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

项目总结/摘要 胶质母细胞瘤是最常见的原发性脑肿瘤，也是最致命的癌症之一。最近我们 发现生物相容性基质显着改善肿瘤归巢神经干细胞移植到 手术后的GBM腔允许它们递送抑制肿瘤的抗癌基因产物， 复发然而，使tNSC移植、迁移、药物释放和细胞增殖最大化的最佳支架构型仍然存在。 随后GBM死亡仍然未知。使用临床相关的人tNSC、基质和小鼠模型， GBM切除/复发，我们已经发现3D结构和支架组成显著增强了GBM切除/复发， tNSC在手术腔中的持久性。在这里，我们假设通过独特的3D优化功能 定制设计的支架的打印将通过tNSC实现对手术后GBM的上级抑制 疗法利用连续液体界面印刷（CLIP），一种新颖的连续制造方法， 高空间分辨率，我们建议制造一组具有不同结构，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 每个设计特征对体外和体内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合并到单个矩阵中的优化矩阵 免疫耗竭小鼠中患者来源的人异种移植物和免疫缺陷小鼠中同基因GBM同种异体移植物的免疫- 有能力的动物我们提出了以下目标：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功效的影响， 3）研究3D基质/tNSC疗法在免疫活性GBM患者中的有效性和安全性。 GBM切除/复发模型。我们的研究结果将产生治疗性tNSC/支架 本发明提供了一种能够稳健杀死GBM的移植策略，其可以转化用于人类患者测试。它还将 揭示调节tNSC不同方面的支架特征，使我们能够调节tNSC癌症 通过矩阵设计进行治疗。

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.