Synergistic effects of dual-presenting VEGF- and BDNF-mimetic peptide epitopes from self-assembling peptide hydrogels on peripheral nerve regeneration

Lü, Jiaju; Yan, Xiaoqing; Sun, Xiaojuan; Shen, Xueqin; Yin, Heyong; Wang, Chenhao; Liu, Yifan; Lu, Chang; Fu, Hua; Yang, Shuhui; Wang, Yu; Sun, Xiaodan; Zhao, Lingyun; Lu, Shibi; Mikos, Antonios G.; Peng, Jiang; Wang, Xiumei

doi:10.1039/c9nr04521j

Cited by 63 publications

(39 citation statements)

References 52 publications

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“…Additionally, the chitosan degradation products could facilitate peripheral nerve regeneration by improving macrophage-constructed microenvironments 42 . The chitosan tube in this study has been verified to be helpful for peripheral nerve regeneration in previous studies 11 , 13 , 36 , 37 . Therefore, the chitosan tube was used as guidance conduit in this study.…”

Section: Introductionsupporting

confidence: 64%

“…The physicochemical properties of self-assembling backbone and functional motifs were shown in Table S2 . The common RADARADARADARADA backbone of the peptides used in this study contains a hydrophobic side with an array of alanine (A) and a side with alternating negatively charged aspartic acids (D) and positively charged arginine (R), allowing the peptide to form a stable β-sheet structure via both electrostatic and hydrophobic interactions 13 . The functionalized peptides RAD-IKV, RAD-RGI, and RAD-IKV-GG-RGI were synthesized by directly extending the C-terminus of RAD, with the two glycine residues between the backbone and the functional motifs designed to maintain flexibility.…”

Section: Resultsmentioning

confidence: 99%

“…Sun et al developed SAP hydrogels with RGD and IKVAV motifs for nerve regeneration, which could enhance SC recruitment 23 . Lu et al applied RGI and VEGF-mimetic peptide (KLT) epitopes to modify RAD peptide to construct neurovascular microenvironment for nerve repair, which could regulate and direct neural and vascular cell behavior and improve the recovery effect synergistically 13 . Lu et al combined RGI and NGF-mimetic peptide (CTD) to synergistically improve the regeneration of sensory and motor nerves 37 .…”

Section: Discussionmentioning

confidence: 99%

“…In the pursuit of an effective nerve conduit, various physical and biological strategies have been employed 12 . Progress in research associated with elucidating the intrinsic mechanism of peripheral nerve repair has increased the focus on the design of scaffold materials that simulate the repair process such as constructing the neurovascular microenvironment 13 . Unlike axons in the central nervous system (CNS), injured peripheral nerves exhibit the capacity to regenerate largely due to the supportive population of Schwann cells (SCs), which are primary glial cells in the peripheral nervous system (PNS).…”

Section: Introductionmentioning

confidence: 99%

“…The previous study proposed an SAP nanofiber hydrogel functionalized with BDNF mimicking peptide RGI to improve axon regeneration and motor functional recovery; however, its regenerative effect was not as good as that of autografting, indicating a limitation in the use of a single factor in repairing nerve injury 36 . Other studies showed that combined use of RGI and other peptide motifs derived from growth factors, such as NGF and VEGF, promoted nerve regeneration 13 , 37 . Therefore, we expanded our previous efforts to establish synergetic scaffolds harboring LN and BDNF mimicking peptide motifs to simulate effects of the extracellular matrix and neurotrophic factors at the same time for evaluation in a rat model of sciatic nerve injury.…”

Section: Introductionmentioning

confidence: 99%

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Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

et al. 2020

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The regenerative capacity of the peripheral nervous system is closely related to the role that Schwann cells (SCs) play in construction of the basement membrane containing multiple extracellular matrix proteins and secretion of neurotrophic factors, including laminin (LN) and brain-derived neurotrophic factor (BDNF). Here, we developed a self-assembling peptide (SAP) nanofiber hydrogel based on self-assembling backbone Ac-(RADA) 4 -NH 2 (RAD) dual-functionalized with laminin-derived motif IKVAV (IKV) and a BDNF-mimetic peptide epitope RGIDKRHWNSQ (RGI) for peripheral nerve regeneration, with the hydrogel providing a three-dimensional (3D) microenvironment for SCs and neurites. Methods: Circular dichroism (CD), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to characterize the secondary structures, microscopic structures, and morphologies of self-assembling nanofiber hydrogels. Then the SC adhesion, myelination and neurotrophin secretion were evaluated on the hydrogels. Finally, the SAP hydrogels were injected into hollow chitosan tubes to bridge a 10-mm-long sciatic nerve defect in rats, and in vivo gene expression at 1 week, axonal regeneration, target muscular re-innervation, and functional recovery at 12 weeks were assessed. Results: The bioactive peptide motifs were covalently linked to the C-terminal of the self-assembling peptide and the functionalized peptides could form well-defined nanofibrous hydrogels capable of providing a 3D microenvironment similar to native extracellular matrix. SCs displayed improved cell adhesion on hydrogels with both IKV and RGI, accompanied by increased cell spreading and elongation relative to other groups. RSCs cultured on hydrogels with IKV and RGI showed enhanced gene expression of NGF, BDNF, CNTF, PMP22 and NRP2, and decreased gene expression of NCAM compared with those cultured on other three groups after a 7-day incubation. Additionally, the secretion of NGF, BDNF, and CNTF of RSCs was significantly improved on dual-functionalized peptide hydrogels after 3 days. At 1 week after implantation, the expressions of neurotrophin and myelin-related genes in the nerve grafts in SAP and Autograft groups were higher than that in Hollow group, and the expression of S100 in groups containing both IKV and RGI was significantly higher than that in groups containing either IKV or RGI hydrogels, suggesting enhanced SC proliferation. The morphometric parameters of the regenerated nerves, their electrophysiological performance, the innervated muscle weight and remodeling of muscle fibers, and motor function showed that RAD/IKV/RGI and RAD/IKV-GG-RGI hydrogels could markedly improve axonal regeneration with enhanced re-myelination and motor functional recovery through the synergetic effect of IKV and RGI functional motifs. Conclusions: We found that the dual-functionalized SAP hydrogels promoted RSC adhesion, my...

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Section: Introductionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

et al. 2020

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Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

Ayoubi‐Joshaghani

Seidi

Azizi

et al. 2020

Adv Funct Materials

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Novel advanced hydrogels can provide a versatile platform for controlled delivery and release of various cargos, with a myriad of biomedical applications. These gel-based nanostructures possess good biocompatibility, biodegradability, flexibility, multifunctionality, can respond to internal or external stimuli, and can adapt to their surrounding environment. This new generation of hydrogels is not only capable of serving as targeted drug delivery vehicles, but they can also perform a variety of tasks within living cells and organisms. In this review, advanced hydrogels are classified as static, dynamic, multistage, or bioinspired. They can be used as cell-free gene expression platforms for gene therapy. Administration of nanogel-based sprays can act as an immunovaccine priming macrophages toward the M1 phenotype to avoid cancer recurrence following surgery. Nanogels can also serve as a dual biosensing and capture platform for liquid biopsies, and can recognize and remove circulating cancer cells from the blood of cancer patients.

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Hydrogel‐Based Growth Factor Delivery Platforms: Strategies and Recent Advances

Shan

2023

Advanced Materials

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Growth factors play a crucial role in regulating a broad variety of biological processes and have been regarded as powerful therapeutic agents in tissue engineering and regenerative medicine in the past decades. However, their application is limited by their short half‐lives and potential side effects in physiological environments. Hydrogels have been identified as having the promising potential to prolong the half‐lives of growth factors and mitigate their adverse effects by restricting them within the matrix to reduce their rapid proteolysis, burst release, and unwanted diffusion. This review discusses recent progress in the development of growth factor‐containing hydrogels for various biomedical applications, including wound healing, brain tissue repair, cartilage and bone regeneration, and spinal cord injury repair. In addition, the review introduces strategies for optimizing growth factor releases including affinity‐based delivery, carrier‐assisted delivery, stimuli‐responsive delivery, spatial structure‐based delivery, and cellular system‐based delivery. Finally, the review presents current limitations and future research directions for growth factor‐delivering hydrogels.This article is protected by copyright. All rights reserved

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Synergistic effects of dual-presenting VEGF- and BDNF-mimetic peptide epitopes from self-assembling peptide hydrogels on peripheral nerve regeneration

Abstract: We developed the functionalized self-assembling peptide nanofiber hydrogel RAD/KLT/RGI that was dual-functionalized with VEGF- and BDNF-mimetic peptide epitopes for peripheral nerve regeneration.

Cited by 63 publications

References 52 publications

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

Hydrogel‐Based Growth Factor Delivery Platforms: Strategies and Recent Advances

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