Self-assembling Peptide Nanofiber Hydrogels for Nerve Regeneration

用于神经再生的自组装肽纳米纤维水凝胶

基本信息

批准号：
10237909
负责人：
Jeffrey Dale Hartgerink
金额：
$ 36.13万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237909
关键词：
Affect Amaze Amino Acid Sequence Animal Model Anti-Bacterial Agents Antibodies Area BMP2 gene Binding Biological Biological Assay Biomimetics Blood Vessels Cell Culture Techniques Cells Cellular Infiltration Chemistry Clinical Medicine Communication Complication Cyst Data Defect Disease Drooling Eating Ensure Esthesia Evaluation Extracellular Matrix Proteins Funding Gel Growth Factor Hydrogels Impairment In Vitro Individual Inflammatory Response Injectable Intelligence Laminin Lead Left Leucocytic infiltrate Lip structure Literature Mandible Mastication Medical Research Modeling Modulus Mus Nanostructures Nanotechnology Natural regeneration Nerve Nerve Regeneration Neurites Neurons Neurosciences Operative Surgical Procedures Oral cavity Organ Oryctolagus cuniculus Outcome PC12 Cells Pain Patients Peptides Performance Peripheral Nervous System Population Production Property Publishing Quality of life Rapid screening Rattus Receptor Cell Regenerative Medicine Series Subcutaneous Injections Syringes Technology Tenascin Testing Tissue Engineering Tissues Tongue Tooth structure Trigeminal nerve structure Vascular Endothelial Growth Factors angiogenesis base biological systems biomaterial compatibility clinical translation clinically relevant clinically translatable cytokine design drinking experience experimental study immunoreaction in vivo in vivo Model in vivo evaluation in vivo regeneration inferior alveolar nerve interdisciplinary approach materials science nanofiber nerve injury neurogenesis neurosensory peptide structure receptor recruit regeneration model regenerative relating to nervous system repaired response scaffold sciatic nerve injury success synthetic peptide tissue regeneration tumor wisdom tooth

项目摘要

Project Summary / Abstract This renewal proposal builds on our successes in developing a nanostructured material we call “MultiDomain Peptides” or MDPs. Amongst the many discoveries during our first funding period, we found that these hydrogels have remarkable properties in vivo, in particular: 1) The MDP amino acid sequence can be tailored for rapid or slow degradation. 2) The hydrogel is entirely infiltrated by host cells within 7 days where the large number of cells interacting with the MDP matrix provides for powerful and rapid response to the matrix. 3) No fibrous encapsulation is observed up to 42 days in vivo allowing for good communication between our nanostructured matrix and the biological system. 4) Biomimetic amino acid sequences can be added to the base MDP structure allowing it to provoke desired biological responses such as angiogenesis and neurogenesis. Published data from our previous funding period and unpublished preliminary data presented here demonstrate the extremely powerful angiogenic and neurogenic properties of carefully designed MDPs which is unprecedented elsewhere in the literature and is the basis for the current proposal. A key feature of our approach is that the MDP hydrogel is composed of just a single designed, synthetic peptide. There is no need for additional growth factors or cells, either of which increases the challenge of clinical translation due to unforeseen and undesirable biological responses such as immune reaction, host rejection or tumor formation. The current proposal has four aims which can be summarized as follows. In aim 1 we prepare a new series of nanofibrous MDP hydrogels each containing a unique mimic of a growth factor or extracellular matrix protein. The chemistry, nanostructure and materials properties are characterized in this aim. In aim 2 we test the the MDP’s ability to activate expected cellular receptors. We also assess their performance in subcutaneous injections in healthy mice. We assess inflammatory response, cellular infiltration, cytokine expression, angiogenesis and neurogenesis. Based on these results antibody depletion studies will allow us to dissect the mechanism of action. Aim 3 moves our study of tissue regeneration in the specific context of neural regeneration. Two major sets of experiments are proposed. The first utilizes a cell culture model of neurite sprouting to allow rapid screening of candidate MDPs. The second is a sciatic nerve injury model in rats. This in vivo test of neuroregeneration allows more rapid and economical assessment of regeneration before moving the more clinically relevant rabbit model. In aim 4 we examine nerve regeneration of the inferior alveolar nerve of the rabbit. MDP hydrogels with demonstrated angiogenic and neurogenic properties will be used to accelerate regeneration. Our interdisciplinary team combines expertise in chemistry, materials science, nanotechnology, neuroscience and clinical medicine. We will generate data that will provide the framework for further advances in nanostructured tissue engineering generally as well as advances specific to neural regeneration.

项目摘要 /摘要该更新提案是基于我们在开发一种纳米结构材料方面取得的成功，我们称为“多域肽”或MDPS。在我们第一个资金期间的许多发现中，我们发现这些水凝胶在体内具有显着的特性，特别是：1）MDP氨基酸序列可以量身定制快速或缓慢的降解。 2）水凝胶在7天内完全被宿主细胞浸润与MDP矩阵相互作用的细胞数量为矩阵提供了强大而快速的响应。 3）否在体内观察到长达42天的纤维封装，可以在我们之间进行良好的沟通纳米结构基质和生物系统。 4）可以将仿生氨基酸序列添加到基础MDP结构允许它引起所需的生物学反应，例如血管生成和神经发生。从我们以前的资金期和未发表的初步数据中发布的数据在这里展示了精心设计的MDP的极其强大的血管生成和神经源特性一个关键特征的我们的方法是MDP水凝胶仅由一个设计的合成肽组成。没有需要其他生长因子或细胞，这两种都会增加由于不可预见且不良的生物学反应，例如免疫反应，宿主排斥或肿瘤形成。当前的提案具有四个目标，可以总结如下。在目标1中，我们准备了一个新系列纳米纤维MDP水凝胶每个都包含生长因子或细胞外基质蛋白的独特模仿。化学，纳米结构和材料特性在此目标中具有特征。在AIM 2中，我们测试 MDP激活预期的蜂窝接收器的能力。我们还评估它们在皮下的表现健康小鼠的注射。我们评估炎症反应，细胞浸润，细胞因子表达，血管生成和神经发生。基于这些结果，抗体部署研究将使我们能够剖析作用机理。 AIM 3在神经的特定背景下移动我们对组织再生的研究再生。提出了两组主要的实验集。第一个利用神经蛋白的细胞培养模型发芽以快速筛选候选MDP。第二个是大鼠的坐骨神经损伤模型。这在移动之前，对神经变性的体内测试可以对再生进行更快和经济评估临床上相关的兔子模型越多。在AIM 4中，我们检查下肺泡神经的神经再生兔子。具有活血管生成和神经源特性的MDP水凝胶将用于加速再生。我们的跨学科团队结合了化学，材料科学，纳米技术，神经科学方面的专业知识和临床医学。我们将生成将为进一步进步提供框架的数据纳米结构的组织工程以及特定于神经再生的进步。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Scaffolds to control inflammation and facilitate dental pulp regeneration.

DOI：
10.1016/j.joen.2014.01.019
发表时间：
2014-04
期刊：
Journal of endodontics
影响因子：
4.2
作者：
Colombo JS;Moore AN;Hartgerink JD;D'Souza RN
通讯作者：
D'Souza RN

Covalent Capture of Aligned Self-Assembling Nanofibers.

DOI：
10.1021/jacs.7b04655
发表时间：
2017-06-14
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Li IC;Hartgerink JD
通讯作者：
Hartgerink JD

A nanostructured synthetic collagen mimic for hemostasis.

DOI：
10.1021/bm500091e
发表时间：
2014-04-14
期刊：
BIOMACROMOLECULES
影响因子：
6.2
作者：
Kumar, Vivek A.;Taylor, Nichole L.;Jalan, Abhishek A.;Hwang, Lyahn K.;Wang, Benjamin K.;Hartgerink, Jeffery D.
通讯作者：
Hartgerink, Jeffery D.

Highly angiogenic peptide nanofibers.

DOI：
10.1021/nn506544b
发表时间：
2015-01-27
期刊：
ACS NANO
影响因子：
17.1
作者：
Kumar, Vivek A.;Taylor, Nichole L.;Shi, Siyu;Wang, Benjamin K.;Jalan, Abhishek A.;Kang, Marci K.;Wickremasinghe, Navindee C.;Hartgerink, Jeffrey D.
通讯作者：
Hartgerink, Jeffrey D.

Drug-triggered and cross-linked self-assembling nanofibrous hydrogels.

DOI：
10.1021/jacs.5b01549
发表时间：
2015-04-15
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Kumar VA;Shi S;Wang BK;Li IC;Jalan AA;Sarkar B;Wickremasinghe NC;Hartgerink JD
通讯作者：
Hartgerink JD