Advances in polymer-based hydrogel systems for adipose-derived mesenchymal stem cells toward bone regeneration

Table 1 Hydrogel systems and their efficacy, guiding future scaffold design in bone tissue engineering

Scaffold compositions	Fabrication methods	In vitro models	In vivo models	Inferences	Ref.
Chondroitin-6-sulfate (CHA)/glycol CS (GCS)/maleic anhydride-modified polyethylene glycol (DF-PEG) (CHA/SF/GCS/DF-PEG) hydrogels	Freeze drying	BM-MSCs, human embryonic kidney cells (HEK293), mouse osteoblastic progenitor cells, mouse macrophages (RAW264.7)	Adult mouse fracture model (BALB/c)	Hydrogel with BM-MSC-exo regulated macrophage polarization and angiogenesis to enhance bone regeneration	[63]
Methacrylate-silk fibroin/nano-HAp hydrogels	Photo-crosslinking	RAW 264.7 cells, BM-MSCs	Rat femoral defect	Elevated osteochondral repair by macrophage M2 polarization has been reported	[64]
Ultrasound-triggered ultrashort peptide SESSE nanofiber hydrogels	Ionic gelation method	BM-MSCs	C57BL/6J mouse bone defect model	Increased M2 polarization led to secretion of BMP-2 and IGF-I, and enhanced bone regeneration	[65]
Alpha-tricalcium phosphate/COL bioceramic ink/sanitizer-based hydrogels	3D-bioceramic printing	MC3T3 cells	-	Improved mechanical properties, increased cellular growth and osteogenic activity have been reported	[66]
Nano-HAp/GEL methacrylate/oxidized sodium ALG hydrogels loaded with BMP7	Photo-crosslinking	Rat BM-MSCs	Rat distal femur defect model	Enhanced osteogenic differentiation and bone formation have been reported	[67]
GEL-Bletilla striata polysaccharide-mesoporous bioactive glass hydrogels	Schiff base reaction and hydrogen bonding	Bone marrow-derived macrophages	Rat cranial defect model	Enhanced immunomodulation and bone regeneration were reported	[68]
Poly (L-glutamic acid) (PLG) grafted with tyramine (PLG-g-TA) polymer, VEGF, and strontium-doped borosilicate bioactive glass nanoparticles	Enzyme cross-linking	Rat BM-MSCs, human umbilical vein endothelial cells, and Raw264.7 cells	Rat cranial bone defects	Enhanced vascularization, osteogenesis, and angiogenesis have been reported	[69]
Amino-functionalized barium titanate nanoparticle hydrogels	Schiff base reaction and hydrogen bonding	BM-MSCs	Rat calvarial defect model	Enhanced ALP, BMP2, OPN, OCN, and COL-I expression and new bone formation have been reported	[70]

ALG: Alginate; BM-MSC: Bone marrow-derived mesenchymal stem cell; CS: Chitosan; GEL: Gelatin; Hap: Hydroxyapatite; VEGF: Vascular endothelial growth factor; 3D: Three-dimensional.

Table 2 Preclinical investigations employing adipose-derived mesenchymal stem cells in hydrogel-based scaffolds for bone tissue engineering applications

Cell sources	Hydrogel compositions	Fabrication methods	In vitro models	In vivo models	Inferences	Ref.
Immortalized adipose-derived stem cells (AD-SCs)	Immortalized AD-SCs were embedded within the dextran hydrogel for photobiomodulation (PBM) treatment	Physical gelation of dextran-based hydrogel (commercially prepared)	AD-SCs	-	Optimized PBM combined with dextran hydrogels enhanced osteogenic differentiation of AD-SCs by upregulating osteogenic markers (RUNX2, BGLAP, BGN, and SOST)	[97]
SIRT1 + adipose-derived mesenchymal stromal stem cells (ASCs)	SIRT1 + ASCs in ALG hydrogels	Polymerization	ASCs	5-year-old mare with subchondral bone cyst	Pretreatment of ASCs with resveratrol and 5-azacitidine, followed by encapsulation in 3D-ALG hydrogel, promoted the replacement of subchondral bone cysts with normal bone tissue and facilitated complete recovery	[98]
Human adipose-derived stem cells (hAD-SCs)	hAD-SCs seeded with COL-GEL composite scaffolds containing fluorapatite (FA) nanoparticles	Blending of COL and GEL with FA nanoparticles followed by crosslinking to form a composite hydrogel scaffold	hAD-SCs	-	Increased ALP activity and calcium deposition as well as the expression of osteogenic genes, including Runx2, Col-I, ALP, and OCN, and the synthesis of proteins, such as OCN have been reported	[99]
hAD-SCs	VEGF-ADSCs were seeded on whitlockite (WH-C)	Cryogelation	hAD-SCs	Mouse calvarial bone defect model	VEGF-transduced AD-MSCs seeded on WH-C-reinforced GEL/heparin cryogels enhanced osteogenesis and angiogenesis, leading to significantly improved bone regeneration in a mouse calvarial defect model	[100]
hAD-SCs	O-carboxymethyl CS (O-CMC)/acetylsalicylic acid/hAD-SCs hydrogel	Chemically cross-linked hydrogel formation using EDC/NHS chemistry followed by freeze-drying to fabricate a porous 3D-scaffold	-	Wistar rat skull defect model	The ASA-crosslinked O-CMC hydrogel seeded with hAD-SCs significantly enhanced cranial bone regeneration in rats, as evidenced by CT imaging and histological analyses	[101]
Rabbit AD-SCs from inguinal adipose tissue	HA-grafted-CS-grafted-poly(N-isopropylacrylamide) (HA-g-CS-g-PNIPAM) hydrogel with platelet-rich plasma and biphasic calcium phosphate	HA-g-CS-g-PNIPAM hydrogel synthesized via EDC/NHS coupling and free radical polymerization, exhibiting thermo-gelling sol-to-gel transition at approximately 37 °C	Rabbit AD-SCs	Rabbit calvarial bone defect model	The injectable HA-g-CS-g-poly (N-isopropylacrylamide) (HA-CPN) hydrogel scaffold incorporated with platelet-rich plasma and biphasic calcium phosphate significantly enhanced proliferation, osteogenic differentiation, and mineralization of adipose-derived stem cells in vitro and promoted robust bone regeneration in vivo	[102]
hAD-SCs	CS and β-glycerol phosphate	In situ thermosensitive gelation	hAD-SCs cultured in 2D monolayer and 3D-CS/β-GP hydrogel	-	The quantum dots-βcyclodextrin-histidine labeled hAD-SCs laden CS hydrogel (QD-βCD-His@Dex) nanocarrier enhanced osteogenic differentiation compared to that with free Dex, sustained ALP activity and calcium deposition in a 3D-hydrogel, and upregulated RUNX2 and OPN gene expression	[103]
Immortalized AD-MSCs	Fast-dextran hydrogel disc	Direct encapsulation	Immortalized AD-MSCs	-	Elevated ATP levels, improved cell viability, and preserved membrane integrity have been reported	[104]

ALG: Alginate; BTE: Bone tissue engineering; COL: Collagen; CS: Chitosan; CT: Computed tomography; GEL: Gelatin, HA: Hyaluronic acid; AD-MSC: Adipose-derived mesenchymal stem cell; 3D: Three-dimensional; VEGF: Vascular endothelial growth factor.