Table 1.

Strategies to Deliver the Secretome for Regenerative Engineering Applications.

Delivery systema	Animal model	In vivo effect	Refs
IV injection of human deciduous dental pulp stem cell-CM	Mouse rheumatoid arthritis model	Improved clinical symptoms of arthritis Improved histological scores of synovial inflammation, bone erosion, and cartilage damage Reduced osteoclastogenesis in the joints Induced M2 macrophages	[80]
IV injection of human cardiac progenitor cell-exosomes	Rat model of drug-induced cardiotoxicity	Improved cardiac function Attenuated myocardial fibrosis, inflammation, and iNOS expression	[81]
IV injection of MSC-EVs	Mouse model of traumatic brain injury	Decreased IL-1β levels in brain Persevered the pattern separation function and spatial learning ability of the mice	[82]
Direct injection of human UC-MSCs into the soleus muscle	Rat model of muscle atrophy	Improved muscle mass, muscle fiber size, and metabolic activity Improved muscle regeneration by activating satellite cells, stimulating myoblast proliferation and modulating the PI3K/Akt pathway	[119]
Weekly intra-articular injections of exosomes derived from human embryonic stem cell-derived MSCs	Rat critical-sized osteochondral defect	Improved neotissue formation, and cartilage and subchondral bone regeneration Increased cartilage ECM deposition of s-GAG and type II collagen Enhanced cellular proliferation and attenuated apoptosis in the cartilage lesion and overlying synovium Increased M2 macrophage infiltration and decreased M1 macrophages in the cartilage and synovium Reduced levels of inflammatory IL-1 p and TNF-a cytokines in synovial fluids	[85]
Weekly subcutaneous secretome injections of human fetal skin-derived stem cells and UC-MSCs	Rat radiation-induced skin injury	Improved rate and quality of wound healing Enhanced angiogenesis	[88]
Topical administration of human ADSC-CM and HUVEC-CM	Diabetic swine full-thickness wound healing model	Accelerated wound closure Attenuated acute inflammation Significantly decreased the production of TNF-α in the treated wounds	[90]
Atelocollagen-based sponge soaked with hMSC-CM	Rat calvarial bone defect	Increased new bone formation Enhanced early migration of endogenous MSCs to the lesion Depletion of VEGF singly, or depletion of IGF-1, VEGF, and TGF-β1 collectively from the CM diminished its bone regenerative capabilities	[93–95]
β-TCP scaffold soaked with hMSC-CM	Rabbit maxillary sinus floor elevation model	Increased early bone formation Increased angiogenesis and cell proliferation during the early phase of bone regeneration	[96]
β-TCP scaffold soaked with hMSC-CM	Human maxillary sinus floor elevation model	Enhanced new bone formation in the center of the augmented area	[97]
NaOH-treated PLGA membrane soaked with rat BMSC-CM	Rat calvarial bone defect	Increased new bone formation	[99]
3D-printed PLA scaffold loaded with PEI-engineered EVs	Rat calvarial bone defect	Enhanced new bone formation, deposition of bone nodules, and integration with the host Indications of a new vascular network formation	[100]
Silk fibroin-based hydrogel loaded with human UC-MSC-CM	Rat model of age-related osteoporosis	Reduced attenuation in bone loss Improved bone mineral density, and trabecular bone volume, thickness, and number	[102]
Gelatin and Laponite-based hydrogel loaded with hADSC-CM from spheroid culture	Rat myocardial infarction	Improved cardiac function parameters including ejection fraction, fractional shortening, and cardiac output Increased blood vessel density Decreased infarct size	[69]
Hydroxyethyl cellulose hydrogel loaded with hADSC-exosomes	Rat excisional wound-splinting model	Accelerated wound healing	[120]
PLGA microparticles coated with hMSC membrane fragments and loaded with hMSC-secretome	Mouse myocardial infarction	Increased infarct wall thickness Reduced infarct size Increased vessel density	[103]
PLGA microparticles coated with hCSC membrane fragments and loaded with hCSC-secretome	Mouse myocardial infarction	Ameliorated ventricular dysfunction Increased blood vessel density and flow Improved remuscularization and infarct thickness reduced scar size Reduced apoptosis Increased proliferation of endogenous cardiomyocytes	[104]

^aADSC, adipose-derived stem cell; β-TCP, β-tricalcium phosphate; CM, conditioned media; CSC, cardiac stem cell; ECM, extracellular matrix; EVs, extracellular vesicles; IL-1β, interleukin-1β; HUVEC, human umbilical vein endothelial cell; IGF-1, insulin-like growth factor; iNOS, inducible NO synthase; MSC, mesenchymal stem cell; PEI, polyethyleneimine; PI3K, phosphatidylinositol 3-kinase; PLA, polylactic acid; PLGA, poly(lactic-co-glycolic acid); s-GAG, s-glycosaminoglycan; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; UC-MSC, umbilical cord mesenchymal stem cell; VEGF, vascular endothelial growth factor.