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Table 1 Details of landmark study and clinical studies with high levels of evidence*

From: Stem cell therapy for treating osteonecrosis of the femoral head: From clinical applications to related basic research

Type of study Author Journal Publication Date Technique Sample Size Age (years) Staging Etiology Processing of MSCs Number of Cells Complications Follow-up Conclusions
Level IV (Landmark study) Hernigou et al. [8] Clin Orthop Relat Res 2002 CD + BMC implantation A total of 116 patients (189 hips) 31 (16 to 61) SteiInberg I: 59; SteiInberg II: 86; SteiInberg III: 12; SteiInberg IV: 32 Steroid: 31; Alcohol: 56; Idiopathic: 10; SCD: 64; Organ transplantation: 21; Others: 7 150-mL bone marrow aspirate to a concentrated myeloid sus- pension of approximately 30 mL of stem cells The average total number of colony-forming units injected by hip was estimated to be 25 × 103 cells. No specific complication. 7 years (5 to 11 years) Higher risk of failure for patients with corticosteroid treatment and stage III-IV. Correlation between the greater number of progenitor cells and smaller lesions with better outcomes.
Level I Pepke et al. [18] Orthopedic Reviews 2016 Control group: CD alone Treatment group: CD + BMC implantation Control group: 14 hips; Treatment group: 11 hips Control group: 44.5 ± 3.3; Treatment group: 44.3 ± 3.4 ARCO II 25 Chemotherapy: 2; Immunosuppressive therapy: 4 12 ml of bone marrow concentrate suspension was concentrated from 200 to 220 mL of marrow havesed from the iliac crest. 118.9 × 106 cells/ml (a total of 10 ml was injected). NR 24 months No significant benefit from the additional injection of BMC in the short term.
Level I Tabatabaee et al. [16] J Arthroplasty 2015 Control group: CD alone Treatment group: CD + concentrated bone marrow aspirates Control group: 14 hips; Treatment group: 14 hips Control group: 26.8 ± 5.8; Treatment group: 31 ± 11.4 ARCO I 5; ARCO II 16; ARCO III 7 Steroid: 19; Idiopathic: 9 Bone marrow concentrate suspension concentrated from approximately 200 mL of bone marrow aspirate. 2 million cells/ml (injected volume was not reported). No serious complications were noted in either of the clinical groups. 24 months BMC injection with CD could be an effective therapy for the early stages of AVN; score improvement.
Level I Mao et al. [15] J Bone Mine Res 2015 Control group: Porous tantalum rod implantation; Treatment group: Porous tantalum rod implantation + intra-arterial injection of peripheral blood MSCs Control group: 41 hips; Treatment group: 48 hips Control group: 36.12 ± 11.34; Treatment group: 34.60 ± 11.50 ARCO I 18; ARCO II 52; ARCO III 19 Steroid: 31; Alcohol: 32; Idiopathic: 26 Injections of G-CSF for 4 days to mobilize PBSCs, and then, a collection process was performed. Injected cells: 2.47 × 108 mononuclear cells, which contained 1.71 ± 0.7 × 106 CD34+ cells. No complication was observed. 36 months Combination treatment provides superior results regarding clinical outcomes such as pain, function, activity, and motion compared with biomechanical support alone.
Level I Ma et al. [14] Stem Cell Res Ther 2014 Control group: CD + autologous bone graft Treatment group: CD + autologous bone graft with BMC Control group: 24 hips; Treatment group: 25 hips Control group: 34.78 ± 11.48; Treatment group: 35.60 ± 8.05 Ficat I: 7; Ficat II: 32; Ficat III: 10 Steroid: 26; Alcohol: 7; Idiopathic: 12 Centrifuged and then loaded into the cylindrical bone. The average number of bone marrow cells loaded into the cylindrical bone was approximately 3 × 109 nucleated cells. No complication was observed. 24 months Implantation of the autologous BMC graft combined with CD is effective to prevent further AVN. The stage of AVN might affect the outcome, while etiological factors do not.
Level I Rastogi et al. [13] Musculoskelet Surg 2013 Control group: CD and unprocessed bone marrow injection Treatment group: CD + isolated mononuclear cells Control group: 30 hips; Treatment group: 30 hips Control group: 33.0 ± 7.71; Treatment group:34.67 ± 7.02 NR Steroid: 18; Alcohol: 8; Idiopathic: 26; Smoking: 8 Treatment group: 5 ml of isolated mononuclear cells (The entire procedure took 1 h). Control group: 30–50 ml of unprocessed bone marrow. Treatment group: 1.1 × 108 cells. Control group: not reported. No complications were noted in both group. 24 months Control and treatment group scores show significant differences when compared with preoperative scores, without statistically significant inter-group differences in clinical scores.
Level I Sen et al. [12] J Arthroplasty 2012 Control group: CD alone Treatment group: CD + autologous bone marrow mononuclear cell Control group: 25 hips; Treatment group: 26 hips NR ARCO I, II Steroid: 14; Alcohol: 6; Idiopathic: 1; Pregnancy: 1; Cushing disease: 1; Trauma: 17 2 ml of mononuclear cells was havested from 120 to 180 ml of bone marrow aspirates in appromixmately 2 h. Injected cells: 5 × 108 mononuclear cell to keep to keep the CD34 + cell count more than 5 × 107 . No complications were observed. 24 months BMC instillation can result in better clinical outcomes and hip survival, with only 1 THR in the treatment group vs 6 in the control group. Better outcomes in traumatic AVN than in non-traumatic AVN.
Level I Zhao et al. [11] Bone 2012 Control group: CD alone Treatment group: CD with cultured bone-marrow derived MSCs Control group: 44 hips; Treatment group: 53 hips Control group: 33.8 ± 7.7; Treatment group: 32.7 ± 10.5 ARCO IC 5; ARCO IIA 30; ARCO IIB 46; ARCO IIC 23 Steroid: 24; Alcohol: 19; Idiopathic: 30; Trauma: 20; Caisson disease: 11 10 mL of subtrochanteric bone marrow was aspirated and allowed to proliferate in vitro for two weeks. Implanted cells: 2 × 106 cells. No complications were observed. 60 months Ex vivo expansion of bone marrow-derived MSCs and implantation provide significant improvements in pain and other joint symptoms and delay or avoid the progression of osteonecrosis and THA.
Level I Gangji et al. [10] Bone 2011 Control group: CD alone Treatment group: CD + BMC implantation Control group: 11 hips; Treatment group: 13 hips Control group: 45.7 ± 2.8; Treatment group: 42.2 ± 2.6 ARCO I 4; ARCO II 20 Steroid: 20; Alcohol: 2; Idiopathic: 2 Concentrated to a final volume of 49.7 ± 2.3 ml. Contained 1.9 ± 0.2 × 109 mononuclear cells, including 1.0 ± 0.1% of CD34+ cells. No complications were observed. 60 months BMC implantation in the necrotic lesion provides better results in early osteronecrosis and delays its progression. Reduced pain and decreased volume of the necrotic lesion.
Level II Houdek et al. [23] Clin Orthop Relat Res 2018 A consecutive cohort, CD + BMC + PRP A total of 22 patients (35 hips) 43 (22 to 66) Pennsylvania Stage 1 or Stage 2 Steroid 60 to 120 cc of bone marrow was concentrated to 6 to12 cc of BMC 2.5 × 106 to 6.8 × 107 cells. NR 3 years (2 to 4 years) Successful results were seen when the nucleated cell count was high and the modified Kerboul grade was low.
Level II Pilge et al. [49] Ortho Rev. 2016 Control group: CD + iloprost iv. Treatment group: CD + iloprost iv. + BMC implantation Control group: 10 hips; Treatment group: 10 hips 38.35 (15 to 58) ARCO II: 12; ARCO III: 6; ARCO IV: 2 Steroid: 5; Chemotherapy: 6; Idiopathic: 8; Smoke: 1 60 ml of bone marrow aspirate was concentrated. Between 7 and 10 mL. No serious adverse reaction to iloprost infusion. Patients had flush symptoms and 2 patients complained of a mild headache during infusion. 30.6 (4–69) months An improvement in clinical scores was shown in the treatment group but not in the control group.
Level II Gangji et al. [17] J Bone Joint Surg Am 2004 Control group: CD alone Treatment group: CD + BMC implantation Control group: 8 hips; Treatment group: 10 hips Control group: 48.8 ± 11.2; Treatment group: 40.9 ± 9.8 ARCO I: 2; ARCO II: 16 Steroid: 14; Alcohol: 2; Idiopathic: 2 Approximately 400 mL of marrow was obtained from the anterior iliac crest and concentrated to a mean final volume of 51 ± 1.8 mL. 2.0 ± 0.3×  109, including 1.0% ± 0.2% CD34+ cells. No major side effects was observed. Two patients complained of pain at the site of the bone-marrow aspiration; coagulase- negative staphylococc was cultured form the bone marrow in one patient; A hematoma was observed at the site of the CD in another patient 24 months CD + BMC provides significant decreases in the level of pain and other joint symptoms. The volume of necrotic lesions significantly improved only in the treatment group.
  1. *High levels of evidence refers to Levels I and II; AVN, avascular necrosis of the femoral head; CD, core decompression; MSC, mesenchymal stem cell; BMC, bone marrow concentrate; ARCO, Association Research Circulation Osseous; SCD, sickle cell disease; G-CSF, granulocyte-colony stimulating factor; THA, total hip arthroplasty; NR, not reported