New preclinical porcine model of femoral head osteonecrosis to test mesenchymal stromal cell efficiency in regenerative medicine

Poignard, Alexandre; Lebouvier, Angélique; Cavet, Madeleine; Rahmouni, Alain; Flouzat-Lachaniette, Charles-Henri; Bierling, Philippe; Rouard, Hélène; Hernigou, Philippe; Chevallier, Nathalie

doi:10.1007/s00264-014-2352-8

Cited by 15 publications

(13 citation statements)

References 26 publications

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“…However, nONFH is rare in pigs. To have a statistically relevant result of the effectiveness of BMSCs on this painful disease, it is necessary to test this approach on one of the models of ONFH which has been developed in either emu or pig and to conduct a study on a large number of animals [ 26 , 44 ]. As the effectiveness of BMSCs has been proven and we and others showed the safety of this approach, the second strategy could be to go directly to the clinic [ 6 , 7 , 13 , 14 , 18 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Pigs were managed in accordance with the instructions of the ethics committee. Access to FH was done in accordance with the previously described protocol by a percutaneous approach of the hip [ 26 ]. Pigs received an injection of 140 × 10 6 autologous pBMSCs (n = 1) or hBMSCs (n = 2) in 7 mL of 5% human serum albumin (Albunorm; Octapharma, Boulogne-Billancourt, France), and one pig served as a negative control.…”

Section: Methodsmentioning

confidence: 99%

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Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection

et al. 2015

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IntroductionOsteonecrosis of the femoral head (ONFH) is a degenerative disease progressing to a femoral head (FH) collapse. Injection of osteoprogenitor cells like bone marrow mesenchymal stromal cells (BMSCs) into the FH appears to be a good therapeutic treatment. However, safety and efficacy of BMSCs to treat bone defect are the main preclinical data required for clinical application. Efficacy and the lack of risk of cell transformation after amplification of BMSCs have been extensively described. The main objectives of this study were to develop a simple and usable procedure for clinicians and control its feasibility by evaluating the biodistribution of BMSCs after injection into the FH in a large animal model. The impact of this approach was evaluated on one natural pig ONFH.MethodsBMSCs were directly injected in the pig FH, and then the biodistribution of grafted cells was detected by quantitative real-time polymerase chain reaction, cytometry, or a combination of classic histology analysis and in situ hybridization (ISH). BMSC efficacy on bone regeneration was evaluated by magnetic resonance imaging (MRI) and histology.ResultsAfter 30-minute and 24-hour follow-up, grafted cells were detected at the injection site and no BMSCs were detected in filter organs or body fluids. The combination of classic histology analysis and ISH showed a good homogeneity of cell distribution in FH. Local delivery of BMSCs onto a bone scaffold associated with bone formation in vivo confirmed the preferential tropism of BMSCs to the bone tissue as well as their efficacy to form bone. Treatment of a natural pig ONFH by autologous BMSCs indicated a beginning of bone healing as early as 2 weeks with a complete healing after 9 weeks. At this stage, MRI and histological analysis were similar to those of a normal FH.ConclusionsIntra-osseous injection of BMSCs in FH seems to be a good strategy for ONFH treatment as the safety concerning the biodistribution of BMSCs is ensured. Moreover, the efficacy of BMSCs in natural ONFH seems to indicate that this is a promising approach. Altogether, these results constitute the preclinical data necessary for the setup of a clinical application with expanded BMSCs in the context of advanced therapy medicinal products.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection

et al. 2015

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“…Drescher et al [79] treated pigs with corticosteroids and observed contraction of femoral head lateral epiphyseal arteries in treated animals, but noted no evidence of ONFH in these pigs. In another report by Poignard et al [80], 18 female pigs were used to creat ONFH by cryo-injury, the authors noted localized and sustainable subchondral necrosis of the femoral head, reproducing all stages of the human disease. Moreover, the good correlation between histological and MRI results indicates that the pig is a relevant model for human ONFH.…”

Section: Other Animal Modelsmentioning

confidence: 95%

Animal models of steroid-induced osteonecrosis of the femoral head—a comprehensive research review up to 2018

Gong

et al. 2018

International Orthopaedics (SICOT)

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Osteonecrosis of the femoral head (ONFH) is a significant cause of both pain and disability that often affects young adults during what ought to be their most productive age. Two broad categories of ONFH exist: traumatic and non-traumatic. Traumatic ONFH results from acute mechanical disruption of the femoral head's blood supply. Many factors that increase the risk of non-traumatic osteonecrosis have been identified. Steroid-induced osteonecrosis of the femoral head (SONFH) is the most common form of non-traumatic ONFH. Many hypotheses as to the pathogenesis of SONFH have been proposed, including intravascular thrombosis, abnormal fat metabolism, intramedullary adipocyte hypertrophy, and osteoporosis; however, the exact mechanism of SONFH is still not clearly understood. Animal models using rats, mice, rabbits, chickens, pigs, and emus have been used to study SONFH. Unfortunately, these models each have limitations. Therefore, it is necessary to establish a reproducible model that better simulates human disease. The present review is intended to summarize the currently available models, evaluative indicators, and application of current understanding to both the prevention and treatment of SONFH.

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“…Non-cellular therapeutic strategies using growth factors have been proposed; however, there has been little progress with regard to the verification of animal experiments, primarily because of the absence of an animal model for femoral head-specific necrosis [9,16] and secondarily because of the lack of a technique to locally deliver the growth factor [17]. The angiogenic and osteogenic actions of rhFGF-2 have been the subject of numerous reports for bone and joint disease.…”

Section: Discussionmentioning

confidence: 99%

A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head

Kuroda

Asada

et al. 2015

International Orthopaedics (SICOT)

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Purpose We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH). Methods Patients with ONFH (precollapse stage ≤2) received a single local administration of 800 μg of rhFGF-2-impregnated gelatin hydrogel and were followed up for one year. The surgery was performed using a minimally invasive technique involving a 1-cm skin incision, and walking was allowed from day one postoperatively. The primary outcomes included occurrence of adverse events and complications. The secondary outcomes included changes in the Harris hip scores, visual analog scale for pain scores, University of California, Los Angeles (UCLA) activity scores, and radiological images. Results We included ten patients, of which five experienced 14 adverse events, including one complication from spinal anesthesia. However, patients completely recovered from all adverse events. The mean clinical scores significantly improved by one year postoperatively compared with the pre-operative scores (before vs. after: visual analog score for pain, 21.2 vs. 5.3 mm; UCLA activity score, 5.5 vs. 6.6; Harris hip score, 81.0 vs. 96.9 points). There was only one case of femoral head collapse; however, this occurred in a hip with extensive necrosis. Stage progression and collapse did not occur in the other nine cases. Computed tomography confirmed bone regeneration in the femoral heads. Conclusions Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse ONFH was feasible and safe.

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New preclinical porcine model of femoral head osteonecrosis to test mesenchymal stromal cell efficiency in regenerative medicine

Cited by 15 publications

References 26 publications

Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection

Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection

Animal models of steroid-induced osteonecrosis of the femoral head—a comprehensive research review up to 2018

A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head

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