Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery - PubMed (original) (raw)
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Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery
Tatiana N Demidova-Rice et al. Adv Skin Wound Care. 2012 Aug.
Abstract
This is the second of 2 articles that discuss the biology and pathophysiology of wound healing, reviewing the role that growth factors play in this process and describing the current methods for growth factor delivery into the wound bed.
Figures
Figure 1. SIMPLIFIED REPRESENTATION OF PDGF SIGNALING CASCADE
Several cell types—platelets, macrophages, keratinocytes, and endothelial cells—produce ligands—PDGF-AA, PDGF-AB, and PDGF-BB during wound healing. These ligands interact with 1 or several of 3 types of PDGF receptors: PDGFR-αα, PDGFR-αβ, and PDGFR-ββ. PDGF-AA can activate only PDGFR-αα; PDGF-AB can interact with both PDGFR-αα and PDGFR-αβ, whereas PDGF-BB activates all 3 receptor kinds. This specificity of ligand-receptor interactions is shown with dotted arrows. Receptor-ligand interactions, receptor dimerization, and phosphorylation lead to activation of phospholipase Cγ, phosphatidy-linositol-3-kinase, and mitogen-activated kinase pathways, which in turn induce increased cellular migration, proliferation, and growth factor production.
Figure 2. FGF SIGNALING AND WOUND HEALING
Five FGF family members are expressed upon dermal injury. Fibroblast growth factors 1 and 2 belong to FGF-1 subfamily and are produced by macrophages, keratinocytes, endothelial cells, and fibroblasts to stimulate both epithelial and mesenchymal cells. Members of FGF-7 subfamily (FGF-2, FGF-10, and FGF-22) mainly affect epithelial cells. Interactions between FGF ligands and FGF receptor lead to receptor dimerization and are enhanced by heparan sulfate proteoglycan (HSPG). Receptor-ligand interactions lead to activation of phosphatidylinositol-3-kinase and mitogen-activated kinase pathways and induce an increase in cell migration, proliferation, and production of growth factors and matrix remodeling enzymes, including MMPs.
Figure 3. VEGF, VEGF RECEPTORS, AND THE CELLULAR RESPONSES TO INJURY
Cellular effects of the members of VEGF family are mediated by 3 VEGF receptors—VEGFR-1, VEGFR-2, and VEGFR-3. Activation of VEGFR-1 and VEGFR-2 mainly induces wound-healing angiogenesis and neovascularization, whereas VEGFR-3 is important for lymphangiogenesis. Ligand-receptor interactions and their specificities are shown with arrows. Note the interaction between VEGF-A and VEGF-R2 is enhanced in the presence of coreceptors neuropilins 1 and 2 (Np-1,2).
Figure 4. EGF SIGNALING AND WOUND-HEALING RESPONSES
Members of the EGF family are synthesized in a membrane-bound form. Their release from a membrane and activation is performed by matrix metalloproteinases of MMP and ADAM families. Activated epidermal growth factors (EGFs)—EGF, transforming growth factor α (TGF-α), and heparin-binding EGF (HB-EGF)—interact with 1 or more Erb receptors (arrows). Note that Erb2 receptor does not bind EGF ligands and acts as a dimer-forming partner or a coreceptor. Ligand-receptor interactions initiate several signaling pathways, including mitogen-activated protein kinase pathways (MAPK), Erk1/2, and phosphatidylinositol-3-kinase leading to increase in post-injury migration, proliferation, and production of MMPs and inflammatory mediators. Interestingly, Erb receptors can be activated by matrix fragments that contain EGF-like repeats.
Figure 5. SCHEMATIC REPRESENTATION OF TGF-A–DEPENDENT SIGNAL TRANSDUCTION
The members of the TGF-β family (TGF-β1, TGF-β2, TGF-β3, bone morphogenetic proteins [BMP], and activins) bind and activate TGF-β receptor type II, which then recruit (curved arrow) and transphosphorylate receptor type I. Following injury and during wound healing, ligand-receptor interactions lead to the activation of canonical (SMAD-mediated) or noncanonical pathways, which in turn induce changes in cell proliferation, matrix production, cell differentiation, and cytoskeletal rearrangements. The effects of TGF-β on cell proliferation (*) are cell type and growth factor concentration dependent.
Figure 6. CHEMICAL STRUCTURES OF PROTEINACEOUS MATRICES USED FOR DRUG DELIVERY AND WOUND HEALING
(A) Schematic representation of the chemical structure of collagen. The molecule is composed of helices containing collagenous glycine-X-Y sequences (blue and red lines). These helices then coil again into a triple helix (bundle) stabilized by hydrogen bonds (dotted lines). (B) Schematic representation of a fibrin molecule. A fibrin bundle is formed after cleavage of the fibrinogen by thrombin and is composed of fibrinogen monomers containing 1 E domain (red) and 2 D domains (green and blue). The bundle is stabilized by plasma transglutaminase (gray).
Figure 7. METHODS OF GROWTH FACTOR INCORPORATION INTO PROTEINACEOUS MATRIX-BASED BIOMATERIALS
Incorporation of growth factors into proteinaceous matrices (scaffolds) can be achieved via several mechanisms. (a) Rehydration of nonmodified matrices involves soaking of dry matrices in aqueous solutions of growth factors. (b) Growth factors can be genetically modified by addition of matrix-binding moieties (ie, collagen-binding domain of fibronectin) and then combined with unmodified scaffolds. On the other hand, (c) matrix itself can be altered with growth factor–binding molecules, such as heparin, thus increasing its affinity for growth factors.
Figure 8. POLYSACCHARIDE-BASE MATRICES USED FOR GROWTH FACTOR DELIVERY
(A) Carboxymethyl cellulose (CMC) is a polymer composed of 2-glucopyranose residues (cellulose) with hydroxyl groups substituted by carboxymethyl groups. The CMC monomers are connected with β-(1-4)-glycosidic bonds. The structure of CMC sodium salt is shown. (B) Chitosan polymers consisting of _N_-acetyl-D-glucosamine and β-(1,4)-linked d-glucosamine. (C) Alginate sodium salt polymers containing 1-4 linked β-D-mannuronic acid and α-L-glucuronic acid residues.
Figure 9. SYNTHETIC POLYMERS USED FOR DRUG DELIVERY
(A) Chemical structure of poly-lactic acid. (B) Chemical structure of poly-glycolic acid. (C) Chemical structure of a copolymer of poly(lactic acid) and poly(glycolic acid), and poly(lactide-co-glycolic acid). (D) Chemical structure of polyethylene glycol.
References
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- Gao Z, Sasaoka T, Fujimori T, et al. Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J Biol Chem. 2005;280:9375–89. -PubMed
- Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16:585–601. -PubMed
- Bennett SP, Griffiths GD, Schor AM, Leese GP, Schor SL. Growth factors in the treatment of diabetic foot ulcers. Br J Surg. 2003;90:133–46. -PubMed
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