Implantation Of Bone Marrow Mononuclear Cells Research Articles

Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia.

Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011. To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI. We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021. We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo). We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach. We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency. We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.

Prognostic Factors and Predictors of Mortality in Patients with Critical Limb Ischemia: A Current Clinical Perspective

Critical limb ischemia (CLI) is an end-stage peripheral arterial disease (PAD). Mortality, limb loss, pain, and diminished health-related quality of life are highly prevalent in CLI patients. 20 to 50% CLI Mortality is intensely observed within the first six months to five years of CLI diagnosis, respectively. Prognostic treatments, including autologous bone marrow mononuclear cell implantation (BMMNCI), low-intensity pulsed ultrasound (LIPUS) technology, and medication therapy using Cilostazol, are available. In addition, required prognostic factors such as timely access to medical care can control the death. Impaired mobility, old age, low BMI, CKD (end-stage), T2DM, COPD (oxygen-dependent), HF, smoking, high Wound, Ischemia, and Foot Infection are the additional predictors for CLI-related mortality. Due to the poor survival and prognosis, it is crucial to identify the prognostic factors that will lead to better clinical benefits, including amputation-free survival rate and improved quality of life. This review highlights the current clinical perspective on the prognostic factors and predictors of mortality in CLI patients.

Autologous Bone Marrow Mononuclear Cells (BMMCs) for the Treatment of Uncomplicated Grade 2 Ununited Anconeal Process (UAP) in Six Dogs: Preliminary Results.

The aim of this study was to report the results of autologous bone marrow mononuclear cell (BMMC) transplantation as a minimally invasive treatment for grade 2 UAP in dogs. This was an observational case series on six German shepherd dogs affected by grade 2 UAP as defined according to their clinical condition as well as radiographic and CT findings. Bone marrow was collected from the iliac crest and the mononuclear fraction was separated with density gradient centrifugation. Cells were suspended in fibrin glue before BMMC administration and implanted via transcutaneous injection under IB or CT guidance, using a spinal needle directly inserted into the ossification centre between the anconeal process and the olecranon. Clinical and radiographic follow-up was performed for up to 6 months. Microradiographic assessment was performed on one dog that died of other causes. A progressive reduction of pain within 3 weeks after BMMC administration was observed in all dogs, with gradually increased weight bearing on the affected limb. Radiographic and CT follow-up revealed the progressive fusion of the ossification centre at 90 days without any signs of secondary OA. The examination of microradiographs showed newly formed bone tissue in which a residue of calcified cartilage was present at the site of BMMC implantation. On the basis of these results, BMMC therapy for grade 2 UAP may be considered to be an effective and minimally invasive treatment option for dogs.

REX-001, a BM-MNC Enriched Solution, Induces Revascularization of Ischemic Tissues in a Murine Model of Chronic Limb-Threatening Ischemia.

Background: Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation. BM-MNC implantation has shown to be efficient in promoting angiogenesis and ameliorating ischemic symptoms in CLTI patients. However, the variability seen between clinical trials makes necessary a further understanding of the mechanisms of action of BM-MNC, and moreover, to improve trial characteristics such as endpoints, inclusion/exclusion criteria or drug product compositions, in order to implement their use as stem-cell therapy.Materials: Herein, the effect of REX-001, a human-BM derived cell suspension enriched for mononuclear cells, granulocytes and CD34+ cells, has been assessed in a murine model of CLTI. In addition, a REX-001 placebo solution containing BM-derived red blood cells (BM-RBCs) was also tested. Thus, 24 h after double ligation of the femoral artery, REX-001 and placebo were administrated intramuscularly to Balb-c nude mice (n:51) and follow-up of ischemic symptoms (blood flow perfusion, motility, ulceration and necrosis) was carried out for 21 days. The number of vessels and vascular diameter sizes were measured within the ischemic tissues to evaluate neovascularization and arteriogenesis. Finally, several cell-tracking assays were performed to evaluate potential biodistribution of these cells.Results: REX-001 induced a significant recovery of blood flow by increasing vascular density within the ischemic limbs, with no cell translocation to other organs. Moreover, cell tracking assays confirmed a decrease in the number of infused cells after 2 weeks post-injection despite on-going revascularization, suggesting a paracrine mechanism of action.Conclusion: Overall, our data supported the role of REX-001 product to improve revascularization and ischemic reperfusion in CLTI.

Relationship between cell number and clinical outcomes of autologous bone-marrow mononuclear cell implantation in critical limb ischemia

Cell therapy using intramuscular injections of autologous bone-marrow mononuclear cells (BM-MNCs) improves clinical symptoms and can prevent limb amputation in atherosclerotic peripheral arterial disease (PAD) patients with critical limb ischemia (CLI). The purpose of this study was to evaluate the effects of the number of implanted BM-MNCs on clinical outcomes in atherosclerotic PAD patients with CLI who underwent cell therapy. This study was a retrospective observational study with median follow-up period of 13.5 years (range, 6.8–15.5 years) from BM-MNC implantation procedure. The mean number of implanted cells was 1.2 ± 0.7 × 109 per limb. There was no significant difference in number of BM-MNCs implanted between the no major amputation group and major amputation group (1.1 ± 0.7 × 109 vs. 1.5 ± 0.8 × 109 per limb, P = 0.138). There was also no significant difference in number of BM-MNCs implanted between the no death group and death group (1.5 ± 0.9 × 109 vs. 1.8 ± 0.8 × 109 per patient, P = 0.404). Differences in the number of BM-MNCs (mean number, 1.2 ± 0.7 × 109 per limb) for cell therapy did not alter the major amputation-free survival rate or mortality rate in atherosclerotic PAD patients with CLI. A large number of BM-MNCs will not improve limb salvage outcome or mortality.

Long-Term Clinical Outcomes of Autologous Bone Marrow Mononuclear Cell Implantation in Patients With Severe Thromboangiitis Obliterans.

Patients with severe Buerger disease, also known as thromboangiitis obliterans (TAO), are at risk of major limb amputation. It has been shown that autologous bone marrow mononuclear cell (BM-MNC) implantation improves the condition of critical limb ischemia in TAO patients. This study was conducted to further clarify the long-term (>10 years) results of autologous BM-MNC implantation in patients with TAO.Methods and Results:An observational study was conducted of the long-term results of BM-MNC implantation in 47 lower limbs of 27 patients with TAO. The mean (±SD) follow-up period was 12.0±8.6 years. There was no major amputation event up to 10 years of follow-up in patients treated with BM-MNC implantation. The overall amputation-free survival rates were significantly higher in patients who underwent BM-MNC implantation than in internal controls and historical controls. There was no significant difference in amputation-free survival rates between the historical and internal controls. There was also no significant difference in overall survival between patients who underwent BM-MNC implantation and the historical controls. BM-MNC transplantation successfully prevented major limb amputation over a period of >10 years in patients with severe TAO who had no other therapeutic options.

Review of the Long-term Effects of Autologous Bone-Marrow Mononuclear Cell Implantation on Clinical Outcomes in Patients with Critical Limb Ischemia

Critical limb ischemia (CLI) is associated with a high risk of limb amputation. It has been shown that cell therapy is safe and has beneficial effects on ischemic clinical symptoms in patients with CLI. The aim of this study was to further investigate the outcomes of intramuscular injection of autologous bone-marrow mononuclear cells (BM-MNCs) in a long-term follow-up period in atherosclerotic peripheral arterial disease (PAD) patients who have no optional therapy. This study was a retrospective and observational study that was carried out to evaluate long-term clinical outcomes in 42 lower limbs of 30 patients with atherosclerotic PAD who underwent BM-MNC implantation. The median follow-up period was 9.25 (range, 6–16) years. The overall amputation-free rates were 73.0% at 5 years after BM-MNC implantation and 70.4% at 10 years in patients with atherosclerotic PAD. The overall amputation-free rates at 5 years and at 10 years after implantation of BM-MNCs were significantly higher in atherosclerotic PAD patients than in internal controls and historical controls. There were no significant differences in amputation rates between the internal control group and historical control group. The rate of overall survival was not significantly different between the BM-MNC implantation group and the historical control group. Implantation of autologous BM-MNCs is feasible for a long-term follow-up period in patients with CLI who have no optional therapy.

Use of autologous bone marrow stem cell implantation for osteonecrosis of the knee in sickle cell disease: a preliminary report

BackgroundThe purpose of our study was to evaluate safety, feasibility and clinical results of bone marrow mononuclear cell (BMC) implantation for early-stage osteonecrosis of the knee (OK) secondary to sickle cell disease.MethodsThirty-three SCD patients (45 knees) with OK treated with BMC implantation in the osteonecrotic lesion were clinically and functionally evaluated through the American Knee Society Clinical Score (KSS), Knee Functional Score (KFS) and Numeric Rating Scale (NRS) pain score. MRI and radiographic examinations of the knee were assessed during a period of five years after intervention.ResultsNo complications or serious adverse event were associated with BMC implantation. From preoperative assessment to the latest follow-up, there was a significant (p < 0.001) improvement of clinical KSS (64.3 ± 9.7, range: 45–80 and 2.2 ± 4.1, range: 84–100, respectively), KFS (44.5 ± 8.0, range: 30–55 and 91.6 ± 5.8, range: 80–100, respectively) and reduction of NRS pain score (6.7 ± 1.2, range: 4–9 and 3.4 ± 1.0, range: 2–5, respectively). In total, 87% of patients (29/33) consistently experienced improvements in joint function and activity level as compared to preoperative score. No patient had additional surgery following BMC implantation. Radiographic assessment showed joint preservation and no progression to subchondral collapse at most recent follow-up.ConclusionsThe technique of BMC implantation is a promising, relatively simple and safe procedure for OK in SCD patients. Larger and long-term controlled trials are needed to support its clinical effectiveness.Trial registrationClinicalTrials.gov NCT02448121. Retrospectively registered 19 May 2015.

Long-term follow-up of patients with Buerger's disease after autologous stem cell therapy.

Objective:We investigated the long-term results of autologous bone marrow mononuclear cells (ABMMNCs) implantation in patients with Buerger’s disease (BD).Methods:Twenty-eight patients (25 males and 3 females) who had BD and critical unilateral limb ischemia were investigated between April 2003 and August 2005. The patients were administered multiple injections of CD34+ and CD45+ positive ABMMNCs into the gastrocnemius muscle, the intermetatarsal region, and the dorsum of the foot (n=26) or forearm (n=2) and saline injection into the contralateral limb.Results:The mean follow-up time was 139.6±10.5 months. No complication related to stem cell therapy was observed during the follow-up. The ankle–brachial pressure index evaluated at 6 months and 120 months was compared to the baseline scores (p<0.001 and p=0.021, respectively). Digital subtraction angiography (DSA) was performed for all patients at baseline, 6 months, and 120 months. The angiographic improvement was 78.5% and 57.1% at 6 and 120 months, respectively. Patients demonstrated a significant improvement in the quality of life parameters at 6 months compared to baseline (p=0.008) and 120 months compared to the baseline (p=0.009). The 10-year amputation-free rate was 96% (95% CI=0.71-1) in ABMMNC-implanted limbs and 93% (95% CI=0.33–0.94) in saline-injected limbs (p=1).Conclusion:Autologous stem cell therapy could be an alternative therapeutic method for BD at long-term follow-up.

Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia - Results of a Randomized, Double-Blind, Placebo-Controlled Trial.

Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.Methods and Results:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52-0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29-0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO2, and ankle-brachial index value) were not statistically different between groups. Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.

骨・軟骨疾患の再生医療

Cardiovascular regenerative therapy has the potential to improve the treatment of peripheral artery disease (PAD), ischemic heart disease (IHD) and severe heart failure. Autologous implantation of bone marrow-mononuclear cells into ischemic limbs was reported as an effective application by the secretion of various angiogenic factors or cytokines. On the other hand, bone marrow cells and skeletal myoblasts transplantation for cardiac angiogenic therapy, injected directry into cardiac ischemic lesion, was generally insufficient to repair severe myocardial damage. To improve the efficacy of cardiac cell therapy, cell sheet technology was developed to reduce the damage of the transplanted cells. The discovery of iPS cells and cardiac master genes have changed the field of cardiac regenerative medicine. Because cardiomyocytes are terminally differentiated cells with limited regenerative capacity in adult heart, implantation of cardiomyocyte cell-sheet differentiated from iPS cells or the other pluripotent cell types, is expected as a new strategy of cardiac cell therapy. Moreover, direct cardiac reprograming which means cardiac fibroblasts induced converting directry into cardiomyocytes in damaged cardiac tissue, was discovered recentry. Here, this review summarizes recent advances in cardiovascular regenerative therapy and discusses the perspectives and challenges of new technology in basic biology and clinical applications.

Imaging Angiogenesis Using 99mTc-Macroaggregated Albumin Scintigraphy in Patients with Peripheral Artery Disease.

One problem of vascular angiogenesis therapy is the lack of reliable methods for evaluating blood flow in the microcirculation. We aimed to assess whether (99m)Tc-macroaggregated albumin perfusion scintigraphy ((99m)Tc-MAA) predicts quantitated blood flow after therapeutic angiogenesis in patients with peripheral artery disease. Forty-six patients with peripheral artery disease were treated with bone marrow mononuclear cell implantation (BMCI). Before and 4 wk after BMCI, blood flow was evaluated via transcutaneous oxygen tension (TcPO2), ankle-brachial index, intravenous (99m)Tc-tetrofosmin perfusion scintigraphy ((99m)Tc-TF), and intraaortic (99m)Tc-MAA. Four weeks after BMCI, TcPO2 improved significantly (20.4 ± 14.4 to 36.0 ± 20.0 mm Hg, P < 0.01), but ankle-brachial index did not (0.65 ± 0.30 to 0.76 ± 0.24, P = 0.07). Improvement in (99m)Tc-TF count (0.60 ± 0.23 to 0.77 ± 0.29 count ratio/pixel, P < 0.01) and (99m)Tc-MAA count (5.21 ± 3.56 to 10.33 ± 7.18 count ratio/pixel, P = 0.02) was observed in the foot region but not the lower limb region, using both methods. When these data were normalized by subtracting the pixel count of the untreated side, the improvements in (99m)Tc-TF count (-0.04 ± 0.26 to 0.08 ± 0.32 count ratio/pixel, P = 0.04) and (99m)Tc-MAA count (1.49 ± 3.64 to 5.59 ± 4.84 count ratio/pixel, P = 0.03) in the foot remained significant. (99m)Tc-MAA indicated that the newly developed arteries were approximately 25 μm in diameter. BMCI induced angiogenesis in the foot, which was detected using (99m)Tc-TF and (99m)Tc-MAA. (99m)Tc-MAA is a useful method to quantitate blood flow, estimate vascular size, and evaluate flow distribution after therapeutic angiogenesis.

Autologous bone marrow mononuclear cell implantation therapy is an effective limb salvage strategy for patients with severe peripheral arterial disease

This study was conducted to determine if intramuscular and intra-arterial stem cell injections delay or prevent major limb amputations, improve ankle-brachial index measurements, relieve rest pain, and improve ulcer healing. A prospective case series with interventions occurring between December 2007 and September 2012 and a 3-month minimum follow-up was conducted at an urban tertiary care referral hospital. Patients with severe limb-threatening peripheral arterial disease, without other options for revascularization, were eligible for enrollment. Dual intramuscular and intra-arterial injection of bone marrow mononuclear cells harvested from the iliac crest was performed. Major limb amputation at 3 months was the primary outcome measure. Secondary outcome measures included ankle-brachial index measurements, rest pain, and ulceration healing. Kaplan-Meier survivorship was performed to ascertain overall survivorship of the procedure. No complications related to the procedure were reported. Of 49 patients (56 limbs) enrolled, two patients (two limbs) died, but had not undergone major amputation, and five limbs (8.9%) underwent major amputation within the first 3 months. Three-month follow-up evaluations were conducted on the remaining 49 limbs (42 patients). Median postprocedure revised Rutherford and Fontaine classifications were significantly lower compared with median baseline classifications. After 3 months, seven patients (nine limbs) died but had not undergone major amputation, and seven limbs (14.3%) underwent major amputation. At a mean follow-up of 18.2 months, the remaining 33 limbs (29 patients) had not undergone a major amputation. Freedom from major adverse limb events (MALE) was 91.1% (95% confidence interval, 79.9-96.2) at 3 months and 75.6% (95% confidence interval, 59.4-86.1) at 12 months. This procedure was designed to improve limb perfusion in an effort to salvage limbs in patients for whom amputation was the only viable treatment option. The results of this analysis indicate that it is an effective strategy for limb salvage for patients with severe peripheral arterial disease.

Functional recovery of patients with ischemic cardiomyopathy treated with coronary artery bypass surgery and concomitant intramyocardial bone marrow mononuclear cell implantation--a long-term follow-up study.

Intramyocardial bone marrow mononuclear cells (BMMNC) implantation concomitant to coronary artery bypass grafting (CABG) surgery as an option for regenerative therapy in chronic ischemic heart failure was tested in a very few number of studies, with not consistent conclusions regarding improvement in left ventricular function, and with a follow-up period between 6 months and 1 year. This study was focused on testing of the hypothesis that intramyocardial BMMNC implantation, concomitant to CABG surgery in ischemic cardiomyopathy patients, leads to better postoperative long-term results regarding the primary end-point of conditional status-functional capacity and the secondary endpoint of mortality than CABG surgery alone in a median follow-up period of 5 years. A total of 30 patients with ischemic cardiomyopathy and the median left venticular ejection fraction (LVEF) of 35.9 ± 4.7% were prospectively and randomly enrolled in a single center interventional, open labeled clinical trial as two groups: group I of 15 patients designated as the study group to receive CABG surgery and intramyocardial implantation of BMMNC and group II of 15 patients as the control group to receive only the CABG procedure. All the patients in both groups received the average of 3.4 ± 0.7 implanted coronary grafts, and all of them received the left internal mammary artery (LIMA) to the left anterior descending (LAD) and autovenous to other coronaries. The group with BMMNC and CABG had the average of 17.5 ± 3.8 injections of BMMNC suspension with the average number of injected bone marrow mononuclear cells of 70.7 ± 32.4 x 10(6) in the total average volume of 5.7 ± 1.5 mL. In this volume the average count of CD34+ and CD133+ cells was 3.96 ± 2.77 x 10(6) and 2.65 ± 1.71 x 10(6), respectively. All the patients were followed up in 2.5 to 7.5 years (median, 5 years). At the end of the follow-up period, siginificantly more patients from the group that received BMMNC were in the functional class I compared to the CABG only group (14/15 vs 5/15; p = 0.002). After 6 months the results on 6-minute walk test (6-MWT) were significantly different between the groups (435 m in the BMMNC and CABG group and 315 m in the CABG only group; p = 0.001), and continued to be preserved and improved on the final follow-up (520 m in the BMMNC and CABG group vs 343 m in the CABG only group; p < 0.001). Cardiovascular mortality was also significantly reduced in the BMMNC and CABG group (p = 0.049). Implanatation of BMMNC concomitant to CABG is a safe and feasible procedure that demonstates not only the improved functional capacity but also a reduced cardiac mortality in a 5-year follow-up in patients with ischemic cardiomyopathy scheduled for CABG surgery.

Therapeutic vascular angiogenesis for intractable macroangiopathy-related digital ulcer in patients with systemic sclerosis: a pilot study

SSc causes intractable ischaemic ulcers. To avoid major amputation, we examined the safety and efficacy of therapeutic vascular angiogenesis for digital ulcers due to SSc. A single-centre, open-label pilot study was conducted in patients with an ischaemic digital ulcer [n = 40, mean age 65 years (s.d. 8), Rutherford class III-5 or III-6) due to lcSSc (n = 11) or arteriosclerosis obliterans (ASO; n = 29). Bone marrow mononuclear cells (0.4-5.1 × 10(10) cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, (99m)Tc-tetrofosmin scintigraphy and transcutaneous oxygen tension (TcPO2) before and 4 weeks after treatment. Also, the 2-year outcome was compared. There was a case of amputation in each group within 4 weeks after therapy. The pain scale significantly decreased in both groups [lcSSc 93 mm (s.d. 9) to 11 (s.d. 16), P < 0.01; ASO 77 mm (s.d. 22) to 16 (s.d. 13), P < 0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (s.d. 14), P < 0.01; ASO 18 mmHg (s.d. 10) to 29 (s.d. 21), P < 0.05). At the 2-year follow-up, the limb amputation rate was 9.1% in lcSSc and 20.7% in ASO (P = 0.36), while the recurrence rate was 18.2% in lcSSc and 17.2% in ASO (P = 0.95). All-cause mortality was 27.3% in lcSSc and 17.2% in ASO (P = 0.65). In patients with lcSSc, bone marrow mononuclear cell implantation provides clinical benefit and is safe, without major adverse reactions, and may become an effective strategy. UMIN-CTR, http://www.umin.ac.jp/ctr/index-j.htm, no. UMIN000004112.

Treatment of osteonecrosis of the femoral head with thorough debridement, bone grafting and bone-marrow mononuclear cells implantation

Osteonecrosis of the femoral head (ONFH) is a disease with a wide-ranging etiology and poorly understood pathogenesis seen commonly in young patients. Various head-preserving procedures have been used to avert the need for total hip replacement. These include vascularized and non-vascularized bone grafting procedures, bone marrow containing osteogenic precursors implanted into the necrotic lesion. We use drills, curettes, broaches under image intensifier to perform a thorough debridement of all necrotic lesion, pack autogenous cortical and cancellous bone which were harvested from the ipsilateral iliac crest tightly into the femoral head, implant bone-marrow mononuclear cells containing mesenchymal stem cells into the necrotic lesion. The study included 15 patients (20 hips, 10 males, 5 females, mean age 35 years, range 23-58 years) with stage II-III ONFH according to the association research circulation osseous classification. The outcome was determined by changes in the Harris hip score (HHS), by progression in radiographic stages, and by the need for hip arthroplasty. The mean follow-up was 24 months (range 9-36 months). The mean HHS increased from 64 to 85 points. The overall clinical success rate is 80 %. There were no infection, femoral neck fracture or other complications. Thorough debridement, autogenous bone grafting and bone-marrow mononuclear cells implantation is an effective procedure in patient with small lesion, early-stage ONFH.

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Core decompression and implantation of bone marrow mononuclear cells with porous hydroxylapatite composite filler for the treatment of osteonecrosis of the femoral head

Implanted bone marrow mononuclear cells (BMMCs) may promote both osteogenesis and angiogenesis in the femoral head. The aim of this study was to investigate the effectiveness of core decompression and implantation of BMMCs with porous hydroxyapatite bone filler for the treatment of osteonecrosis of the femoral head (ONFH). Patients with ONFH underwent core decompression and implantation of nano-hydroxyapatite/polyamide bone filler with or without BMMCs. Primary outcomes were changes in Harris hip and visual analogue scale (VAS) pain scores. Secondary outcomes included radiological and clinical success rates, adverse events, and complications. Demographic/baseline characteristics were similar between groups (BMMC, n = 17 with 26 ONFH hips; control, n = 17 with 27 ONFH hips). Harris hip scores were significantly increased (P < 0.05) in both groups of patients after surgery (last follow-up). The magnitude of increase was significantly greater in the BMMC as compared with the control group (28.6 ± 0.5 vs. 18.4 ± 1.7 %, P < 0.001). VAS scores were significantly decreased (P < 0.05) in both groups after surgery (last follow-up). The magnitude of decrease was significantly greater in the BMMC as compared with the control group (-66.3 ± 1.4 vs. -51.7 ± 2.9 %, P < 0.001). Radiological and clinical success rates were significantly higher in the BMMC as compared with the control group (82.5 vs. 40.7 % and 75.4 vs. 37.0 %, respectively, P < 0.001). Postoperative collapse of the femoral head was less common in the BMMC as compared with the control group (17.5 vs. 59.3 %, P < 0.01). Both core decompression with or without implantation of BMMC are effective treatment for ONFH. However, core decompression with implantation of BMMCs and porous hydroxyapatite bone filler may be a more effective treatment for ONFH.

Effects of Autologous Bone Marrow Mononuclear Cells Implantation on Cholangiocytes Apoptosis in Model of Intrahepatic Ischemic Type Biliary Lesion in Rabbits

AimTo investigate the effects of autologous bone marrow mononuclear cells (BM-MNCs) implantation on regulation of cholangiocyte apoptosis in a model of intrahepatic ischemic type biliary lesion (ITBL) in rabbits. Materials and MethodsThirty Japanese white rabbits were divided randomly into 3 groups (10 per group) including controls (group A), ITBL model (group B), and BM-MNCs implantation groups (group C). All rabbits underwent the same surgical procedure to prepare the liver for graft removal during transplantation. Subsequently, no additional vascular intervention was performed in group A. In group B, the hepatic artery and common bile duct were clamped with microvascular clips for 2 hours, where after the clips were removed to recover the blood supply. Group C received, BM-MNCs (108 cells per rabbit) injected through the hepatic artery after removing the clips. The animals were killed 4 weeks after operation. The survival rate, histopathologic examination, cholangiocyte apoptosis with terminal uridine nick-end labeling (TUNEL) staining and expressions of Bcl-2 and Bax proteins were examined using immunohistochemical staining. ResultsGroup A animals showed a survival of 100%; the rates in groups B and C were both 90%. Histopathologic examination revealed normal intrahepatic cholangiocytes in group A, obviously damaged ones in group B, and alleviated damage in group C. TUNEL staining indicated apoptosis of cholangiocytes in group B was more serious than that in group A or group C. Immunohistochemical staining demonstrated significantly decreased Bcl-2 expression in group B compared with that in group A; Bcl-2 expression in group C returned to the level of group A. Simultaneously, the Bax expression presented adverse results; the ratios of Bcl-2/Bax were ranked as group A > group C > group B. ConclusionImplantation of autologous BM-MNCs significantly reduced apoptosis of intrahepatic cholangiocytes and prevented or abated intrahepatic ITBL.

Autologous bone marrow mononuclear cell implantation for intracerebral hemorrhage—A prospective clinical observation

BackgroundThis study was designed to assess the clinical effect of bone marrow mononuclear cells including mesenchymal stem cell (MSCs) in patients with intracerebral hemorrhage (ICH). MethodsOne hundred patients were divided into a study (n=60) or a control group (n=40). Bone marrow mononuclear cells from the same patient were injected to the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.9days after ICH. National Institute Stroke Scale (NIHSSS) and Barthel index was used to assess neurologic impairment and daily activities, respectively, before and 6months after intervention. ResultsSix months after implantation, the NIHSS score in the study group was lower than in the control group (10.09±8.86 vs 14.35±10.14, P<0.01), whereas the Barthel scores were higher (57.39±23.51 vs 46.90±20.29, P<0.01). Neurological and functional improvement was observed in 52 (86.7%) of the study group patients, and in 17 (42.5%) of the control group patients (P=0.001). No allergic or other adverse effects were observed in the study group. ConclusionAutologous bone marrow mononuclear cell implantation reduced neurological impairment and improved activities of daily living in a selected group of ICH patients. Further studies are required to ascertain the long-term safety and efficacy of this treatment.