Combination therapy of hydrogel and stem cells for diabetic wound healing

Table 1 Summary of studies regarding therapy combining hydrogels and stem cells for diabetic wound healing

Stem cell information, types, dosage in cells/wound	Hydrogel composition	Hydrogel types	Application methods	Animal	Wound size diameter, location	Full re-epithelialization efficiency	Outcome	Ref.
UMSCs from human, xenogeneic, 1 × 106	Self-assembled nanopeptide hydrogels based on RADA16-I, RGD, and KLT peptide solutions	Self-assembled nanopeptide hydrogels with easy biomimetic functionalization	Cells were encapsulated into the in situ forming hydrogels	NOD/SCID mice	8 mm, dorsal	10 d	Accelerated skin wound healing by inhibiting inflammation and promoting angiogenesis	[14]
BMSCs from rats, allogenic, 2 × 105	N-chitosan/ HA-ALD hydrogel	Hemostasis and antimicrobial hydrogels	Cells were encapsulated into the in situ forming hydrogels	STZ-induced diabetic rats	5 mm, foot	12 d	Promoted wound healing; stimulated the secretion of growth factors from rBMSCs, and modulated the inflammatory environment by inhibiting the expression of M1 macrophages and promoting the expression of M2 macrophages, resulting in granulation tissue formation, collagen deposition, nucleated cell proliferation, neovascularization	[37]
ADSCs from human, xenogeneic, 3 × 105	GG-HA spongy hydrogel	Vascularization hydrogels	Cells were seeded onto the top of spongy-like hydrogel sheets	STZ-induced diabetic mice	9 mm, dorsal	4 wk	Accelerated excisional skin wound healing; induced the healing phase switch from the inflammatory to the proliferative phase; presented a thicker epidermis with a high number of proliferative keratinocytes in the basal layer; increased the number of intraepidermal nerve fibers in the regenerated epidermis	[41]
BMSCs from rabbits, allogenic, 1 × 106	SNAP-loaded chitosan-PVA hydrogel	Vascularization hydrogels	Cells were intradermally injected and topically covered with hydrogel sheets	Alloxan monohydrate induced diabetic rabbits	20 mm, dorsal	14 d	Augmented the wound closure, decreased inflammation, and upregulated expression of CD31, VEGF and TGFβ-1; promoted angiogenesis by forming new capillaries and improving the microvascular and vessel maturation; showed an abundant expression of collagen type I on day 14	[44]
ADSCs from human, xenogeneic, 5 × 105	Curcumin-incorporated 3D bioprinting GelMA hydrogel	Antioxidant hydrogels	Cells were encapsulated into hydrogel sheets	STZ-induced diabetic nude mice	15 mm, dorsal	21 d	Promoted wound healing; improved hADSCs apoptosis and increased the amount of collagen	[46]
ADSCs from human, xenogeneic, 2.5 × 105	hDAM hydrogel	Intact ECM-derived hydrogels from living tissues	Cells were suspended in the in situ forming hydrogels	KK/Upj-Ay/J mice (diabetic mice)	8 mm, dorsal	14 d	Accelerated wound closure and improved skin architecture regeneration, including better restoration of cutaneous appendages, increase of dermis thickness, and augmenting neovascularization	[62]
UMSCs from human, xenogeneic, 5 × 106	GelMA/Chi-C hydrogel	Vascularization hydrogels	Cells were mixed with the in situ forming hydrogels	Diabetic mice (db/db)	8 mm, dorsal	14 d	Promoted the wound healing process by inhibiting protein expression of TNF-α and IL-1β to decrease inflammation. Accelerated angiogenesis and re-epithelialization, promoted collagen deposition, and induced regeneration of skin appendages such as hair follicles	[63]
PDSCs from human, xenogeneic, 1 × 106	Chitosan/collagen/β-GP hydrogel	Thermosensitive and pH-responsive hydrogels	3D spheroids were encapsulated in the in situ forming hydrogels	Diabetic mice (db/db)	7 mm, dorsal	3 wk	Accelerated wound closure by enhancing angiogenesis and paracrine effects. The hydrogel provided an environment favorable for the attachment and proliferation of encapsulated hPDSCs, accelerating cell proliferation and paracrine factor secretion	[67]
ADSCs from rats, allogenic, 5 × 105	Gelatin hydrogel	Adaptive hydrogel microspheres with degradation rates well-matched to tissue regeneration	Hydrogel microspheres	STZ-induced diabetic rats	8 mm, dorsal	14 d	Significantly accelerated wound healing by promoting M2 macrophage polarization, collagen deposition, angiogenesis associated with peripheral nerve recovery, and hair follicle formation. The microspheres well embedded in the tissue, exhibited good biocompatibility and adaptive biodegradation rates	[77]
BMSCs from human, xenogeneic, 5 × 105	PEGDA hydrogel	Bioinert synthetic hydrogels	Cells were encapsulated into hydrogel sheets	Genetically diabetic mice (BKS.Cg-m +/+Leprdb/J)	1 cm × 1 cm1, dorsal	14 d	Accelerated wound healing; the co-encapsulation of hBMSCs and insulin secreting cells resulted in healing wounds without scab or scar	[79]
ADSCs from human, xenogeneic, 3 × 105	PEG-gelatin hydrogel	Vascularization hydrogels	Cells were mixed with the in situ forming hydrogels	Diabetic mice (db/db)	6 mm, dorsal	15 d	Significantly accelerated wound closure; the encapsulated cells attached and diffused well inside the hydrogel, improving cell retention in vivo; reduced inflammatory cell infiltration and enhanced neovascularization	[80]

¹Wound size (side length × side length).

3D: Three dimensional; ADSCs: Adipose-derived stem cells; β-GP: β-glycerophosphate; BMSCs: Bone marrow-derived mesenchymal stem cells; Chi-C: Chitosan-catechol; ECM: Extracellular matrix; GelMA: Gelatin methacryloyl; GG-HA: Gellan gum-hyaluronic acid; HA-ALD: Hyaluronic acid-aldehyde; hADSCs: Human adipose-derived stem cells; hBMSCs: Human bone marrow-derived mesenchymal stem cells; hDAM: Human decellularized adipose tissue matrix; hPDSCs: Human placenta-derived mesenchymal stem cells; N-chitosan: N-carboxyethyl chitosan; PDSCs: Placenta-derived mesenchymal stem cells; PEG: Poly(ethylene glycol); PEGDA: Polyethylene glycol diacrylate; PVA: Polyvinyl alcohol; rBMSCs: Rat bone marrow-derived mesenchymal stem cells; SNAP: S-nitroso-N-acetyl-penicillamine; STZ: Streptozotocin; UMSCs: Umbilical cord-derived mesenchymal stem cells; VEGF: Vascular endothelial growth factor.