Table 2.
Study Designs, Methodologies, and Outcomes of Animal Studies Assessing Intervertebral Disc Regenerative Potential of Mesenchymal Stem Cells
| Study, year | Last follow-up | Follow-up methodology | Sample randomization/grading blindness | Outcome or complication and conclusions |
|---|---|---|---|---|
| Acosta et al., 2011 [62] | 12 months | Histology, biochemistry, anatomy IHC, and FISH | Randomized but not blinded | MSC-treated group showed inferior survival and proteoglycan reconstitution compared with group treated with juvenile articular chondrocytes |
| Allon et al., 2010 [51] | 5 weeks | Histology, biochemistry, and RT-qPCR | Not randomized but blinded | BCP promotes MSC differentiation and retention hence increased disc height |
| Bendtsen et al., 2011 [47] | 12 weeks | T1 serial MRI, DCE-MRI, and fluoroscopy | Randomized but not blinded | Improved blood flow, volume, and nutrient permeability of endplates |
| Crevensten et al., 2004 [48] | 4 weeks | X-ray and fluoroscopy | Not randomized nor blinded | Transplanted MSCs proliferated but hyaluronan gel is not an ideal carrier |
| Feng et al., 2011 [53] | 16 weeks | MRI, X-ray, histology, biochemistry, and RT-PCR | Not randomized nor blinded | MSCs displayed similar disc regeneration compared with NP-treated discs and can serve as replacement for NP cells |
| Ganey et al., 2009 [65] | 48 weeks | MRI, RX, histology, biochemistry, and fluoroscopy | Not randomized but blinded (Graded by 2 individuals) | Implant integrated into extant NP and induced Col II protein deposition |
| Ghosh et al., 2012 [64] | 6 months | MRI and histology | Not randomized but blinded (Graded by 2 individuals) | Immunoselected MSCs using STRO-3 as marker restored disc height index by contributing to the regeneration of new extracellular matrix |
| Hee et al., 2010 [46] | 8 weeks | Anatomy, radiology, histology, and fluoroscopy | Randomized and blinded | BM-MSC injection combined with external axial distraction displayed superior regenerative effect than axial distraction regimen alone |
| Henriksson et al., 2009 [61] | 6 months | MRI, histology, IHC, and RT-qPCR | Not randomized nor blinded | Hydrogel carrier facilitated survival and chondrogenesis of the transplanted MSCs |
| Hiyama et al., 2008 [63] | 8 weeks | Anatomy, MRI, RX, histology, IHC, ICC biochemistry, and RT-PCR | Not randomized but blinded (Graded by 2–3 individuals) | Disc degeneration is halted with triggered Fas-Ligand protein expression upon transplantation, contributing to immune-privilege of MSC transplantation |
| Ho et al., 2008 [57] | 16 weeks | X-ray, histology, and IHC | Not randomized but blinded | Proteoglycan and collagen production was restored in both early and late IDD after MSC injection but decrease of disc height was not prevented in late IDD |
| Jeong et al., 2009 [50] | 8 weeks | MRI, X-ray, histology, and IHC | Not randomized nor blinded | Disc degeneration halted for 8 weeks despite injected MSCs survived up to 2 weeks only |
| Jeong et al., 2010 [40] | 6 weeks | MRI, RX, histology, and IHC | Not randomized but blinded (Graded by 2 individuals) | ADSCs maintained viability until 2 weeks post-transplantation with prolonged synthesis of proteoglycan |
| Miyamoto et al., 2010 [66] | 24 weeks | MRI, RX, and histology | Not randomized nor blinded | Synovial MSCs displayed similar preventive effect compared with BM-MSCs, promoting NP cells to secrete Col II protein |
| Sakai et al., 2003 [55] | 8 weeks | Histology, IHC, and laser scan microscopy | Not randomized nor blinded | Atelocollagen gel permit MSC survival up to 4 week, proliferation, differentiation, and matrix production |
| Sakai et al., 2005 [56] | 48 weeks | Histology, IHC, biochemistry, and RT-PCR | Not randomized nor blinded | Transplanted MSCs proliferated and differentiated into chondrocyte-like cells but not osteocyte nor adipocyte |
| Sakai et al., 2006 [54] | 24 weeks | MRI, X-ray, histology, IHC, biochemistry, and RT-PCR | Not randomized nor blinded | Disc degeneration halted with proteoglycan restoration but no lipid or calcium formation |
| Serigano et al., 2010 [60] | 12 weeks | MRI, RX, histology, biochemistry, anatomy, IHC, and fluoroscopy | Not randomized but blinded (Graded by 2 individuals) | Transplantation of 106 cells produced optimal protective effect on disc structure with localization within central NP region |
| Sobajima et al., 2008 [58] | 24 weeks | RX and histology | Not randomized nor blinded | MSCs localized into transition zone and inner AF region and exhibited a spindle morphology |
| Vadalà et al., 2011 [42] | 9 weeks | Anatomy, MRI, RX, and histology | Not randomized nor blinded | Osteophytes composed of mineralized tissue developed from injected MSCs |
| Wei et al., 2009 [52] | 6 weeks | Histology, IHC, and immunofluoroscopy | Not randomized nor blinded | CD34− MSCs differentiated and survived better than CD34+ BM-HSCs but no macrophage infiltration was detected in both groups |
| Yang et al., 2009 [49] | 24 weeks | X-ray, histology, IHC, biochemistry, and RT-PCR | Not randomized nor blinded (Graded by 2 individuals) | Injected MSCs arrested progressive IDD via MSC chondrogenesis and stimulation of endogenous NP cells |
| Yang et al., 2010 [59] | 12 weeks | MRI, RX, histology, and IHC | Randomized but not blinded | MSC-Fibrin with TGF-β1 supplement decreased rate of apoptosis of NP cells hence arrested further degeneration |
| Zhang et al., 2005 [37] | 6 months | Histology, RT-PCR, ELISA, and DNA-PCR | Randomized but not blinded | Labeled BM-MSCs survived in vivo for 6 months but did not show increase in cell number. Production of proteoglycan and Col II increased in BM-MSC-treated disc but not Col II |
ADSC, adipose-derived stem cells; FISH, fluorescent in situ hybridization; HSC, hematopoietic stem cell; ICC, immunocytochemistry; IDD, intervertebral disc degeneration; IHC, immunohistochemistry; MRI, magnetic resonance imaging; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, quantitative reverse transcription polymerase chain reaction; RX, radiography.