Stem cell therapy for osteonecrosis of femoral head: Opportunities and challenges

Abstract

Osteonecrosis of the femoral head (ONFH) is a progressive disease with a complex etiology and unclear pathogenesis, resulting in severe hip pain and dysfunction mainly observed in young patients. Although total hip arthroplasty (THA) is the most effective treatment for patients with ONFH in the terminal stage, the results of THA in young patients or active populations are often not favorable, with some complications related to the prosthesis. With the development of biotechnology, an increasing number of studies pay attention to use of stem cells for the treatment of ONFH. Stem cells are characterized by the ability to self-renew and differentiate into multiple cell types, including differentiation into osteoblasts and endothelial cells to mediate bone repair and angiogenesis. Furthermore, stem cells can offer growth factors to promote blood supply in the necrotic regions by paracrine effects. Therefore, stem cell therapy has become one of the hip-preserving alternatives for ONFH. This review summarized the current trends in stem cell therapy for ONFH, from clinical applications to related basic research, and showed that an increasing number of studies have confirmed the effectiveness of stem cell therapy in ONFH. However, many unsolved problems and challenges in practical applications of stem cell therapy still exist, such as patient selection, standardized procedures, safety assessment, and the fate of transplanted cells in the body. Additional studies are required to find ideal cell sources, appropriate transplantation methods, and the optimal number of cells for transplantation.

Keywords: ALP, alkaline phosphatase; AMSCs, adipose-derived MSCs; BCP, biphasic calcium phosphate; BMC, bone marrow concentrate; BMMNCs, bone marrow mononuclear cells; BMP-2, bone morphogenetic protein-2; BMSCs, bone marrow-derived mesenchymal stem cells; CD, Core decompression; CPC, calcium phosphate; CSS, cap-shaped separation; Cell implantation; Cell therapy; DBM, demineralized bone matrix; Femoral head; HHS, Harris hip score; IP-CHA, interconnected porous calcium hydroxyapatite; MRI, magnetic resonance imaging; MSCs, Mesenchymal stem cells; MVD, microvessel density; ONFH, Osteonecrosis of the femoral head; Osteonecrosis; PBMSCs, peripheral blood-derived MSCs; PLGA, poly lactide-co-glycolide; RCT, randomized controlled trial; SCPP, strontium-doped calcium polyphosphate; SVF, stromal vascular fractions; Stem cells; THA, total hip arthroplasty; TMCs, transformed mesenchymal cells; TNF, tumor necrosis factor; Tissue engineering; UCMSCs, umbilical cord-derived mesenchymal stem cells; VAS, visual analogue scale; VEGF, vascular endothelial growth factor; WOMAC, Western Ontario and McMaster Universities Arthritis Index; XACB, xenogeneic antigen-extracted cancellous bone; bFGF, basic fibroblast growth factor; β-TCP, beta-tricalcium phosphate.

Fig. 1

Etiology and mechanisms of ONFH. Figure is from Ref. [13]. ONFH: osteonecrosis of the femoral head.

Fig. 2

The main source of stem cells for transplantation. ONFH: osteonecrosis of the femoral head. BMSCs: bone marrow-derived mesenchymal stem cells; AMSCs: adipose-derived mesenchymal stem cells; PBMSCs: peripheral blood-derived mesenchymal stem cells; UCMSCs: umbilical cord-derived mesenchymal stem cells.

Fig. 3

Combination of core decompression and bone marrow buffy coat for the treatment of ONFH. (A) The X-ray showed that core decompression was performed by the Kirschner wire and 10-mm diameter trephine in the operation; (B) The long cylindrical bone obtained by core decompression was implanted into the bone tunnel after mixing with bone marrow. Figure is from Ref. [47]. ONFH: osteonecrosis of the femoral head.

Fig. 4

Combination of arterial perfusion of PBMSCs and porous tantalum rod for the treatment of ONFH (36 months after operation). (A) Without vascular regeneration was observed in the control group, and the box showed the collapsed femoral head; (B) Vascular regeneration around the femoral head was found in the combination treatment group, and the box showed the intact and round femoral head. Figure is from Ref. [37]. PBMSCs: peripheral blood-derived mesenchymal stem cells; ONFH: osteonecrosis of the femoral head.

Fig. 5

Combination of transplantation of autologous MSCs cultured with β-TCP ceramics and a free vascularized fibula for the treatment of ONFH. (A) A large necrotic area of femoral head was found in the preoperative X-ray. (B) Although the sclerosis area and osteophytes were found in the latest X-ray, the patient did not feel uncomfortable. Figure is from Ref. [58]. MSCs: mesenchymal stem cells; β-TCP: beta-tricalcium phosphate; ONFH: osteonecrosis of the femoral head.

Fig. 6

Controlled release of rhFGF-2 for the treatment of ONFH. (a) Pre-operative planning. (b) Preparation of rhFGF-2-impregnated gelatin hydrogel. (c) Pieces of the rhFGF-2-impregnated gelatin hydrogel. (d) Intra-operative fluoroscopic image after drilling. (e) Percutaneous administration of the gelatin hydrogel. Figure is from Ref. [78]. rhFGF-2: recombinant human fibroblast growth factor-2; ONFH: osteonecrosis of the femoral head.