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. 2021 Nov 27;24:101713. doi: 10.1016/j.jcot.2021.101713

Cell therapy for osteonecrosis of femoral head and joint preservation

You Seung Chun a, Dong Hwan Lee a,∗, Tae Gu Won a, Chan Sik Kim a, Asode Ananthram Shetty b, Seok Jung Kim a
PMCID: PMC8646149  PMID: 34926146

Abstract

Osteonecrosis of femoral head (ONFH) is a disease of the femoral head and can cause femoral head collapse and arthritis. This can lead to pain and gait disorders. ONFH has various risk factors, it is often progressive, and if untreated results in secondary osteo-arthritis. Biological therapy makes use of bone marrow concentrate, cultured osteoblast and mesenchymal stem cell (MSC) obtained from various sources. These are often used in conjunction with core decompression surgery. In this review article, we discuss the current status of cell therapy and its limitations. We also present the future development of biological approach to treat ONFH.

Keywords: Osteonecrosis, Femoral head, Cell therapy, Stem cell, Core decompression, Pathogenesis

1. Introduction

Osteonecrosis of femoral head (ONFH) is a disease that often causes femoral head collapse and arthritis, which are accompanied by pain and the resulting gait disorder. ONFH is often progressive and there are various risk factors of ONFH.1,2 The main causes of ONFH identified so far include corticosteroid use and alcohol abuse, and there are other causes, such as hematologic diseases and trauma.1 As the pathophysiology is not clearly identified due to its multiple etiology, there are difficulties in treating ONFH. Currently, total hip arthroplasty (THA) is one of the most popular treatment options, and lot of patients of ONFH patients receive THA.3 Because ONFH often occurs in younger and middle-aged adults, the THA treatment clearly has some limitations. Of course, the THA implants have been gradually improved to have prolonged survivorship and advanced functions and thus its use has gradually increased.4, 5, 6, 7, 8 However, artificial joints are basically not the natural joints of patients and can have functional limitations, cause discomfort and complications after surgery. In the case of the ONFH in younger age adults, THA has a serious drawback. No matter how longer the survivorship of the implants gets, a revision of THA becomes most likely. As a result, studies have long been conducted to develop various treatments that would allow the retainment of natural joints for ONFH patients. Patients in the pre-collapse stage need a regenerative treatment option that can prevent the progression of ONFH. Regarding this, various treatment methods ranging from conservative care to surgical treatments have been studied.9,10 But there are no established treatments and more effective treatment options need to be developed.11

Core decompression is the most common surgery performed on patients in the pre-collapse stage.9 Core decompression was first described by Ficat and Alert,12 and its effectiveness was proved to some extent by a lot of studies afterwards.1,13 The basic concept of core decompression is to reduce the increased intra-medullary pressure and re-establish the blood flow, thus preventing the progression of the disease and inducing regeneration. For core decompression, a bone graft is performed or various biologic and synthetic products, such as DBM, tantalum rods, are used to induce new bone formation and vessel ingrowth in decompressed channels.14 Beginning in the 2000s, a growing attention is paid to stem cell therapy in various medical fields including orthopedics.15,16 The treatment of ONFH also adopted cell therapy that uses bone marrow concentrate, cultured osteoblast and mesenchymal stem cell (MSC) obtained from various sources and began to apply them to channels after core decompression surgery. In addition, various scaffolds are used and studies are conducted on arterial infusion in addition to the direct application to channels.17,18 As attention is paid to ONFH treatment that uses MSC, we intend to present our views about the current stutus of cell therapy and the limitations of stem cell therapy and the future development of treatment of ONFH.

1.1. Pathogenesis of ONFH & MSC

Various causes have been identified in the progression, and the pathogenesis of ONFH. However the exact pathogenesis has not been clearly identified. Several previous studies found that the basic mechanism is the avascular necrosis caused by circulatory disruption and thus ONFH is also called avascular necrosis (AVN). The most common causes include corticosteroid use, alcohol abuse and trauma, and there are various other causes, such as sickle cell disease, coagulopathy, radiation, and anti-retroviral therapy.1,19 Numerous studies have been conducted to elucidate the pathogenesis. Based on what has been found, it can be said that several factors interact. There occur fat enlargement and osteocyte fatty deposition in relation to lipid metabolism, and these lead to an increase in intra-medullary pressure.20 In addition, there occur the formation of fat emboli, intra-vascular damage, and thrombi formation and decreased angiogenesis.21 Circulatory disruption occurs in that process, and coagulation fibrinolysis occurs due to steroid use, causing bone necrosis. In this process, an inflammatory response occurs and molecular signaling pathways mediated by several cytokines are activated. This induces cell apoptosis and decreases angiogenesis.22,23 In addition, the number of MSCs decreases and osteogenic differentiation potential decreases in these hypoxic, necrotic, and inflammatory environments. This means that new bone formation is inhibited.24, 25, 26, 27 We think that individual factors of pathogenesis may interact with one other (Fig. 1).

Fig. 1.

Fig. 1

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Schematic pathogenesis of ONFH.

From the pathogenesis showing that a decreased number of MSCs, inhibited osteogenic differentiation potential and reduced angiogenesis act as factors of ONFH, it can be seen that MSC is an important factor in the occurrence of ONFH. This is the basis for treatment using MSC. In particular, such a treatment is highly valued as a regenerative treatment option because MSC can differentiate into osteoblasts to form new bones and into endothelial cells to cause angiogenesis.28 Treatment using MSC is used and studied more actively in other medical fields than in ONFH treatment. A lot of studies are being conducted in the treatment of the articular cartilage of knee joints, and recently, attention is paid to the paracrine effect of MSC injection.29,30## In the pathogenesis of ONFH, inflammatory response acts as an important factor. Therefore, it is expected that the paracrine effect of MSC will also exhibit a therapeutic effect.

Several studies have shown that MSC proliferation and differentiation potential increase in hypoxic conditions.31 In particular, those studies proved an increase in osteogenic differentiation potential, and some studies have shown that the same results can be obtained using adipose-derived stem cells.32, 33, 34 ONFH is a disease associated with a hypoxic condition resulting from circulatory disruption, and naturally, the hypoxic condition persists even after decompression surgery. Therefore, it can be expected that treatment using MSC will be effective. However, when the blood supply of ONFH is reduced, the survival rate of implanted cells can be low. Consequently, it is necessary to track the fate of implanted stem cells. In relation to this, there is a study that tracked the survival, proliferation, and osteoblast differentiation of MSC in an ONFH animal model using GFP-labeled MSC.35 Numerous clinical studies need to be performed to track the fate of implanted cells by using cell tracking and other methods like that study.

1.2. ONFH treatment with stem cell therapy

Stem cell therapy for ONFH began around 2000 and is gradually increasing to have various methods.36 But stem cell therapy is not very active in ONFH compared to other medical fields. This is partly attributable to the quality improvement of THA implants.37 In addition, the number of ONFH patients is not large and stem cell therapy can be applied to only those in the early stage of ONFH. For these reasons, the number of performed stem cell therapy is small. However, studies on stem cells are actively performed and significantly progressed compare to the 2000s. So, applying stem cells to ONFH treatment will improve a therapeutic effect. Currently, there is no clear guide on stem cell therapy, and the following sets out information on stem cell therapy in some aspects.

1.3. Stem cell selection & application

Stem cell therapy is used in various forms for ONFH treatment. Types of MSCs used for ONFH treatment include bone marrow-derived MSC (BMSC), adipose-derived MSC (AMSC), allogeneic human umbilical cord-derived MSC (UCMSC), and peripheral blood MSC (PMSC). Among them, BMSC is the most commonly used. BMSC is often used in the form of BMAC. Bone marrow aspirates (BMA) can be used in the original form are or used in a staged procedure by using cultured osteoblast. We also used BMSC in the form of BMAC for ONFH treatment and effectively delayed the progression of the disease as a result of a 5-years follow-up(Fig. 2). Hauzeur et al. reported in a paper that no clinical.

Fig. 2.

Fig. 2

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Case of BMSC treatment for ONFH.

(a) Preoperative AP radiograph shows sclerosis and small cystic changes in left femoral head. (b) Preoperative MRI shows osteonecrosis in left femoral head. (c) Postoperative AP radiograph. BMAC procedure was performed after core decompression, and allograft impaction was also performed. (d) 5years follow up radiograph shows slight flattening and arthritic changes in left femoral head. But, in the patient, disease progression was slow and pain was tolerable, so THA surgery could be avoided.

difference was found in the effects between BMAC and cultured osteoblast.38 A recent paper on the ONFH treatment using cultured osteoblast reported a 71.1% improvement of the disease condition in Stages I and II and a 58% improvement in Stages III and IV.39 As both studies used subjective indexes and a small number of subjects, further studies need to be conducted to compare the effects of BMAC and cultured osteoblast.

AMSC is a stem cell extracted from adipose tissues, and the use of AMSC is increasing because it is easy to obtain and less invasive.40 AMSC has similar osteogenic potential to BMSC and has been proven to cause osteogenesis and angiogenesis in ONFH treatment using an animal model.41,42 The use in the form of adipose-derived stromal vascular fraction (ADSVF) is also being tried and shown to be effective.43 Recently, a clinical study using culture expanded autologous AMSCs has been published. As a result of 2-years follow up, there was no radiological difference in ONFH lesion size. But, there was no complication occurred, and 82% hips did not need THA.44 However, more clinical studies need to be conducted before using AMSC or ADSVF for ONFH treatment, and more comparative studies need to be conducted to prove the therapeutic effect of AMSC in ONFH treatment in comparison with BMSC. PMSC has the advantage of being easy to obtain and less invasive, but more studies need to be conducted before it is used, like AMSCs.

Treatment using UCMSC has several clear advantages. It is non-invasive and has no ethical problem, and MSC itself is of good quality because MSC is not obtained from patients with the disease. UCMSC has low-immunogenecity and safety, so there is no problem when applying it. In addition, when we applied UCMSC to treatment, one-stage application for all is possible. Currently, numerous studies on treatment using UCMSC are underway in medical fields and some of them have been conducted for ONFH treatment.45,46 Cai et al. performed co-transplantation of UCMSC and BMSCs and clinically demonstrated its therapeutic effect.47 Chen et al. performed intra-arterial infusion of UCMSC and found that it is an effective treatment for ONFH.48 UCMSC is a stem cell with clear advantages, and we think that it will occupy a large proportion in stem cell therapy after numerous studies are conducted.

A meta-analysis of ONFH, in 13 RCTs 619patients (855 hips) published,49 show clear evidence in support of stem cell therapy to slow down the femoral head collapse and total hip replacement. Ideal age is found to be less than 40 years and optimal cell count of 108 for this treatment. In most European countries concentrated (minimally manipulated) cells, does not require regulatory authority approval, however cultured cells come under Human Tissue Authority (HTA) purview, as it is considered as advanced therapy medicinal product (ATMP).

Numerous studies are conducted about various scaffolds that are used in the topical application of MSC. In the beginning, auto/allo-bone graft as a carrier was used, and later, various synthetic scaffolds were developed and used.50,51 Various scaffolds have been used, such as DBM, tantalum rods, biphasic calcium phosphate (BCP), poly-lactide-co-glycolide (PLGA), trontium-doped calcium polyphosphate (SCPP), beta-tricalcium phosphate (b-TCP) etc.11,52,53 Recently, various technological developments were made, such the incorporation of 3D printing technology and the bony ingrowth induced through structural development such as porosity.54, 55, 56 This advancement in scaffolds makes the potential of stem cell therapy more positive.

1.4. Stem cell dose

The number of stem cells is one of the most important factors in stem cell therapy. Because there is a limit to the stem cell proliferation capacity and differentiation potential, and the occurrence of angiogenesis is somewhat constant. So, an appropriate number of stem cells should be transplanted to cause sufficient repair, that is, bone formation. The appropriate number has been established to some extent for current studies, and stem cells of 10^6–10^9 are transplanted in most studies, with the number 10^8 used the most. Most studies found effective results, but some of them did not.57,58 Lim, Kim, Lee & Kwon et al. conducted a retrospective comparative study on two groups: the multiple drilling + BMAC group and the CD + bone graft group. No significant difference was found between the two groups. The number of injected stem cells was 1.69∗10^7 (range, 0.1∗10^7–7.5∗10^7) in the study, and the small number of cells can be the reason. The authors of the paper also reported an increased therapeutic effect when more cells were transplanted.58 We think that a cell count needs to be adjusted according to the range by considering the volume of the necrotic area of ONFH rather than simply determining a cell count. Hernigou et al. suggested in a paper that 3∗10^8 stem cells be transplanted, considering the average range of a necrotic area and the proportion of cancellous bone.59 As in the above paper, the authors recommended setting a transplantation guide by calculating the necrotic area and a required cell count in each case. Of course, there is a safety issue, so further studies need to be conducted about the appropriate number of cells to be injected.

1.5. Pre-treatment/adjuvant treatment & genetic modification

A lot of studies are conducted on the pre-treatment and adjuvant treatment that can improve the proliferation and differentiation of MSC. Several studies have reported that the osteogenesis or angiogenesis of MSC increased when cytokines, such as BMP, VEGF, bFGF, and TNF, were pretreated.60 In addition to cytokine pretreatment, many studies are conducted to increase the osteoblast differentiation potential of MSC by applying small molecules along with MSC, or to increase the therapeutic effect by modulating the inflammatory response through applying small molecules.61, 62, 63 A lot of studies are also conducted to increase the therapeutic effect of MSC through gene modification.64 Some studies have reported that the transfection of VEGF-165/BMP-2 gene, BMP-2/bFGF gene increased osteogenic differentiation of BMSC and improved the treatment effect.65,66 In addition to improving MSC through modification, a lot of studies have been conducted on cell free treatment using MSC derived exosomes, and they proved its effectiveness.67, 68, 69

2. Conclusion

Since the 2000s when the research on MSC began to be actively conducted, numerous studies have been conducted and considerable developments have been made in various fields related to MSC. Because the onset of ONFH occurs mainly in young and middle-aged adults, a treatment option to prevent the progression of the disease and save natural joints must be available to patients in the pre-collapse stage. Still, there are no clearly established treatments in stem cell therapy, there are a lot of studies that prove the effect, but it is difficult to say that the effect has been clearly identified. The cell application method and amount have not been determined for applying stem cells to ONFH treatment. However, numerous studies are conducted to improve the osteogenic differentiation, proliferation and angiogenic effect of MSC and therefore, it is highly likely that progress will be made in the ONFH treatment using stem cells. If we approach the biological treatment of ONFH treatment with cell therapy, we can think of a curative treatment option for ONFH, which has been currently considered a difficult problem to solve. Stem cell therapy potentially can offer a curative treatment to this condition in the future.

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