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

• 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
• 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

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.

项目概要/摘要 周围神经损伤（PNI）影响着美国数百万人，间隙较大的 PNI 需要手术修复。 尽管生物和合成移植物被广泛用于修复具有大间隙的 PNI，但它们都可能遭受以下问题： 次优的临床结果。自体移植是黄金标准治疗方法，但受到可用性和缺陷的限制 修复尺寸，而合成移植物的生物可降解性、强度、生物活性和功能性较差。因此， 该提案的长期目标是设计具有增强大间隙神经再生能力的移植物。 物理和化学刺激可以增强神经再生反应，因此，结合这些 工程化移植物的方式可能会解决当前的一些治疗局限性。电刺激（ES）可以 增强神经传导、神经营养素释放和神经挤压损伤的功能恢复，但这些 尚未确定大差距 PNI 的效益。使用 4-氨基吡啶 (4-AP；a 钾通道阻滞剂）对神经元的作用与 ES 相似，并且可以增强压碎 PNI 修复， 但可能与 ES 协同作用。实施这些物理和化学线索以实现有效的大间隙 PNI 修复需要通过手术插入具有适当机械强度的导电支架， 降解、电导率和孔隙特性。该提案旨在通过新颖的、 可生物降解的离子传导（IC）壳聚糖支架和混合工程神经同种异体移植物可修复大 间隙神经缺陷。具有 4-AP 的生物工程 IC 支架可以增加体外神经营养蛋白的释放并增强 早期修复中大间隙 PNI 体内髓鞘形成。初步研究表明，联合应用 4-AP 和 ES 减少了皮下植入支架周围的纤维囊厚度，并增加了 与单独的 4-AP 或 ES 相比，体外神经营养蛋白表达。这表明 4-AP 和 ES 的结合可以改善 功能、生物相容性和积极的免疫反应。因此，推测IC支架 与化学和电信号相结合将调节细胞-材料相互作用以增强轴突再生 速度和功能恢复与自体移植相当。这将在三个具体目标中进行测试：1) 开发和 表征 IC 支架在 4-AP 释放速率、电导率和生物降解方面的变化； 2）评估人 大鼠雪旺细胞对具有 4-AP 和/或 ES 的 IC 支架的体外反应，以模拟体内反应 未来的干预措施； 3) 在 4-AP +/- ES 中测试工程支架和同种异体移植物的安全性和有效性 临界大小的坐骨神经缺损。利用生物活性电学和化学技术对大间隙 PNI 进行工程修复 线索将广泛影响该领域。这些研究将弥合复杂的 ES- 介导的细胞与材料相互作用的微环境，并且对潜在的再生途径的研究很少。 这些发现可能会改善神经缺陷的治疗，并为再生的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

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

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

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

纳米纤维基质制剂用于递送Exendin-4用于肌腱再生：体外和体内评估。

• 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.

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.