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

基本信息

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
项目类别：
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

项目摘要

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矩阵显着改善了肿瘤神经干细胞的移植手术后的GBM腔，使它们能够提供抑制肿瘤的抗癌基因产物复发。然而，最大化TNSC移植，迁移，药物释放和随后的GBM杀戮仍然未知。使用临床相关的人类TNSC，矩阵和小鼠模型 GBM切除/复发，我们发现3D体系结构和脚手架成分显着增强 TNSC在手术腔中的持久性。在这里，我们假设通过唯一的3D优化功能定制设计的脚手架的印刷将获得TNSC对手术后GBMS的良好抑制治疗。利用连续液体接口打印（夹），一种新型的连续制造方法高空间分辨率，我们建议制造一组3D矩阵，具有不同的建筑，生物物理，和机械响应特征在合理地选择了改善TNSC治疗的设计。我们将定义每个设计功能对TNSC持久性，体外和体内杀死的影响，然后测试最终优化的矩阵使用手术切除模型将最有益的特征纳入单个矩阵中免疫缺乏的小鼠中的患者衍生的人异种移植物和免疫中的同种异体移植物能干的动物。我们建议实现以下目的：1）使用夹子制造3D面板具有各种设计功能的印刷矩阵； 2）定义3D设计功能对TNSC功效的影响术后GBM； 3）研究3D矩阵/TNSC治疗对免疫能力的功效和安全性 GBM切除/复发的模型。我们的研究结果将产生治疗性TNSC/支架能够进行强大的GBM杀戮的移植策略可以翻译以进行人体患者测试。它也会发现调节TNSC不同方面的脚手架特征，使我们能够调节TNSC癌症通过矩阵设计的治疗。