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

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.
项目总结/文摘

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:
  • 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.
Fluorescent liposomal nanocarriers for targeted drug delivery in ischemic stroke therapy.
  • DOI:
    10.1039/d3bm00951c
  • 发表时间:
    2023-12-05
  • 期刊:
  • 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.
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:
  • 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:
  • 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.
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Sangamesh Gurappa Kumbar其他文献

Sangamesh Gurappa Kumbar的其他文献

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{{ truncateString('Sangamesh Gurappa Kumbar', 18)}}的其他基金

Polysaccharide putty formulations for tissue regeneration
用于组织再生的多糖腻子配方
  • 批准号:
    10627055
  • 财政年份:
    2023
  • 资助金额:
    $ 41.01万
  • 项目类别:
Biodegradable Matrices for Bone Healing
用于骨愈合的可生物降解基质
  • 批准号:
    9987102
  • 财政年份:
    2019
  • 资助金额:
    $ 41.01万
  • 项目类别:

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职业:解析来自大脑表面的动作电位和高密度神经信号
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