Treatment of venous ulcers with autologous cultured bone marrow stem cells

自体培养骨髓干细胞治疗静脉性溃疡

基本信息

批准号：
8109039
负责人：
Vincent Falanga
金额：
$ 36.88万
依托单位：
ROGER WILLIAMS HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109039
关键词：
Acceleration Acute Affect American Antibodies Area Aspirate substance Autologous Beds Biomedical Engineering Biopsy Biopsy Specimen Blinded Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Carbon Dioxide Caring Cartilage Cell Count Cell Therapy Cells Chronic Clinical Clinical Trials Compression Bandage Dermal Diabetic ulcer Direct Costs Double-Blind Method Effectiveness Elastic Fiber Elastin Endothelium Epithelial Fatty acid glycerol esters Fibrin Fibrin Tissue Adhesive Fibrinogen Fibrosis Flow Cytometry Gel Generations Goals Growth Growth Factor Growth Factor Receptors Healed Human Hypertension Immigration Impaired wound healing In Vitro Infection Institution Investigational Drugs Keratin Knowledge Lead Leg Leg Ulcer Life Lower Extremity Measurement Mesenchymal Stem Cells Methods Molecular Profiling Mus Muscle New Drug Approvals Outcome Pain Pathogenesis Patients Pilot Projects Polymers Protease Inhibitor Publishing Quality of life Randomized Receptor Signaling Reporting Research Signal Transduction Skin Staining method Stains Stem cells Surface Syringes System Testing Thigh structure Thrombin Tissue Engineering Tissues Topical application Varicose Ulcer Veins Venous Work Wound Healing arm base bone c-myc Genes computerized experience healing improved innovation migration molecular marker novel polymerization prognostic repaired response stem cell therapy success therapy development wound

项目摘要

DESCRIPTION (provided by applicant): Venous leg ulcers and other severe chronic wounds affect 5-7 million Americans, and are responsible for a direct cost of at least $20 billion annually. Patients with venous ulcers experience poor quality of life, frequent infections, and loss of work and independence. Clinical outcomes have improved in recent years because of better conventional care and new advanced therapies, such as the use of living bioengineered skin. However, the underlying problem of venous hypertension leads to severe secondary changes, such as tissue fibrosis, propensity for infection, and an increasingly recognized set of phenotypic changes in resident wound cells that impair dermal repair and epidermal resurfacing. Venous ulcers can become very difficult to heal. Indeed, even advanced therapies heal less than 50% of venous ulcers that have been present for more than a year. We have recently developed evidence that the topical application of autologous bone marrow-derived mesenchymal stem cells (MSCs), grown from the patients' own bone marrow aspirate and cultured and expanded in vitro, can lead to dramatic acceleration of healing in chronic wounds, including venous ulcers. During our preliminary work, we have developed a novel fibrin polymer construct for delivering the cultured MSCs to the wound in a spray system. In doing so, we modified an existing fibrin glue construct by decreasing the fibrinogen/thrombin concentrations required for polymerization and by eliminating aprotenin as the protease inhibitor component. Once sprayed into the wound, the MSCs are in a thin fibrin gel that does not affect their viability and is endogenously eliminated, thus releasing the cells to the wound. We are now ready to move forward with a clinical trial that will test the hypothesis that the patients' own MSCs can accelerate the healing of their wounds. We have developed a GMP facility for handling the the growth of MSCs, and we have received an IND from the FDA for our clinical trial. We plan the following two specific aims: 1) Determine the effect of MSCs on the healing of venous ulcers in a three-arm randomized controlled blinded clinical trial. All patients will be treated with conventional leg compression bandages. Cultured autologous MSCs will be delivered to the wound in a fibrin spray, and this group will be compared to control patients receiving leg compression treatment alone or the fibrin spray only. Healing will be assessed by computerized planimetry for wound edge migration and healing rate, wound size reduction, and complete closure; 2) Characterize and closely correlate the expression of wound edge molecular markers of impaired healing and epithelial migration in response to treatment. Baseline and sequential biopsies from the edges of venous ulcers treated in specific aim 1 will be used to determine the epidermal expression of c-myc, 2-catenin, and keratins 6/16 and 17 at the wounds' edges. These measurements, closely correlated with wound size and edge migration, will help us establish promising molecular markers involved in impaired healing and whether the MSCs may work by affecting the expression and localization of these specific molecular markers. PUBLIC HEALTH RELEVANCE: Chronic wounds, such as those that are called venous ulcers and are caused by abnormal veins, are very common. They cause pain, infection, and loss of independence. We have developed a way to isolate, grow, and expand stem cells from the patient's own bone marrow and to deliver millions of these cells to the wound using a novel cell delivery system. This research will test the value and effectiveness of this stem cell treatment in these difficult to heal leg ulcers.

描述（由申请人提供）：腿部静脉溃疡和其他严重慢性伤口影响着 5-700 万美国人，每年造成至少 200 亿美元的直接损失。静脉溃疡患者生活质量差、频繁感染、失去工作和独立性。近年来，由于更好的常规护理和新的先进疗法（例如使用活体生物工程皮肤），临床结果有所改善。然而，静脉高压的根本问题会导致严重的继发性变化，例如组织纤维化、感染倾向以及越来越多地认识到的常驻伤口细胞的一系列表型变化，这些变化会损害真皮修复和表皮重塑。静脉溃疡会变得非常难以愈合。事实上，对于已经存在一年多的静脉溃疡，即使是先进的疗法也只能治愈不到 50%。我们最近发现的证据表明，局部应用自体骨髓源性间充质干细胞（MSC）（从患者自身的骨髓抽吸物中生长并在体外培养和扩增）可以显着加速慢性伤口的愈合，包括静脉性溃疡。在我们的前期工作中，我们开发了一种新型纤维蛋白聚合物结构，用于通过喷雾系统将培养的间充质干细胞递送至伤口。在此过程中，我们通过降低聚合所需的纤维蛋白原/凝血酶浓度并消除作为蛋白酶抑制剂成分的抑肽酶来修改现有的纤维蛋白胶构建体。一旦喷入伤口，间充质干细胞就会处于薄纤维蛋白凝胶中，不会影响其活力，并且会被内源性消除，从而将细胞释放到伤口。我们现在准备推进一项临床试验，以检验患者自身的间充质干细胞可以加速伤口愈合的假设。我们开发了用于处理 MSC 生长的 GMP 设施，并且我们已收到 FDA 的临床试验 IND。我们计划以下两个具体目标：1）在三臂随机对照盲法临床试验中确定间充质干细胞对静脉溃疡愈合的影响。所有患者都将接受传统的腿部加压绷带治疗。培养的自体间充质干细胞将通过纤维蛋白喷雾输送到伤口，并将该组患者与单独接受腿部加压治疗或仅接受纤维蛋白喷雾的对照患者进行比较。将通过计算机平面测量法评估伤口边缘迁移和愈合率、伤口尺寸减小和完全闭合的愈合情况； 2) 表征愈合受损的伤口边缘分子标记物和治疗后上皮迁移的表达并密切相关。来自特定目标 1 中治疗的静脉溃疡边缘的基线和连续活检将用于确定伤口边缘处 c-myc、2-连环蛋白以及角蛋白 6/16 和 17 的表皮表达。这些测量与伤口大小和边缘迁移密切相关，将帮助我们建立参与受损愈合的有希望的分子标记，以及 MSC 是否可以通过影响这些特定分子标记的表达和定位来发挥作用。公共卫生相关性：慢性伤口（例如由异常静脉引起的静脉性溃疡）非常常见。它们会导致疼痛、感染和丧失独立性。我们开发了一种方法，可以从患者自身的骨髓中分离、培养和扩增干细胞，并使用新型细胞输送系统将数百万个此类细胞输送至伤口。这项研究将测试这种干细胞治疗在这些难以治愈的腿部溃疡中的价值和有效性。