Engineered Matrices with Electrical and Chemical Stimulation for Peripheral Nerve Repair

用于周围神经修复的具有电和化学刺激的工程基质

基本信息

批准号：
10592729
负责人：
Sangamesh Gurappa Kumbar
金额：
$ 41.01万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
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：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592729
关键词：
4-Aminopyridine Action Potentials Address Adverse effects Affect Alkanesulfonates Allografting American Animals Autologous Transplantation Biodegradation Biological Biomedical Engineering Cells Chemical Stimulation Chemicals Chitosan Clinical Complex Convulsants Crush Injury Cues Defect Development Disease Electric Stimulation Engineering Ensure Fiber Future Gold Human Hybrids Hydrophobicity Immune response Implant In Vitro Injury Intervention Knowledge Mechanics Mediating Methodology Minor Modality Multiple Sclerosis Musculoskeletal Natural regeneration Nerve Nerve Crush Nerve Regeneration Neural Conduction Neurites Neurons Neurotransmitters Operative Surgical Procedures Outcome Oxidation-Reduction Pathway interactions Patients Pattern Peripheral nerve injury Persons Physical Stimulation Physiological Polymers Potassium Channel Blockers Property Rattus Recovery of Function Regenerative pathway Regenerative response Safety Schwann Cells Site Supporting Cell Testing Therapeutic Thick Tissues Variant Work axon regeneration biodegradable scaffold biomaterial compatibility capsule cell motility controlled release disease transmission functional restoration healing improved improved functioning in vitro Model in vivo in vivo Model injury and repair myelination nerve autograft nerve gap nerve injury nerve repair nerve supply neural graft neurotrophic factor novel peripheral nerve repair regenerative approach relating to nervous system remyelination repair function repaired response safety testing scaffold sciatic nerve standard care subcutaneous translational potential

项目摘要

Project Summary/Abstract Peripheral nerve injuries (PNI) affect millions of people in the US, and PNI with large gaps require surgical repair. Although biological and synthetic grafts are widely used to repair PNI with large gaps, they both can suffer from suboptimal clinical outcomes. Autografts are the gold standard treatment but are limited by availability and defect repair size, while synthetic grafts have poor biodegradability, strength, bioactivity, and functionality. Thus, the long-term objective of this proposal is to engineer grafts with enhanced large-gap nerve regeneration capabilities. Physical and chemical stimulation can enhance nerve regeneration responses, thus, incorporating these modalities into engineered grafts may address some current treatment limitations. Electrical stimulation (ES) can enhance nerve conduction, neurotrophin release, and functional recovery of nerve crush injuries, but these benefits have not been established for large-gap PNI. Chemical stimulation using 4-aminopyridine (4-AP; a potassium channel blocker) appears similar to ES in its effects on neurons and can enhance crush PNI repair, yet may act synergistically with ES. Implementing these physical and chemical cues for effective large-gap PNI repair will require surgical insertion of an electrically conductive scaffold with appropriate mechanical strength, degradation, conductivity, and pore properties. This proposal aims to deliver 4-AP and ES via novel, biodegradable, ionically conducting (IC) chitosan scaffolds and hybrid engineered nerve allografts to repair large- gap nerve defects. Bioengineered IC scaffolds with 4-AP can increase neurotrophin release in vitro and enhance myelination of large-gap PNI in vivo in early-stage repair. Preliminary studies revealed that combined application of 4-AP and ES reduced fiber capsule thickness around subcutaneously implanted scaffolds and increased in vitro neurotrophin expression compared to 4-AP or ES alone. This suggests combining 4-AP and ES improves functionality, biocompatibility, and positive immune responses. Therefore, it was hypothesized that IC scaffolds combined with chemical and electrical cues will modulate cell-material interactions to enhance axon regeneration rate and functional recovery comparable to autografts. This will be tested in three Specific Aims: 1) Develop and characterize IC scaffolds with variations in 4-AP release rate, conductivity, and biodegradation; 2) Assess human and rat Schwann cell responses to IC scaffolds with 4-AP and/or ES in vitro to model in vivo responses and future interventions; and 3) Test safety and efficacy of engineered scaffolds and allografts with 4-AP +/- ES in a critical-sized sciatic nerve defect. Engineered repair of large-gap PNI using bioactive electrical and chemical cues will broadly impact the field. These studies will bridge the knowledge gap between the complex ES- mediated cell-material interaction microenvironment and poorly studied underlying regeneration pathways. These findings may improve the treatment of nerve defects, and inform exploratory work on regenerative strategies for innervation in other musculoskeletal tissues.

项目摘要/摘要周围神经损伤（PNI）会影响美国数百万的人，并且具有较大间隙的PNI需要手术修复。尽管生物学和合成移植物被广泛用于用较大差距修复PNI，但它们俩都可能遭受次优临床结果。自体移植是黄金标准处理，但受到可用性和缺陷的限制维修大小，而合成移植物的生物降解性，强度，生物活性和功能性较差。因此，该提案的长期目标是工程移植物具有增强的大范围神经再生能力。物理和化学刺激可以增强神经再生反应，因此将其纳入对工程移植物的方式可能会解决一些当前的治疗限制。电刺激（ES）可以增强神经传导，神经营养蛋白的释放和神经压伤损伤的功能恢复，但这些尚未确定大范围PNI的好处。使用4-氨基吡啶的化学刺激（4-AP; a 钾通道阻滞剂）与ES对神经元的影响相似，并且可以增强挤压PNI修复，但是可以与ES协同行动。实施这些物理和化学提示，以进行有效的大范围PNI 维修将需要以适当的机械强度进行导电支架的手术插入降解，电导率和孔特性。该建议旨在通过小说传递4-AP和ES，可生物降解的，离子传导（IC）的壳聚糖支架和杂交工程神经同种异体移植物可修复大型间隙神经缺陷。具有4-AP的生物工程IC支架可以在体外增加神经营养蛋白释放并增强在早期修复中体内大间隙PNI的髓鞘化。初步研究表明，合并应用皮下植入支架周围的4-AP和ES减小的纤维胶囊厚度，并增加与单独的4-AP或ES相比，体外神经营养蛋白的表达。这表明组合4-AP和ES改进功能，生物相容性和阳性免疫反应。因此，假设IC支架结合化学和电气提示将调节细胞材料相互作用以增强轴突再生速率和功能恢复与自体移植相当。这将以三个具体目的进行测试：1）开发和表征具有4-AP释放速率，电导率和生物降解的IC支架； 2）评估人以及用4-AP和/或ES在体外对IC支架的Rat Schwann细胞反应，以模拟体内反应和未来的干预措施； 3）在A中具有4-AP +/- ES的工程支架和同种异体的测试安全性和功效临界大小坐骨神经缺陷。使用生物活性电和化学的工程修复大范围PNI 提示将广泛影响该领域。这些研究将弥合复杂的ES-之间的知识差距介导的细胞材料相互作用微环境和研究不足的基本再生途径。这些发现可能会改善神经缺陷的治疗，并为再生探索性工作提供信息其他肌肉骨骼组织的神经支配策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin-Functionalized Bioactive Fiber Matrices with Bone Marrow-Derived Stem Cells in Rat Achilles Tendon Regeneration.

DOI：
10.1021/acsabm.2c00243
发表时间：
2022-06-20
期刊：
ACS APPLIED BIO MATERIALS
影响因子：
4.7
作者：
Ramos, Daisy M;Abdulmalik, Sama;Arul, Michael R;Sardashti, Naseem;Banasavadi-Siddegowda, Yeshavanth Kumar;Nukavarapu, Syam P;Drissi, Hicham;Kumbar, Sangamesh G
通讯作者：
Kumbar, Sangamesh G

Novel Injectable Fluorescent Polymeric Nanocarriers for Intervertebral Disc Application.

DOI：
10.3390/jfb14020052
发表时间：
2023-01-17
期刊：
Journal of functional biomaterials
影响因子：
4.8
作者：
通讯作者：

Hydrogel-Based Strategies for Intervertebral Disc Regeneration: Advances, Challenges and Clinical Prospects.

DOI：
10.3390/gels10010062
发表时间：
2024-01-15
期刊：
GELS
影响因子：
4.6
作者：
Desai, Shivam U.;Srinivasan, Sai Sadhananth;Kumbar, Sangamesh Gurappa;Moss, Isaac L.
通讯作者：
Moss, Isaac L.

Fluorescent liposomal nanocarriers for targeted drug delivery in ischemic stroke therapy.

DOI：
10.1039/d3bm00951c
发表时间：
2023-12-05
期刊：
Biomaterials science
影响因子：
6.6
作者：
通讯作者：

Nanofiber matrix formulations for the delivery of Exendin-4 for tendon regeneration: In vitro and in vivo assessment.

DOI：
10.1016/j.bioactmat.2023.01.013
发表时间：
2023-07
期刊：
BIOACTIVE MATERIALS
影响因子：
18.9
作者：
Abdulmalik, Sama;Gallo, Jack;Nip, Jonathan;Katebifar, Sara;Arul, Michael;Lebaschi, Amir;Munch, Lucas N.;Bartly, Jenna M.;Choudhary, Shilpa;Kalajzic, Ivo;Banasavadi-Siddegowdae, Yeshavanth Kumar;Nukavarapu, Syam P.;Kumbar, Sangamesh G.
通讯作者：
Kumbar, Sangamesh G.