Autologous bone marrow-derived CD133 cells with core decompression as a novel treatment method for femoral head osteonecrosis: a pilot study.

BACKGROUND: Avascular necrosis (AVN) of femoral head is a progressive bone disease due to ischemia of femoral head; patients experience pain and they can not do normal activity. There is not an effective way to treat the cause of this disease. In recent studies, treatment of this disease using pluripotent stem cell-derived mesenchyme is safe and effective, but this method needs more investigation. In this study, the safety and efficacy of CD133+ cells were evaluated as a novel method of stem cell therapy to treat AVN. METHODS: In this prospective quasi-experimental study, the participants were selected among patients with AVN who were referred to the Royan Cell Therapy Center. Autologous bone marrow-derived CD133+ cells were injected into the necrotic site of the femoral head during core decompression (CD). The Visual Analogue Scale (VAS), Harris Hip Score (HHS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and walking distance (WD) were measured before and 2, 6 and 12 months after CD. RESULTS: Overall, nine patients (six men and three women) were investigated in this study. Their mean age was 26 years old. All of them significantly improved in VAS, HHS, WOMAC and WD scores and they could do more activity without pain. Also, imaging findings demonstrated significant reductions in joint injuries. Significant complications were not seen in patients. DISCUSSION: This prospective quasi-experimental study demonstrated that, in patients with AVN, a single bone marrow-derived CD133+ cell injection into the necrotic site of the femoral head during CD is safe and effective in providing significant, clinically relevant pain relief and patients could do more activity over 2, 6 and 12 months. This pilot study suggested further clinical trials over an extended assessment period to approve bone marrow-derived CD133+ cell injection to treat AVN.

Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: The intra-articular implantation of mesenchymal stromal cells (MSCs) as a treatment for knee osteoarthritis (OA) is an emerging new therapy. In this study, patients with knee OA received intra-articular implantations of autologous bone marrow-derived MSCs. We sought to assess the safety and efficacy of this implantation. MATERIALS AND METHODS: This was a phase 1/2 single-center, triple-blind, randomized controlled trial (RCT) with a placebo control. The subjects consisted of patients with knee OA randomly assigned to either an intra-articular implantation of MSCs (40 × 106 cells) or 5 mL normal saline (placebo). Patients were followed up for 6 months after the implantations. The pain level and function improvements for patient-reported outcomes were assessed based on a visual analog scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and its subscales, walking distance, painless walking distance, standing time and knee flexion compared with the placebo group at 3 and 6 months following the implantations. RESULTS: Overall, 43 patients (Kellgren-Lawrence grades 2, 3 and 4) were assigned to either the MSCs (n = 19) or placebo (n = 24) group. Patients who received MSCs experienced significantly greater improvements in WOMAC total score, WOMAC pain and physical function subscales and painless walking distance compared with patients who received placebo. There were no major adverse events attributed to the MSC therapy. CONCLUSION: This randomized, triple-blind, placebo-controlled RCT demonstrated the safety and efficacy of a single intra-articular implantation of 40 × 106 autologous MSCs in patients with knee OA. Intra-articular implantation of MSCs provided significant and clinically relevant pain relief over 6 months versus placebo and could be considered a promising novel treatment for knee OA. We propose that further investigations should be conducted over an extended assessment period and with a larger cohort.

Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial.

BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo-controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement.

Percutaneous Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Implantation Is Safe for Reconstruction of Human Lower Limb Long Bone Atrophic Nonunion.

OBJECTIVE: Nonunion is defined as a minimum of a 9-month period of time since an injury with no visibly progressive signs of healing for 3 months. Recent studies show that application of mesenchymal stromal cells (MSCs) in the laboratory setting is effective for bone regeneration. Animal studies have shown that MSCs can be used to treat nonunions. For the first time in an Iranian population, the present study investigated the safety of MSC implantation to treat human lower limb long bone nonunion. MATERIALS AND METHODS: It is a prospective clinical trial for evaluating the safety of using autologus bone marrow derived mesenchymal stromal cells for treating nonunion. Orthopedic surgeons evaluated 12 patients with lower limb long bone nonunion for participation in this study. From these, 5 complied with the eligibility criteria and received MSCs. Under fluoroscopic guidance, patients received a one-time implantation of 20-50×106 MSCs into the nonunion site. All patients were followed by anterior-posterior and lateral X-rays from the affected limb, in addition to hematological, biochemical, and serological laboratory tests obtained before and 1, 3, 6, and 12 months after the implantation. Possible adverse effects that included local or systemic, serious or non-serious, and related or unrelated effects were recorded during this time period. RESULTS: From a safety perspective, all patients tolerated the MSCs implantation during the 12 months of the trial. Three patients had evidence of bony union based on the after implantation Xrays. CONCLUSION: The results have suggested that implantation of bone marrow-derived MSCs is a safe treatment for nonunion. A double-blind, controlled clinical trial is required to assess the efficacy of this treatment (Registration Number: NCT01206179).

Mesenchymal Stromal Cells Implantation in Combination with Platelet Lysate Product Is Safe for Reconstruction of Human Long Bone Nonunion.

OBJECTIVE: Nonunion is defined as a minimum of 9 months since injury without any visible progressive signs of healing for 3 months. Recent literature has shown that the application of mesenchymal stromal cells is safe, in vitro and in vivo, for treating long bone nonunion. The present study was performed to investigate the safety of mesenchymal stromal cell (MSC) implantation in combination with platelet lysate (PL) product for treating human long bone nonunion. MATERIALS AND METHODS: In this case series clinical trial, orthopedic surgeons visited eighteen patients with long bone nonunion, of whom 7 complied with the eligibility criteria. These patients received mesenchymal stromal cells (20 million cells implanted once into the nonunion site using a fluoroscopic guide) in combination with PL product. For evaluation of the effects of this intervention all the patients were followed up by taking anterior-posterior and lateral X-rays of the affected limb before and 1, 3, 6, and 12 months after the implantation. All side effects (local or systemic, serious or non-serious, related or unrelated) were observed during this time period. RESULTS: From a safety perspective the MSC implantation in combination with PL was very well tolerated during the 12 months of the trial. Four patients were healed; based on the control Xray evidence, bony union had occurred. CONCLUSION: Results from the present study suggest that the implantation of bone marrow-derived MSCs in combination with PL is safe for the treatment of nonunion. A double blind, controlled clinical trial is required to assess the efficacy of this treatment (Registration Number: NCT01206179).

Long-Term Follow-up of Intra-articular Injection of Autologous Mesenchymal Stem Cells in Patients with Knee, Ankle, or Hip Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a debilitating disease that typically affects a large number of the middle-aged and elderly population. Current treatment strategies have had limited success in these patients. This study aims to investigate the safety of treatment with autologous bone marrow (BM)-derived mesenchymal stem cells (MSCs) transplanted in patients with OA of the knee, ankle, or hip. METHODS: We enrolled 18 patients with different joint involvements (knee, ankle, or hip OA) and one was lost to follow-up. BM samples were taken from the patients, after which BM-derived MSCs were isolated and cultured. Each patient received one MSC injection. Patients were followed with clinical examinations, MRI and laboratory tests at 2, 6, 12, and 30 months post-transplantation. RESULTS: We observed no severe adverse events such as pulmonary embolism, death, or systemic complications. A limited number of patients had very minor localized adverse effects such as rash and erythema. There were no changes in liver function, hematology, or biochemistry analyses before and after cell therapy. There was no evidence of tumor or neoplastic changes in the patients during the 30-month follow-up period. All patients exhibited therapeutic benefits such as increased walking distance, decreased visual analog scale (VAS), and total Western Ontario and McMaster Universities OA Index (WOMAC) scores which were confirmed by MRI. CONCLUSIONS: Our study has shown that injection of MSCs in different OA affected joints is safe and therapeutically beneficial. However, further studies are needed with larger sample sizes and longer follow-up periods to confirm these findings.

Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a progressive disorder of the joints caused by gradual loss of articular cartilage, which naturally possesses a limited regenerative capacity. In the present study, the potential of intra-articular injection of mesenchymal stem cells (MSCs) has been evaluated in six osteoarthritic patients. METHODS: Six female volunteers, average age of 54.56 years, with radiologic evidence of knee OA that required joint replacement surgery were selected for this study. About 50 ml bone marrow was aspirated from each patient and taken to the cell laboratory, where MSCs were isolated and characterized in terms of some surface markers. About 20-24 × 10(6) passaged-2 cells were prepared and tested for microbial contamination prior to intra-articular injection. RESULTS: During a one-year follow-up period, we found no local or systemic adverse events. All patients were partly satisfied with the results of the study. Pain, functional status of the knee, and walking distance tended to be improved up to six months post-injection, after which pain appeared to be slightly increased and patients' walking abilities slightly decreased. Comparison of magnetic resonance images (MRI) at baseline and six months post-stem cell injection displayed an increase in cartilage thickness, extension of the repair tissue over the subchondral bone and a considerable decrease in the size of edematous subchondral patches in three out of six patients. CONCLUSION: The results indicated satisfactory effects of intra-articular injection of MSCs in patients with knee OA.