Table 2.

Selected spatiotemporally controlled delivery strategies for in vitro and in vivo cartilage repair applications

Biologics Delivered	Delivery Platform	In vitro/In vivo Model	Spatial Strategy	Temporal Strategy	Reference
TGF-β1, IGF-1	Gelatin microparticles encapsulated in bilayered OPF hydrogels	Rabbit femoral medial condyle osteochondral defect	Growth factors delivered from the chondral layer of bilayered OPF construct	Burst release of TGF-β1 with sustained release of IGF-1	[26]
TGF-β3, IGF-1	Gelatin microparticles encapsulated in bilayered OPF hydrogels	Rabbit femoral medial condyle osteochondral defect	Growth factors delivered from chondral layer of bilayered OPF construct	Burst release or sustained release of TGF-β3 with sustained release of IGF-1	[44]
TGF-β1, IGF-1	PLGA microsphere-fused 3D scaffold	In vitro	N.A.	Burst or sustained release of TGF-β1; Burst or sustained release of IGF-1	[147]
BMP-7, TGF-β2	Pluronic F68-heparin-chitosan nanoparticles encapsulated in alginate hydrogel	Rabbit trochlear groove osteochondral defect	N.A.	Burst release of BMP-2 with sustained release of TGF-β2	[125]
TGF-β3, PTHrP	Alginate microspheres encapsulated in HA hydrogel	Mouse subcutaneous model	N.A.	Burst release of TGF-β3 with simultaneous release of PTHrP	[137]
BMP-2, IGF-1	Silk microspheres incorporated into aqueous-derived silk porous scaffold	In vitro	Single BMP-2 gradient; Single IGF-1 gradient; Continuous BMP-2/IGF-1 transitional reverse gradient	N.A.	[126]
BMP-2, TGF-β1	PLGA microsphere-based bioactive plug	Rabbit femoral condyle osteochondral defect model	Continuous BMP-2/TGF-β1 transitional reverse gradient	N.A.	[121]
bFGF	Chitosan-heparin nanoparticles in loose/dense bilayered collagen scaffold	Rabbit trochlear groove osteochondral defect model	Directional bFGF release via the loose collagen layer - Compared release toward or away from subchondral bone	Burst release followed by sustained release of bFGF	[168, 169]
BMP-2, microfracture	Heparin-conjugated fibrin (long-term delivery) or fibrin (short-term delivery)	Rabbit trochlear groove osteochondral defect model	N.A.	Burst or sustained release of BMP-2 with bone marrow exposure	[34]
TGF-β1, BMP-4	Affinity binding bilayered alginate sulfate	Rabbit trochlear groove osteochondral defect model	TGF-β1 affinity-bound into chondral layer; BMP-4 affinity-bound into subchondral layer	N.A.	[103]
BMP-2 or TGF-β1	PLGA microspheres encapsulated in alginate matrix overlaid on porous PLGA cylinder	Rabbit trochlear groove osteochondral defect model	TGF-β1, low dose (2.5 μg) BMP-2, or high dose (5 μg) BMP-2 delivered from PLGA in chondral layer	Burst release followed by sustained release of TGF-β1 or BMP-2	[33]