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.

项目总结/文摘

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.