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Review
. 2023 Dec 28;9(3):e10642.
doi: 10.1002/btm2.10642. eCollection 2024 May.

Growth factors and growth factor gene therapies for treating chronic wounds

James A Mullin  1 , Erfan Rahmani  2 , Kristi L Kiick  2   3 , Millicent O Sullivan  1   2
Affiliations
Review

Growth factors and growth factor gene therapies for treating chronic wounds

James A Mullin et al. Bioeng Transl Med. .

Abstract

Chronic wounds are an unmet clinical need affecting millions of patients globally, and current standards of care fail to consistently promote complete wound closure and prevent recurrence. Disruptions in growth factor signaling, a hallmark of chronic wounds, have led researchers to pursue growth factor therapies as potential supplements to standards of care. Initial studies delivering growth factors in protein form showed promise, with a few formulations reaching clinical trials and one obtaining clinical approval. However, protein-form growth factors are limited by instability and off-target effects. Gene therapy offers an alternative approach to deliver growth factors to the chronic wound environment, but safety concerns surrounding gene therapy as well as efficacy challenges in the gene delivery process have prevented clinical translation. Current growth factor delivery and gene therapy approaches have primarily used single growth factor formulations, but recent efforts have aimed to develop multi-growth factor approaches that are better suited to address growth factor insufficiencies in the chronic wound environment, and these strategies have demonstrated improved efficacy in preclinical studies. This review provides an overview of chronic wound healing, emphasizing the need and potential for growth factor therapies. It includes a summary of current standards of care, recent advances in growth factor, cell-based, and gene therapy approaches, and future perspectives for multi-growth factor therapeutics.

Keywords: chronic wounds; gene therapy; growth factors.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

FIGURE 1
FIGURE 1
Cytokine and growth factor signaling in acute and chronic wound healing. Figure prepared using Biorender.com.
FIGURE 2
FIGURE 2
Biomaterials for single growth factor (GF) delivery. (a) Time dependent wound closure data for gelatin gel sheets loaded with varying concentrations of fibroblast GF (FGF). Adapted with permission, copyright 2016 Elsevier. (b) Release profiles and (c) healing rates for KGF loaded chitosan and silica‐chitosan hybrid wound dressings. Adapted with permission, copyright 2019 Elsevier. (d) An SEM image and (e) the associated release curve of FGF loaded poly(ethylene glycol)‐poly(dl‐lactide) electrospun fibers. Adapted with permission, copyright 2011 Elsevier.
FIGURE 3
FIGURE 3
Exogenous multi‐growth factor (GF) delivery approaches. (a) Faster wound closure is obtained with a combination of VEGF and EGF using a system with chitosan microparticles loaded into dextran hydrogels. Adapted with permission, copyright 2013 Elsevier. (b) Release curves for GFs encapsulated in collagen and HA nanofibers (NFs) or gelatin NPs within the collagen and HA NFs and (c) the associated wound closure data. Adapted with permission, copyright 2014 Elsevier. (d) Wound closure data for methylcellulose‐chitosan hydrogels loaded with no cargo (Hydrogel 1), silver and curcumin loaded polydopamine (PDA) NPs (Hydrogel 2), VEGF (Hydrogel 3), and VEGF with silver and curcumin loaded PDA NPs (Hydrogel 4). Adapted with permission, copyright 2023 Elsevier.
FIGURE 4
FIGURE 4
Commonly observed release and growth factor (GF) expression profiles from various delivery approaches. (a) Exogenous growth factor delivery approaches including direct loading, particle‐in‐gel loading, and combination systems. (b) Gene therapy approaches including bolus delivery, hydrogel delivery, and tethered gene carrier systems. Figure prepared using Biorender.com.
FIGURE 5
FIGURE 5
Examples of various polymer and lipid‐based gene delivery strategies. (a) Wound closure images and (b) data for methacrylic acid anhydride modified hyaluronic acid/N‐hydroxymethylacrylamide modified dextran hydrogels encapsulating no cargo (Gel alone), resveratrol (Gel‐Res), or resveratrol and PEI/plasmid DNA encoding VEGF (Gel‐Res/pDNA‐VEGF). Adapted with permission, copyright 2019 Elsevier. Real‐time PCR analysis of (c) stromal cell‐derived factor‐1α (SDF‐1α) and (d) VEGF for PBAE polyplexes loaded with sonic hedgehog and β‐galactosidase. Adapted with permission, copyright 2012 Elsevier. (e) Wound closure images and (f) data for ionizable lipid‐based nanoparticles (LNP), VEGF‐mRNA (mRNA), and ionizable lipid‐based nanoparticles encapsulated with VEGF‐mRNA (LNP/mRNA). Adapted with permission, copyright 2023 Elsevier.
FIGURE 6
FIGURE 6
Examples of various biomaterial‐based gene delivery strategies. (a, b) Temporal release of siRNA loaded nanoparticles with varying amount of trehalose from porous polyester urethane scaffold (a) in vitro and (b) in vivo. Adapted with permission, copyright 2013 John Wiley and Sons. (c) PDGF expression of NIH 3T3 cells seeded on collagen‐fibrin co‐gels loaded with polyplexes of different CMP modifications (0, 20, and 50%) and (d) wound closure images of mice treated with saline, collagen‐fibrin co‐gels, PDGF loaded co‐gel, and PDGF polyplex loaded co‐gel. Adapted with permission, copyright 2020 American Chemical Society.
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