Table 3.

Various immunomodulation strategies based on the controlled release of biological molecules from hydrogels for the treatment of chronic wounds

Biological molecules	Type	Composition	Results	Reference
Cytokines	IL-10	Dextrin nanogel	Slow release of IL-10 reduced TNF-α synthesis and down-regulated class II major histocompatibility complex molecules expression on macrophages	[181a]
	IL-10	Collagen– silica hydrogel including PEI-DNA complexes	Decreased TNF-α and IL-1β gene expression confirmed successful inhibition of inflammation.	[181d]
	IL-10	Nanocomposite hydrogel based on plasmid DNA-PEI-SiNP, collagen	Controlled release of IL-10 resulted in downregulation of TNF-α expression	[181e]
	IL-2	An injectable hydrogel based on collagen, HA, and heparin	Sustained release of IL-2 in a two-week period decreased CD4+ and CD8+ T cells and increased FoxP3+ Treg in lymph nodes of mice. Increase immune tolerance in autoimmune diabetes	[249]
	SDF-1α	liposomes	Improve the granulation tissue formation and accelerate diabetic wound healing	[250]
	SDF-1α	liposome/GelMA	Effectively induce MSC migration. Controlled release of SDF-1α modulated intracellular cell signaling pathways in MSCs.	[251]
	IL-4 and MCP-1	Nanofibrous peptide hydrogel	Controlled release of IL-4 and MCP-1 led to spatiotemporal activation of THP-1 macrophages and improvement of proresolution M2	[183]
Antibody	anti-TNF-α antibody	Chitosan	Slow release of anti-TNF-α antibody accelerated chronic wound treatment	[189a]
	anti-TNF-α antibody	Shear-thinned glycosyl–nucleoside–lipid amphiphiles	Release of entrapped anti-TNF-α accelerated autoimmune disease treatment	[189b]
	anti-TNF-α antibody	HA hydrogel	Controlled release of anti-TNF-α antibody reduced inflammation in burns.	[189c]
Anti-inflammatory factor	Resolvin D1	Chitosan	Release of resolvin D1 decreased M1 cells and increased in M2 cells. Decrease pro-inflammatory cytokines expression leading to less inflammatory cells in implant sites.	[191]
	Catechol	Chitosan and oxidized HA	Support hBMSCs against oxidative stress damages induced by ROS	[194]
	GM-CSF + BDC peptide	Alginate-Au NPs hydrogel	Induce Treg response via delivering peptide antigen to dendritic cells (DCs). The hydrogel was proposed for the treatment of autoimmune diseases such as type 1 diabetes mouse model.	[108]
Peptides	L-12 peptides	Crosslinked polyanionic DNA nanostructure	Significant antimicrobial properties against S. aureus infections and noticeable anti-inflammatory response to accelerate the healing rates	[203]
	LL-37 peptides	Chitosan	Significant antibacterial properties. Inhibit TNF-α release from macrophage, improve the density of newly-formed capillary with naked LL-37 and promote the expression of key macromolecules in the angiogenesis process.	[204]
	Pep4, Pep4M	HA hydrogel	No need for whole elastase inhibition in normal wound healing process	[252]
Gene	PDRN a	An assembling nanofiber gel	Improve the new vessel formation and treatment of diabetic foot ulcers in a mouse model.	[253]
	siRNA	LPEI hydrogel	Responsible for a high concentration of MMPs in diabetic ulcers leading to accelerated remodeling at injured site.	[212]
	siRNA	Star-shaped hydrogel	Controlled release of siRNA reduced the expression of MMP-9 and accelerated diabetic wound healing.	[254]
	siRNA	CD-(D3)7 a star-shaped hydrogel	Control the siRNA release from hydrogel leading to decreased expression of MMP-9 to accelerate diabetic wound healing.	[255]
	siRNA	A pH-sensitive nanogel	Local release of siRNA induced gene knockdown	[209a]
	miR-29b	Collagen	Regulate ECM remodeling and wound contraction in vivo	[256]
	Cell + miRNA delivery	Supramolecular hydrogel	Control miRNA release	[257]
	miRNA-132	Neutral lipid emulsion mixed with pluronic F-127 gel	Improve re-epithelialization in damaged tissue	[223]
	miR-223*	GelMA- HA nanoparticles	Improve the expression of anti-inflammatory gene Arg-1 and decrease the proinflammatory markers	[74b]
	miR-302a and miR-155	Light-activatable miRNA-loaded plasmonic gold nanocarriers	A sequentially release of miRNAs, using a NIR laser. Regulation of gene expression.	[258]
Cytokine + growth factor	TGF-β1 and IL-10	Functionalized PEG	Control dendritic cell maturation via reduced expression of IL-12 and MHCII.	[181b]
Cytokine +drug	IL-4, Dexamethasone	Self-assembled and injectable hydrogel	Successful anti-inflammatory macrophage polarization. Appropriate for the treatment of type 1 diabetes	[259]
Antibody +growth factor	anti-TNF-ɑ and HGF	Self-assembling peptide/heparin hydrogel	Effectively improve the tissue repairing process	[190]
Anti-inflammatory factor+ cytokine	FTY720+SDF-1α	Hep−N-functionalized PEG-DA hydrogel	Increase the recruitment of anti-inflammatory monocytes, improve early accumulation of the differentiated wound healing CD206+ macrophages, promote the vascularization.	[196]

^a: A linear DNA sequence from human placenta, which can efficiently stimulate the adenosine A2A receptor