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Stem cell therapy for treating osteonecrosis of the femoral head: From clinical applications to related basic research
© The Author(s). 2018
- Published: 25 October 2018
Osteonecrosis of the femoral head (ONFH) is a refractory disease that is associated with collapse of the femoral head, with a risk of hip arthroplasty in younger populations. Thus, there has been an increased focus on early interventions for ONFH that aim to preserve the native articulation. Stem cell therapy is a promising treatment, and an increasing number of recent studies have focused on this topic. Many clinical studies have reported positive outcomes of stem cell therapy for the treatment of ONFH. To improve the therapeutic effects of this approach, many related basic research studies have also been performed. However, some issues must be further explored, such as the appropriate patient selection procedure, the optimal stem cell selection protocol, the ideal injection number, and the safety of stem cell therapy. The purpose of this review is to summarize the available clinical studies and basic research related to stem cell therapy for ONFH.
- Cell therapy
- Mesenchymal stem cells
Osteonecrosis of the femoral head (ONFH) is a refractory disease that is characterized by compromised subchondral microcirculation, necrosis of the bone, and microfracture accumulation without sustained remodeling [1, 2]. ONFH is a global problem, and an estimated 20,000 to 30,000 new patients are diagnosed with osteonecrosis annually in the United States ; in addition, 8.12 million cases of nontraumatic ONFH are diagnosed annually among the Chinese general population aged 15 years and older .
Although total hip arthroplasty (THA) can provide satisfactory clinical outcomes for hip dysfunction patients, one challenge for surgeons is that ONFH occurs predominantly in patients aged 30 to 40 years. The outcomes of THA for these young and active patients are not ideal, primarily due to the limited lifetime and durability of the prosthesis. Thus, there has been an increasing focus on early interventions for ONFH that aim to preserve the native articulation. A wide variety of joint-preserving methods have been reported, including pharmacologic or physical treatment and surgical techniques ranging from core decompression (CD) to various vascularized and nonvascularized bone-grafting procedures . However, the outcomes of these studies have varied. Thus, studies that aim to identify a better treatment are ongoing.
Stem cells are a group of cells with the ability to self-renew and form differentiated cells. These cells play important roles in development and disease. They are also important “seed” cells in the process of regenerative therapy. Stem cell research is currently focused mainly on adult stem cells, embryonic stem cells and induced pluripotent stem cells. Adult stem cells, which include mesenchymal stem cells (MSCs), have been reported as a promising approach for the regeneration of various tissues. MSCs were first described in human bone marrow and called bone marrow stem cells (BMSCs); these cells can be isolated from many other sources, including adipose tissue, the synovial membrane and the umbilical cord, in addition to the bone marrow [6, 7]. Since the injection of autologous MSCs combined with standard CD for treating ONFH was first described in 1993 and the first mid-term results were reported in 2002 , there has been an increased focus on this approach ; with the development of both the technology and the concept, stem cell therapy has been shown to be a promising approach for treating ONFH.
The aim of this paper is to present a review of current clinical and basic research related to stem cell therapy for treating ONFH.
Details of landmark study and clinical studies with high levels of evidence*
Type of study
Processing of MSCs
Number of Cells
Level IV (Landmark study)
Hernigou et al. 
Clin Orthop Relat Res
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.
Pepke et al. 
CD + BMC implantation
44.5 ± 3.3;
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).
No significant benefit from the additional injection of BMC in the short term.
Tabatabaee et al. 
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.
BMC injection with CD could be an effective therapy for the early stages of AVN; score improvement.
Mao et al. 
J Bone Mine Res
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.
Combination treatment provides superior results regarding clinical outcomes such as pain, function, activity, and motion compared with biomechanical support alone.
Ma et al. 
Stem Cell Res Ther
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.
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.
Rastogi et al. 
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
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.
Control and treatment group scores show significant differences when compared with preoperative scores, without statistically significant inter-group differences in clinical scores.
Sen et al. 
Control group: CD alone
Treatment group: CD + autologous bone marrow mononuclear cell
Control group: 25 hips;
Treatment group: 26 hips
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.
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.
Zhao et al. 
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.
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.
Gangji et al. 
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.
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.
Houdek et al. 
Clin Orthop Relat Res
A consecutive cohort, CD + BMC + PRP
A total of 22 patients (35 hips)
43 (22 to 66)
Pennsylvania Stage 1 or Stage 2
60 to 120 cc of bone marrow was concentrated to 6 to12 cc of BMC
2.5 × 106 to 6.8 × 107 cells.
3 years (2 to 4 years)
Successful results were seen when the nucleated cell count was high and the modified Kerboul grade was low.
Pilge et al. 
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.
Gangji et al. 
J Bone Joint Surg Am
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
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.
Thus, although some controversy exists, it seems that the general outcomes of the use of stem cells to treat ONFH are positive. The reasons for the different conclusions may be the heterogeneity among studies, including differences in patient selection, cell harvesting, cell processing, and cell delivery. Thus, these heterogeneities warrant further investigation.
Numerous studies confirmed that the outcome of treatment was ascociated with patient condition. The most important factor may be the stage of ONFH. Ma et al. reported that the stage of ONFH might affect the outcome of stem cell therapy . Hauzeur et al. reported that the implantation of bone marrow aspirate concentrate (BMAC) after CD did not produce any improvement in the evolution of stage III ONFH . Thus, stage III and stage IV cases may be prone to poor outcomes, and early-stage (stage I or II) patients should be a more appropriate choice. In addition, Sen et al.  reported that patients with posttraumatic osteonecrotic hips had better outcomes than did patients with nontraumatic hips, which suggested that etiology is another a factor that affects clinical outcomes. Furthermore, Houdek et al. suggested that patients with a low modified Kerboul grade may achieve better results . It seems that the stage, size, morphology and even etiology of ONFH may be important factors associated with the treatment outcome. Thus, to achieve better results, it is critical to select appropriate cases.
Moreover, it has been reported that aging is associated with decreases in the number of MSCs isolated from a donor and the proliferation ability of those cells [24, 25]. Stenderup et al.  found that although MSC function was decreased in cells isolated from older donors in vitro, this difference did not affect the ability of the cells to differentiate in vivo. The authors concluded that MSCs isolated from older donors maintained normal cellular function but showed a proliferative defect. In addition, Aksu et al.  found that sex may affect the differentiation potential of human adipose-derived stem cells. However, Sen et al.  reported that patient variables, such as sex differences, side of involvement, and opposite side involvement, had no effect on outcomes. Whether these factors influence the treatment efficiency in ONFH patients has not been well studied. Additional studies that are focused on subgroup analysis and the proper inclusion criteria for stem cell therapy in ONFH patients are needed in the future.
Various types of MSCs have been used to treat ONFH, including bone marrow-derived MSCs (BMMSCs), adipose-derived MSCs (ADMSCs), allogeneic human umbilical cord-derived MSCs (hUCMSCs) and peripheral blood MSCs (PBMSCs). Among the various kinds of MSCs derived from different tissues, BMMSCs are the most commonly used type. BMMSCs are used mostly as bone marrow concentrate (BMC) and are more rarely cultured or used simply as bone marrow aspirates . Rastogi et al.  compared isolated mononuclear cells with unprocessed bone marrow injections and found that there were considerable improvements in hip function, as measured by the Harris hip score, in both groups. There was a decrease in the lesion size in the processed isolated mononuclear cell group, and 3 of 30 hips in the unprocessed bone marrow injection group required total hip replacement. It seems that the more effective procedure had better outcomes than did unprocessed bone marrow injection for the treatment of ONFH.
In addition to BMMSCs, ADMSCs are another choice for cytotherapy in patients with ONFH. This method of acquiring MSCs is not only less expensive but also less invasive and painful than that used for bone marrow harvesting . An in vitro study demonstrated that adipose-derived MSCs may provide a more robust growth rate and bone differentiation potential than bone marrow-derived MSCs . As adipose-derived MSCs are more abundant and show a superior functional phenotype for this purpose, they may prove to be a more effective therapeutic approach. Although the results of these studies were promising, there is a lack of well-designed prospective in vivo clinical studies to further confirm this conclusion.
Moreover, it has been demonstrated that the osteogenesis and proliferation of MSCs are decreased in alcohol-induced and steroid-induced ONFH patients [30–33]. Therefore, the transfusion of autologous stem cells isolated from these patients may have different therapeutic effects. Thus, allogeneic stem cells derived from healthy humans may be an alternative for treating ONFH. Interestingly, there is evidence for the accumulation of low-immunogenicity MSCs, which allows the MSCs to be transplanted between human leukocyte antigen (HLA)-incompatible individuals . hUCMSCs may be a good candidate for this approach, because umbilical cord (UC) collection is easy and ethically feasible. The yield of UCMSCs is high, and the cells have low immunogenicity. UCMSCs are easy to separate and can be amplified in vitro; placental UCMSCs can typically be passaged for 30–40 generations, while adult BMMSCs can grow only 6–10 generations with the same performance.
Cai et al.  evaluated the cotransplantation of autologous BMMSCs and allogeneic UCMSCs for treating ONFH and observed therapeutic effects without severe adverse effects at 12 months after transplantation. Chen et al.  analyzed the clinical effects of transplanting allogeneic hUCMSCs for the treatment of ONFH and achieved clear results with no obvious side-effects after a three-year follow-up. However, there were only 30 cases and 9 cases in the studies of Cai et al. and Chen et al., respectively. Studies with larger numbers of patients and longer follow-up times are needed to further evaluate the efficiency and safety of the use of allogeneic hUCMSCs in treating ONFH.
Number of injected cells
The prevalence of connective tissue progenitors in the bone marrow in the iliac crests of patients was approximately one per 30,000 nucleated cells . Hernigou et al. reported that according to the mean nucleated cell count per ml (18 × 106 cells), the bone marrow harvested from the iliac crest by aspiration contained an average of approximately 600 progenitors per ml . If expansion is performed in vitro, more cells will be harvested.
It was reported that good outcomes may be associated with high nucleated cell counts [20, 23]. However, the optimum number of cells for injection remains unknown. The average volume repair was 15 cm3 in a series of osteonecrosis patients, as indicated by MRI observations and histologic observations that demonstrated that the proportion of trabecular bone was 1/3 in the femoral head, with the other 2/3 being fat and hematologic cells . Based on a mean bone matrix of 33% in cancellous bone, it was estimated that there are approximately 20 million osteoblasts or osteocytes per cm3 of new bone . Thus, approximately 3 × 108 (20 million cells/cm3 × 15 cm3) osteoblasts or osteocytes are needed for new bone repair. However, achieving an objective number of osteoblasts or osteocytes depends not only on the number of stem cells injected but also on how many times the stem cells can proliferate and how many cells can effectively differentiate into osteoblasts or osteocytes, especially in the ischemic and anoxic microenvironment of the necrotic area of the femoral head. On the other hand, whether the injection of more stem cells is better and whether there is a safe threshold for the maximum injection of stem cells remain unknown.
Based on current reported studies, except for patients injected with approximately 24 × 103 to 25 × 103 cells in early studies reported by Hernigou et al. [8, 40], the number of cell used in most other studies ranged from 106 to 109, and the most frequently used number was 108 cells [11–13, 18, 20]. Thus, based on current data, the injection of 106 to 109 cells may be reasonable. However, the optimal number still needs to be investigated.
Delivery techniques and combined treatment
Various techniques for cell delivery have been reported in recent studies, and such techniques were commonly combined with CD [10–12, 16, 18]. Other techniques included impaction allogeneic bone grafting [41, 42], autoiliac cancellous bone grafts [43, 44], porous tantalum rod implantation procedures , porous tantalum rod implantation combined with vascularized iliac grafting , interconnected porous calcium hydroxyapatite (IP-CHA)  and porous nanohydroxylapatite .
In addition to the topical application of MSCs in the necrotic zone of the femoral head, some studies also applied the MSCs through arterial injection. Cai et al. transplanted MSCs into the medial circumflex femoral artery, the lateral circumflex femoral artery or the obturator artery through digital subtraction angiography and observed a therapeutic effect on avascular necrosis of the femoral head (ANFH) without severe adverse effects . Mao et al. reported the intra-arterial infusion of PBMSCs and found that this approach could enhance the efficacy of biomechanical support during the treatment of ONFH . These two studies demonstrated that intra-artery infusion could be another effective way to treat ONFH. In addition, these studies also provided evidence that MSCs could effectively act on ischemic areas. However, determining whether the topical application or intra-arterial infusion of MSCs is more effective requires further investigation.
Some studies also combined local injection with platelet-rich plasma (PRP) , pharmacological treatments, such as intravenous iloprost  and oral bisphosphonates , or physical therapy, such as low-intensity pulsed ultrasound (LIPUS) . Most of these studies reported satisfactory outcomes, but some studies had lower levels of evidence; thus, whether such combinations support better outcomes must be further confirmed. Moreover, comparisons between various methods have rarely been reported.
Note that, in general, regardless of which delivery technique and combined treatment were used, all of the approaches yielded improved results.
One of the major concerns in cell therapy is safety. Stem cells have some features of cancer cells, including a long lifespan, relative apoptosis resistance, and the ability to replicate for extended periods of time. In addition, similar growth regulators and control mechanisms are involved in both cancer and stem cell maintenance. Therefore, stem cells may undergo malignant transformation, which is often seen as a key obstacle to the safe use of stem-cell-based medicinal products . It was reported that the transplantation of embryonic stem cells may increase the risk of teratoma formation . Other concerns, including immune rejection and genetic modification, also limit the clinical use of directly transplanted stem cells for ONFH.
After a review of current studies that used stem cells in the treatment of ONFH, we found that most studies reported that no severe complications were observed. Only a few studies reported that patients had complications, such as flushing, mild headache and fever [44, 49]. Thus, based on the current studies, it seems that the application of stem cells for the treatment of ONFH is relatively safe. However, additional studies and long-term follow-up are still needed to further confirm this conclusion.
In addition, for cell therapy, which requires cell expansion in vitro, the entire process must be supervised to ensure that the cells maintain their overall phenotype and functional potential and to ensure that the cultured cells remain untransformed with no microbiological contamination . Thus, standardization with respect to the quantitative and qualitative characterization of cellular therapies may need to be established in the future.
Extensive research activities over the last decade have explored the potential of MSCs and have shown promising results in both animal experiments and clinical applications. Although some controversy exists, it seems that the general outcomes of the use of stem cells to treat ONFH are positive in terms of not only efficiency, but also safety.
For clinical applications, the different conclusions may be due to the heterogeneity among studies. It seems that patients in ARCO I and ARCO II stages and patients with a low modified Kerboul grade are good candidates for this technique. BMMSCs were still the most commonly used cells, while other types of stem cells, such as ADMSCs, show a more promising prospect, with a robust growth rate and bone differentiation potential, and could be considered as an alternative to BMMSCs. In addition, it was reported that the good outcomes may be associated with high nucleated cell counts. Although the most proper number of cells for injection was not determined, based on the current available data, injection of 106 to 109 cells may be reasonable. Further clinical applications should be aware of the appropriate patient selection procedure, the optimal stem cell selection protocol and the ideal injection number to achieve better outcomes.
For the related basic research, inspiring advanced progress has been made. Preconditioning of MSCs and accurate selection of a subpopulation may enhance treatment efficiency for ONFH. Use of genetic engineering to modify MSCs, such as BMP-2 and VEGF, also constituted good attempts to use MSCs more efficiently. Recently, cell-free treatment has played an increasingly important role in regenerative therapy and may develop as an alternative to stem cell therapy. However, much work must be done before these experimental approaches can be applied in clinical practice, in terms of not only efficiency, but also safety. Standardization with respect to the quantitative and qualitative characterization of cellular therapies is urgently needed in the future.
This study was supported by the National Natural Science Foundation of China (81572148) for the writing, polishing and publication of the manuscript.
RL and QXL summarized the references and were major contributors in writing the manuscript. XZL, GBL, HT and YW searched and sorted the references and were involved in drafting the manuscript. SBL and JP made substantial contributions to the conception, design and critical revision of the manuscript. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.
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