al.  Controlling interlayer diffusion to achieve sustained, multiagent delivery from layer-by-layer thin films , 2006, Proceedings of the National Academy of Sciences.

[7]  Evzen Amler,et al.  Core/shell nanofibers with embedded liposomes as a drug delivery system. , 2012, Biomacromolecules.

[8]  M. Longaker,et al.  Regulation of Vascular Endothelial Growth Factor Expression in Cultured Keratinocytes. , 1995, The Journal of Biological Chemistry.

[9]  Olivera Stojadinovic,et al.  PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing , 2008, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[10]  A. Singer,et al.  Cutaneous wound healing. , 1999, The New England journal of medicine.

[11]  W. Park,et al.  Preparation of Polymer Nanofibers Containing Silver Nanoparticles by Using Poly(N-vinylpyrrolidone) , 2005 .

[12]  P. Supaphol,et al.  Wound-dressing materials with antibacterial activity from electrospun gelatin fiber mats containing silver nanoparticles , 2008 .

[13]  V. Bergdall,et al.  Regulation of scar formation by vascular endothelial growth factor , 2008, Laboratory Investigation.

[14]  D. Irvine,et al.  Layer-by-layer-assembled multilayer films for transcutaneous drug and vaccine delivery. , 2009, ACS nano.

[15]  S. Ramakrishna,et al.  Fabrication of a nanofibrous scaffold with improved bioactivity for culture of human dermal fibroblasts for skin regeneration , 2011, Biomedical materials.

[16]  Andreas Greiner,et al.  Electrospinning: a fascinating method for the preparation of ultrathin fibers. , 2007, Angewandte Chemie.

[17]  L. Phillips,et al.  Platelet-derived growth factor BB for the treatment of chronic pressure ulcers , 1992, The Lancet.

[18]  J. Goh,et al.  Growth factor delivery through electrospun nanofibers in scaffolds for tissue engineering applications. , 2009, Journal of biomedical materials research. Part A.

[19]  Rebeccah L. Brown,et al.  PDGF and TGF-α Act Synergistically to Improve Wound Healing in the Genetically Diabetic Mouse , 1994 .

[20]  J. Boateng,et al.  Wound healing dressings and drug delivery systems: a review. , 2008, Journal of pharmaceutical sciences.

[21]  Jian Fang,et al.  In vivo wound healing and antibacterial performances of electrospun nanofibre membranes. , 2010, Journal of biomedical materials research. Part A.

[22]  J. Lee,et al.  Gel characterisation and in vivo evaluation of minocycline-loaded wound dressing with enhanced wound healing using polyvinyl alcohol and chitosan. , 2010, International journal of pharmaceutics.

[23]  P. Owens,et al.  Epidermal Smad4 deletion results in aberrant wound healing. , 2010, The American journal of pathology.

[24]  M. Zilberman,et al.  Antibiotic-eluting bioresorbable composite fibers for wound healing applications: microstructure, drug delivery and mechanical properties. , 2009, Acta biomaterialia.

[25]  B. Winston,et al.  Growth factor regulation and manipulation in wound repair: to scar or not to scar, that is the question , 2001 .

[26]  Cato T Laurencin,et al.  Bioresorbable nanofiber-based systems for wound healing and drug delivery: optimization of fabrication parameters. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[27]  Walter Steurbaut,et al.  Chitosan as antimicrobial agent: applications and mode of action. , 2003, Biomacromolecules.

[28]  Yazhou Wang,et al.  A novel controlled release drug delivery system for multiple drugs based on electrospun nanofibers containing nanoparticles. , 2010, Journal of pharmaceutical sciences.

[29]  Shuhui He,et al.  Electrospun fibers with plasmid bFGF polyplex loadings promote skin wound healing in diabetic rats. , 2012, Molecular pharmaceutics.

[30]  C. Murphy,et al.  The use of native chemical functional groups presented by wound beds for the covalent attachment of polymeric microcarriers of bioactive factors. , 2013, Biomaterials.

[31]  G F Pierce,et al.  Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. , 1992, The American journal of pathology.

[32]  Lara Yildirimer,et al.  Skin regeneration scaffolds: a multimodal bottom-up approach. , 2012, Trends in biotechnology.

[33]  Jyothi U. Menon,et al.  Effects of surfactants on the properties of PLGA nanoparticles. , 2012, Journal of biomedical materials research. Part A.

[34]  D. Mooney,et al.  Hydrogels for tissue engineering. , 2001, Chemical reviews.

[35]  T. Nguyen,et al.  Porous core/sheath composite nanofibers fabricated by coaxial electrospinning as a potential mat for drug release system. , 2012, International journal of pharmaceutics.

[36]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[37]  C. Murphy,et al.  Polymeric multilayers that localize the release of chlorhexidine from biologic wound dressings. , 2012, Biomaterials.

[38]  C. Lim,et al.  Tissue scaffolds for skin wound healing and dermal reconstruction. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[39]  Wei Zhi,et al.  Promotion of skin regeneration in diabetic rats by electrospun core-sheath fibers loaded with basic fibroblast growth factor. , 2011, Biomaterials.

[40]  Masanori Fujita,et al.  Photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 stimulates wound healing in healing-impaired db/db mice. , 2003, Biomaterials.

[41]  A. Khademhosseini,et al.  Hydrogels in Regenerative Medicine , 2009, Advanced materials.

[42]  Jie Li,et al.  Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix , 2003, Microscopy research and technique.

[43]  Marco Romanelli,et al.  Wound bed preparation: a systematic approach to wound management , 2003, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[44]  Thomas A. Mustoe, MD, FACS,et al.  Pharmacologic enhancement of wound healing. , 1995, Annual review of medicine.

[45]  Won Ho Park,et al.  Electrospinning of collagen nanofibers: effects on the behavior of normal human keratinocytes and early-stage wound healing. , 2006, Biomaterials.

[46]  D. Herndon,et al.  A review of gene and stem cell therapy in cutaneous wound healing. , 2009, Burns : journal of the International Society for Burn Injuries.

[47]  A. Wellmann,et al.  Priming with a Combination of Proangiogenic Growth Factors Enhances Wound Healing in Streptozotocin-Induced Diabetes in Mice , 2011, European Surgical Research.