Growth factors are endogenous signaling molecules that regulate cellular responses required for wound healing processes such as migration, proliferation, and differentiation. However, exogenous application of growth factors has limited effectiveness in clinical settings due to their low in vivo stability, restricted absorption through skin around wound lesions, elimination by exudation prior to reaching the wound area, and other unwanted side effects. Sophisticated systems to control the spatio-temporal delivery of growth factors are required for the effective and safe use of growth factors as regenerative treatments in clinical practice, such as biomaterial-based drug delivery systems (DDSs). The current review describes the roles of growth factors in wound healing, their clinical applications for the treatment of chronic wounds, and advances in growth factor-loaded DDSs for enhanced wound healing, focusing on micro- and nano-particulate systems, scaffolds, hydrogels, and other miscellaneous systems.

To understand the production and characteristics of protein hydrolysates pertaining to individual fish species, we selected and analyzed the most important commercial fish species according to the market value based on the Statistics on International Exports of Fishery Commodities by Food and Agriculture Organization. Accordingly, salmon, shrimp, cod, tuna, squid, and herring are marine species with high global value. Peptides obtained from their by-products were predominant in hydrophobic amino acids such as alanine, phenylalanine, methionine, proline, valine, tyrosine, tryptophan, leucine, and isoleucine. Bioactive peptides are short with a length of 2-20 amino acids. They remain inactive when they are within their parent proteins. Low molecular weight (0.3-8 kDa) peptides from hydrolyzed protein are easily digestible, readily absorbed by the body and are water-soluble. The hydrophobic nature contributes to their bioactivity, which facilitates their interactions with the membrane lipid bilayers. Incomplete hydrolysis results in low yields of hydrophobic amino acids. The glycosylation type of the resulting peptide fragment determines the different applications of the hydrolysate. The degree of conservation of the glycosidic residues and the size of the peptides are influenced by the method used to generate these hydrolysates. Therefore, it is crucial to explore inexpensive novel methodologies to generate bioactive peptides. According to the current studies, a unified approach (in silico estimation coupled with peptidomics) can be used for the identification of novel peptides with diverse physiological and technological functions. From an industrial perspective, the reusability of immobilized enzymes and membrane separation techniques (e.g., ultrafiltration) on marine by-products can offer low operating costs and higher yield for large-scale production of bioactive peptides. This review summarizes the production processes and essential characteristics of protein hydrolysates from fish by-products and presents the advances in their application.

We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site. To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model. The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.