Table 4.

Biological activities of commercial and orange peel’s hesperidin related to wound healing potential.

Hesperidin/ Extract Type	Hesperidin Levels Tested	Testing Model	Main Biological Properties	Formulation	Potential Applications	Bioavailability/Molecular Pathways/Other Relevant Properties	Ref.
Commercial hesperidin	1–10% (w/v)	3T3 cells Wistar rats S. aureus P. aeruginosa	Hemocompatible; Antimicrobial; Cell proliferation and collagen synthesis increase in a dose-dependent manner; In vivo enhanced performance of would therapy in a dose-dependent manner; Granulation tissue and epidermal proliferation; Wound contraction, epidermal layer formation and remodeling	Alginate/Chitosan/ Hesperidin Hydrogel: 2:1 (v/v) alginate and chitosan solutions (sodium alginate (2% (w/v)) in deionized water; chitosan (2% (w/v)) in 0.5% (v/v) acetic acid) + hesperidin (1 or 10% weight of polymer Alg/Chit) + calcium chloride 50 mM (CaCl2) and 10 μL glutaraldehyde with NaOH 1 M (crosslink).	Skincare Pharmaceutical/ Therapeutic Agent	Neovascularization enhancement in a dose-dependent manner; between 8.9 and 17.2% of hesperidin has been released within the first 3 to 6 h, followed by a sustained release of 77.03 ± 8.71%, over 14 days	[95]
Commercial hesperidin	10 mg/mL	Ex vivo goat skin Wistar albino rats	Improvement of therapeutical treatment for anti-inflammatory activity; The gels were close to a neutral pH (6.8), presenting a low risk of skin irritation	Optimal emulsion formulation: 100 mg stearic acid; 50 mg cholesterol, 125 mg soya lecithin; 100 mg hesperidin in 10 mL ethanol. Optimal topical nanoemulgel: Ratio 1:1 of Carbopol to hydroxypropylmethyl cellulose.	Skincare Pharmaceutical/ Therapeutic Agent	Potential as a carrier for topical drug delivery system; the hesperidin release from the optimal emulsion was 98.6% after 6 h; regarding ex vivo permeation studies of hesperidin nanoemulgel, the cumulative drug that permeated through the skin was 98.9% after 4 h	[101]
Commercial hesperidin	25–100 µg/mL 1	Ex vivo rat skin	Hemocompatible; Acceleration of wound closure in a dose-dependent manner; Reduction in inflammation and infection; Improvement of wound contraction, epidermal layer formation, remodeling, and collagen synthesis, in a dose-dependent manner	Hesperidin-loaded PAMAM Dendrimer (Hsp-PAMAM): hesperidin at 2.5, 5, 7.5, or 10% (w/v) was loaded into PAMAM dendrimer. Hsp-PAMAM based hydrogel bandages: sodium alginate; deionized water; chitosan solution and acetic acid.	Skincare Pharmaceutical/ Therapeutic Agent	Safe and compatible for topical delivery; hesperidin shows an outburst pattern in the first 5 h, followed by delayed release, from the bandages; after 24 h, 86.367% of hesperidin was released; rat skin showed a deposition of the drug in the epidermis up to 15–25 µm; the drug was conserved in between the epidermis and dermis, which is ideal for full-thickness wound therapy	[102]
Commercial hesperidin	5% (w/v)	Swiss albino mice	Wound-healing acceleration; Enhancement of wound contraction; Induction of cell proliferation	Hydrogel: hesperidin (5 g); deionized water (10 mL) and polyethylene glycol 400 (PEG) (380–420 g/mol).	Skincare Pharmaceutical/ Therapeutic Agent	Increased nitric oxide, glutathione and SOD levels; repression of NF-kB and COX-2	[103]
Commercial hesperidin	0.5% (w/w)	Dermal fibroblasts from donated human skin	Fibroblasts proliferation induction; Migration without terminal differentiation and collagen synthesis; Increased progression of wound confluence and closure	Niacinamide (3.0% w/w), L-carnosine (1.0% w/w), hesperidin (0.5% w/w) and Biofactor HSP® (0.05% w/w).	Skincare Pharmaceutical/ Therapeutic Agent	N/A	[104]
Commercial hesperidin	30–120 mM	S. aureus E. coli HUVECs cells Sprague–Dawley rats	Antibacterial; DPPH scavenging activity; No significant cytotoxicity; Cell proliferation and migration activity improvement; Acceleration of wound closure after infection by S. aureus; Re-epithelization enhancement; Stimulation of collagen synthesis and deposition; Stimulation of angiogenesis and hair follicle synthesis	Nanoparticles: silver nitrate (AgNO3) (2 mL, 3.397 mg/mL) and hesperidin solution (10 mL, 17.6 mg/mL). Note: The nanoparticles were Incorporated into a hydrogel.	Skincare Pharmaceutical/ Therapeutic Agent	Activation of basic fibroblast growth factor (bFGF) and Stirt 1 expression; suppression of the expression of pro-inflammatory factors (NF-ƙB, MMP9, TNF-α, and IL-6)	[105]
Commercial hesperidin	Formulation’s oral intake: 50 mg/kg/day	Sprague–Dawley rats	Necrosis reduction in epidermis and dermis; No congestion or hemorrhage, after 14 days	Oral intake: Bacitracin combined with hesperidin.	Skincare Pharmaceutical/ Therapeutic Agent	Decrease in IL-1 beta and TNF-α levels	[106]
Commercial hesperidin	0.5% (w/w)	Sprague–Dawley rats	Reduction in wound surface area; Increased wound contraction; Potentiation of wound epithelization by the 28th day; Promotion of cellular infiltration and proliferation	Scaffold: collagen in 0.05-M acetic acid (0.6% (w/w)), chondroitin-6-sulfate (in 0.05-macetic acid). Scaffolds in cosmeceutical formulation: niacinamide (3.0% w/w), L-carnosine (1.0% w/w), hesperidin (0.5% w/w) and Biofactor HSP®(0.05% w/w). Scaffolds crosslinking: 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide and N-hydroxysuccinimide (EDAC/NHS) and 0.5% glutaraldehyde (GA).	Skincare Pharmaceutical/ Therapeutic Agent	N/A	[107]
Commercial hesperidin	Oral intake: 25–100 mg/kg/day	Sprague–Dawley rats	Wound half-closure time improvement in a dose-dependent manner; Oxido-nitrosative stress reduction; Hydroxyproline levels (collagen synthesis marker) increase; Angiogenesis and re-epithelization induction	N/A	Skincare Pharmaceutical/ Therapeutic Agent	VEGF-c, Ang-1, Tie-2, TGF-β and Smad 2/3 mRNA expression upregulation	[108,109]
Commercial hesperidin	Oral intake: 10–80 mg/kg/day	Rats	Wound healing promoted in Diabetes-induced animals; Wound half-closure time improvement	N/A	Skincare Pharmaceutical/ Therapeutic Agent	Reduction in MDA, MPO, TNF-α, and IL-6 levels in a dose-dependent manner; stimulation of VEGF, GSH, HDP, and SOD expression in a dose-dependent manner	[110]
Commercial hesperidin	5–10% (w/w)	Swiss albino mice	Epithelization time reduction; Enhancement of wound contraction; Wound-healing activity improved in a dose-dependent manner in the S.aureus infected wound model (antibacterial activity)	Ointments containing: 5% (w/w) or 10% (w/w) hesperidin.	Skincare Pharmaceutical/ Therapeutic Agent	N/A	[111]
Commercial hesperidin	50–250 µg/mL 2	In vitro non-cellular assays	Strong DPPH scavenging activity	Nanoparticles optimal formulation: hesperidin (15 mg); chitosan (20 mg); soya lecithin (10 mg) and surfactant (1 mL)	Skincare Pharmaceutical/ Therapeutic Agent	In vitro, hesperidin presents an outburst pattern in the first 4 h followed by delayed release from nanoparticles; the optimal formulation was stable, safe to use and could improve the topical bioavailability of hesperidin due to its nano-size with a larger surface area; the formulation is a suitable hesperidin delivery agent, leading to improved wound healing	[112]

¹ Concentrations of hesperidin-loaded PAMAM dendrimer-based hydrogel bandages; ² Concentrations of hesperidin-loaded nanoparticles. 3T3—Murine fibroblast cell line. HUVECs—Human umbilical vein endothelial cells; N/A—Non-added.