Hydrogel-Loaded Exosomes: A Promising Therapeutic Strategy for Musculoskeletal Disorders

Table 4

The preparation strategy of the current mainstream exo-hydrogel controlled release system.

Form of preparation	Preparation method	Advantages	Disadvantages	Application	References
Hydrogel microbeads	Traditional methods	Low cost; Fast preparation speed; High mechanical strength	The bioactivity and release of exos were affected by the inability to obtain uniform small-size microbeads	Bone damage; Colitis	[225, 226]
	Emulsion
	Microfluid flow
	Electrostatic droplet extrusion
	Coaxial air injection
	In situ polymerization
	Nonequilibrium microfluidic technology	Uniform in size	It is more complex than traditional methods	AF injury	[222, 227]
		The scale can be controlled below 100 μm		Bone damage
		Ensure exos activity		Cartilage damage and so on
Hydrogel fiber	Electric spinning yarn; Microfluidic spinning; Wet spinning; Gel spinning; Hydrodynamic spinning	Be able to inject; Can stay longer to ensure exos’ long-term release; The properties are diversified after modification	Swelling is high, and sudden release of the drug may occur after injection; The difference in mechanical strength; Additional modification steps are required	Bone defect of weight-bearing bone of lower limb; Myocardial tissue injury	[227–230]
Hydrogel nanoparticles	Physical or chemical crosslinking, such as polymerization of emulsion; Distillation-precipitation polymerization	High expansibility	Crosslinks are difficult to control; The controlled release performance is not good	Defect of bone; Fracture; Tendon injury; Myocardial injury; Cartilage damage (microtia)	[12, 13, 231, 232]
		High biocompatibility
		High mechanical properties
		Simple preparation
		High load drug
		Adjustable size
3D scaffolds were prepared by emulsion lyophilization	Hybrid	Easy to store; Application in laboratory; Strong stability	There are limitations to interconnectivity; Does not provide the structure of the native organization; Time-consuming	Myocardial repair; Repair of cartilage	[13, 229]
	Freeze drying
	Salt leaching
	Foaming of gas
Spinning nanofiber scaffolds	Electrospinning	Biodegradation kinetics is adjustable	High temperature may damage the structure and exos’ activity during modification	Defect of bone	[233–235]
		High biocompatibility		Periodontitis
		Adjustable porosity		AF injury
3D printing technology	Technique of extrusion	Fluid and slurry can be distributed in three dimensions, which is suitable for the treatment of various musculoskeletal disorders	Low accuracy; Mechanical damage caused by shear force affects the therapeutic effect	Bone damage	[236–240]
				Tendon injury
				Cartilage damage
	Traditional bioink printing	Fast	Low strength	Bone damage; OA	[241–244]
	Drop ink as needed	High accuracy	Thermal/mechanical damage to exos
	Continuous inkjet	Low cost	Hydrogels that are cured may collapse
	Response to microporous molding	High strength	High cost; The operation is difficult	No large-scale controlled trials have been conducted	[245]
		Pore size is suitable for cell migration and proliferation
		Viscoelasticity can be matched to biological tissue
	Photocuring-assisted printing; Stereoscopic lithography; Digital light processing	No nozzle can avoid exos damage	High cost; The front-end design work is heavy	Muscle injury; Defect of bone; Cartilage damage; Tendon injury	[246–254]
		Higher printing speed
		High precision
		The 3D structure is stacked smoothly
		Uncured hydrogels do not collapse