**8. Nanomaterials incorporated with growth factors for healing**

Healing occurs as a cellular response to wounding/injury, and it involves a variety of cells such as macrophages, fibroblasts, keratinocytes, and neutrophils. In general, the wound-healing process is regulated by various factors, such as microbial infections, wound type, patient conditions, lesser growth factors, and cytokine release. Impaired or delayed wound healing is very much affected by the decreased production of different growth factors by the cells that will ultimately cause the lengthening of healing time and leads to various other complications [171]. Various growth factors such as VEGF, EGF, PDGF, FGF, and TGF-β play a great role in promoting the wound-healing process *via* decreasing inflammation, promoting cell proliferation of fibroblasts and epithelial cells, increasing angiogenesis and ultimately reepithelialization [158]. Topical administration of growth factors as wound dressings is quite unsatisfactory due to their low biodegradability, instability of protein structure under certain physiological conditions, and enzymatic degradation [172]. In this regard, new drug delivery systems to deliver growth factors at the target wound site in a controlled fashion were developed using nanotechnology (**Figures 2** and **3**) [173].

In this context, gold NPs have been used to conjugate the keratinocyte growth factor. The gold NPs effectively promoted the proliferation of keratinocytes in contrast to unloaded gold NPs or keratinocyte growth factor. *In vivo* full-thickness wound model resulted in enhanced of healing by promoting re-epithelialization by the application of growth factor conjugated NPs. In this study, gold NPs were favored for use due to their biocompatibility and versatile nature for surface functionalization [174]. In another study, recombinant human EGF-loaded nanostructured lipid carriers (NLCs) were checked for their wound-healing efficacy in full-thickness excisional wound porcine model. *In vivo* healing experiments showed that topical application of 20 μg of recombinant human epidermal growth factor (rhEGF)-NLC enhanced the percentage rate of wound closure by day 25 as compared to administration of 75 μg of free rhEGF and NLC by migration and proliferation of fibroblast cells and deposition of collagen in the newly healed wound [129]. Human EGF was loaded into thiolated heparin and diacrylated PEG hydrogels *via* photopolymerization for wound healing. *In vivo* full-thickness wounds in mice showed accelerated wound closure as compared to EGF solution due to sustained release of EGF from biocompatible hydrogel [175]. In a similar manner, wound dressing composed of chitosan-hyaluronic acid composite sponge containing VEGF encapsulated fibrin NPs was designed for diabetic wounds. From the released studies, it was found that 64% of the encapsulated VEGF in NPs was released in 72 h with an initial burst release of 29% in 2 h, which was supposed for the initial sprouting of blood vessels. *In vitro* studies showed that endothelial cells seeded on these hydrogels showed capillary-like tube formation beneficial in woundhealing angiogenesis [176]. From all these studies, it can be inferred that NPs enhance the release of growth factors and thus accelerate the wound-healing process.
