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We investigated the impact of mesenchymal stem cell (MSC) therapy on treating bilateral human hip osteonecrosis, analyzing 908 cases. This study assesses factors such as tissue source and cell count, comparing core decompression with various cell therapies. This research emphasizes bone repair according to pre-treatment conditions and the specificities of cell therapy in osteonecrosis repair, indicating a potential for improved bone repair strategies in hips without femoral head collapse. This study utilized a single-center retrospective analysis to investigate the efficacy of cellular approaches in the bone repair of osteonecrosis. It examined the impact on bone repair of tissue source (autologous bone marrow concentrate, allogeneic expanded, autologous expanded), cell quantity (from none in core decompression alone to millions in cell therapy), and osteonecrosis stage and volume. Excluding hips with femoral head collapse, it focused on patients who had bilateral hip osteonecrosis, both pre-operative and post-operative MRIs, and a follow-up of over five years. The analysis divided these patients into seven groups based on match control treatment variations in bilateral hip osteonecrosis, primarily investigating the outcomes between core decompression, washing effect, and different tissue sources of MSCs. Younger patients (<30 years) demonstrated significantly better repair volumes, particularly in stage II lesions, than older counterparts. Additionally, bone repair volume increased with the number of implanted MSCs up to 1,000,000, beyond which no additional benefits were observed. No significant difference was observed in repair outcomes between different sources of MSCs (BMAC, allogenic, or expanded cells). The study also highlighted that a 'washing effect' was beneficial, particularly for larger-volume osteonecrosis when combined with core decompression. Partial bone repair was the more frequent event observed, while total bone repair of osteonecrosis was rare. The volume and stage of osteonecrosis, alongside the number of injected cells, significantly affected treatment outcomes. In summary, this study provides comprehensive insights into the effectiveness and variables influencing the use of mesenchymal stem cells in treating human hip osteonecrosis. It emphasizes the potential of cell therapy while acknowledging the complexity and variability of results based on factors such as age, cell count, and disease stage.

Purpose: There is an increasing number of reports on the treatment of knee osteoarthritis (OA) using mesenchymal stem cells (MSCs). However, it is not known what would better drive osteoarthritis stabilization to postpone total knee arthroplasty (TKA): targeting the synovial fluid by injection or targeting on the subchondral bone with MSCs implantation., Methods: A prospective randomized controlled clinical trial was carried out between 2000 and 2005 in 120 knees of 60 patients with painful bilateral knee osteoarthritis with a similar osteoarthritis grade. During the same anaesthesia, a bone marrow concentrate of 40 mL containing an average 5727 MSCs/mL (range 2740 to 7540) was divided in two equal parts: after randomization, one part (20 mL) was delivered to the subchondral bone of femur and tibia of one knee (subchondral group) and the other part was injected in the joint for the contralateral knee (intra-articular group). MSCs were counted as CFU-F (colony fibroblastic unit forming). Clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (including MRIs) at two year follow-up. Subsequent revision surgeries were identified until the most recent follow-up (average of 15 years, range 13 to 18 years)., Results: At two year follow-up, clinical and imaging (MRI) improvement was higher on the side that received cells in the subchondral bone. At the most recent follow-up (15 years), among the 60 knees treated with subchondral cell therapy, the yearly arthroplasty incidence was 1.3% per knee-year; for the 60 knees with intra-articular cell therapy, the yearly arthroplasty incidence was higher (p = 0.01) with an incidence of 4.6% per knee-year. For the side with subchondral cell therapy, 12 (20%) of 60 knees underwent TKA, while 42 (70%) of 60 knees underwent TKA on the side with intra-articular cell therapy. Among the 18 patients who had no subsequent surgery on both sides, all preferred the knee with subchondral cell therapy., Conclusions: Implantation of MSCs in the subchondral bone of an osteoarthritic knee is more effective to postpone TKA than injection of the same intra-articular dose in the contralateral knee with the same grade of osteoarthritis.

Background and Study Aim: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture., Patients and Methods: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni)., Results: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation., Conclusion: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers., Competing Interests: Declaration of Competing Interest The authors confirm that there are no known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome. The authors do not communicate any conflict of interest about this work and manuscript., (Copyright © 2020. Published by Elsevier Ltd.)

Background: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis., Methods: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority., Findings: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging)., Interpretation: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic., Funding: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876)., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Total knee arthroplasty (TKA) implanted in patients with secondary osteonecrosis (ON) related to corticosteroids have relatively poor outcome (20% revision rate) at a mean follow-up of only eight years. With the hypothesis that subchondral bone marrow injection might improve knees in these patients, we evaluated 30 patients who had bilateral knee osteoarthritis with severe joint space narrowing and received TKA in one knee and subchondral bone marrow concentrate injection in the contralateral knee., Material and Methods: A prospective randomized controlled clinical trial was carried out in 60 knees of 30 patients (mean age 28 years, 18-41) who presented bilateral osteoarthritis secondary to knee ON related to corticosteroids in relation with different severe medical conditions. During the same anesthesia, one knee received TKA; for the other knee, a bone marrow graft containing an average of 6500 MSCs/mL (counted as CFU-F, range 3420 to 9830) was delivered to the subchondral bone of the femur and tibia. The length of anesthesia related to each procedure (bone marrow aspiration and subchondral injection of concentrated bone marrow versus total knee arthroplasty) was measured. Peri-operative outcomes, morbidity, complications, and safety of the two procedures were compared. Subsequent admissions for revision surgery were identified. At the most recent follow-up (average of 12 years, range 8 to 16 years), clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (MRIs for knees with subchondral bone marrow injection)., Results: Anesthesia related to the TKA side was longer than for the cell therapy group. Medical and surgical complications were more frequent after TKA. A higher number of thrombophlebitis was observed on the side with TKA (15%) versus none on the side with cell therapy (0%). At the most recent follow-up (average of 12 years, range 8 to 16 years), six (out of 30) TKA knees needed subsequent surgery versus only one with cell therapy. The Knee Score had improved and remained similar in the TKA and cell therapy groups (respectively 80.3 points ± 11 versus 78.3 ± 23); 21 patients preferred the knee with cell therapy and 9 preferred the knee with TKA. Knees with cell therapy had improvement on cartilage and bone marrow lesions observed at the site of bone marrow subchondral injection., Conclusions: Subchondral autologous bone marrow concentrate was an effective procedure for treating young patients with knee osteoarthritis following secondary ON of the knee related to corticosteroids with a lower complication rate and a quicker recovery as compared with TKA.

Purpose: Despite multiple possible treatments, the risk of collapse remains the main problem of osteonecrosis. Heart failure (HF). In an effort to address the reverse this issue, curative strategies with regenerative medicine are increasingly being considered. The aim of this technology is to halt or reverse progression of the disease to collapse., Material and Methods: The pioneering report by Hernigou published in 2002 was the first pilot study suggesting that injection of bone marrow stem cells was a safe approach able to improve osteonecrosis in patients with early stages. Since then, an impressive number of studies and trials employing unselected BM-derived cells (1000 the last 2 years) showed that delivery of those cells to the site of osteonecrosis during core decompression was somehow able to ameliorate the patient with osteonecrosis. In order to translate the promise of this cell therapy into better clinical benefit, many questions need to be addressed. In this review, we therefore analyzed current clinical experience of the literature and our experience of 4000 cases to address these questions and particularly the number of cells that should be injected., Results: After almost 20 years of clinical research in this field, we are still far from having drawn conclusions on the number of cells we should inject in regenerating hip osteonecrosis. Findings are difficult to interpret due to heterogeneity of causes of osteonecrosis, as well as differences in the cells count, sample quality, and stages of osteonecrosis. The authors address specific issues, as cell quality, cell numbers, volume of osteonecrosis, concentration of cells, and ex vivo expansion. Bone marrow mesenchymal stem cells are supposed to be "functionally competent," but are collected from the bon, marrow of patients with diseases and risk factors of osteonecrosis. The recipient organ (bone osteonecrosis) is a tissue where several alterations have already occurred. These questions are addressed in this review., Conclusion: In this review, we analyzed current clinical experience regarding cell therapy and address issues that should be a guide for future cell-based therapeutic application in osteonecrosis.

Purpose: Symptomatic osteonecrosis related to corticosteroids has a high risk of progression to collapse in absence of treatment. The purposes of this study were to evaluate the results of autologous bone marrow grafting of the symptomatic hip in adult patients with osteonecrosis and to compare the results with core decompression alone in the contralateral symptomatic hip., Materials and Methods: A total of 125 consecutive patients (78 males and 47 females) with bilateral osteonecrosis (ON) and who had both hips symptomatic and at the same stage on each side (stage I or II) were included in this study from 1988 to 1998. The volume of osteonecrosis was measured with MRI in both hips; the smaller size ON was treated with core decompression, and the contralateral hip with the larger ON was treated with percutaneous mesenchymal cell (MSC) injection obtained from bone marrow concentration. The average total number of MSCs (counted as number of colony forming units-fibroblast) injected in each hip was 90,000 ± 25,000 cells (range 45,000 to 180,000 cells)., Results: At the most recent FU (average 25 years after the first surgery, range 20 to 30 years), among the 250 hips included in the study, 35 hips (28%) had collapsed at the most recent follow-up after bone marrow grafting, and 90 (72%) after core decompression (CD). Ninety-five hips (76%) in the CD group underwent total hip replacement and 30 hips (24%) in the bone marrow graft group (p < 0.0001). Hips undergoing only CD were approximately three times more likely to undergo a primary THA (odds ratio: 10.0278; 95% CI: 5.6117 to 17.9190; p < 0.0001) as compared with hips undergoing an initial bone marrow grafting. For the 90 hips treated with bone marrow injection and without collapse, the mean volume of repair evaluated by MRI at the most recent follow-up was 16.4 cm 3 (range 12 to 21 cm 3 ) corresponding to a decrease of the pre-operative average volume from 22.4 cm 3 (range 35-15 cm 3 ) to 6 cm 3 (range 12-0 cm 3 ); as percentage of the volume of the femoral head, the decrease moved from 44.8 to 12%., Conclusion: Core decompression with bone marrow injection improved the outcome of the disease as compared with core decompression alone in the same patient.

Purpose: There is a significantly higher incidence of delayed unions, non-unions, and increased healing time in diabetic patients compared with non-diabetic patients. Studies suggest that diabetics suffer from deficiencies of pancreatic stem/progenitor cells, and a clinically relevant question arises concerning the availability and functionality of progenitor cells obtained from bone marrow of diabetics for applications in bone repair., Methods: We have evaluated the cellularity and frequency of osteogenic mesenchymal stem cells (MSCs) in bone marrow from 54 diabetic patients (12 with type 1 and 42 with type 2) with tibial non-unions. These patients were treated with bone marrow MSCs (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes and marrow cellularity were compared to 54 non-diabetic, matched patients with tibial non-unions also treated with BMC., Results: After adjusting for age and sex, no differences were identified with respect to bone marrow cellularity and MSC number among the diabetic and non-diabetic groups and both groups received approximately the same number of MSCs on average. BMC treatment promoted non-union healing in 41 diabetic patients (76 %) and 49 non-diabetic patients (91 %), but the non-diabetic patients healed more quickly and produced a larger volume of callus., Conclusion: We recommend that diabetic patients be treated with an increased number of progenitor cells by increasing the bone marrow aspiration volume. We also anticipate a need to extend the time of casting and non-weight bearing for diabetic patients as compared with non-diabetic patients.

Avascular necrosis of the femoral head is caused by a multitude of etiologic factors and is associated with collapse with a risk of hip arthroplasty in younger populations. A focus on early disease management with the use of stem cells was proposed as early as 1985 by the senior author (PH). We undertook a systematic review of the medical literature to examine the progress in cell therapy during the last 30 years for the treatment of early stage osteonecrosis.

Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease (SCD). To delay hip arthroplasty, core decompression combined with concentrated total bone marrow (BM) treatment is currently performed in the early stages of the osteonecrosis. Cell therapy efficacy depends on the quantity of implanted BM stromal cells. For this reason, expanded bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) can be used to improve osteonecrosis treatment in SCD patients. In this study, we quantitatively and qualitatively evaluated the function of BMSCs isolated from a large number of SCD patients with osteonecrosis (SCD-ON) compared with control groups (patients with osteonecrosis not related to SCD (ON) and normal donors (N)). BM total nuclear cells and colony-forming efficiency values (CFE) were significantly higher in SCD-ON patients than in age and sex-matched controls. The BMSCs from SCD-ON patients were similar to BMSCs from the control groups in terms of their phenotypic and functional properties. SCD-ON patients have a higher frequency of BMSCs that retain their bone regeneration potential. Our findings suggest that BMSCs isolated from SCD-ON patients can be used clinically in cell therapy approaches. This work provides important preclinical data that is necessary for the clinical application of expanded BMSCs in advanced therapies and medical products.

Purpose: Clinical studies in diabetic patients have demonstrated that there is a high incidence of complications in distal tibia and ankle fracture treatments. One strategy to mitigate issues with wound healing and infection in diabetic patients is to use a percutaneous technique in which autologous, bone marrow-derived, concentrated cells are injected at the site of non-unions., Methods: Eighty-six ankle non-union in diabetic patients were treated with bone marrow mesenchymal stem cells (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes of the 86 diabetic non-union patients treated with BMC were compared with 86 diabetic matched non-unions treated with a standard bone iliac crest autograft., Results: Treatment with BMC promoted non-union healing in 70 among 86 diabetic patients (82.1 %) with a low number of complications. Of the 86 diabetic patients treated with iliac bone graft, 53 (62.3 %) had healing; major complications were observed: 5 amputations, 11 osteonecroses of the fracture wound edge and 17 infections., Conclusions: In diabetic patients with ankle non-unions, treatment with BM-MSCs from bone marrow concentrate may be preferable in view of the high risks of major complications after open surgery and iliac bone grafting, and improved healing rates compared with standard iliac bone autograft treatment.

Introduction: Osteonecrosis 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., Methods: BMSCs 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., Results: After 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., Conclusions: Intra-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.

Introduction: Hip osteonecrosis is a pathological condition resulting from cellular impairment due to reduction in osteoblast activity and local mesenchymal stem cell populations. Cell-based therapies might aid in overcoming these deficiencies by providing stem cells and other progenitor cells to potentially improve the local cellular environment in the affected hip., Methods: A PubMed search, using the search terms "hip osteonecrosis" and "mesenchymal stem cells", was conducted in December 2013. A total of 15 publications were identified and reviewed for clinical outcomes., Findings: Clinical studies of patients with osteonecrosis treated with mesenchymal stem cells showed beneficial effects. No unexpected adverse events were identified in these studies. Core decompression was the usual method for autologous bone marrow cell implantation into the femoral head. However, other methods have been used such as arterial or venous delivery. A rationale for the use of cytotherapy, as well as the different descriptions of the techniques of implantation MSCs (autologous vs. allogenic, concentration vs. expansion), is provided in the context of treating hip osteonecrosis. Current problems and future challenges with cytotherapy and associated techniques are discussed. This article is part of a Special Issue entitled "Stem Cells and Bones"., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to evaluate the efficiency of biologic augmentation of rotator cuff repair with iliac crest bone marrow-derived mesenchymal stem cells (MSCs). The prevalence of healing and prevention of re-tears were correlated with the number of MSCs received at the tendon-to-bone interface., Methods: Forty-five patients in the study group received concentrated bone marrow-derived MSCs as an adjunct to single-row rotator cuff repair at the time of arthroscopy. The average number of MSCs returned to the patient was 51,000 ± 25,000. Outcomes of patients receiving MSCs during their repair were compared to those of a matched control group of 45 patients who did not receive MSCs. All patients underwent imaging studies of the shoulder with iterative ultrasound performed every month from the first postoperative month to the 24th month. The rotator cuff healing or re-tear was confirmed with MRI postoperatively at three and six months, one and two years and at the most recent follow up MRI (minimum ten-year follow-up)., Results: Bone marrow-derived MSC injection as an adjunctive therapy during rotator cuff repair enhanced the healing rate and improved the quality of the repaired surface as determined by ultrasound and MRI. Forty-five (100 %) of the 45 repairs with MSC augmentation had healed by six months, versus 30 (67 %) of the 45 repairs without MSC treatment by six months. Bone marrow concentrate (BMC) injection also prevented further ruptures during the next ten years. At the most recent follow-up of ten years, intact rotator cuffs were found in 39 (87 %) of the 45 patients in the MSC-treated group, but just 20 (44 %) of the 45 patients in the control group. The number of transplanted MSCs was determined to be the most relevant to the outcome in the study group, since patients with a loss of tendon integrity at any time up to the ten-year follow-up milestone received fewer MSCs as compared with those who had maintained a successful repair during the same interval., Conclusion: This study showed that significant improvement in healing outcomes could be achieved by the use of BMC containing MSC as an adjunct therapy in standard of care rotator cuff repair. Furthermore, our study showed a substantial improvement in the level of tendon integrity present at the ten-year milestone between the MSC-treated group and the control patients. These results support the use of bone marrow-derived MSC augmentation in rotator cuff repair, especially due to the enhanced rate of healing and the reduced number of re-tears observed over time in the MSC-treated patients.

Purpose: There is concern that regenerative cell-based therapies at the site of malignant primary bone tumours could result in increased risk of local tumour recurrence. We therefore investigated the long-term risks for site-specific recurrences in patients who had received an autologous bone marrow derived mesenchymal stem cell suspension to improve healing at the host-to-allograft bone junction of the reconstruction after bone tumour resection., Methods: A total of 92 patients were treated from 1993 to 2003 with bone marrow-derived mesenchymal stem cells after bone tumour resection. Patients were monitored for cancer incidence from the date of first operation (1993) until death, or until 31 December 2013. The mean follow-up time was 15.4 years (range ten to 20 years). The average number of MSCs returned to the patient was 234,000 MSCs ± 215,000. The primary outcome was to evaluate the risk of tumorigenesis recurrence at the cell therapy treatment sites with radiographs and/or MRIs. The relative risk of cancer recurrence was expressed as the ratio of observed and expected number of cases according to three different control populations., Results: Thirteen recurrences were found at the treatment sites among the 92 patients. The expected number of recurrences based on incidence in the three cohort populations was between 15 and 20 for the same cancer, age and sex distribution. The standardized incidence ratio (equal to observed cancers divided by expected cancers) for the entire follow-up period and for all recurrences was between 0.65 and 0.86 (95 % CI 0.60-1.20)., Conclusion: This study found no increased cancer local recurrence risk in patients after application of autologous cell-based therapy using bone marrow-derived mesenchymal stem cells at the treatment site after an average follow-up period of 15.4 years, ranging from ten to 20 years.

Purpose: The procedure of bone allografting associated with a reinforcement device is widely used for acetabulum revision. However in absence of biologic fixation of the allograft, failure of the reconstruction may occur. We made the hypothesis that it would be possible to load these grafts with bone marrow derived mesenchymal stem cells (MSC) to rescue the osteogenic capacity of an allogenic dead bone and therefore enhance incorporation of allografts with the host bone and decrease the number of failures related to the allograft., Method: We identified 60 patients who had undergone acetabular component revision for aseptic failure of cemented implants associated with massive periacetabular osteolysis and Paprosky type 3A or 3B classification (without pelvic discontinuity) between 1996 and 2001. The study group of 30 patients received MSCs in the allograft and at the host graft junction. The average total number of MSCs received by each patient was 195,000 cells (range 86,000-254,000 cells). The control group of 30 patients had no MSCs in the allograft. Patients were matched for the size of periacetabular osteolysis (Paprosky type 3A or 3B). We compared the evolution of the allografts and evaluated cup migration and revision of the hips as end points at a minimum of 12 years or until failure., Result: Better radiographic graft union rates and less allograft resorption were observed with allografts loaded with stem cells. Allograft resorption was significantly decreased in the group with allograft loaded with MSCs (1.2 cm(2) -range 0-2.3 cm(2)-of resorption on radiographs in the group with MSCs; versus 6 cm(2), range 2.1-8.5 cm(2) in the group without MSCs). The rate of mechanical failure was highest (p = 0.01) among the 30 patients with allograft without stem cells (9/30; 30 %) compared with no failures for patients with allograft loaded with stem cells. Revision of the cup was necessary in nine patients in the control group. No revision was performed in the 30 patients of the study group with MSCs., Conclusion: For acetabular defect reconstruction, loading the allograft with MSCs has resulted in a lower rate of failure as compared with allograft without MSCs.

Purpose: Abdominal aortic aneurysms (AAAs) expand because of aortic wall destruction. Enrichment in Vascular Smooth Muscle Cells (VSMCs) stabilizes expanding AAAs in rats. Mesenchymal Stem Cells (MSCs) can differentiate into VSMCs. We have tested the hypothesis that bone marrow-derived MSCs (BM-MSCs) stabilizes AAAs in a rat model., Material and Methods: Rat Fischer 344 BM-MSCs were isolated by plastic adhesion and seeded endovascularly in experimental AAAs using xenograft obtained from guinea pig. Culture medium without cells was used as control group. The main criteria was the variation of the aortic diameter at one week and four weeks. We evaluated the impact of cells seeding on inflammatory response by immunohistochemistry combined with RT-PCR on MMP9 and TIMP1 at one week. We evaluated the healing process by immunohistochemistry at 4 weeks., Results: The endovascular seeding of BM-MSCs decreased AAA diameter expansion more powerfully than VSMCs or culture medium infusion (6.5% ± 9.7, 25.5% ± 17.2 and 53.4% ± 14.4; p = .007, respectively). This result was sustained at 4 weeks. BM-MSCs decreased expression of MMP-9 and infiltration by macrophages (4.7 ± 2.3 vs. 14.6 ± 6.4 mm(2) respectively; p = .015), increased Tissue Inhibitor Metallo Proteinase-1 (TIMP-1), compared to culture medium infusion. BM-MSCs induced formation of a neo-aortic tissue rich in SM-alpha active positive cells (22.2 ± 2.7 vs. 115.6 ± 30.4 cells/surface units, p = .007) surrounded by a dense collagen and elastin network covered by luminal endothelial cells., Conclusions: We have shown in this rat model of AAA that BM-MSCs exert a specialized function in arterial regeneration that transcends that of mature mesenchymal cells. Our observation identifies a population of cells easy to isolate and to expand for therapeutic interventions based on catheter-driven cell therapy., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Mesenchymal stromal cells are defined as non-hematopoietic progenitors characterised by their adherence to plastic in culture, their expression of non-specific markers and their differentiation potential into cells of mesodermic lineage. Resident in numerous tissues, mesenchymal stromal cells are now available from several sources, including both adult and foetal tissues. After their administration, mesenchymal stromal cells preferentially migrate to injured tissues. Mesenchymal stromal cells have therapeutic effects in numerous animal models of tissue injury by a mechanism not yet clearly understood. Mechanisms likely involved in repair can be the production of paracrine, anti-inflammatory and anti-apoptotic factors, as well as cell replacement by their differentiation potential. Mesenchymal stromal cells possess immunosuppressive properties on both innate and adaptative immunity in vitro and in animal models of autoimmunity. Currently their immunosuppressive properties allow testing of mesenchymal stromal cells in allogenic context, although this use requires further investigations. Mesenchymal stromal cells can be isolated and expanded in vitro in clinical grade conditions. They represent a promising candidate for the cellular therapy of diseases, such as acute myocardial infarction, diabetes, graft versus host disease or neurodegenerative diseases. Critical points including the standardization of production and long term toxicity have to be resolved before their large scale use in clinical conditions., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)