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Systematic Review

Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review

[version 1; peer review: awaiting peer review]
Kurosh Mojtabavi1,2, Morteza Gholami3,4, Zahra Ghodsi1,5, [...] Narges Mahmoodi1,6, Sina Shool1,7, Saeed Kargar-Soleimanabad
https://orcid.org/0000-0001-5602-3816
1,8, Niloufar Yazdanpanah9,10, Alexander R. Vaccaro11, Vafa Rahimi-Movaghar
https://orcid.org/0000-0001-9086-7318
1,5,12-15
Kurosh Mojtabavi1,2, Morteza Gholami3,4, [...] Zahra Ghodsi1,5, Narges Mahmoodi1,6, Sina Shool1,7, Saeed Kargar-Soleimanabad
https://orcid.org/0000-0001-5602-3816
1,8, Niloufar Yazdanpanah9,10, Alexander R. Vaccaro11, Vafa Rahimi-Movaghar
https://orcid.org/0000-0001-9086-7318
1,5,12-15
PUBLISHED 07 Jan 2022
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS AWAITING PEER REVIEW

Abstract

Background: In many cases, central nervous system (CNS) injury is unchanging due to the absence of neuronal regeneration and repair capabilities. In recent years, regenerative medicine, and especially hydrogels, has reached a significant amount of attention for their promising results for the treatment of spinal cord injury (SCI) currently considered permanent. Hydrogels are categorized based on their foundation: synthetic, natural, and combination. The objective of this study was to compare the properties and efficacy of commonly used hydrogels, like collagen, and other natural peptides with synthetic self-assembling peptide hydrogels in the treatment of SCI. 
Methods: Articles were searched in PubMed, Scopus, Web of Science, and Embase. All studies from 1985 until January 2020 were included in the primary search. Eligible articles were included based on the following criteria: administering hydrogels (both natural and synthetic) for SCI treatment, solely focusing on spinal cord injury treatment, and published in a peer-reviewed journal. Data on axonal regeneration, revascularization, elasticity, drug delivery efficacy, and porosity were extracted.
Results: A total of 24 articles were included for full-text review and data extraction. There was only one experimental study comparing collagen I (natural hydrogel) and polyethylene glycol (PEG) in an in vitro setting. The included study suggested the behavior of cells with PEG is more expectable in the injury site, which makes it a more reliable scaffold for neurites.
Conclusions: There is limited research comparing and evaluating both types of natural and self-assembling peptides (SAPs) in the same animal or in vitro study, despite its importance. Although we assume that the remodeling of natural scaffolds may lead to a stable hydrogel, there was not a definitive conclusion that synthetic hydrogels are more beneficial than natural hydrogels in neuronal regeneration.

Keywords

Hydrogels, Collagen, Peptides, Spinal cord Injuries, Systematic review

Corresponding author: Vafa Rahimi-Movaghar
Competing interests: Alexander R. Vaccaro is a board member of AOSpine, Innovative Surgical Design, Association of Collaborative Spine Research, DePuy; Consultant at Medtronics, Stryker Spine, Globus, Stout Medical, Gerson Lehrman Group, Guidepoint Global, Medacorp, Innovative Surgical Design, Orthobullets, Ellipse, Vertex, Medtronics; Royalty at Stryker Spine, Biomet Spine, Globus, Aesculap, Thieme, Jaypee, Elsevier, Taylor Francis. All remaining authors declare that they have no financial or non-financial/personal conflict exists and also no commercial associations that might pose a conflict of interest in connection with the submitted article.
Grant information: This work was supported by Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences [99-1-101-47039].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:  © 2022 Mojtabavi K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Mojtabavi K, Gholami M, Ghodsi Z et al. Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review [version 1; peer review: awaiting peer review]. F1000Research 2022, 11:16 (https://doi.org/10.12688/f1000research.74087.1) First published: 07 Jan 2022, 11:16 (https://doi.org/10.12688/f1000research.74087.1) Latest published: 07 Jan 2022, 11:16 (https://doi.org/10.12688/f1000research.74087.1)

Introduction

Injuries to the central nervous system (CNS) are challenging to rehabilitate. In the absence of neuronal regeneration and repair capabilities, the damage and resulting complications are permanent in many cases. There have not been any new treatments for spinal cord injury (SCI) in the past decade, and many studies in molecular medicine currently consider some spinal cord conditions as untreatable.1

A permissive growth substrate is critical to promote regeneration at the injury site.2 Many types of research have been conducted to advance and evaluate different natural and synthetic hydrogel systems,3 such as polysaccharides,4,5 synthetic polymers,6 proteins,7 peptides,8 and its derivatives.9–11

Hydrogels are categorized as natural and synthetic structures with properties for extensive water absorption and resistance to dissolution.12 We consider a perfect hydrogel to provide the following features: 1) high absorption capacity, 2) low soluble content and residue, 3) suitable biodegradability based on tissue type and the absence of toxic species formation, 4) local and sustained drug-release, 5) immunologically inert, and 6) substantial cost-benefit.12–14

Both natural and synthetic hydrogels have different characteristics, and some of them are compatible with the features listed above.

Self-assembling peptides (SAPs) can spontaneously self-assemble in the aqueous solution to form highly organized structures, such as hydrogels. Due to their great water-holding capacity, outstanding biocompatibility,15–17 and similarities to the native extracellular matrix (ECM),18 these hydrogels have gained tremendous recognition in recent years. The advantages of these artificial hydrogels are their transmutative characteristics, such as porosity, elasticity, and drug delivery pace.19

For a previous project, we asked several distinguished companies in China, Denmark, Canada, and more to design and produce high concentration hydrogels. However, they could not produce SAPs with a desirable concentration percentage for cell culture purposes, which in some cases can be considered as a challenge of providing this type of scaffolds.

On the other hand, many studies have applied natural hydrogels like collagen-based hydrogel designed based on the Nature Protocols20 for drug delivery in spinal cord injuries in animals, and the results have been somewhat promising. Due to their soft tissue-like formation characteristics, agarose, alginate, and collagen hydrogels have been acknowledged as likely scaffolds in the CNS and the peripheral nervous system (PNS).21–23 Therefore, we performed this review to determine how these two very different, yet very promising, scaffolds would perform in similar conditions.

Method

Ethical considerations

The Ethics Committee of Tehran University of Medical Sciences, approved the study with reference number 99-1-101-388. This systematic review has been conducted according to the PRISMA 2020 Checklist.24,25

Eligibility criteria

In the review, articles had to meet the following inclusion criteria: 1) administering hydrogels (both natural and synthetic) for SCI treatment, 2) specifically focused on spinal cord injury, and 3) original articles published in a peer-reviewed journal. Exclusion criteria included: 1) studies on injuries other than SCI, 2) studies focusing on only tissue-engineered self-assembling peptides, 3) studies focused only on natural hydrogels.

There was no limitation of language for included studies.

Electronic searches

We performed this systematic review to evaluate axonal regeneration, revascularization, porosity, elasticity, and drug delivery efficacy of natural and synthetic hydrogels. Our search strategy in different databases utilized Medical Subject Headings (MeSH, from PubMed), Excerpta Medica Tree (Emtree, from Embase), keywords of related articles and reviews, and experts' opinions. A systematic search of the literature was performed on PubMed, Scopus, Web of Science, and Embase for published articles from 1985 until January 2020. The detailed search syntax is presented in the Extended data.24 We also manually checked the references of primarily included studies and relevant reviews to identify additional relevant articles. After removing duplicate articles, the remaining articles were transferred to an EndNote file (version X9, Thomson Reuters, USA).

Selection and data collection process

After eliminating duplicates, the records were divided into two groups. Each group was reviewed by two independent reviewers (in two teams) based on the keywords, and 24 papers were selected eligible for full-text review. The resulting records were then divided again and each full text was reviewed by two independent reviewers (in two teams) for data extraction. Differences of opinion between two reviewers of each team was solved by consultation with the corresponding author.

Data items

We designed a data collection sheet, and the items below were collected to compare natural and self-assembling hydrogels:

  • • Axonal regeneration: The axon (proximal fragment) regrowth from the injury site toward its target following the original pathway.

  • • Revascularization: restoration of the flow of blood to a previously ischemic tissue after a traumatic injury.

  • • Porosity: a fraction of the volume of voids over the total volume. Hydrogel porosity is critical for local angiogenesis and has a substantial effect on the mechanical properties

  • • Elasticity: the ability of a hydrogel to resume its standard shape after implantation.

  • • Invasion/Elongation of astrocytes, fibroblasts, endothelial or Schwann cells

  • • Efficacy of drug delivery

Results

Out of a total number of 2742 identified articles, 2718 records were excluded based on title and abstract screening, and the full text of the remaining 24 records were investigated by the same four reviewers as two review groups. In total, 23 were excluded at this stage and only one record was selected for full-text review (Figure 1). Of the 23 articles excluded, 18 were because they did not evaluate a natural hydrogel in their study,26–43 and five because they had not administrated a SAP in the study.44–48

aad7e405-8d99-44c2-8bef-a51d6c459016_figure1.gif

Figure 1. Flowchart of the article screening process following identification of studies via database search.

According to the single record included (Table 1), axonal regeneration of the administrated scaffolds was reported individually based on the type and the combination of scaffolds.

Table 1. General information of the only one included study.

TitleFirst authorYear of StudyCountryStudy CharacteristicsType of Study
Comparison of neurite growth in three dimensional natural and synthetic hydrogelsWenda ZhouAug 2012United StatesExperimentalIn Vitro

In this study, with the addition of fibronectin (FN) at various concentrations to PEG gels, and collagen I in various concentrations and stiffness, cell behavior and axonal regeneration were investigated in an in vitro environment shown in Table 2. The article found that adding FN to collagen has a biphasic response due to specific interactions in collagen and the growing neurites, contrary to PEG, which has a more expectable behavior regarding the FN addition within the graft.

Table 2. Axonal regeneration and elasticity of scaffold.

Results
Type of Scaffold		Neurite lengths growElasticity
3% PEG + 0 μg/ml FN, 90≃ 90 μm10^2 Pa>
3% PEG + 1 μg/ml FN, 95≃ 95 μm10^2 Pa>
3% PEG + 10 μg/ml FN, 130≃ 130 μm10^2 Pa>
3% PEG + 100 μg/ml FN, 145≃ 145 μm10^2 Pa>
4% PEG + 0 μg/ml FN, 80≃ 80 μm10^3 Pa>
4% PEG + 1 μg/ml FN, 110≃ 110 μm10^3 Pa>
4% PEG + 10 μg/ml FN, 130≃ 130 μm10^3 Pa>
4% PEG + 100 μg/ml FN, 135≃ 135 μm10^3 Pa>
5% PEG + 0 μg/ml FN, 85≃ 85 μm≃ 10^3 Pa
5% PEG + 1 μg/ml FN, 90≃ 90 μm≃ 10^3 Pa
5% PEG + 10 μg/ml FN, 100≃ 100 μm≃ 10^3 Pa
5% PEG + 100 μg/ml FN, 125≃ 125 μm≃ 10^3 Pa
0.4 mg/ml Col. + 0 μg/ml FN,≃ 187 μm10 Pa>
0.4 mg/ml Col. + 1 μg/ml FN,≃ 160 μm10 Pa>
0.4 mg/ml Col. + 10 μg/ml FN,≃ 165 μm10 Pa>
0.4 mg/ml Col. + 100 μg/ml FN≃ 155 μm10 Pa>
0.6 mg/ml Col. + 0 μg/ml FN,≃ 200 μm10 Pa>
0.6 mg/ml Col. + 1 μg/ml FN,≃ 187 μm10 Pa>
0.6 mg/ml Col. + 10 μg/ml FN,≃ 185 μm10 Pa>
0.6 mg/ml Col. + 100 μg/ml FN≃ 155 μm10 Pa>
0.8 mg/ml Col. + 0 μg/ml FN,≃ 168 μm10 Pa>
0.8 mg/ml Col. + 1 μg/ml FN,≃ 180 μm10 Pa>
0.8 mg/ml Col. + 10 μg/ml FN,≃ 190 μm10 Pa>
0.8 mg/ml Col. + 100 μg/ml FN≃ 165 μm10 Pa>
1 mg/ml Col. + 0 μg/ml FN,≃ 160 μm10 Pa>
1 mg/ml Col. + 1 μg/ml FN,≃ 168 μm10 Pa>
1 mg/ml Col. + 10 μg/ml FN,≃ 195 μm10 Pa>
1 mg/ml Col. + 100 μg/ml FN,≃ 185 μm10 Pa>
1.25 mg/ml Col. + 0 μg/ml FN,≃ 160 μm≃ 10 Pa
1.25 mg/ml Col. + 1 μg/ml FN,≃ 185 μm10 Pa>
1.25 mg/ml Col. + 10 μg/ml FN,≃ 178 μm10 Pa>
1.25 mg/ml Col. + 100 μg/ml FN,≃ 180 μm10 Pa>
1.5 mg/ml Col. + 0 μg/ml FN,≃ 180 μm10^2 Pa>
1.5 mg/ml Col. + 1 μg/ml FN,≃ 188 μm10^2 Pa>
1.5 mg/ml Col. + 10 μg/ml FN,≃ 185 μm10^2 Pa>
1.5 mg/ml Col. + 100 μg/ml FN,≃ 188 μm10^2 Pa>
2 mg/ml Col. + 0 μg/ml FN,≃ 155 μm10^2 Pa>
2 mg/ml Col. + 1 μg/ml FN,≃ 175 μm10^2 Pa>
2 mg/ml Col. + 10 μg/ml FN,≃ 175 μm10^2 Pa>
2 mg/ml Col. + 100 μg/ml FN,≃ 158 μm10^2 Pa>

PEG gels were examined at 3%, 4%, and 5% concentration with 0, 1, 10, 100 μg/ml FN added; 3% PEG+ 100 μg/ml FN presented the most significant neurite length growth by 145 μm. It is also worth remarking that adding any concentrations of FN to PEG gels had a positive effect on axonal regeneration than PEG gels with no FN added.

Collagen I was examined at 0.4-2 mg/ml concentrations with 0, 1, 10, 100 μg/ml FN added; As mentioned above, the addition of FN had a biphasic response in collagen, with reducing neurite growth length in lower concentrations (0.4-0.6 mg/ml) compared to collagens with no FN, while increasing neurites length in mid and high collagen concentrations (1.0-2.0 mg/ml).

While the addition of FN impacted the overall growth within the different gels, there were no differences noted in viability with increasing FN concentrations. No differences were found between PEG gel concentrations. Moreover, cells within collagen gels had higher viability overall.

Discussion

We believe biomaterials and natural hydrogels are expected to not dissolve quickly and remain for a long time when injected into the injured spinal cord whilst directly delivering drugs into it, and render a sufficient environment for axonal regeneration and revascularization of the damaged tissues. Also, these scaffolds help with the need for a physical matrix to which neurons and endogenous repairing cells can adhere.49

In this regard, designing a hydrogel must meet some fundamental principles, such as biocompatibility, so it does not trigger an immune response from the host49; specifically designed mechanical and physicochemical characteristics allow both spinal cord stabilization and cell adherence and growth.26

The biodegradability of these materials must be considered, and the biomaterial degrades as new tissue grows, mimicking the natural mechanisms of breakdown and synthesis of ECM in the natural tissue.50–54

In a previous study, Merchand et al. used collagen as scaffolds to fill the gap transected in the spinal cord of Sprague-Dawley rats, and extended the stability of collagen (2-3 months) by adding a cross-linking agent to the gel which helped axonal regrowth over a six months' timeline.56

The biocompatibility characteristics of natural hydrogels allow for cell adhesion and migration.57 Moreover, not only can natural hydrogels be used to bridge the gap in the lesion site for cell regeneration, but they are also considered for sustained drug delivery.58

However, synthetic hydrogels, such as poly (hydroxyethyl methacrylate) (PHEMA) based hydrogels, are favorites for the treatment of SCI and drug delivery to the lesion site due to their ability to be mass produced and their ability to have their properties modified.59

Our study indeed had some limitations. Regenerative studies for SCI primarily focus on different characteristics of one specific type of hydrogel and, comparing different features of these types of hydrogels were completely overlooked, or if these two types of hydrogels are used together in a study, it is in the form of a new combinatorial hydrogel scaffold.

There are no definitive findings regarding synthetic hydrogels' advantage over natural hydrogels in SCI treatment in animals or humans. Still, there might be some inadequate shreds of evidence to report that one of these types has an advantage over the other. However, more studies with the specific objective to compare synthetic and natural hydrogels is necessary to find their advantages and disadvantages in a mutual condition. Until then, both synthetic and natural scaffolds are in the race for the ultimate scaffolds.

This study sheds light on a notable absence of evaluation following our objectives and intentions performing this review.

Conclusion

We assume that remodeling natural scaffolds may lead to sensible axonal regeneration, progress such as reducing the scar tissue, and a stable graft at the injury site; however, there was not a definite evidence regarding the benefits of neuronal regeneration in synthetic hydrogels compared to natural hydrogels.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Zenodo: Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review. https://doi.org/10.5281/zenodo.5759312.25

This project contains the following extended data:

  • - search strategy.docx

Reporting guidelines

Zenodo: PRISMA checklist for ‘Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review’. https://doi.org/10.5281/zenodo.5759312.25

Data are available under the terms of the Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Grant information

This work was supported by Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences. The grant number is 99-1-101-47039.

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Mojtabavi K, Gholami M, Ghodsi Z et al. Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review [version 1; peer review: awaiting peer review] F1000Research 2022, 11:16 (https://doi.org/10.12688/f1000research.74087.1)
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    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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