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.

项目概要背部和颈部疼痛是全球残疾的主要原因，其医疗保健价值超过 1,350 亿美元开支。椎间盘突出（IVD）引起的致残性背痛可以通过以下方法缓解：椎间盘切除术是去除突出的 IVD 组织的手术标准护理。椎间盘切除术虽然有效，但不修复由疝出引起的纤维环 (AF) 缺陷，这可能导致 IVD 加速退化、再生和复发性疼痛。细胞接种的粘性水凝胶是一种有前途的策略预防这些并发症，因为它们可以立即封闭 AF 缺陷并长期输送细胞康复。设计用于 IVD 细胞递送的水凝胶具有挑战性，因为通常使用软生物材料用于 IVD 损伤空间内的细胞输送风险。相反，高模量生物材料旨在承受高强度的脊柱负荷会阻碍封装细胞的愈合能力。本次活动的总体目标研究提案是独特地整合细胞微胶囊、可降解微珠的原理 (MB) 和高模量生物材料来设计促进 IVD 再生的下一代生物材料和功能修复。目标 1 将评估氧化海藻酸盐的保护能力和降解动力学 (OxAlg) MB。目标 2 将表征京尼平交联纤维蛋白 (FibGen)-OxAlg 构建体的作用大孔隙度对 AF 细胞表型的影响并构建生物力学。目标 3 将评估生物学和 FibGen-OxAlg 的生物力学修复反应。我们的全球假设是 OxAlg MB 将保护来自 FibGen 水凝胶交联的 AF 细胞随后降解（目标 1）。所得大孔 FibGen-OxAlg 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前体细胞的生物和生物力学修复体内 IVD 器官培养（目标 3）。这项工作意义重大，因为它开发了一种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愈合有限且机械强度高的其他肌肉骨骼组织的要求，这与 NIAMS 的使命高度一致。这个提议非常具有创新性，因为没有虽然存在修复和再生 AF 缺陷的策略，但很少有已发表的研究使用载有细胞的 MB 作为致孔剂模板化水凝胶结构，但没有人在 IVD 修复中使用此类结构。验证此方法的有效性负载大型动物 IVD 器官培养系统中的生物材料策略具有创新性且意义重大，因为使用这种培养系统的已发表研究很少，以这种方式进行测试将加速临床翻译。完成拟议的目标将为候选人提供严格的多学科培训生物材料合成、细胞微胶囊化、生物力学测试和IVD器官培养。补充有拟议的教学和指导经验，该奖学金将加速有前途的博士的职业生涯坚定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.