Autologous Bone Marrow Mononuclear Cells Research Articles

A Personalized Cell-Based Therapy for Ischemic Heart Failure With Reduced Ejection Fraction: Safety and Feasibility Outcomes of the Roll-In Cohort of the CardiAMP Cell Therapy Trial and Review of Similar Trials.

CardiAMP Cell Therapy for Heart Failure trial is a prospective, multicenter, randomized, controlled, double-blinded trial that has been granted breakthrough designation by the United States Food and Drug Administration. This trial evaluates clinical outcomes of intramyocardial delivery of a high dose of autologous bone marrow mononuclear cells in chronic postmyocardial infarction heart failure patients. This trial represents the first attempt to personalize marrow-derived cell-based therapy for the treatment of ischemic heart failure with reduced ejection fraction. The roll-in cohort of 10 patients demonstrated improvements in 6-minute walk distance at 6 months (+47.8 m, P = 0.01), 12 months (+46.4 m, P = 0.06), and 24 months (+31 m), and improvements in New York Heart Association class at 3 months (P = 0.015) and 6 months (P = 0.037). Four patients were reduced to New York Heart Association class I at 24 months and Minnesota Living with Heart Failure Questionnaire score was improved in 6 of 10 patients at 24 months. The improved clinical outcomes demonstrated in CardiAMP are consistent with previous clinical trials including the Transendocardial Autologous Cells in Ischemic Heart Failure (TAC-HFT) trial, Prospective Randomized Trial of Direct Endomyocardial Implantation of Bone Marrow Cells for Treatment of Severe Coronary Artery Diseases (PROTECT-CAD), and REGENERATE-Ischemic Heart Disease trial.

Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.

Fetal progenitor cells for treatment of chronic limb ischemia.

This study investigated the therapeutic potential of fetal progenitor cells (FPCs) in the treatment of chronic non-healing wounds and ulcers associated with chronic limb ischemia (CLI). The research aimed to elucidate the mechanism of action of FPCs and evaluate their efficacy and safety in CLI patients. The researchers isolated FPCs from aborted human fetal liver, brain, and skin tissues and thoroughly characterized them. The preclinical phase of the study involved assessing the effects of FPCs in a rat model of CLI. Subsequently, a randomized controlled clinical trial was conducted to compare the efficacy of FPCs with standard treatment and autologous bone marrow mononuclear cells in CLI patients. The clinical trial lasted 12 months, with a follow-up period of 24-36 months. The primary outcomes included wound healing, frequency of major and minor amputations, pain reduction, and the incidence of complications. Secondary outcomes involved changes in local hemodynamics and histological, ultrastructural, and immunohistochemical assessments of angiogenesis. In the animal model, FPC treatment significantly enhanced angiogenesis and accelerated healing of ischemic wounds compared to controls. The clinical trial in CLI patients demonstrated that the FPC therapy achieved substantially higher rates of complete wound closure, prevention of major amputation, pain reduction, and improvement in ankle-brachial index compared to control groups. Notably, the study reported no serious adverse events. FPC therapy exhibited remarkable efficacy in promoting the healing of ischemic wounds, preventing amputation, and improving symptoms and quality of life in patients with CLI. The proangiogenic and provasculogenic effects of FPCs may be attributed to their ability to secrete specific growth factors. These findings provide new insights into the development of cellular therapeutic angiogenesis as a promising approach for the treatment of peripheral arterial diseases.

Autologous intraarterial pancreatic bone-marrow mononuclear cells infusion in T2D patients: Changes on beta-cells function, insulin resistance, and inflammatory marker

BackgroundType 2 diabetes (T2D) is a progressive disease. Many drugs currently being used for the management of T2D have minimal effect on pancreatic beta cells regeneration. Cell-based therapies might provide potential benefits in this aspect. MethodsA pilot study in five T2D patients with 12 months follow-up was performed to evaluate the effect of autologous bone marrow mononuclear stem cells (BM-MNCs) infusion into pancreatic arteries on the insulin requirement, beta-cell function, insulin resistance, and systemic inflammatory marker (CRP). ResultsThe primary endpoint, a 50 % reduction of total insulin doses from baseline, was not achieved in this study. However, a trend of increasing fasting C-peptide (p = 0.07) and C-peptide 60′ (p = 0.07) and 90′ (p = 0.07) after a mixed-meal tolerance test was observed 12 months post-infusion compared to baseline levels. A similar result was observed for the homeostatic model assessment of beta cell function (HOMA1-B), an index for beta cell function. No improvement was observed for insulin resistance measured by homeostasis model assessment of insulin resistance (HOMA1-IR) and systemic inflammatory parameter. ConclusionIntraarterial pancreatic autologous BM-MNCs infusion might potentially improve beta cell function in T2D patients, although further study is needed to confirm this finding.

Inflammatory mediators drive neuroinflammation in autism spectrum disorder and cerebral palsy

Inflammation conditions are associated with autism spectrum disorder (ASD) and cerebral palsy (CP), primarily observed in the peripheral immune system. However, the extent of neuro-inflammation and neuro-immune dysregulation remains poorly studied. In this study, we analyzed the composition of cerebrospinal fluid (CSF) to uncover the inflammatory mediators driving the neuro-immune system in ASD and CP patients. Our findings revealed that ASD patients had elevated levels of four inflammatory cytokines (TNF-α, IL-4, IL-21, and BAFF) compared to controls, while CP patients exhibited increased levels of eight inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, IL-6, IL-17A and IL-12), one anti-inflammatory cytokine (IL-10), and five growth factors (GFs) (NGF-β, EGF, GDF-15, G-CSF and BMP-9) compared to both controls and ASD patients. Additionally, intrathecal infusion of autologous bone marrow mononuclear cells (BMMNCs) led to a slight decrease in TGF-β and GDF-15 levels in the CSF of ASD and CP patients, respectively. Our study provides new insights into the molecular composition of CSF in ASD and CP patients, with the potential to develop more effective diagnosis methods and improved treatment for these diseases.Clinical trial registration CSF samples used in this study are from clinical trials NCT03225651, NCT05307536, NCT02569775, NCT03123562, NCT02574923, NCT05472428 and previous reports [7, 9, 17–19].

Коррекция гепатоцеллюлярной недостаточности путем внутрипортального введения мононуклеарных клеток аутологичного костного мозга при циррозе печени: опыт ГБУЗ ГКБ им. С.П. Боткина ДЗМ

Hepatic failure is one of the most common manifestation of liver cirrhosis. Currently, there are no medication or invasive procedure, which can reliably improve liver function. Research on the use of autologous bone marrow mononuclear stem cells to correct the morphofunctional manifestations of acute and chronic liver failure is encouraging. This clinical case demonstrates the safety and clinical effectiveness of intraportal administration of autologous bone marrow mononuclear cells obtained by apheresis after stimulation with granulocyte-macrophage colony-stimulating factor.

PET imaging of microglia using PBR28suv determines therapeutic efficacy of autologous bone marrow mononuclear cells therapy in traumatic brain injury

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of rats: Sham, CCI-alone and CCI-BMMNCs (AUTO). One hundred twenty days after injury, rodents were imaged with PBR28 and their cognitive behavior assessed utilizing the Morris Water Maze. Subsequent ex vivo analysis included brain volume and immunohistochemistry. BMMNCs therapy attenuated PBR28suv in comparison to CCI alone and it improved spatial learning as measured by the Morris Water Maze. Ex vivo analysis demonstrated preservation of brain volume, a decrease in amoeboid-shaped microglia in the dentate gyrus and an increase in the ratio of ramified to amoeboid microglia in the thalamus. PBR28suv is a viable option to measure efficacy of BMMNCs therapy after TBI.

A novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells

BackgroundChronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI.MethodsWe performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford’s classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford’s classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire).ResultsNo adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford’s classification, a significant increase in TcPO2 values‬, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation.ConclusionsOur results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group.Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).

Osteochondral Regeneration Ability of Uncultured Bone Marrow Mononuclear Cells and Platelet-Rich Fibrin Scaffold.

Platelet-rich fibrin (PRF) and bone marrow mononuclear cells are potential scaffolds and cell sources for osteochondral regeneration. The main aim of this paper is to examine the effects of PRF scaffolds and autologous uncultured bone marrow mononuclear cells on osteochondral regeneration in rabbit knees. Three different types of PRF scaffolds were generated from peripheral blood (Ch-PRF and L-PRF) and bone marrow combined with uncultured bone marrow mononuclear cells (BMM-PRF). The histological characteristics of these scaffolds were assessed via hematoxylin-eosin staining, PicroSirius red staining, and immunohistochemical staining. Osteochondral defects with a diameter of 3 mm and depth of 3 mm were created on the trochlear groove of the rabbit's femur. Different PRF scaffolds were then applied to treat the defects. A group of rabbits with induced osteochondral defects that were not treated with any scaffold was used as a control. Osteochondral tissue regeneration was assessed after 2, 4, and 6 weeks by macroscopy (using the Internal Cartilage Repair Society score, X-ray) and microscopy (hematoxylin-eosin stain, safranin O stain, toluidine stain, and Wakitani histological scale, immunohistochemistry), in addition to gene expression analysis of osteochondral markers. Ch-PRF had a heterogeneous fibrin network structure and cellular population; L-PRF and BMM-PRF had a homogeneous structure with a uniform distribution of the fibrin network. Ch-PRF and L-PRF contained a population of CD45-positive leukocytes embedded in the fibrin network, while mononuclear cells in the BMM-PRF scaffold were positive for the pluripotent stem cell-specific antibody Oct-4. In comparison to the untreated group, the rabbits that were given the autologous graft displayed significantly improved healing of the articular cartilage tissue and of the subchondral bone. Regeneration was gradually observed after 2, 4, and 6 weeks of PRF scaffold treatment, which was particularly evident in the BMM-PRF group. The combination of biomaterials with autologous platelet-rich fibrin and uncultured bone marrow mononuclear cells promoted osteochondral regeneration in a rabbit model more than platelet-rich fibrin material alone. Our results indicate that autologous platelet-rich fibrin scaffolds combined with uncultured bone marrow mononuclear cells applied in healing osteochondral lesions may represent a suitable treatment in addition to stem cell and biomaterial therapy.

Outcomes of autologous bone marrow mononuclear cell administration in the treatment of neurologic sequelae in children with spina bifida

BackgroundTo evaluate the safety and efficacy of autologous bone marrow mononuclear cell (BMMNC) infusion in the management of neurological sequelae in children with spina bifida (SB).MethodsBMMNCs were harvested from bilateral anterior iliac crests. Two intrathecal BMMNC administrations were performed with an interval of 6 months. The measurements of outcomes included clinical assessments, cystomanometry and rectomanometry.ResultsEleven children with SB underwent autologous BMMNC infusions from 2016 to 2020. There were no severe adverse events during the study period. The number of patients requiring assistance to expel stools decreased from 11 before cell infusion to 3 after the second cell infusion. The number of patients who had urine leakage decreased from 9 patients at baseline to 3 patients after the second BMMNC infusion. The mean bladder capacity increased from 127.7 ± 59.2 ml at baseline to 136.3 ± 54.8 ml at six months and to 158.3 ± 56.2 ml at 12 months after BMMNC infusions. Detrusor pressure (pdet) decreased from 32.4 ± 22.0 cm H2O at baseline to 21.9 ± 11.8 cm H2O after 12 months of follow-up. At baseline, six patients could walk independently. After the 2nd infusion, eight patients could walk independently.ConclusionIntrathecal infusions of autologous bone marrow mononuclear cells are safe and may improve bowel, bladder, and motor function in children with SB.Trial registration: NCT, NCT05472428. Registered July 25, 2022- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT05472428.

Clinical outcomes of autologous platelet-rich plasma and bone marrow mononuclear cells grafting combined with core decompression for Association Research Circulation Osseous II-IIIA stage non-traumatic osteonecrosis of the femoral head.

This study aimed to investigate the efficacy and safety of autologous platelet-rich plasma (PRP) and bone marrow mononuclear cells (BMMCs) grafting combined with core decompression (CD) in the treatment of Association Research Circulation Osseous (ARCO) II-IIIA stage non-traumatic osteonecrosis of the femoral head (ONFH). The clinical data of 44 patients (44 hips) with non-traumatic ONFH from December 2018 to December 2019 were retrospectively reviewed. Twenty-four patients underwent CD combined with autologous PRP and BMMCs grafting (PRP+BMMCs group), and 20 patients underwent core decompression alone (CD group). During a minimum follow-up of 36 months, radiographic outcomes were evaluated using X-ray, radiographic failure rates were compared, and Harris hip score (HHS) and visual analog scale (VAS) were selected to evaluate clinical outcomes. The percentage of patients with minimal clinically important difference (MCID) in both groups was analyzed. Clinical failure was defined as further total hip arthroplasty (THA) with Kaplan-Meier survival analysis. Surgical complications were recorded. All patients had well healed wounds, and no complications such as infection and thrombosis occurred. HHS and VAS scores in both the PRP+BMMCs and CD groups were better than those preoperatively (P<0.05). At the last follow-up, the HHS and VAS scores of the PRP+BMMCs group were significantly better than those of the CD group (P<0.05). In ARCO II-IIIA stage, 66.7% of the PRP+BMMCs group and 30.0% of the CD group achieved the MCID (P<0.05). The clinical and imaging failure rates in the PRP+BMMCs group were 12.5% and 20.8%, respectively, compared with 40.0% and 50.0% in the CD group (P<0.05). In ARCO II stage, the MCID, clinical and imaging failure rates of PRP+BMMCs group and CD group were 66.7% and 33.3% (P<0.05), 4.8% and 33.3% (P<0.05), 14.3% and 44.4% (P<0.05), respectively. The PRP+BMMCs group had better hip survival rate compared with CD group (P<0.05). CD combined with autologous PRP and BMMCs grafting is a safe and effective method for the treatment of ARCO II-IIIA stage non-traumatic ONFH, especially for ARCO II stage, effectively reducing the collapse rate of the femoral head and delaying or even avoiding THA.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction

Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference=2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial

Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Role of Vascular Endothelial Growth Factor-C during Stem Cell Therapy Using Autologous Bone Marrow Mononuclear Cells in Patients with Lower Limb Lymphedema

Introduction: Vascular endothelial growth factor-C (VEGF-C) is the primary lymphangiogenic factor that stimulates lymphangiogenesis by signaling via specific receptor, vascular endothelial growth factor receptor 3 (VEGFR3). This study was conducted to evaluate the change in the level of VEGF-C before and after autologous bone marrow mononuclear cell transplantation for treatment of Lower limb lymphedema. Patient and methods: Forty patients with lower limb lymphedema were divided into two groups. Group I included 20 patients with chronic lower limb lymphedema who underwent autologous bone marrow mononuclear cell transplantation. Group II included 20 patients with chronic lower limb lymphedema who were exposed only to compression therapy as a control group. VEGF-C level in the diseased limbs was measured in both groups at the beginning of the study then 3 and 6 months respectively. Results: Group I included 20 patients, 8 patients were male (40%) and 12 patients were females (60%) with mean age 29.5 ± 12.15 while group II included 20, 10 patients were male (50%) and 10 patients were females (50%) with mean age 39.5 ± 11.5. In group I, the specimens were taken at 3 and 6 months after transplantation showed a marked decrease in the VEGF-C level with statistically significant p value, 0.02 and 0.001 respectively. In group II the level of VEGF-C after compression therapy alone at 3 and 6 months interval showed fluctuation with statistically non-significant p value, 0.64 and 0.55 respectively. Conclusion: VEGF-C is essential for regulation of lymphangiogenesis. The level of VEGF-C was found elevated in patients with lymphedema and decrease after autologous mononuclear bone marrow cells, however these results were statically non-significant.

Abstract 10915: Microvascular Obstruction Identifies a Subgroup of Patients Who Benefit From Intracoronary Stem Cell Delivery Following ST-Elevation Myocardial Infarction

Aims: Microvascular obstruction (MVO) following ST-elevation myocardial infarction (STEMI) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction. We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. Methods and Results: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs as part of 3 clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot (n=157), the multi-center French BONAMI trial (n=91) and the SWISS-AMI trial (n=108). All patients received 100 - 150 million intracoronary autologous BMCs or placebo / control 3 - 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n=210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (all p &lt; 0.01) (TABLE). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7 %; p &lt; 0.05). Similarly, the changes in left-ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were consistent with significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo ( % change; LVEDV = -9.7%; p &lt; 0.05 and LVESVI = -14.7 %; p = 0.006). In contrast, patients without MVO experienced no benefit of BMC administration compared to placebo. Conclusion: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who may benefit from intracoronary stem cell delivery of BMCs.

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.

Autologous bone marrow mononuclear cells in the treatment of chronic limb-threatening ischaemia: a proof-of-concept trial

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): 1. Iniciativa Andaluza en Terapias Avanzadas 2. Fundación Progreso y Salud Background Chronic limb threatening ischaemia (CLTI) is a debilitating condition often leading to gangrene which necessitates amputation. Endovascular or surgical interventions remain the standard treatment, however, not all patients are suitable for such procedures. The aim of cell-based therapies is to harvest progenitor cells either from the patient (i.e., autologous) or other sources and re-administer them at a higher concentration near/at the ischemic site(s) to potentiate vasculogenesis. Aim The objective of this trial was to assess the efficacy, safety, and feasibility of treating CLTI with autologous bone marrow mononuclear cells (BM-MNC). Methods This multicentre, phase II, open-label, randomized clinical trial conducted between 2009 and 2011 consisted of adult diabetic patients with CLTI Rutherford grade II or III of at least one lower limb who were not suitable for surgical revascularization. Sixty eligible patients were randomly assigned to one of three treatment groups (1x108, or 5x108, or 1x109 BM-MNCs) or to the control group (standard of care treatment). The cell-product was prepared from the baseline bone marrow aspirate of the treated patients and injected intra-arterially proximal to the vessel occlusion under general anaesthesia &amp;lt;72 hours after bone marrow aspiration. The control patients did not undergo bone marrow aspiration. Ulcer healing and amputation variables were evaluated in all patients at baseline and months 1, 3, 6, 9 and 12. Results The sample demographics were similar in each arm. A total of 50 males and 10 females were enrolled into the trial, with mean age of 63.9 (SD=9.4) years, and mean body mass index of 27.8 Kg/m2 (SD=4.1). The average years living with diabetes was 18.6 years, and time since diagnosis of CLTI was 0.78 years (SD: 1.12 years). A clinically meaningful treatment effect was observable at 6 months, and at 12 months baseline ulcers in 75% of treated patients were completely healed, compared to 14% of control patients (P=0.0142). Furthermore, the ulcers of the treated patients were on average 19.66 mm smaller than those of the control patients (P&amp;lt;0.0001). These results corresponded to angiographical outcomes where vasculogenesis was observed in approximately half of the treated patients who improved in Rutherford Grade. There were no differences in amputation rates across arms. No pertinent covariates which might have impacted the outcomes were identified. No treatment-associated adverse events occurred in the trial. Conclusion Autologous BM-MNC is an effective therapeutic alternative in patients unsuitable for surgical or endovascular revascularization.

Acellular cartilage matrix biomimetic scaffold with immediate enrichment of autologous bone marrow mononuclear cells to repair articular cartilage defects.

Functional repair of articular cartilage defects is always a great challenge in joint surgery clinically. Tissue engineering strategies that combine autologous cell implantation with three-dimensional scaffolds have proven effective for repairing articular cartilage tissue. However, it faces the problem of cell sources and scaffold materials. Autologous chondrocytes and bone marrow are difficult to popularize clinically due to limited donor sources and low mononuclear cell (MNC) concentrations, respectively. The density gradient centrifugation method can increase the concentration of MNCs in fresh bone marrow by nearly a hundredfold and achieve immediate enrichment. In addition, acellular cartilage matrix (ACM), with good biocompatibility and a cartilage-specific microenvironment, is considered to be an ideal candidate scaffold for cartilage regeneration. In this study, hybrid pigs were used to establish articular cartilage defect models of different sizes to determine the feasibility and maximum scope of application of ACM-based biomimetic scaffolds combined with MNCs for inducing articular cartilage regeneration. Importantly, ACM-based biomimetic scaffolds instantly enriched MNCs could improve the repair effect of articular cartilage defects in situ, which established a new model of articular cartilage regeneration that could be applied immediately and suited for large-scale clinical promotion. The current study significantly improves the repair effect of articular cartilage defects, which provides scientific evidence and detailed insights for future clinical applications of ACM-based biomimetic scaffolds combined with MNCs.

Autologous Bone Marrow Mononuclear Cells (BMMC)-Associated Anti-Inflammatory Nanoparticles for Cardiac Repair after Myocardial Infarction.

To investigate the effect of transplantation of stem cells from the bone marrow mononuclear cells (BMMC) associated with 15d-PGJ2-loaded nanoparticles in a rat model of chronic MI. Chronic myocardial infarction (MI) was induced by the ligation of the left anterior descending artery in 40 male Wistar rats. After surgery, we transplanted bone marrow associated with 15d-PGJ2-loaded nanoparticle by intramyocardial injection (106 cells/per injection) seven days post-MI. Myocardial infarction was confirmed by echocardiography, and histological analyses of infarct morphology, gap junctions, and angiogenesis were obtained. Our results from immunohistochemical analyses demonstrated the presence of angiogenesis identified in the transplanted region and that there was significant expression of connexin-43 gap junctions, showing a more effective electrical and mechanical integration of the host myocardium. This study suggests that the application of nanoparticle technology in the prevention and treatment of MI is an emerging field and can be a strategy for cardiac repair.

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.