Abstract
Administration of exogenous growth factors (GFs) to a damaged site has been investigated for skin tissue regeneration. Among the many types of GFs and cytokines, epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and hepatocyte growth factor could be specifically used for stimulating molecules in wound healing as well as for recovery of damaged skin tissues. It is speculated that delivered GFs could stimulate various cellular functions, including proliferation, migration, deposition of extracellular matrix molecules, and remodeling of collagen synthesis. Although the physiological wound healing process is complex, engineering strategies for proper delivery of multiple therapeutic GFs could enhance the quality and quantity of regenerated skin tissues. As compared to single delivery of a GF, recent studies have proven that any combination of multiple GFs and/or therapeutic chemical factors synergistically facilitates the regeneration of damaged skin tissues. In order to maximize the stability, bioactivity, intrinsic therapeutic functionality, and efficiency of internal delivery of cargo GFs, it is essential to utilize tissueengineered biomaterials and related composites as implantable platforms. Successful fabrication and development of skin tissue engineering applications as well as subsequent surgical implantation of these platforms might provide clinical treatment for superior skin regeneration. Therefore, the present review summarizes the biological functions, related signaling mechanisms, and recent developments of tissue engineering applications for multiple GF delivery.
Similar content being viewed by others
References
Fife, C. E., M. J. Cartel, D. Walker, and B. Thomson (2012) Wound care outcomes and associated cost among patients treated in us outpatient wound centers: Data from the US wound registry. Wounds 24: 10–17.
Singer, A. J. and R. A. Clark (1999) Cutaneous wound healing. New Eng. J. Med. 341: 738–746.
Chen, F. M., M. Zhang, and Z. F. Wu (2010) Toward delivery of multiple growth factors in tissue engineering. Biomat. 31: 6279–6308.
Tziotzios, C., C. Profyris, and J. Sterling (2012) Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part II. Strategies to reduce scar formation after dermatologic procedures. J. Am. Acad. Dermatol. 66: 13–24.
Zielins, E. R., E. A. Brett, A. Luan, M. S. Hu, G. G. Walmsley, K. Paik, K. Senarath-Yapa, D. A. Atashroo, T. Wearda, H. P. Lorenz, D. C. Wan, and M. T. Longaker (2015) Emerging drugs for the treatment of wound healing. Exp. Opin. Emerg. Drugs 20: 235–246.
Caussa, J. E. and E. H. Vila (2015) Epidermal growth factor, innovation and safety. Med. Clin-Barcelona 145: 305–312.
Mendoza, M. C., E. E. Er, and J. Blenis (2011) The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation. Trends Biochem. Sci. 36: 320–328.
Bodnar, R. J. (2013) Epidermal growth factor and epidermal growth factor receptor: The yin and yang in the treatment of cutaneous wounds and cancer. Adv. Wound Care 2: 24–29.
Barrientos, S., O. Stojadinovic, M. S. Golinko, H. Brem, and M. Tomic-Canic (2008) Growth factors and cytokines in wound healing. Wound Rep. Regen. 16: 585–601.
Hardwicke, J., D. Schmaljohann, D. Boyce, and D. Thomas (2008) Epidermal growth factor therapy and wound healing—past, present and future perspectives. Surgeon 6: 172–177.
Xie, Y., Z. Upton, S. Richards, S. C. Rizzi, and D. I. Leavesley (2011) Hyaluronic acid: evaluation as a potential delivery vehicle for vitronectin: Growth factor complexes in wound healing applications. J. Control. Rel.: Offic. J. Control. Rel. Soc. 153: 225–232.
Morell, C. M., L. Fabris, and M. Strazzabosco (2013) Vascular biology of the biliary epithelium. J. Gastroenterol. Hepatol. 28 Suppl 1: 26–32.
Patel-Hett, S. and P. A. D’Amore (2011) Signal transduction in vasculogenesis and developmental angiogenesis. Internat. J. Develop. Biol. 55: 353–363.
Impellitteri, N. A., M. W. Toepke, S. K. Lan Levengood, and W. L. Murphy (2012) Specific VEGF sequestering and release using peptide-functionalized hydrogel microspheres. Biomat. 33: 3475–3484.
Losi, P., E. Briganti, A. Magera, D. Spiller, C. Ristori, B. Battolla, M. Balderi, S. Kull, A. Balbarini, R. Di Stefano, and G. Soldani (2010) Tissue response to poly(ether)urethane-polydimethylsiloxanefibrin composite scaffolds for controlled delivery of proangiogenic growth factors. Biomat. 31: 5336–5344.
Kazlauskas, A. (2017) PDGFs and their receptors. Gene 614: 1–7.
Ishii, Y., T. Hamashima, S. Yamamoto, and M. Sasahara (2017) Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor. Pathol. Internat. 67: 235–246.
Demoulin, J. B. and A. Essaghir (2014) PDGF receptor signaling networks in normal and cancer cells. Cytokine & Growth Factor Rev. 25: 273–283.
Ostendorf, T., F. Eitner, and J. Floege (2012) The PDGF family in renal fibrosis. Pediat. Nephrol. 27: 1041–1050.
Farooqi, A. A., S. Waseem, A. M. Riaz, B. A. Dilawar, S. Mukhtar, S. Minhaj, M. S. Waseem, S. Daniel, B. A. Malik, A. Nawaz, and S. Bhatti (2011) PDGF: The nuts and bolts of signalling toolbox. Tumour Biol.: The J. Internat. Soc. Oncodevelop. Biol.Med. 32: 1057–1070.
Berlanga-Acosta, J., J. G. -Cowley, D. G. del Barco-Herrera, J. Martín-Machado, and G. Guillen-Nieto (2011) Epidermal Growth Factor (EGF) and Platelet-Derived Growth Factor (PDGF) as tissue healing agents: Clarifying concerns about their possible role in malignant transformation and tumor progression. J. Carcinogen. Mutagen. 2: 1000115.
Judith, R., M. Nithya, C. Rose, and A. B. Mandal (2010) Application of a PDGF-containing novel gel for cutaneous wound healing. Life Sci. 87: 1–8.
Lee, J., J. J. Yoo, A. Atala, and S. J. Lee (2012) The effect of controlled release of PDGF-BB from heparin-conjugated electrospun PCL/gelatin scaffolds on cellular bioactivity and infiltration. Biomat. 33: 6709–6720.
Kaltalioglu, K., S. Coskun-Cevher, F. Tugcu-Demiroz, and N. Celebi (2013) PDGF supplementation alters oxidative events in wound healing process: A time course study. Arch. Dermatol. Res. 305: 415–422.
Heynen, G. J., A. Fonfara, and R. Bernards (2014) Resistance to targeted cancer drugs through hepatocyte growth factor signaling. Cell Cycle 13: 3808–3817.
Nakamura, T., K. Sakai, T. Nakamura, and K. Matsumoto (2011) Hepatocyte growth factor twenty years on: Much more than a growth factor. J. Gastroenterol. Hepatol. 26 Suppl 1: 188–202.
Molnarfi, N., M. Benkhoucha, H. Funakoshi, T. Nakamura, and P. H. Lalive (2015) Hepatocyte growth factor: A regulator of inflammation and autoimmunity. Autoimmun. Rev. 14: 293–303.
Li, J. F., H. F. Duan, C. T. Wu, D. J. Zhang, Y. Deng, H. L. Yin, B. Han, H. C. Gong, H. W. Wang, and Y. L. Wang (2013) HGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through beta1-integrin/ILK pathway. BioMed Res. Internat. 2013: 470418.
Baek, J. H., C. Birchmeier, M. Zenke, and T. Hieronymus (2012) The HGF receptor/Met tyrosine kinase is a key regulator of dendritic cell migration in skin immunity. J. Immunol. 189: 1699–1707.
Hubel, J. and T. Hieronymus (2015) HGF/Met-signaling contributes to immune regulation by modulating tolerogenic and motogenic properties of dendritic cells. Biomed. 3: 138–148.
Rah, D. K., I. S. Yun, C. O. Yun, S. B. Lee, and W. J. Lee (2014) Gene therapy using hepatocyte growth factor expressing adenovirus improves skin flap survival in a rat model. J. Kor. Med. Sci. 29 Suppl 3: S228–236.
Yun, Y. R., J. E. Won, E. Jeon, S. Lee, W. Kang, H. Jo, J. H. Jang, U. S. Shin, and H. W. Kim (2010) Fibroblast growth factors: Biology, function, and application for tissue regeneration. J. Tissue Eng. 2010: 218142.
Ornitz, D. M. and N. Itoh (2015) The fibroblast growth factor signaling pathway. Wiley Interdiscipl. Rev. Develop. Biol. 4: 215–266.
Singla, D. K., R. D. Singla, L. S. Abdelli, and C. Glass (2015) Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart. PloS one 10: e0120739.
Zhang, H. Y., X. Zhang, Z. G. Wang, H. X. Shi, F. Z. Wu, B. B. Lin, X. L. Xu, X. J. Wang, X. B. Fu, Z. Y. Li, C. J. Shen, X. K. Li, and J. Xiao (2013) Exogenous basic fibroblast growth factor inhibits ER stress-induced apoptosis and improves recovery from spinal cord injury. CNS Neurosci. Therap. 19: 20–29.
Hankenson, K. D., K. Gagne, and M. Shaughnessy (2015) Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv. Drug Del. Rev. 94: 3–12.
De Smet, F., B. Tembuyser, A. Lenard, F. Claes, J. Zhang, C. Michielsen, A. Van Schepdael, J. M. Herbert, F. Bono, M. Affolter, M. Dewerchin, and P. Carmeliet (2014) Fibroblast growth factor signaling affects vascular outgrowth and is required for the maintenance of blood vessel integrity. Chem. Biol. 21: 1310–1317.
Falcon, B. L., M. Swearingen, W. H. Gough, L. Lee, R. Foreman, M. Uhlik, J. C. Hanson, J. A. Lee, D. B. McClure, and S. Chintharlapalli (2014) An in vitro cord formation assay identifies unique vascular phenotypes associated with angiogenic growth factors. PloS one 9: e106901.
Takikawa, M., S. Nakamura, M. Ishihara, Y. Takabayashi, M. Fujita, H. Hattori, T. Kushibiki, and M. Ishihara (2015) Improved angiogenesis and healing in crush syndrome by fibroblast growth factor-2-containing low-molecular-weight heparin (Fragmin)/ protamine nanoparticles. J. Surg. Res. 196: 247–257.
Xie, L., M. Zhang, B. Dong, M. Guan, M. Lu, Z. Huang, H. Gao, and X. Li (2011) Improved refractory wound healing with administration of acidic fibroblast growth factor in diabetic rats. Diabetes Res. Clin. Pract. 93: 396–403.
Matsumoto, S., R. Tanaka, K. Okada, K. Arita, H. Hyakusoku, M. Miyamoto, Y. Tabata, and H. Mizuno (2013) The Effect of Control-released basic fibroblast growth factor in wound healing: Histological analyses and clinical application. Plast. Reconstr. Surg. Global Open 1: e44.
Nakamizo, S., G. Egawa, H. Doi, Y. Natsuaki, Y. Miyachi, and K. Kabashima (2013) Topical treatment with basic fibroblast growth factor promotes wound healing and barrier recovery induced by skin abrasion. Skin Pharmacol. Physiol. 26: 22–29.
Fuhr, M. J., M. Meyer, E. Fehr, G. Ponzio, S. Werner, and H. J. Herrmann (2015) A modeling approach to study the effect of cell polarization on keratinocyte migration. PloS one 10: e0117676.
Peplow, P. V. and M. P. Chatterjee (2013) A review of the influence of growth factors and cytokines in in vitro human keratinocyte migration. Cytokine 62: 1–21.
Akita, S., K. Akino, and A. Hirano (2013) Basic fibroblast growth factor in scarless wound healing. Adv. Wound Care 2: 44–49.
Shi, H. X., C. Lin, B. B. Lin, Z. G. Wang, H. Y. Zhang, F. Z. Wu, Y. Cheng, L. J. Xiang, D. J. Guo, X. Luo, G. Y. Zhang, X. B. Fu, S. Bellusci, X. K. Li, and J. Xiao (2013) The anti-scar effects of basic fibroblast growth factor on the wound repair in vitro and in vivo. PloS one 8: e59966.
Abe, M., Y. Yokoyama, and O. Ishikawa (2012) A possible mechanism of basic fibroblast growth factor-promoted scarless wound healing: The induction of myofibroblast apoptosis. Europ. J. Dermatol. 22: 46–53.
Mirdailami, O., M. Soleimani, R. Dinarvand, M. R. Khoshayand, M. Norouzi, A. Hajarizadeh, M. Dodel, and F. Atyabi (2015) Controlled release of rhEGF and rhbFGF from electrospun scaffolds for skin regeneration. J. Biomed. Mat. Res. Part A. 103: 3374–3385.
Choi, J. S., S. H. Choi, and H. S. Yoo (2011) Coaxial electrospun nanofibers for treatment of diabetic ulcers with binary release of multiple growth factors. J. Mater. Chem. 21: 5258–5267.
Lai, H. J., C. H. Kuan, H. C. Wu, J. C. Tsai, T. M. Chen, D. J. Hsieh, and T. W. Wang (2014) Tailored design of electrospun composite nanofibers with staged release of multiple angiogenic growth factors for chronic wound healing. Acta Biomat. 10: 4156–4166.
Ribeiro, M. P., P. I. Morgado, S. P. Miguel, P. Coutinho, and I. J. Correia (2013) Dextran-based hydrogel containing chitosan microparticles loaded with growth factors to be used in wound healing. Mat. Sci. Eng. C-Mater. 33: 2958–2966.
Yang, D. H., D. I. Seo, D. W. Lee, S. H. Bhang, K. Park, G. Jang, C. H. Kim, and H. J. Chun (2017) Preparation and evaluation of visible-light cured glycol chitosan hydrogel dressing containing dual growth factors for accelerated wound healing. J. Ind. Eng. Chem. 53: 360–370.
Goel, A., A. B. Kunnumakkara, and B. B. Aggarwal (2008) Curcumin as “Curecumin”: From kitchen to clinic. Biochem. Pharmacol. 75: 787–809.
Cheppudira, B., M. Fowler, L. McGhee, A. Greer, A. Mares, L. Petz, D. Devore, D. R. Loyd, and J. L. Clifford (2013) Curcumin: A novel therapeutic for burn pain and wound healing. Expert Opin. Investigat. Drugs 22: 1295–1303.
Li, X., X. Ye, J. Qi, R. Fan, X. Gao, Y. Wu, L. Zhou, A. Tong, and G. Guo (2016) EGF and curcumin co-encapsulated nanoparticle/hydrogel system as potent skin regeneration agent. Internat. J. Nanomed. 11: 3993–4009.
Xie, Z., C. B. Paras, H. Weng, P. Punnakitikashem, L. C. Su, K. Vu, L. Tang, J. Yang, and K. T. Nguyen (2013) Dual growth factor releasing multi-functional nanofibers for wound healing. Acta Biomat. 9: 9351–9359.
Losi, P., E. Briganti, C. Errico, A. Lisella, E. Sanguinetti, F. Chiellini, and G. Soldani (2013) Fibrin-based scaffold incorporating VEGF- and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomat. 9: 7814–7821.
Hollier, B., D. G. Harkin, D. Leavesley, and Z. Upton (2005) Responses of keratinocytes to substrate-bound vitronectin: Growth factor complexes. Experim. Cell Res. 305: 221–232.
Ogino, S., N. Morimoto, M. Sakamoto, C. Jinno, Y. Sakamoto, T. Taira, and S. Suzuki (2018) Efficacy of the dual controlled release of HGF and bFGF impregnated with a collagen/gelatin scaffold. J. Surg. Res. 221: 173–182.
Kiso, M., T. S. Hamazaki, M. Itoh, S. Kikuchi, H. Nakagawa, and H. Okochi (2015) Synergistic effect of PDGF and FGF2 for cell proliferation and hair inductive activity in murine vibrissal dermal papilla in vitro. J. Dermatol. Sci. 79: 110–118.
Shi, J., J. Li, H. Guan, W. Cai, X. Bai, X. Fang, X. Hu, Y. Wang, H. Wang, Z. Zheng, L. Su, D. Hu, and X. Zhu (2014) Antifibrotic actions of interleukin-10 against hypertrophic scarring by activation of PI3K/AKT and STAT3 signaling pathways in scarforming fibroblasts. PloS one 9: e98228.
So, K., D. A. McGrouther, J. A. Bush, P. Durani, L. Taylor, G. Skotny, T. Mason, A. Metcalfe, S. O'Kane, and M. W. Ferguson (2011) Avotermin for scar improvement following scar revision surgery: A randomized, double-blind, within-patient, placebocontrolled, phase II clinical trial. Plast. Reconstr. Surg. 128: 163–172.
Kieran, I., A. Knock, J. Bush, K. So, A. Metcalfe, R. Hobson, T. Mason, S. O’Kane, and M. Ferguson (2013) Interleukin-10 reduces scar formation in both animal and human cutaneous wounds: Results of two preclinical and phase II randomized control studies. Wound Rep.Regen. 21: 428–436.
Shi, J. H., H. Guan, S. Shi, W. X. Cai, X. Z. Bai, X. L. Hu, X. B. Fang, J. Q. Liu, K. Tao, X. X. Zhu, C. W. Tang, and D. H. Hu (2013) Protection against TGF-beta 1-induced fibrosis effects of IL-10 on dermal fibroblasts and its potential therapeutics for the reduction of skin scarring. Arch. Dermatol. Res. 305: 341–352.
Lee, M. S., T. Ahmad, J. Lee, H. K. Awada, Y. Wang, K. Kim, H. Shin, and H. S. Yang (2017) Dual delivery of growth factors with coacervate-coated poly(lactic-co-glycolic acid) nanofiber improves neovascularization in a mouse skin flap model. Biomat. 124: 65–77.
Finnson, K. W., S. McLean, G. M. Di Guglielmo, and A. Philip (2013) Dynamics of transforming growth factor beta signaling in wound healing and scarring. Adv. Wound Care 2: 195–214.
Arno, A. I., G. G. Gauglitz, J. P. Barret, and M. G. Jeschke (2014) New molecular medicine-based scar management strategies. Burns 40: 539–551.
Chen, W. C., B. G. Lee, D. W. Park, K. Kim, H. Chu, K. Kim, J. Huard, and Y. Wang (2015) Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair. Biomater. 72: 138–151.
Kim, K., W. C. W. Chen, Y. Heo, and Y. D. Wang (2016) Polycations and their biomedical applications. Prog. Polym. Sci. 60: 18–50.
Shin, S., J. U. Shin, Y. Lee, W. Y. Chung, K. H. Nam, T. G. Kwon, and J. H. Lee (2017) The effects of multi-growth factorscontaining cream on post-thyroidectomy Scars: A preliminary study. Ann. Dermatol. 29: 314–320.
Satish, L. (2015) Chemokines as therapeutic targets to improve healing efficiency of chronic wounds. Adv. Wound Care 4: 651–659.
Laiva, A. L., F. J. O'Brien, and M. B. Keogh (2017) Innovations in gene and growth factor delivery systems for diabetic wound healing. J. Tissue Eng. Regen. Med. doi: 10.1002/term.2443.
Pereira, R. F., C. C. Barrias, P. L. Granja, and P. J. Bartolo (2013) Advanced biofabrication strategies for skin regeneration and repair. Nanomed. 8: 603–621.
Zamani, M., M. P. Prabhakaran, and S. Ramakrishna (2013) Advances in drug delivery via electrospun and electrosprayed nanomaterials. Internat. J. Nanomed. 8: 2997–3017.
Liu, W., X. Wu, and Z. Gao (2011) New potential antiscarring approaches. Wound Rep. Regen. 19 Suppl 1: s22–31.
Gauglitz, G. G., H. C. Korting, T. Pavicic, T. Ruzicka, and M. G. Jeschke (2011) Hypertrophic scarring and keloids: Pathomechanisms and current and emerging treatment strategies. Mol. Med. 17: 113–125.
Ibrahim, M. M., J. Bond, A. Bergeron, K. J. Miller, T. Ehanire, C. Quiles, E. R. Lorden, M. A. Medina, M. Fisher, B. Klitzman, M. A. Selim, K. W. Leong, and H. Levinson (2014) A novel immune competent murine hypertrophic scar contracture model: A tool to elucidate disease mechanism and develop new therapies. Wound Rep. Regen. 22: 755–764.
Van Den Broek, L. J., F. B. Niessen, R. J. Scheper, and S. Gibbs (2012) Development, validation and testing of a human tissue engineered hypertrophic scar model. ALTEX 29: 389–402.
Hartwell, R., M. S. Poormasjedi-Meibod, C. Chavez-Munoz, R. B. Jalili, A. Hossenini-Tabatabaei, and A. Ghahary (2015) An insitu forming skin substitute improves healing outcome in a hypertrophic scar model. Tissue Eng. Part A. 21: 1085–1094.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Park, U., Kim, K. Multiple growth factor delivery for skin tissue engineering applications. Biotechnol Bioproc E 22, 659–670 (2017). https://doi.org/10.1007/s12257-017-0436-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12257-017-0436-1