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

项目总结 如果不治疗，软骨损伤会逐渐退化，导致骨性关节炎的发生。临床 关节镜下清创(摘除)和灌洗(冲洗)治疗部分软骨损伤 关节有液体)缓解疼痛，但不能修复或保护组织免受进一步退化。关节内干 细胞注射由于其微创的性质和抗炎作用而被广泛采用。 干细胞的再生能力。然而，对临床数据的系统研究表明， 这种方法提供有限的软骨组织修复和高度不同的结果。因此，类似于 清创和灌洗，单靠MSC注射不足以修复或阻止组织的进展 对大多数患者来说，病情恶化。造成这种情况的主要原因之一是移植的干细胞未能定位到 软骨损伤的部位，限制了其治疗效果。此外，现场缺乏增援 组织损伤会使软骨暴露在退行性超负荷下，这会逐渐加剧 组织损伤。我们开发了一种以透明质酸(HA)为基础的治疗性生物粘合剂，它可以在局部 以微创方式送至软骨损伤部位，提供机械加固 并提供细胞黏附肽，以增强输送的干细胞在软骨部位的定位 修理。通过拟议的工作，我们将首先评估材料在蛋白质类滑液中的稳定性。 设置以确定材料的治疗窗口，第二，评估干细胞定位后 使用山羊模型在负重的活体环境中进行关节内干细胞注射。在目标1中，软骨 软骨移植造成的损伤将用生物粘附剂治疗，并在滑液中孵化或 不添加炎症细胞因子白介素1β。在治疗后的不同时间点(最多28 天)，骨髓间充质干细胞(MSCs)将在治疗后的皮损上种植24小时， 并将评估细胞附着、材料存在和组织加固。在目标2中，四个部分厚度 将在山羊的双侧滑车沟处造成软骨损伤，四个损伤中的两个将受到 生物黏附治疗。手术闭合后，标记的骨髓间充质干细胞将通过关节内输送到每个关节。 注射。7天后，动物将被安乐死，关节组织将被评估为MSC定位，而 软骨组织将通过组织学和免疫组织学染色来评估细胞和组织基质。 这些研究将证明生物粘附剂在滑膜中的稳定性和细胞定位潜力。 轴承环境，验证了我们的材料配方的可行性。这项SBIR第一阶段的完成 将直接为进入第二阶段奖项奠定基础，这将扩大制造规模，开始 调节策略，并评价长期体内治疗效果的评估。总体而言，生物粘附性 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方面的突破性进展。

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.