Implantation Of Bone Marrow 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.

Therapy with bone marrow mesenchymal stem cells in bone regeneration in children with osteonecrosis secondary to sickle cell disease.

This study aimed to describe the evolution of bone regeneration in children with hip osteonecrosis associated with sickle cell disease, treated with bone marrow-derived mesenchymal stem cell implants at the Professor Edgar Santos University Hospital Complex. A non-randomized clinical trial was conducted with 48 patients of both sexes, aged between 11 and 18years, diagnosed with femoral head osteonecrosis secondary to sickle cell disease. Patient selection was based on strict criteria, including confirmed diagnosis of sickle cell anemia and a stage of osteonecrosis compatible with the proposed treatment. Bone regeneration assessment was performed through radiographic examinations and magnetic resonance imaging, following the Ficat & Arlet criteria and the Salter-Thompson classification. Statistical analysis revealed a significant association between the patients' age and positive treatment outcomes, suggesting that autologous bone marrow cell implantation is a safe and effective approach in the early stages of osteonecrosis. The majority of patients (87.5%) reported complete pain relief, while 10.42% experienced significant symptom improvement. Only one patient (2.08%) did not observe improvement. The results indicate that cell therapy can regenerate or slow the progression of bone necrosis, reducing the need for more invasive surgical procedures. The study demonstrates the potential of bone marrow-derived mesenchymal stem cell implantation in treating hip osteonecrosis in children with sickle cell disease, emphasizing the importance of long-term monitoring of bone structure stability.

Efficacy of treatment of lower-limb critical ischaemia by methods of indirect revascularization

The study was aimed at comparing the efficacy of implantation of autologous bone marrow cells with that of revascularizing osteotrephination in treatment of lower limb chronic critical ischaemia in patients with a poor distal vascular bed. We analysed the results of comprehensive examination and treatment of a total of 60 patients presenting with lower limb chronic critical ischaemia due to atherosclerotic lesions of the femoropopliteal-tibial segment. According to the technology of treatment, the patients were divided into two statistically homogenous groups of 30 people each. Group One patients underwent standard revascularizing osteotrephination and Group Two patients in accordance with the original technique received intramuscular implantation of 40 ml of autologous bone marrow cells, with this volume distributed in 2-ml injections to 20 points of the muscles of the crus and femur along the internal and external surface. The use of the original technique of treatment made it possible to achieve the clinical status in the form of moderate or minimal improvement 6 months after bone marrow cells implantation in 29 (96.7%) patients and after 12 months in 28 (93.3%) patients, whereas after revascularizing osteotrephination in 25 (83.3%) and 20 (66.7%) patients, respectively. In the remote period after 12 months, the limb was saved in 28 (93.3%) and 26 (86.7%) patients in Group Two and Group One, respectively. The patients of the second group as compared with those of the first group after 12 months demonstrated a statistically significant increase in the physical health component by 19.8% and the mental health component by 9.8%. Implantation of autologous bone-marrow cells in chronic critical limb ischaemia is pathogenetically substantiated and makes it possible to optimize the results of treatment of patients.

One-year results of the treatment of critical lower limb ischemia with indirect revascularization methods

The OBJECTIVEwas to compare the efficiency of autologous bone marrow cell implantation and lumbar sympathectomy in the treatment of chronic critical lower limb ischemia.MATERIAL AND METHODS. The complex examination and treatment of 66 patients with critical lower limb ischemia, divided into 2 statistically homogeneous groups, was analyzed. The first group underwent sympathectomy, and the second – autologous bone marrow cell transplantation.RESULTS. After 1 year, in patients of the second group, compared with the first, the clinical status increased by 51.5 %, the number of amputations decreased by 3 %, the physical component of health increased by 7.9 %, the psychological component – by 17.7 %.CONCLUSION. The autologous bone marrow cell transplantation was pathogenetically substantiated and effective.

The results of intramyocardial implantation of autologous bone marrow cells treated with erythropoietin in the surgical treatment of coronary artery disease with severe lesion of vessels

Aim. To assess safety and efficacy of intramyocardial implantation of autologous bone marrow cells treated with erythropoietin in surgery for coronary artery disease (CAD).Materials and methods. Eighty patients with CAD with diffuse and (or) distal lesions of the right coronary artery were randomly assigned to two groups: patients of group 1 (n=40) underwent coronary bypass surgery, implantation of autologous bone marrow cells treated with erythropoietin into the lower wall of the left ventricle, patients of group 2 (control group, n=40) underwent bypass surgery of the left coronary artery. Evaluation of the clinical status, perfusion and contractility of the myocardium was performed initially, 6 and 12 months after surgery.Results. Six months after the operation, we found more pronounced decrease of functional class (FC) of angina and improvement in the 6-min walk distance in the main group compared with the control group.Twelve months after surgery, the severity of angina remained at the same level in both groups. In the control group, 45,2% of patients had FC I, 52,3% of patients did not have angina. In both groups, angina return was detected in 1 patient (FC III). According to the results of two-step myocardial scintigraphy with Technetril (Tc99), 6 months after surgery, a significant improvement in myocardial perfusion was observed. In the control group, after 6 months, no significant dynamics of perfusion of the lower wall of the left ventricle was detected.Twelve months after the surgical treatment of the right coronary artery in patients from the group 1 revealed a decrease in the stress defect and the stable perfusion defect. In patients from the control only a significant stress defect was found to decrease.Conclusion. The study demonstrated decrease of FCs, significant improvement in perfusion, functional state of the myocardium and 6-min walk distance in patients of group 1.

Clinical and functional evaluation of intramyocardial implantation of autologous bone marrow cells treated with erythropoietinduring the CAD surgery (6-month results)

Aim.Clinical and functional evaluation of the implantation of autologous bone marrow cells treated with erythropoietin in laser channels during coronary bypass grafting in patients with end-stage coronary lesion.Materials and methods.60 patients with coronary artery disease with diffuse and (or) distal right coronary artery disease were randomized into two groups: patients of group 1 (n = 30) underwent coronary bypass grafting, implantation of autologous bone marrow cells treated with erythropoietin in laser channels, patients of the 2nd group (n = 30) were operated with coronary bypass grafting of the left coronary artery system. Assessment of the clinical status, myocardial perfusion and contractility was performed initially, 6 months after the operation.Results.Six months after the operation, there was a more pronounced decrease in angina pectoris (CCS) in the main group compared to the control group, also we revealed a 6-minute walk test scores improvement. Based on two-stage scintigraphy (Tc99) in the main group before the surgical treatment, a rest perfusion defect was 8.5% [3.5, 18.5], a stress-induced perfusion defect – 7.0% [6.0, 12, 3]. In the control group, the rest defect was 9.1% [5.6, 12.4], the stress-induced perfusion defect was 7.3% [6.1, 8.7]. 6 months after surgery rest perfusion defect at the indirect revascularization group was 6.0% [2.5, 16.5] (p = 0.008), a stress-induced defect was 4.0% [1.5, 6.3] (p = 0.05). In the control group, the rest defect was 8.7% [5.3, 10.3], the stress-induced perfusion defect was 6.8% [5.3, 9.1] (p = 0.21). The results of scintigraphy with MIBG showed a left ventricle innervation defect (PID) significant decrease in the main group: initially 15.4% [14.2, 16.3], after 6 months 11.7% [9.3, 13, 2] (p = 0.045). In the control group, there was an unreliable decrease in PID: initially 14.3% [10.2, 17.3], after 6 months 13.8% [9.1, 14.2] (p = 0.14).Conclusion.Our preliminary results revealed more pronounced effect of the new indirect revascularization method expressed as in myocardial perfusion improve, myocardial sympathetic innervation restoration and clinical status improvement in comparison with control group.

Transmiocardial laser revascularization in combination with bone marrow cells implantation in the ischemic heart disease surgery: long-term results

Transmiocardial laser revascularization in combination with bone marrow cells implantation in the ischemic heart disease surgery: long-term results

Autologous Bone Marrow Cell Stimulation and Allogenic Chondrocyte Implantation for the Repair of Full-Thickness Articular Cartilage Defects in a Rabbit Model.

The aim of this study was to evaluate the results of autologous bone marrow cell stimulation and allogenic chondrocyte implantation using 3-dimensional gel-type fibrin matrix in an animal model. Eighteen rabbits were divided into 2 treatment groups. One group was treated with a microfracture and covering of it with gel-type fibrin (AutoBMS; n = 9), and the other group was treated with allogenic chondrocytes mixed gel-type fibrin at the cartilage defect (AlloCI; n = 9). The control group was untreated cartilage defect at the other side knee of each object. Twelve weeks after treatment, the cartilage was evaluated using the International Cartilage Repair Society (ICRS) scoring system, immunohistochemical staining, and modified O'Driscoll grading system. The ICRS scores were similar in the AutoBMS (9.44 ± 2.44) and the AlloCI (9.33 ± 1.67) groups ( P < 0.05). Immunohistochemical staining confirmed higher expression of cartilaginous collagen for both groups. The average difference (AutoBMS, 31.89 ± 6.54; AlloCI, 32.89 ± 5.25) in the modified O'Driscoll scores appeared to be nonsignificant ( P > 0.05); however, both treatment groups showed significantly higher scores with respect to their control group (18.45 ± 1.65; 18.97 ± 1.58) ( P < 0.05). This experimental study suggests autologous bone marrow cells stimulation and implantation of allogenic chondrocytes are both useful methodologies for regenerating hyaline-like cartilage in full-thickness cartilage defects in animal model.

LONG-TERM RESULTS OF TRANSMYOCARDIAL LASER REVASCULARIZATION COMBINED WITH IMPLANTATION OF AUTOLOGOUS BONE MARROW MONONUCLEAR FRACTION IN THE TREATMENT OF CHRONIC ISCHEMIC HEART DISEAS

Aim. Clinical and instrumental assessment of long-term results of autologous bone marrow cells (BMC) implantation in laser channels in surgery of ischemic heart disease with diffuse and distal coronary disease.Materials and Methods. In the period of 2007–2008 35 CHD patients with diffuse and distal coronary disease underwent BMC implantation in laser channels during coronary artery bypass grafting (CABG). The control group consisted of 29 patients. All patients in this group underwent only direct myocardial revascularization (DMR). In the long-term period we examined only 30 patients of the first group. Clinical and instrumental assessment of the method efficacy was carried out in 2 weeks, 6 months and 6 years after surgery.Results. FC (NYHA) mean value in indirect revascularization group significantly decreased from 2.57 ± 0.61 preoperatively to 1.77 ±0.66 in6 months after surgery (p = 0.043). After 6 years FC (NYHA) was not significantly changed – 1.84 ± 0.42 (p = 0.053). Perfusion scintigraphy revealed a slight decrease of stable perfusion defect (SPD) in the immediate postoperative period, a more pronounced reduction of SPD in 6 months after surgery. The average value of SPD before surgery was 20.46 ± 10.75%, in 2 weeks after the operation – 19.07 ± 9.69%, in 6 months after surgery – 15.22 ± 9.49%. In the long-term period (6 years) SPD was 14.8 ± 8.43% (p = 0.047). A similar pattern was observed in the analysis of transient perfusion defect: baseline – 30 ± 2.2%, in 6 months – 15 ± 1.3%, in the long term period – 20 ± 6.1% (p = 0.047). The average value of left ventricular ejection fraction (LVEF) before surgery was 55 ± 10.4%, in 2 weeks after the operation – 55.7 ± 9.3%, in 6 months – 56.7 ± 10%, after 6 years – 54 ± 12%. The dynamics is unauthentic (p = 0.068).Conclusion. BMC implantation in laser channels in addition to CABG is a safe and effective method of surgical treatment in case of CABG inability. The effect of indirect revascularization is formed in the first 6 months after surgery and remains at the same level for 6 years.

Effect of Stem Cell Therapy on Bone Mineral Density: A Meta-Analysis of Preclinical Studies in Animal Models of Osteoporosis.

BackgroundPreclinical studies of the therapeutic role of stem cell based therapy in animal models of osteoporosis have largely yielded inconsistent results. We performed a meta-analysis to provide an overview of the currently available evidence.MethodsPubmed, Embase and Cochrane Library databases were systematically searched for relevant controlled studies. A random-effect model was used for pooled analysis of the effect of stem cell based therapy on bone mineral density (BMD). Stratified analyses were performed to explore the effect of study characteristics on the outcomes.ResultsPooled results from 12 preclinical studies (110 animals in stem cell treatment groups, and 106 animals in control groups) indicated that stem cell based treatment was associated with significantly improved BMD (standardized mean difference [SMD] = 1.29, 95% Confidence Interval [CI]: 0.84–1.74, P < 0.001) with moderate heterogeneity (Cochrane’s Q test: P = 0.02, I2 = 45%) among the constituent studies. Implantation of bone marrow cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, and human umbilical cord blood-derived CD34+ cells, were all associated with improved BMD as compared to that in the controls (P < 0.05 for all); the only exception being the use of embryonic stem cell transplantation (P > 0.05). Egger’s test detected potential publication bias (P = 0.055); however, ‘trim and fill’ analysis yielded similar results after statistically incorporating the hypothetical studies in the analysis (SMD = 1.24, 95% CI: 0.32–2.16, P < 0.001).ConclusionsStem cell transplantation may improve BMD in animal models of osteoporosis. Our meta-analysis indicates a potential therapeutic role of stem cell based therapy for osteoporosis, and serves to augment the rationale for clinical studies.

Preliminary Results of Multiple Epiphyseal Drilling and Autologous Bone Marrow Implantation for Osteonecrosis of the Femoral Head Secondary to Sickle Cell Disease in Children.

Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) during childhood. The natural history of ONFH in SCD is poor with progression to femoral head collapse and deformity that ultimately may lead to hip osteoarthritis. Multiple epiphyseal drilling with autologous bone marrow implantation may enhance the mechanism of osteogenic repair. The purpose of this study was to describe early clinical and radiographic outcomes in pediatric patients with ONFH secondary to SCD after multiple epiphyseal drilling and AMBI. Nine boys and 2 girls (14 hips) with a mean age of 12.7 years (range, 9.7-18 y) at the time of surgery were evaluated. All patients were followed for at least 1 year after surgery and the mean duration of follow-up was 25 months (range, 12-47 mo). Clinical outcome was assessed by the pain domain from the Children's Hospital Oakland Hip Evaluation Scale and by hip range of motion. The extent of femoral head involvement was assessed by measuring the arc of necrosis and the amount of collapse on anteroposterior and frog lateral radiographs. The University of Pennsylvania system was used to assess the osteonecrosis stage. Wilcoxon signed-rank tests were used to compare radiographic and clinical variables. Compared with preoperative measures, multiple epiphyseal drilling with AMBI resulted in significant improvement in pain (P=0.0010), internal hip rotation (P=0.0005), external hip rotation (P=0.0010), and flexion (P=0.0015). The amount of lateral collapse (P=0.4609), anterior collapse (P=0.4258), and the arc of necrosis (P=0.2251) were not significant after surgery. The majority of the hips had either improvement in the Steinberg stage of disease (4/14 hips) or no further progression (7/14 hips) at the latest follow-up. There were no surgical complications. Multiple epiphyseal drilling with autologous bone marrow cell implantation allows for short-term clinical improvement and limits radiographic progression of ONFH associated with SCD in children with minimal morbidity.

P17: Antitumor activity of allogeneic bone marrow cells immobilized in porous-permeable TiNi-based alloy scaffold

The most effective method in treatment of inoperable cancer is currently miniallogeneic transplantation. This type of treatment focuses on reaction of “graft-versus-tumor”. According to preliminary data, such treatment leads to long-term remission in patients with metastatic cancer, who did not respond to previous therapy. Anti-tumor immune response after transplant may be extended or enhanced by additional infusion of donor lymphocytes. Research has shown that introduction of donor lymphocytes achieves complete remission of the tumor, even in case of relapse after allogeneic transplantation from the same donor, but these effects are unstable and not so long because of rapid elimination of donor lymphocytes [1] . The main problem is the preservation of cell transplantation viability and functional activity of the cells in patient’s body, and protecting them from recipient’s immune system. In recent years, most suitable for this purpose are the three-dimensional porous biomaterials (3D-scaffold). Specific pore space does not allow immunity effectors quickly destroy the cells in scaffold [2] , [3] . Research Institute of medical materials and implants with shape memory at the Tomsk State University created a porous-permeable incubators (scaffold) of TiNi-based shape memory alloy (TiNi). The material has unique properties: permeable porous structure by open interconnected pores, characterized by high degree of wettability with tissue media and nanoporous inner surface of the pore walls, exhibits high adhesion to various cell types, so all mentioned meet requirements of the bio-chemical and bio-mechanical compatibility. Porous TiNi-based scaffolds allow continually to keep the functionality cells and prolong their action [4] , [5] . The purpose of this study was to investigate possibility of modulation of antitumor response in allogeneic bone marrow transplantation in porous-permeable incubator of TiNi. Results Intraperitoneal injection of allogeneic bone marrow (BM) reduces metastasis by 30% and has easy 10%-antitumor effect. At the same time, the implantation of bone marrow cells on incubator of TiNi (BM + TiNi) leads to more pronounced antitumor (25%) and significant antimetastatic effects (45%). Life span of animals with tumors and implanted bone marrow cells on incubator TiNi is increased by 60% Since bone marrow cells do not have direct antiproliferative effect on tumor target cells in vitro, it is assumed that one of the mechanisms effecting the bone marrow transplantation on neoplastic process is the stimulation of endogenous effectors of antitumor immunity. The study of morphological parameters immunocompetent organs showed that administration of allogeneic bone marrow cells can reduce thymic regression, decrease splenomegaly at animals with transplanted tumors. Conclusion Allogeneic transplantation of bone marrow cells on porous incubator was shown to prolong and enhance antitumor and antimetastatic action compared to injecting the cells. This effect is directly due to the stimulation of antitumor immunity, that is described by the study of immunity factors. The results show perspectives of porous TiNi-based scaffolds in complex treatment of neoplastic diseases.

The cardiac repair benefits of inflammation do not persist: evidence from mast cell implantation.

Multiple mechanisms contribute to progressive cardiac dysfunction after myocardial infarction (MI) and inflammation is an important mediator. Mast cells (MCs) trigger inflammation after MI by releasing bio-active factors that contribute to healing. c-Kit-deficient (Kit(W/W-v) ) mice have dysfunctional MCs and develop severe ventricular dilatation post-MI. We explored the role of MCs in post-MI repair. Mouse wild-type (WT) and Kit(W/W-v) MCs were obtained from bone marrow (BM). MC effects on fibroblasts were examined in vitro by proliferation and gel contraction assays. MCs were implanted into infarcted mouse hearts and their effects were evaluated using molecular, cellular and cardiac functional analyses. In contrast to WT, Kit(W/W-v) MC transplantation into Kit(W/W-v) mice did not improve cardiac function or scar size post-MI. Kit(W/W-v) MCs induced significantly reduced fibroblast proliferation and contraction compared to WT MCs. MC influence on fibroblast proliferation was Basic fibroblast growth factor (bFGF)-dependent and MC-induced fibroblast contractility functioned through transforming growth factor (TGF)-β. WT MCs transiently rescue cardiac function early post-MI, but the benefits of BM cell implantation lasted longer. MCs induced increased inflammation compared to the BM-injected mice, with increased neutrophil infiltration and infarct tumour necrosis factor-α (TNF-α) concentration. This augmented inflammation was followed by increased angiogenesis and myofibroblast formation and reduced scar size at early time-points. Similar to the functional data, these beneficial effects were transient, largely vanishing by day 28. Dysfunctional Kit(W/W-v) MCs were unable to rescue cardiac function post-MI. WT MC implantation transiently enhanced angiogenesis and cardiac function. These data suggest that increased inflammation is beneficial to cardiac repair, but these effects are not persistent.

The role of “cell therapy” in osteonecrosis of the femoral head

Background and purpose — The value of core decrompression for treatment of osteonecrosis of the femoral head (ONFH) is unclear. We investigated by a literature review whether implantation of autologous bone marrow aspirate, containing high concentrations of pluripotent mesenchymal stem cells, into the core decompression track would improve the clinical and radiological results compared with the classical method of core decompression alone. The primary outcomes of interest were structural failure (collapse) of the femoral head and conversion to total hip replacement (THR).Patients and methods — All randomized and non-randomized control trials comparing simple core decompression with autologous bone marrow cell implantation into the femoral head for the treatment of ONFH were considered eligible for inclusion. The methodological quality of the studies included was assessed independently by 2 reviewers using the Cochrane Collaboration tool for assessing risk of bias in randomized studies. Of 496 relevant citations identified, 7 studies formed the basis of this review.Results — The pooled estimate of effect size for structural failure of the femoral head favored the cell therapy group, as, in this treatment group, the odds of progression of the femoral head to the collapse stage were reduced by a factor of 5 compared to the CD group (odds ratio (OR) = 0.2, 95% CI: 0.08–0.6; p = 0.02). The respective summarized estimate of effect size yielded halved odds for conversion to THR in the cell therapy group compared to CD group (OR = 0.6, 95% CI: 0.3–1.02; p = 0.06).Interpretation — Our findings suggest that implantation of autologous mesenchymal stem cells (MSCs) into the core decompression track, particularly when employed at early (pre-collapse) stages of ONFH, would improve the survivorship of femoral heads and reduce the need for hip arthroplasty.

Relationship between perioperative cardiovascular risk factors and bone marrow cells from patients undergoing coronary artery bypass grafting surgery.

Cell therapy through the implantation of autologous bone marrow cells has long been used in clinical trials for the treatment of ischemic heart diseases. However, as the outcomes of cell implantation vary among patients, risk factors that might influence the level and function of bone marrow progenitor cells should be determined, to identify patients who would benefit the most from this treatment. We collected clinical and laboratory data from 44 patients scheduled to undergo sternotomy for coronary artery bypass grafting (CABG). Bone marrow was aspirated from the sternum during the operation, and bone marrow mononuclear cells (BMMNCs) were isolated through density centrifugation. A negative correlation was observed between the number of BMMNCs and age (N = 44, r = -0.788, P = 0.001). The level of CD34+ cells in BMMNCs was 0.94 ± 0.39%, CD133+ cells 0.46 ± 0.28%, and CD34+CD133+ cells 0.53 ± 0.26%. The levels of CD34+ and CD133+ cells in diabetic patients were significantly lower than those in nondiabetic patients. Female gender, advanced age, and poor heart function were related with reduced progenitor cell clonogenic function. A positive correlation was observed between the level of CD34+ cells and BMMNC migration ability. Aging and diabetes were the major risk factors that influence the level and function of bone marrow resident progenitor cells in patients with coronary heart disease undergoing CABG. Further study is needed to determine whether these two factors can influence the outcome of bone marrow cell therapy for ischemic heart disease.

Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats.

Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs) expressing human basic fibroblast growth factor (hbFGF). After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS) controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF) expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001); however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.

101-P: BENEFICIAL EFFECTS OF AUTOLOGOUS BONE MARROW CELL INFUSION IN PATIENTS WITH CHRONIC CRITICAL LIMB ISCHEMIA: LONG TERM FOLLOW-UP

Aim Previous clinical studies indicate that implantation of Bone Marrow Cells (BMCs) into ischemic limbs may improve peripheral ischemia. We previously demonstrated that intraarterial administration of autologous BMC and antioxidants and L-arginine therapy is safe and effective in patients with advanced atherosclerotic peripheral artery disease (PAD) with positive effects until 18 months. Here, we assessed the long-term follow-up of patients until 36 months. Methods In the original study protocol (NCT00306085), we studies 18 patients with PAD (advanced III/IV Fontaine stage) and an additional group of 18 patients taking maximal drug therapy that refused BMC therapy as control. Therapeutic neo-angiogenesis was estimate by clinical assessment, angiography and laser Doppler/capillaroscopy. Results At 18 months of follow-up, among conservative control patients, 10 underwent amputation in comparison with two BMC-treated patients (55.6 vs. 13.3%; p=0.014). Ischemic ulcers improved in 13 patients (after 6-12 months). The follow-up at 36 months of remaining patients confirmed a favorable trends in patients treated with BMCs in comparison to controls (p Conclusions This follow-up study confirmed safety and feasibility of intraarterial autologous BMCs in patients with critical ischemia and advanced atherosclerotic PAD.

AB1171 Use of bone marrow cells (BMCS) added to platelet-rich plasma (PRP) for treatment of bone degenerative processes in jia patient: 18-month follow-up

BackgroundIn Regenerative Medicine one or more regenerative factors can be applied inside a cartilagine or bone defect to obtain a more rapid and complete healing. Bone Marrow Cells (BMC) added...

Abstract 3305: Sustained production of a soluble IGF-I receptor by gutless adenovirus - transduced host cells protects from tumor growth in the liver .

Abstract The IGF-I receptor (IGF-IR) plays an important role in malignant disease by increasing cancer cell survival and promoting metastasis. It is presently the target of several drugs in clinical trials. Gene therapy is currently being developed for cancer treatment using different nanoparticle vectors designed to deliver therapeutic genes that could induce cell death, increase sensitivity to chemotherapy, block angiogenesis or enhance the anti-cancer immunological response. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. A third generation gutless adenovirus was selected to deliver the sIGFIR gene because of its reduced immunogenicity and preferential tropism for the liver, the main source of endocrine IGF-1. We found that HEK-293 cells transduced by this, but not by control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective strategy for blockade of cancer cell growth. Citation Format: Ni Wang, Yifan Lu, Amelie Pilotte, Maxime Pinard, Rénald Gilbert, Bernard Massie, Pnina Brodt. Sustained production of a soluble IGF-I receptor by gutless adenovirus - transduced host cells protects from tumor growth in the liver . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3305. doi:10.1158/1538-7445.AM2013-3305

Sustained production of a soluble IGF-I receptor by gutless adenovirus-transduced host cells protects from tumor growth in the liver

The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.