Cargando…

Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model

Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulati...

Descripción completa

Detalles Bibliográficos
Autores principales: Bae, Il-Hong, Park, Jin Woo, Kim, Dae-Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184407/
https://www.ncbi.nlm.nih.gov/pubmed/25288883
http://dx.doi.org/10.2147/IJN.S68399
_version_ 1782337836566970368
author Bae, Il-Hong
Park, Jin Woo
Kim, Dae-Yong
author_facet Bae, Il-Hong
Park, Jin Woo
Kim, Dae-Yong
author_sort Bae, Il-Hong
collection PubMed
description Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular-weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51±1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free–growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic.
format Online
Article
Text
id pubmed-4184407
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-41844072014-10-06 Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model Bae, Il-Hong Park, Jin Woo Kim, Dae-Yong Int J Nanomedicine Original Research Exogenous administration of growth factors has potential benefits in wound healing; however, limited percutaneous absorption, inconsistent efficacy, and the need for high doses have hampered successful clinical use. To overcome these restrictions, we focused on the development of a topical formulation composed of highly skin-permeable multimeric nanocomplex of growth factors. In the present study, we fused low-molecular-weight protamine (LMWP) with epidermal growth factor (EGF), insulin-like growth factor 1 (IGF-I), and platelet-derived growth factor A ligand (PDGF-A) (producing recombinant [r]LMWP-EGF, rLMWP-IGF-I, and rLMWP-PDGF-A, respectively) via genetic modification. Then, we used in vitro cell proliferation studies to assess the biological activity and the benefits of the combination. The LMWP-conjugated growth factors were complexed with low-molecular-weight heparin (LMWH) and formulated with Poloxamer 188 as a delivery vehicle. After confirming the enhanced skin permeability, in vivo studies were performed to assess whether the LMWP-conjugated growth factor nanocomplex formulations accelerated the healing of full-thickness wounds in mice. The LMWP-conjugated growth factors were biologically equivalent to their native forms, and their combination induced greater fibroblast proliferation. rLMWP-EGF showed significantly enhanced permeability and cumulative permeation, and the rates for rLMWP-IGF-I and rLMWP-PDGF-A, across excised mouse skin, were 124% and 164% higher, respectively, than for the native forms. The LMWP-fused growth factors resulted in formation of nanocomplexes (23.51±1.12 nm in diameter) in combination with LMWH. Topical delivery of growth factors fused with LMWP accelerated wound re-epithelialization significantly, accompanied by the formation of healthy granulation tissue within 9 days compared with a free–growth factor complex or vehicle. Thus, the LMWP-conjugated growth factor nanocomplex can induce rapid, comprehensive healing and may be a candidate wound-healing therapeutic. Dove Medical Press 2014-09-25 /pmc/articles/PMC4184407/ /pubmed/25288883 http://dx.doi.org/10.2147/IJN.S68399 Text en © 2014 Bae et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Bae, Il-Hong
Park, Jin Woo
Kim, Dae-Yong
Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title_full Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title_fullStr Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title_full_unstemmed Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title_short Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
title_sort enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184407/
https://www.ncbi.nlm.nih.gov/pubmed/25288883
http://dx.doi.org/10.2147/IJN.S68399
work_keys_str_mv AT baeilhong enhancedregenerativehealingefficacyofahighlyskinpermeablegrowthfactornanocomplexinafullthicknessexcisionalmousewoundmodel
AT parkjinwoo enhancedregenerativehealingefficacyofahighlyskinpermeablegrowthfactornanocomplexinafullthicknessexcisionalmousewoundmodel
AT kimdaeyong enhancedregenerativehealingefficacyofahighlyskinpermeablegrowthfactornanocomplexinafullthicknessexcisionalmousewoundmodel