A BioAdhesive to Localize and Direct Stem Cells to Treat Damaged Cartilage

一种生物粘合剂，可定位并引导干细胞治疗受损软骨

基本信息

批准号：
10384733
负责人：
Antonina Tsinman
金额：
$ 29.96万
依托单位：
FORSAGEN LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10384733
关键词：
Acute Adhesives Adoption Aftercare American Animals Anti-Inflammatory Agents Articulation Attention Attenuated Award Bilateral Biocompatible Materials Bone Marrow Cartilage Cartilage injury Cell Adhesion Cell-Matrix Junction Cells Clinical Data Clinical Management Collaborations Colorado Complex Debridement Defect Degenerative polyarthritis Deposition Deterioration Development Direct Costs Environment Excision Exposure to Failure Flushing Formulation Goals Goat Growth Histologic Hour Hyaluronic Acid Hydrogels In Vitro Incubated Inflammatory Infrastructure Injections Injury Intellectual Property Interleukin-1 beta Intra-Articular Injections Irrigation Joints Label Left Legal patent Lesion Licensing Ligands Liquid substance Mechanics Mesenchymal Stem Cells Miniature Swine Modeling Nature Operative Surgical Procedures Outcome Patients Peptides Phase Physical activity Prevention Process Prunella vulgaris Psychological reinforcement Regenerative capacity Reporting Research Personnel Research Proposals Risk Site Small Business Innovation Research Grant Staining and Labeling Stains Surface Synovial Fluid System Technology Therapeutic Therapeutic Effect Thick Time Tissues Translating Treatment Cost Treatment Efficacy Universities Weight-Bearing state Work articular cartilage base cartilage degradation cartilage regeneration cartilage repair clinical investigation cytokine effective therapy histological stains improved in vivo innovation interest manufacturing scale-up minimally invasive pain relief porcine model preservation programs regeneration potential regenerative repair model repaired reparative process socioeconomics stem cell delivery stem cells tissue repair treatment strategy

Acute Adhesives Adoption Aftercare American Animals Anti-Inflammatory Agents Articulation Attention Attenuated Award Bilateral Biocompatible Materials Bone Marrow Cartilage Cartilage injury Cell Adhesion Cell-Matrix Junction Cells Clinical Data Clinical Management Collaborations Colorado Complex Debridement Defect Degenerative polyarthritis Deposition Deterioration Development Direct Costs Environment Excision Exposure to Failure Flushing Formulation Goals Goat Growth Histologic Hour Hyaluronic Acid Hydrogels In Vitro Incubated Inflammatory Infrastructure Injections Injury Intellectual Property Interleukin-1 beta Intra-Articular Injections Irrigation Joints Label Left Legal patent Lesion Licensing Ligands Liquid substance Mechanics Mesenchymal Stem Cells Miniature Swine Modeling Nature Operative Surgical Procedures Outcome Patients Peptides Phase Physical activity Prevention Process Prunella vulgaris Psychological reinforcement Regenerative capacity Reporting Research Personnel Research Proposals Risk Site Small Business Innovation Research Grant Staining and Labeling Stains Surface Synovial Fluid System Technology Therapeutic Therapeutic Effect Thick Time Tissues Translating Treatment Cost Treatment Efficacy Universities Weight-Bearing state Work articular cartilage base cartilage degradation cartilage regeneration cartilage repair clinical investigation cytokine effective therapy histological stains improved in vivo innovation interest manufacturing scale-up minimally invasive pain relief porcine model preservation programs regeneration potential regenerative repair model repaired reparative process socioeconomics stem cell delivery stem cells tissue repair treatment strategy

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项目摘要

PROJECT SUMMARY Cartilage injuries progressively degenerate if left untreated, leading to the onset of osteoarthritis. Clinical management of partial-thickness cartilage lesions via arthroscopic debridement (removal) and lavage (flushing joint with fluid) relieve pain but fail to repair or protect the tissue against further degeneration. Intraarticular stem cell injections have gained widespread adoption due to their minimally-invasive nature and the anti-inflammatory and regenerative potential of stem cells. However, systematic investigations of clinical data have demonstrated that this approach provides limited repair of the cartilage tissue and highly variable outcomes. Thus, similar to debridement and lavage, MSC injections alone is not enough to repair or halt the progression of tissue deterioration for most patients. One of the major reasons for this is failure of delivered stem cells to localize to the site of cartilage injury, which limits their therapeutic efficacy. Moreover, the lack of reinforcement at the site of tissue damage leaves the cartilage exposed to degenerative overloading, which progressively exacerbates tissue damage. We developed a hyaluronic acid (HA)-based therapeutic termed BioAdhesive that can be locally delivered to the site of cartilage damage, in a minimally-invasive manner, providing mechanical reinforcement and presenting cell-attachment peptides to enhance localization of delivered stem cells to the site of cartilage repair. Through the proposed work, we will first evaluate the material stability in a proteinaceous synovial fluid setting to determine the therapeutic window of the material and second, assess stem cell localization post intraarticular stem cell injection in a load-bearing in vivo environment using a goat model. In Aim 1, cartilage injuries created in cartilage explants will be treated with the BioAdhesive and incubated in synovial fluid with or without the addition of the inflammatory cytokine, interleukin 1β. At varying time points post treatment (up to 28 days), bone marrow-derived mesenchymal stem cells (MSCs) will be seeded on treated lesions for 24 hours, and cell attachment, material presence, and tissue reinforcement will be assessed. In Aim 2, four partial thickness cartilage lesions will be created bilaterally in the trochlear groove of goats and two of the four injuries will receive BioAdhesive treatment. After surgical closure, labeled MSCs will be delivered to each joint via intraarticular injection. After 7 days, animals will be euthanized and joint tissues will be assessed for MSC localization while cartilage tissue will be assessed for cellular and tissue matrix via histological and immunohistological staining. These studies will demonstrate the stability and cell localization potential of the BioAdhesive in a synovial, load- bearing environment, validating the feasibility of our material formulation. The completion of this SBIR Phase I would directly set the stage for progression to a Phase II award, which would scale up manufacturing, beging regulatory strategy, and evaluate the long-term in vivo assessment of therapeutic effects. Overall, BioAdhesive provides an innovative and impactful strategy to stabilize and preserve damaged cartilage, an approach that could be groundbreaking in the management of cartilage injuries.

项目摘要软骨损伤如果未经治疗，会逐渐退化，导致骨关节炎发作。临床通过关节镜调试（去除）和灌洗（冲洗）的部分厚度软骨病变管理与流体的关节）营救疼痛，但无法修复或保护组织免受进一步变性。关节内茎由于细胞注射的最低侵入性和抗炎作用，细胞注射已获得宽度的采用干细胞的再生潜力。但是，对临床数据的系统研究表明这种方法提供了有限的软骨组织和高度可变结果的修复。那类似于清创和灌洗，仅MSC注射不足以修复或停止组织的进展大多数患者的恶化。造成这种情况的主要原因之一是输送干细胞无法本地化软骨损伤部位限制了他们的治疗效率。而且，该网站缺乏加固组织损伤使软骨暴露于退化性超载，这逐渐加剧了组织损伤。我们开发了一种基于透明质酸（HA）的治疗性的称为生物粘附性，可以局部以最小侵入性的方式传递到软骨损坏的部位，提供机械加固并呈现细胞跟踪肽，以增强输送的干细胞的定位到软骨部位维修。通过拟议的工作，我们将首先评估蛋白质滑液中的材料稳定性设置以确定材料的治疗窗口和第二个评估干细胞定位后的设置使用山羊模型在体内承重环境中的关节内干细胞注射。在AIM 1，软骨在软骨外植体中造成的伤害将用生物粘附治疗，并在滑液中孵育没有添加炎性细胞因子，白介素1β。在不同的时间点，治疗后（最多28个）天数），骨髓来源的间充质干细胞（MSC）将在经过处理的病变上播种24小时，将评估细胞附着，材料的存在和组织加固。在AIM 2中，四个部分厚度软骨病变将在山羊的支流凹槽中双侧产生，四个受伤中的两个将受到生物粘附治疗。手术闭合后，将通过关节内将标记的MSC传递到每个关节注射。 7天后，将对动物进行安乐死，并将评估MSC定位的联合时间，而将通过组织学和免疫组织学染色评估软骨组织的细胞和组织基质。这些研究将证明生物粘附在滑膜，负载中的稳定性和细胞定位潜力轴承环境，验证我们物料公式的可行性。 SBIR I期的完成将直接为进步的II阶段奖励奠定基础，该奖项将扩大制造业，开始监管策略，并评估治疗作用的长期体内评估。总体而言，生物粘附提供了一种创新且有影响力的策略来稳定和保存软骨受损的方法，这种方法是在软骨伤害的管理方面可能是开创性的。