Modifying High Modulus Hydrogels for Cell Delivery: Intervertebral Disc Repair with Genipin-Crosslinked Fibrin

修饰高模量水凝胶用于细胞输送：用京尼平交联纤维蛋白修复椎间盘

基本信息

批准号：
10397389
负责人：
Christopher James Panebianco
金额：
$ 0.86万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397389
关键词：
Acute Address Adhesives Alginates Animals Apoptosis Back Pain Binding Biocompatible Materials Biological Biomechanics Bioreactors CASP3 gene Cattle Cell Adhesion Cell Proliferation Cell Survival Cell Therapy Cells Clinical Collagen Confocal Microscopy Crosslinker Defect Deposition Doctor of Philosophy Education Educational process of instructing Encapsulated Engineering Equilibrium Exhibits Extracellular Matrix Fellowship Fibrin Future Gene Expression Genetic Transcription Glycosaminoglycans Goals Healthcare Height Histologic Human Hydrogels Injury Intervertebral disc structure Kinetics Label Lead Measures Mechanics Mentorship Microencapsulations Microspheres Mission Modeling Modulus Morphology Musculoskeletal National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural regeneration Neck Pain Nutrient Operative Surgical Procedures Organ Culture Techniques Outcome Oxides Performance Phenotype Principal Investigator Procedures Property Proteins Publishing Quantitative Reverse Transcriptase PCR Reaction Recovery Recurrent pain Research Research Proposals Risk Screening procedure System Testing Tissue Engineering Tissues Training Ursidae Family Vertebral column Work aggrecan biomechanical test career clinical translation clinically relevant crosslink cytotoxic design disability disc regeneration efficacy validation experience genipin healing improved injured innovation insight intervertebral disk degeneration mechanical load multidisciplinary next generation novel nucleus pulposus prevent regenerative approach repair strategy repaired response scaffold seal socioeconomics soft tissue spinal disk injury standard of care treatment effect

项目摘要

PROJECT SUMMARY Back and neck pain are leading causes of global disability, which account for over $135 billion in healthcare spending. Disabling back pain caused by herniation of the intervertebral disc (IVD) can be alleviated by discectomy, the surgical standard of care that removes herniated IVD tissue. While effective, discectomy does not repair annulus fibrosus (AF) defects caused by the herniation, which can lead to accelerated IVD degeneration, reherniation and recurrent pain. Cell-seeded, adhesive hydrogels are a promising strategy to prevent these complications because they can immediately seal AF defects and deliver cells for long-term healing. Engineering such hydrogels for IVD cell delivery is challenging because soft biomaterials typically used for cell delivery risk herniating in the IVD injury space. On the contrary, high-modulus biomaterials designed to bear high-magnitude spine loads can hinder the healing capacity of encapsulated cells. The overall goal of this research proposal is to uniquely integrate principles of cellular microencapsulation, degradable microbeads (MBs) and high-modulus biomaterials to engineer next-generation biomaterials that promote IVD regeneration and functional repair. Aim 1 will assess the protective capacity and degradation kinetics of oxidized alginate (OxAlg) MBs. Aim 2 will characterize the effects of genipin-crosslinked fibrin (FibGen)-OxAlg construct macroporosity on AF cell phenotype and construct biomechanics. Aim 3 will evaluate the biological and biomechanical repair responses of FibGen-OxAlg. Our global hypotheses are that OxAlg MBs will protect AF cells from FibGen hydrogel crosslinking then degrade (Aim 1). Resultant macroporous FibGen-OxAlg constructs will promote AF cell proliferation and ECM synthesis, leading to enhanced construct biomechanics (Aim 2). This cell delivery strategy will promote biological and biomechanical repair in ex vivo IVD organ culture (Aim 3). This work is significant because it develops an easily translatable tissue engineering strategy to address the critical clinical challenges associated with AF defects; this approach may be broadly applicable to other musculoskeletal tissues that exhibit limited healing and experience high mechanical demands, which strongly aligns with the mission of NIAMS. This proposal is highly innovative because no strategies that repair and regenerate AF defects exist, few published studies use cell-laden MBs as porogens in templated hydrogel constructs, and none use such constructs in IVD repair. Validating the efficacy of this biomaterial strategy in a loaded, large animal IVD organ culture system is innovative and significant because there are few published studies using such a culture system and testing in this manner will accelerate clinical translation. Completion of the proposed aims will provide the candidate with rigorous multidisciplinary training in biomaterial synthesis, cell microencapsulation, biomechanical testing and IVD organ culture. Supplemented with the proposed teaching and mentorship experiences, this fellowship will accelerate the career of a promising PhD Candidate who is strongly committed to musculoskeletal tissue engineering research and education.

项目摘要背部和颈部疼痛是全球残疾的主要原因，占医疗保健的1350亿美元以上开支。通过椎间盘（IVD）引起的椎间盘疼痛禁用背部疼痛。椎间盘切除术，是去除椎间盘突出的IVD组织的手术护理标准。虽然有效，但椎间盘切除术确实不修复由催眠引起的纤维纤维（AF）缺陷，这可能导致IVD加速变性，重新连接和复发性疼痛。细胞种子，粘合水凝胶是一种有前途的策略防止这些并发症，因为它们可以立即密封AF缺陷并为长期提供细胞康复。这种用于IVD电池输送的水凝胶是具有挑战性的，因为软生物材料通常使用用于细胞输送风险在IVD损伤空间中疝。相反，高模化生物材料设计为带有高磁性脊柱负荷会阻碍封装细胞的愈合能力。总体目标研究建议是唯一整合细胞微囊化，可降解的微粒的原理（MBS）和高量化生物材料对工程师的下一代生物材料，促进IVD再生和功能维修。 AIM 1将评估氧化藻酸盐的保护能力和降解动力学（Oxalg）MBS。 AIM 2将表征Genipin-跨纤维蛋白（Fibgen）-oxalg构建体的影响 AF细胞表型和构建生物力学的宏大性。 AIM 3将评估生物学和纤维 - 奥沙格的生物力学修复反应。我们的全球假设是Oxalg MBS将保护来自纤维水凝胶交联的AF细胞然后降解（AIM 1）。由此产生的大孔纤维纤维粘体构建体将促进AF细胞增殖和ECM合成，从而增强构建体生物力学（目标2）。这种细胞输送策略将促进EX的生物学和生物力学修复 Vivo IVD器官培养（AIM 3）。这项工作很重要，因为它会发展出易于翻译的组织解决与AF缺陷相关的关键临床挑战的工程策略；这种方法可能是广泛适用于其他肌肉骨骼组织，表现出有限的愈合和经历高度机械性的要求，这与尼亚姆斯的使命密切相符。该提议具有很高的创新性，因为没有维修和再生AF缺陷存在的策略，很少有发表的研究将含有细胞的MB作为Porogens 模板水凝胶构建体，没有在IVD修复中使用此类构建体。验证此功能大型动物IVD器官培养系统中的生物材料策略具有创新性和意义，因为使用这种培养系统的发表研究很少，以这种方式进行测试将加速临床翻译。拟议的目标的完成将为候选人提供严格的多学科培训生物材料合成，细胞微囊化，生物力学测试和IVD器官培养。补充拟议的教学和指导经验，该奖学金将加速有前途的博士学位强烈致力于肌肉骨骼组织工程研究和教育的候选人。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Teaching Tissue Repair Through an Inquiry-Based Learning Bioadhesives Module.

通过基于探究的学习生物粘合剂模块教授组织修复。

DOI：
10.1007/s43683-022-00087-y
发表时间：
2023
期刊：
Biomedical engineering education
影响因子：
0
作者：
Panebianco,ChristopherJ;Dutta,Poorna;Frost,JillianR;Huang,Angela;Kim,OliviaS;Iatridis,JamesC;Vernengo,AndreaJ;Weiser,JenniferR
通讯作者：
Weiser,JenniferR

Development of an At-home Metal Corrosion Laboratory Experiment for STEM Outreach in Biomaterials During the Covid-19 Pandemic.

在 Covid-19 大流行期间，开发用于生物材料 STEM 推广的家庭金属腐蚀实验室实验。

DOI：
10.18260/1-2--36966
发表时间：
2021
期刊：
Annual Conference & Exposition : final program and proceedings. American Society for Engineering Education
影响因子：
0
作者：
Panebianco,ChristopherJames;Iatridis,JamesC;Weiser,Jennifer
通讯作者：
Weiser,Jennifer

TEACHING PRINCIPLES OF BIOMATERIALS TO UNDERGRADUATE STUDENTS DURING THE COVID-19 PANDEMIC WITH AT-HOME INQUIRY-BASED LEARNING LABORATORY EXPERIMENTS.