Harnessing Continuous Liquid Interface 3D Printing to Improve Tumor-homing Stem Cell Therapy for Post-surgical Brain Cancer

利用连续液体界面 3D 打印改善脑癌术后肿瘤归巢干细胞疗法

• 批准号: 10420701
• 负责人: Shawn Hingtgen
• 金额: $ 46.72万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420701
• 关键词: 3-Dimensional; 3D Print; Advanced Development; Allografting; Animals; Architecture; Biological Assay; Biophysics; Blood; Brain; Cell Survival; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Coculture Techniques; Complex; Custom; Deposition; Enzyme-Linked Immunosorbent Assay; Excision; Gelatin; Genetic Engineering; Glioblastoma; Growth; Homing; Human; Human Engineering; Image; Immune; Immune system; Immunocompetent; Implant; In Vitro; Injections; Kinetics; Liquid substance; Malignant Neoplasms; Malignant neoplasm of brain; Mechanics; Methods; Microscopic; Modeling; Modulus; Mus; Neoplasm Transplantation; Operative Surgical Procedures; Patients; Penetration; Performance; Pharmaceutical Preparations; Postoperative Period; Primary Brain Neoplasms; Printing; Production; Property; Recurrence; Residual Tumors; Residual state; Resolution; Safety; Seeds; Shapes; Solid; Statistical Data Interpretation; Stem cell transplant; Surgically-Created Resection Cavity; TNF-related apoptosis-inducing ligand; Technology; Testing; Therapeutic; Tissues; Translating; Transplantation; Variant; Xenograft procedure; anti-cancer; base; bioluminescence imaging; biomaterial compatibility; brain tissue; cancer cell; cancer invasiveness; cancer stem cell; cancer therapy; clinically relevant; copolymer; design; first-in-human; gene product; hydrogel scaffold; immunocytochemistry; improved; in vivo; migration; mouse model; nerve stem cell; novel; novel therapeutics; porous hydrogel; preclinical study; rational design; response; scaffold; stem cell therapy; stem cells; tumor

Project Summary/Abstract Glioblastoma is the most common primary brain tumor and one of the deadliest forms of cancer. Recently, we found that biocompatible matrices significantly improve the transplant of tumor-homing neural stem cells into the post-surgical GBM cavity allowing them to deliver anti-cancer gene products that suppress tumor recurrence. Yet, the optimal scaffold figuration that maximizes tNSC transplant, migration, drug release, and subsequent GBM kill remain unknown. Using clinically relevant human tNSCs, matrices, and mouse models of GBM resection/recurrence, we have found that 3D architecture and scaffold composition markedly enhance tNSC persistence in the surgical cavity. Here in, we hypothesize that optimizing features through unique 3D printing of custom designed scaffolds will achieve superior suppression of post-surgical GBMs by tNSC therapy. Leveraging Continuous Liquid Interface Printing (CLIP), a novel continuous fabrication method with high spatial resolution, we propose to fabricate a panel of 3D matrices with different architectural, biophysical, and mechanical response features design rationally selected to improve tNSC therapy. We will define the impact of each design feature on tNSC persistence, homing and killing in vitro and in vivo, then test a final optimized matrix incorporating the most beneficial features into a single matrix using surgical resection models of patient-derived human xenografts in immune-depleted mice and syngeneic GBM allografts in immune- competent animals. We propose to undertake the following Aims: 1) Utilize CLIP to fabricate a panel of 3D printed matrices with varied design features; 2) Define the impact of 3D design features on tNSC efficacy for post-operative GBM; 3) Investigate the efficacy and safety of 3D matrix/tNSC therapy in immune-competent models of GBM resection/recurrence. The results of our study will generate a therapeutic tNSC/scaffold transplant strategy capable of robust GBM killing that can be translated for human patient testing. It will also uncover the scaffold features that regulate different aspects of tNSCs, allowing us to modulate tNSC cancer therapy through matrix design.

项目摘要/摘要 胶质母细胞瘤是最常见的原发脑肿瘤，也是最致命的癌症之一。最近，我们 发现生物相容基质显著改善了肿瘤归巢神经干细胞移植到 手术后的GBM腔允许他们提供抑制肿瘤的抗癌基因产品 复发。然而，最大限度地增加tNSC移植、迁移、药物释放和 随后的GBM杀戮事件仍不得而知。使用临床相关的人类tNSCs、矩阵和小鼠模型 基底膜切除/复发，我们发现3D结构和支架成分明显增强 TNSC在手术腔内持续存在。在这里，我们假设通过独特的3D优化功能 打印定制设计的支架将实现tNSC对手术后GBM的卓越抑制 心理治疗。利用连续液体界面印刷(CLIP)，一种新的连续制造方法 高空间分辨率，我们建议制作一个由不同建筑、生物物理、 合理选择机械反应特征设计，提高tNSC治疗效果。我们将定义 每种设计特征在体外和体内对tNSC持久性、归巢和杀伤的影响，然后测试最终的 使用手术切除模型将最有益的特征整合到单个矩阵中的优化矩阵 患者来源的人异种移植在免疫耗竭的小鼠和同基因的GBM异体移植在免疫- 有能力的动物。我们的目标是：1)利用CLIP制作3D面板 具有不同设计特征的打印矩阵；2)定义3D设计特征对tNSC疗效的影响 3)观察3D-Matrix/tNSC治疗免疫功能障碍的疗效和安全性。 基底膜切除/复发模型的建立。我们的研究结果将产生一种治疗性tNSC/支架 移植策略能够强大地杀死GBM，可以翻译成人类患者测试。它还将 揭示调控tNSCs不同方面的支架功能，使我们能够调控tNSC癌症 通过矩阵设计进行治疗。