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

• 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
• 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

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 如果不治疗，腕关节损伤会逐渐退化，导致骨关节炎的发生。临床 通过关节镜清创（清除）和灌洗（冲洗）治疗部分厚度软骨病变 关节内有液体）缓解疼痛，但不能修复或保护组织免受进一步的退化。关节内柄 细胞注射由于其微创性和抗炎性而得到广泛采用。 以及干细胞的再生潜力。然而，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修复和高度可变的结果。类似于 清创和灌洗，MSC注射本身不足以修复或阻止组织的进展 对于大多数患者来说，其主要原因之一是递送的干细胞未能定位于 软骨损伤的部位，这限制了它们的治疗效果。此外，现场缺乏加固， 的组织损伤，使软骨暴露于退行性过载， 组织损伤我们开发了一种透明质酸（HA）为基础的治疗称为生物粘合剂，可以局部 以微创方式递送至软骨损伤部位，提供机械加固 以及呈递细胞附着肽以增强递送的干细胞在软骨部位的定位 修复.通过拟议的工作，我们将首先评估材料在蛋白质滑液中的稳定性 第二，评估干细胞定位后， 使用山羊模型在承重体内环境中进行关节内干细胞注射。目标1：软骨 在软骨外植体中产生的损伤将用生物粘合剂处理， 而不添加炎性细胞因子白细胞介素1β。在治疗后的不同时间点（最多28 天），将骨髓来源的间充质干细胞（MSC）接种在治疗的病变上24小时， 并评估细胞附着、材料存在和组织增强。在目标2中，四个部分厚度 在山羊的滑车沟中会产生双侧软骨损伤， 生物粘合剂治疗。手术闭合后，标记的MSC将通过关节内注射递送到每个关节。 注射7天后，将动物安乐死，并评估关节组织的MSC定位，同时 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合剂在滑膜、负载中的稳定性和细胞定位潜力。 轴承环境，验证我们的材料配方的可行性。SBIR第一阶段的完成 将直接为进展到第二阶段的奖励奠定基础，这将扩大制造业， 调节策略，并评价治疗效果的长期体内评估。总体而言，生物粘合剂 提供了一种创新和有效的策略来稳定和保护受损的软骨，这种方法 可能是软骨损伤治疗的突破性进展