Table 1.
Preclinical studies for different interventions using various model systems to assess therapeutic potentials in IVDD.
| Preclinical in vivo studies on growth factors | ||||
|---|---|---|---|---|
| Animal model | Therapeutic source | Brief outcome | References | |
| Rabbit | PGDF-BB | Alleviated disc degeneration, prevented apoptosis | (70) | |
| OP-1 | Disc height increased Disc height and proteoglycans increased | (71–73) | ||
| BMP-2 | Increase of hypervascularity and fibroblast proliferation | (74) | ||
| GDF-5 | Increased cell proliferation and matrix synthesis | (75) | ||
| PRP | Disc height increased along with chondrocyte proliferation | (76) | ||
| PRP | PRP-ADSC group restored discs compared to controls. | (77) | ||
| Rat | IGF-1, GDF-5, TGFβ, bFGF | Increase of GDF-5 and TGFβ | (78) | |
| GDF-5 | Slows progression of degeneration | (79) | ||
| Mouse | GDF-5 | Disc height increased | (80) | |
| Dog | NTG-101 | Decreased expression of pain related neutrophins | (81) | |
| Preclinical in vitro and in vivo studies on EVs | ||||
| EV source | Method | Animal model | Brief outcome | References |
| AD-MSCs | In vitro | Human | NPCs were protected from oxidative stress by the lyo-secretome | (82) |
| BM-MSCs | In vitro | Mouse | Increase in Col2 and Acan expression | (83) |
| In vivo | Decreased levels of Mmp3 and Mmp6 | |||
| In vitro | Mouse | Reduced inflammatory cytokines and activated MAPK pathway | (84) | |
| In vitro | Rat | Inhibition of apoptosis and ECM catabolism | (85) | |
| In vitro | Rat | Decreased NPC apoptosis | (86) | |
| In vivo | Slowed the decrease in disc height | |||
| In vitro | Rat | Apoptosis decreased for NPCs in treatment group. | (87) | |
| In vivo | Alleviated expression of Tnf-α | |||
| In vitro | Human | Proliferation rate increased | (88) | |
| In vitro | Human | Reduction of ER stress-induced apoptosis | (89) | |
| In vitro | Human | Apoptosis reduced in degenerated disc cells. | (90) | |
| In vitro | Human | Upregulation of COL2A1 and ACAN | (91) | |
| In vitro | Human | Inhibition of AF cell autophagy | (92) | |
| UC-MSCs | In vitro | Human | Prevented damage from high glucose induced injury | (93) |
| USCs | In vitro | Human | Lowered GRP78, GRP94, Caspase 3, and Caspase 12 expression | (94) |
| In vivo | Rat | Alleviated IVDD in vivo | ||
| MSCs | In vitro | Rat | Inhibition of apoptosis Alleviates IVDD | (95) |
| In vivo | Alleviated IVDD hallmarks | |||
| In vitro | Mouse | Inhibited pyroptosis | (96) | |
| In vivo | Alleviated IVDD | |||
| PLMSCs | In vitro | Human | Induces proliferation and migration | (97) |
| In vivo | Mouse | Increased ZNF121 expression | ||
| NCs | In vitro | Canine | Increased GAG and collagen content | (98) |
| Human | Increased GAG and collagen content | |||
| In vitro | Bovine | Only canine CLCs were affected by the mild concentration-dependent anabolic impact of EVs. | (99) | |
| Canine | ||||
| In vitro | Human | Angiogenesis was inhibited by EV conditioned media via miR-140-5p, which also controls WNT/Catenin signaling. | (100) | |
| In vivo | Mouse | Vascularization in degenerated IVDs was inhibited by EV conditioned media. | ||
| NPCs | In vitro | Rat | Upregulation of Acan, Sox9, and Col2a1 compared to controls | (101) |
| In vitro | Human | Increased expression of ACAN, SOX9, COL2A1, HIF1a, CA12, and KRT19 | (88) | |
| In vivo | Rat | miR-223-3p application lowered C-fiber responses | (102) | |
| In vitro | Rat | P21 and P53 relative expression increased in senescent NPC EVs. | (103) | |
| N/A | N/A | NPC autophagy and EV secretion were induced by rapamycin and bafilomycin A1 in an autophagy-dependent manner. | (104) | |
| In vitro | Human | Downregulation of SIRT1 in vitro | (105) | |
| In vivo | Rat | By adsorbing miRNA-141-5p and downregulating SIRT1 in vivo, circRNA_0000253 accelerated IVDD. | ||
| In vitro | Human | Significant cellular uptake | (106) | |
| AFCs | In vitro | Human | Degenerated AFC-EVs stimulated cell migration and increased levels of IL-6, TNF-α, MMP-3, MMP-13, and VEGF, whereas EVs originating from non-degenerated AF cells had the opposite effects. | (107) |
| CEPCs | In vitro | Rat | Apoptotic bodies promoted PPi metabolism, increased Pi and decreased PPi | (108) |
| CESCs | In vitro | Rat | Alleviation of IVDD by the activation of the PI3K/AKT pathway | (109) |
| PMEFs | In vivo | Mouse | Upregulation of Foxf1 and Brachyury | (106) |
| Preclinical in vivo and in vitro studies on gene therapy | ||||
| Therapeutic source | Animal model | Brief outcome | References | |
| Naringin | Rat | Might have a protective effect on IVD. | (110) | |
| Cannabidiol | Rat | High dose can only alleviate IVDD | (111) | |
| EGCG | Rat | Reduction of pain in vivo | (112) | |
| UA | Rat | UA alleviated IVDD | (113) | |
| E2 | Rat | E2 can regulate autophagy of IVD and can be a therapeutic agent in postmenopausal women | (114) | |
| Rat | E2 downregulates catabolic proteins and prevents IVDD | (115) | ||
| Icariin | Rat | Icariin reduced disruption of AF | (116) | |
| Resveratrol | Rabbit | Resveratrol alleviated IVDD | (117) | |
| Rat | Levels of IL-1 and TNF-α proteins decreased | (118) | ||
| CXB | Dog | In dogs with IVDD, the controlled dose of CXB partially inhibited the generation of PGE2. | (119) | |
| Dog | In vivo, the progression of IVDD was reduced by intradiscal regulated release of CXB. Life quality improves without evident signs of regeneration | (120) | ||
| Berberine | Rat | Could alleviate IVDD in animal model | (121) | |
| Metformin | Rat | Showed a protective effect against IVDD | (122) | |
| Gefitinib | Rat | Decreased histological scores in comparison to the control group | (123) | |
| Statin | Rat | Intradiscal injection alleviates IVDD | (124) | |
| Luteoloside | Rat | ECM and NP tissues well preserved | (125) | |
| Curcumin | Rat | Lowered NF-κB-p65 and TNF-α expression | (126) | |
| Preclinical in vivo and in vitro studies on gene therapy | ||||
| Vector | Method | Animal model | Reference | |
| BV | In vivo | Rabbit | (127) | |
| LV | In vivo | Rabbit | (128) | |
| RV | In vitro | Bovine | (129) | |
| AV | In vitro, In vivo | Rabbit | (130) | |
| AAV | In vivo | Rat | (132) | |
| RNAi | In vitro | Rat | (133) | |
| Ultrasound targeted microbubble destruction | In vivo | Rat | (134) | |
| Polyplex micelle | In vitro | Human and rat | (135) | |
| CRISPR/Cas9 | In vitro | Human | (136) | |
ACAN, Aggrecan; ADSC, adipose-derived mesenchymal stromal cell; AV, adenovirus; AAV, adeno-associated virus; AFC, annulus fibrosus cell; bFGF, basic fibroblast growth factor; BM-MSC, bone marrow-derived mesenchymal stem cell; BMP, bone morphogenetic protein; BV, baculovirus; CEPC, cartilage endplate chondrocyte; CESC, cartilage endplate stem cell; CLC, chondrocyte like cell; CXB, celecoxib; COL, collagen; E2, estradiol; ECM, extracellular matrix; ER, endoplasmic reticulum; EV, extracellular vesicle; GAG, glycosaminoglycan; GDF, growth differentiation factor; IGF, insulin like growth factor; IL, interleukin; IVDD, intervertebral disc degeneration; LV, lentivirus; MAPK, mitogen activated protein kinase; MMP, matrix metalloproteinase; MSC, mesenchymal stem cell; NC, notochordal cell; NF-kb, nuclear factor kappa-light-chain-enhancer of activated B cells; OP, osteogenic protein; Pi, inorganic phosphate; PPi, extracellular pyrophosphate; PGDF-BB, platelet-derived growth factor BB; Pi, inorganic phosphate; PI3K/AKT, phosphatidylinositol 3-kinase Akt; PLMSC, placental mesenchymal stem cell; PMEF, primary mouse embryonic fibroblast; PPi, extracellular pyrophosphate; PRP, platelet rich plasma; RNAi, RNA interference; RV, retrovirus; SIRT, Sirtuin; TGF, transforming growth factor; TNF, tumor necrosis factor; UA, urolithin A; UC-MSC, umbilical cord-derived mesenchymal stem cell; USC, urine-derived stem cell.