Table 1.

Review of previously published autologous mesenchymal signaling cell (MSC) and platelet-rich plasma (PRP) intradiscal injection with serious adverse events (SAEs).

Year, Author, Country	Design, Level of Evidence, SAE Review	Allogenic versus Autologous	Biologic	n	Mode of Implantation	Period of Follow-Up	Clinical Outcome	No. SAEs, Type, Mild AEs
MSCs
1. 2006, Haufe, USA22	Case series, IV, prospective	Autologous	BMA	10	Intradiscal injection BMA alone (volume not reported)	12 mo	No improvement in any patient at 1 y	0
2. 2011, Orozco, Spain14	Case series, IV, prospective	Autologous	Cx BD-MSCs	10	Intradiscal injection, limited information	12 mo	85% improvement in pain and disability at 3 mo. Increased water signal in treated discs at 12 mo, but no disc height improvement	0
3. 2012, Subach, USA26	Case report, IV, retrospective	Autologous	Adipose, BM, plasma	1	L3-4 and L5-S1 ID injection, 3 mL at each level, 20-g needle	1 y postsurgical intervention	Normal motor function, patchy decreased sensation	1 SAE, L3-4 disc extrusion, osteomyelitis, discitis, epidural abscess, cauda equina
4. 2016, Elabd, USA15	Case series, IV, retrospective	Autologous	Hypoxic cx BD-MSCs	5	Intradiscal injection BD-MSCs with contrast	4–6 y	Percent improvement measured by self-reported quality of life assessment:	0
							Patient 1: 50%
							Patient 2: 90%
							Patient 3: 40%
							Patient 4: 10%
							Patient 5: 80–90%
							Higher MSC number correlated with better response
5. 2017, Centeno, USA16	Case series, IV, retrospective review	Autologous	Cx BD-MSCs (with PL)	26	1 wk pretreatment PL epidural, intradiscal injection, 1–3 mL cx BMSCs per disc, PL epidural 2 wk postinjection	6 y	Mean FRI change score: 30 at 6 y (significant at 3 mo and 5 y)	1, large HNP at 3 mo; 3 patients with postprocedure pain, resolved; 2 patients (6%) went on to spine surgery
							Mean NPS change score: 3.3 at 6 y (significant at 3 mo, 3, 4, 5, and 6 y)
6. 2017, Kumar, South Korea23	Case series, IV, prospective	Autologous	Cx AD-MSCs (with HA)	10	Intradiscal injection, 2 mL per disc mixed with HA derivative	12 mo	VAS and ODI measured. VAS mean improvement of 3.6 at 12 mo (significant). ODI mean improvement 26 at 12 mo (significant). Six patients of 10 met clinical criteria for >50% improvement in each category	0
7. 2017, Pettine, USA12,24,25	Case series, IV, prospective	Autologous	BMC	26	Intradiscal injection, 2–3 mL BMC with contrast	36 mo (6 lost to sx by 36 mo)	ODI average improvement from baseline 56.7 to 17.5. Average VAS improvement from baseline 82 to 21.9 at 36 mo (for patients not lost to sx), significantly better outcomes again noted in patients who received BMC with >2000 CFUs (assessed from 10 days of in vitro culture from 1 mL BMC per patient and only reached significance at 3 mo)	0, self-limiting postprocedural pain (48 h at harvest site, 7 d intradiscal site). Six patients went on to surgery
8. 2017, Comella, USA21	Case series, IV, prospective	Autologous	SVF + PRP	15	Intradiscal injection with 1–3 mL volume mixed with PRP	6 mo (safety to 12 mo)	Statistically significant decrease in VAS from 5.6 to 3.6	0, self-limiting postprocedural pain in a few patients
9. 2020, Wollf, USA27	Case series, IV	Autologous	BMC	33	Intradiscal injection of 3 mL or less of BMC	12 mo	Non-statistically significant improvements in pain and function over 6 mo. Patients with more severe baseline pain trended towards greater improvement
Total patients  treated				136
Total SAEs								None reported
PRP
1. 2016, Tuakli-Wosornu, USA11	DBRCT, I, prospective	Autologous	PRP	47 (29 initial treated, 44 with crossover)	Intradiscal injection, 1–2 mL contrast and 1–2 mL of PRP in treatment group	12 mo with crossover offered to control group at 8 wk	Statistically significant improvements in pain and function in treatment arm at 8 wk	0
							For PRP group at 1 y, statistically significant improvements in pain and function compared with baseline
2. 2016, Levi, USA30	Case series, IV, prospective	Autologous	LR-PRP	22	Intradiscal injection with 1 mL contrast with gentamicin (5 mg/mL), 0.5 mL lidocaine, 1.5 mL PRP	6 mo	47% success rate at 6 mo, as measured by 50% improvement in VAS and 30% improvement in ODI	0 (1 patient with pain exacerbation 1 mo after)
3. 2016, Kirchner, Spain31	Case series, IV, retrospective	Autologous	Activated PRGF	86	4-mL intradiscal injection PRGF activated with calcium chloride, 2 mL peridural, 0.5 mL facets	6 mo	91% of patients with excellent pain reduction score at 6 mo, decrease in VAS of average 8.4 baseline to 0.8 at 6 mo with statistical significance	0
4. 2017, Akeda, Japan32	Case series, IV, prospective	Autologous	PRP releasate	14	Intradiscal injection, 2 mL PRP releasate only per level	12 mo (average 10 mo)	Significant improvement in VAS and RDQ scores at 12 mo (VAS average decrease of 4.6 points, RDQ average decrease 9.8 points, P < 0.01)	0
5. 2017, Lutz, USA29	Case report, IV, retrospective	Autologous	20× PRP	1	Intradiscal injection, 1.5 mL of PRP per level after contrast	12 mo	Increased T2 signal in treated discs upon follow-up MRI with subjective concordant decrease in pain and increase in functional activities	0
6. 2015, Navani, USA33	Case series, IV, retrospective	Autologous	PRP	6	Intradiscal injection of 2 mL PRP alone	24 wk	50% decrease in pain and improvement in function starting at 6 mo and beyond	0
7. 2019, Beatty, USA28	Case report, IV, retrospective	Autologous	LP-PRP	1	Intradiscal injection 2.5 mL PRP	12 mo	Resolution of infection with antibiotics, no need for surgical intervention	1, infection
8. 2019, Cheng, USA34	Case series, IV, retrospective	Autologous	PRP	29 (treatment arm of 2016, Tuakli-Wosornu paper)	Intradiscal injection, 1–2 mL contrast and 1–2 mL of PRP in treatment group	5–9 y	Persistent statistically significant improvements in pain and function compared with baseline	0 (but 6 patients went on to surgery during follow-up period)
9. 2020, Jain, India35	Case series, IV	Autologous	2.7× LR-PRP	20	Intradiscal injection 1–2mL PRP only activated with calcium chloride	6 mo	Mean decrease NRS of 2.75 and ODI of 17.1 points at 6 mo. Higher PLT concentration correlated with larger improvement	0
Total patients  treated				194
Total SAEs, n  (%)								1 (0.52)

Abbreviations: AD-MSC, adipose-derived mesenchymal stem cell; BD-MSC, bone marrow-derived mesenchymal stem cells; BM, bone marrow; BMA, bone marrow aspirate; BMC, bone marrow concentrate; BMSC, bone-marrow dericed mesenchymal stem cells; CFU, colony forming unit; Cx, cultured; DBRCT, double-blind randomized controlled trial; FRI, functional rating index; HA, hyaluronic acid; HNP, herniated nucleus pulposis; ID, intradiscal; LP, leukocyte poor; LR, leukocyte rich; MRI, magnetic resonance imaging; MSC, mesenchymal signaling cell; NPS, numeric pain scale; ODI, Owestry disability index; NRS, numeric rating scale; PL, platelet lysate; PLT, platelet; PRGF, platelet-rich growth factors; PRP, platelet-rich plasma; RDQ, Roland-Morris Disability Questionnaire; SAE, serious adverse event; SVF, stromal vascular fraction; sx, symptoms; VAS, Visual analog scale.