Table 1. MSC-CM delivered via biomaterial scaffolds for tissue repair in representative examples in various injury models.
h: human, m: mouse, r: rat, BMSC: bone marrow mesenchymal stromal cells, ASC: adipose tissue derived stromal cells, SD-MSC: skin-derived MSC, UCMSC: umbilical cord MSC, PDLSC: periodontal ligament MSC, HUVEC: human umbilical vein endothelial cell, PSC: placental stem cell, TNF-α: tumor necrosis factor-α, IFN-γ: Interferon gamma.
| Injury (species) | MSC-CM source | CM collection/ processing | Biomaterials | In Vitro/ In Vivo Observations | Reference |
|---|---|---|---|---|---|
| Corneal Wounds (rat) | hBMSC | Serum free media, debris cleared by centrifugation, frozen (liquid N2), lyophilized | Hyaluronic acid (HA) and chondroitin sulfate (CS) hydrogel | In vitro, MSC-CM embedded in HA/CS enhanced proliferation of corneal epithelial cells. In vivo, CM in HA/CS hydrogels promoted wound healing in corneas following either mechanical injury or after alkaline burns, to a greater extent compared with either MSC-CM or HA/CS alone, in part mediated by CD44 receptor upregulation and stimulation by HA | [1] |
| Volumetric Muscle Loss (rat) | rASC | Serum free media, debris cleared by centrifugation, concentrated 10x, filtered (0.22 μm), frozen (−80°C) | Type I collagen hydrogel | In vitro, mouse M2-CM enhanced migration and angiogenesis of HUVEC. In vivo, CM-embedded hydrogel promoted repair in muscle defects, by enhanced angiogenesis and myogenesis, and decreased inflammation (M2 macrophage polarization) compared with the hydrogel alone. MSC-embedded gels showed superior healing to CM gels. | [2] |
| Endometrial Injury (rat) | hBMSC | Serum free media, debris cleared by centrifugation, filtered (0.22 μm), frozen (−80°C), lyophilized | HA hydrogel | In vitro, MSC-CM enhanced tube formation and proliferation of HUVEC, growth of human endometrial epithelial cell line AN3CA, and migration of endometrial epithelial cells. In vivo, HA gel allowed sustained-release of CM components and enhanced endometrium healing. | [3] |
| Skin Wounds (mouse) | hSD-MSC | Serum free media, filtered (0.22 μm), concentrated (10-kDa), frozen (−80°C) | Carrageenan (CG) or poly(vinyl alcohol) (PVA) hydrogels | In vitro, CM promoted tube formation by HUVEC. In vivo, CM gels enhanced angiogenesis compared to untreated wounds, but was not different to CM without carrier. MSC-CM w/o hydrogels did not improve wound closures | [4] |
| Skin Wounds (rat) | hUCMSC | Serum free media, debris cleared by centrifugation, filtered (0.22 μm), lyophilized, stored frozen (−80°C) | Hydrogel – composition not provided | In vitro, CM promoted proliferation of HUVEC. In vivo, CM-laden hydrogel promoted angiogenesis, proliferation, wound healing and reduced scar formation in radiation induced skin wounds, with superior performance when compared with a EGF-laden hydrogel positive control. | [5] |
| Renal Ischemia (rat) | hPSC | Serum free media, filtered (0.22 μm), concentrated 10x (3-kDa), frozen (−80°C) | Porcine platelet‐rich plasma (PRP) & thrombin | In vitro, MSC-CM inhibited apoptosis and promoted proliferation in human primary renal cells and HUVEC. In vivo, injection of MSC-CM encapsulated in PRP gel ameliorated renal function and cell viability after acute kidney injury, to a greater extent compared to CM or PRP alone | [6] |
| Myocardial Infarction (rat) | hASC | Serum free media, debris cleared by centrifugation, then lyophilized | Laponite/ gelatin hydrogel | In vitro, hASC spheroid CM exhibited enhanced proliferation, migration, and tube formation of HUVEC. In vivo, spheroid CM-laden hydrogel reduced infarct area and enhanced angiogenesis | [7] |
| Myocardial Infarction (mouse) | hBMSC | Serum free media, debris cleared by centrifugation, then lyophilized | Polylactic-coglycolic acid (PLGA) microparticles | In vitro, MSC-CM encapsulated in PLGA microparticles cloaked in MSC membrane fragments increased cardiomyocyte proliferation and contractility. In vivo, injection of CM-containing microparticles directly into the heart after MI reduced infarct area and enhanced regeneration | [8] |
| Acute Liver Failure (mouse) | hBMSC | Conditioned media filtered (0.22 μm), frozen (−80°C), and lyophilized | PLGA nanoparticles (NPs) | In vitro, MSC-CM in PLGA NPs enhanced proliferation of liver cells. Uptake of NPs by M1 macrophages was inhibited by cloaking NPs with red blood cell (RBC) membrane fragments. In vivo, RBC fragment- cloaked NPs containing MSC-CM enhanced liver cell proliferation and inhibited cell apoptosis, thereby promoting liver regeneration and enhancing survival in a carbon tetrachloride induced liver failure mouse model | [9] |
| Peridontal Defects (rat) | hPDLSC | Serum free media, cleared by centrifugation, filtered (0.22μm), concentrated (10kDa), stored (4°C) | Collagen sponge and fibrin glue (BOLHEA) | In vitro, MSC-CM sponge inhibited IFN-γ-induced TNF-α expression in RAW264.7 murine macrophages. In vivo, MSC-CM enhanced regeneration of periodontal defects in a dose dependent manner while suppressing the inflammatory response (TNF-α expression) | [10] |
| Bone Defects (rat) | rBMSC | Serum free media, debris cleared by centrifugation | Polylactide-co-glycolide (PLGA) membrane | In vitro, CM-loaded PLGA increased proliferation and osteogenic differentiation (ALP) of rBMSCs. In vivo, CM/PLGA implants enhanced healing in calvaria bone defects | [11] |
| Bone Defects (rat) | rBMSC | Hypoxia, serum free media, debris cleared by centrifugation | Fibrinogen/ thrombin gel (GREENPLAST) | In vitro, hypoxia-CM reduced miR-221 expression in rBMSCs, which led to enhanced ICAM-1 expression and cell migration compared to normoxia-derived CM. In vivo, hypoxia-CM encapsulated gel promoted bone regeneration in calvaria defects by stimulation of endogeneous MSCs | [12] |
| Osteoporosis (rat) | hUCMSC | Serum free media, debris cleared by centrifugation, filtered (0.22 μm), lyophilized, frozen (−80°C) | Silk fibroin hydrogels | In vitro, MSC-CM promoted rBMSCs proliferation in a dose-dependent manner, and reduced senescence biomarkers and oxidative stress of aged rBMSCs, while promoting osteogenic, over adipogenic differentiation. In vivo, CM encapsulated silk hydrogels injected into the bone marrow of aged rats significantly increased bone mass | [13] |
| Periodontal Defects (dog) | hMSC | Serum free media, stored fresh (4°C) or frozen (−80°C) | Atelo-collagen sponge (TERUPLUG) | In vitro, MSC-CM promoted migration and proliferation of dog BMSCs and periodontal ligament cells. In vivo, MSC-CM laden biomaterial enhanced bone regeneration in a one-wall intrabony periodontal defect | [14] |
| Periodontal Defects (rat) | hMSC | Serum free media, stored fresh (4°C) or frozen (−80°C) | Atelo-collagen sponge (TERUDERMIS) | In vitro, MSC-CM enhanced migration and proliferation of rBMSCs and rat periodontal ligament cells, and tube formation by HUVECs. In vivo, MSC-CM laden biomaterial enhanced bone regeneration, angiogenesis and mobilization of endogenous MSCs to the periodontal defect | [15] |
| Bone Defects (rat) | hMSC | Serum free media, stored fresh (4°C) or frozen (−80°C) | Atelo-collagen sponge (TERUDERMIS) | In vitro, MSC-CM enhanced migration and osteogenic gene expression of rBMSCs. In vivo, MSC-CM entrapped sponge enhanced bone regeneration in critical-sized calvaria defects | [16] |
| Maxillary Sinus Cavities (rabbit) | hMSC | Serum free media, stored fresh (4C) or frozen (−80°C) | Beta-tricalcium phosphate (β-TCP) particles (OSferion) | In vitro, MSC-CM enhanced migration and proliferation of rabbit BMSCs. In vivo, MSC-CM soaked biomaterial led to earlier angiogenesis and bone regeneration in a sinus floor elevation model but no overall increase in bone formation after 8 weeks | [17] |
| Mandibular Bone Defects (rabbit) | hASC | Hypoxia, serum free media, debris cleared by centrifugation, filtered (0.22 μm), frozen (−20 °C) | Human blood plasma hydrogels | In vitro, hypoxia-CM comprised significantly higher concentrations of angiogenic and osteogenic soluble secretions compared to normoxia CM. In vivo, MSC-CM loaded hydrogel, and likewise ASC transplantation, increased bone formation in defects compared with hydrogel controls | [18] |
| Bone defects (rat) | hBMSC | Serum free media, stored fresh (4°C) or frozen (−80°C) | Agarose hydrogel | In vitro, MSC-CM promoted rBMSCs proliferation, migration and osteogenic gene expression. In vivo, MSC-CM loaded gel promoted healing in calvaria defects more than MSC transplantation. MSC-CM mobilized rBMSCs (administered via the caudal vein) to the defect site | [19] |
| Alveolar Bone Atrophy (human) | hMSC | Serum free media, debris cleared by centrifugation, protein precipitation, lyophilized, frozen (−80°C) | β -TCP or an atelocollagen sponge | Patients requiring bone augmentation prior to dental implant placement were treated with MSC-CM via either β-TCP (5 patients) or collagen sponges (3 patients). Both biomaterials led to early bone formation. CM soaked β-TCP promoted early resorption and replacement of new bone compared with retrospective patient controls treated with β-TCP alone | [20] |
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