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

Kurosh Mojtabavi; Morteza Gholami; Zahra Ghodsi; Narges Mahmoodi; Sina Shool; Saeed Kargar-Soleimanabad; Niloufar Yazdanpanah; Alexander R. Vaccaro; Vafa Rahimi-Movaghar

doi:10.12688/f1000research.74087.1

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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: 1 not approved]

Kurosh Mojtabavi^1,2, Morteza Gholami^3,4, Zahra Ghodsi^1,5, [...] Narges Mahmoodi^1,6, Sina Shool^1,7, Saeed Kargar-Soleimanabad^1,8, Niloufar Yazdanpanah^9,10, Alexander R. Vaccaro¹¹, Vafa Rahimi-Movaghar ^1,5,12-15

Kurosh Mojtabavi^1,2, Morteza Gholami^3,4, [...] Zahra Ghodsi^1,5, Narges Mahmoodi^1,6, Sina Shool^1,7, Saeed Kargar-Soleimanabad^1,8, Niloufar Yazdanpanah^9,10, Alexander R. Vaccaro¹¹, Vafa Rahimi-Movaghar ^1,5,12-15

PUBLISHED 07 Jan 2022

Author details Author details

¹ Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences,, Tehran, Iran
² Cellular and Molecular Research Center & Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
³ Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular‑Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
⁴ Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
⁵ Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
⁶ Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
⁷ Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
⁸ Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
⁹ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
¹⁰ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
¹¹ Department of Orthopedics and Neurosurgery, Thomas Jefferson University and the Rothman Institute, Philadelphia, Pennsylvania, USA
¹² Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
¹³ Universal Scientific Education and Research Network (USERN), Tehran, Iran
¹⁴ Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
¹⁵ Spine Program, University of Toronto, Toronto, Canada

Kurosh Mojtabavi
Roles: Formal Analysis, Investigation, Validation, Writing – Original Draft Preparation

Morteza Gholami
Roles: Methodology, Writing – Review & Editing

Zahra Ghodsi
Roles: Project Administration, Supervision

Narges Mahmoodi
Roles: Validation, Writing – Review & Editing

Sina Shool
Roles: Data Curation

Saeed Kargar-Soleimanabad
Roles: Data Curation

Niloufar Yazdanpanah
Roles: Data Curation

Alexander R. Vaccaro
Roles: Writing – Review & Editing

Vafa Rahimi-Movaghar
Roles: Conceptualization, Supervision, Validation

OPEN PEER REVIEW

REVIEWER STATUS

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: 1 not approved]. 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

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.

Title	First author	Year of Study	Country	Study Characteristics	Type of Study
Comparison of neurite growth in three dimensional natural and synthetic hydrogels	Wenda Zhou	Aug 2012	United States	Experimental	In 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 grow	Elasticity
3% PEG + 0 μg/ml FN, 90	≃ 90 μm	10^{^2} Pa>
3% PEG + 1 μg/ml FN, 95	≃ 95 μm	10^{^2} Pa>
3% PEG + 10 μg/ml FN, 130	≃ 130 μm	10^{^2} Pa>
3% PEG + 100 μg/ml FN, 145	≃ 145 μm	10^{^2} Pa>
4% PEG + 0 μg/ml FN, 80	≃ 80 μm	10^{^3} Pa>
4% PEG + 1 μg/ml FN, 110	≃ 110 μm	10^{^3} Pa>
4% PEG + 10 μg/ml FN, 130	≃ 130 μm	10^{^3} Pa>
4% PEG + 100 μg/ml FN, 135	≃ 135 μm	10^{^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 μm	10 Pa>
0.4 mg/ml Col. + 1 μg/ml FN,	≃ 160 μm	10 Pa>
0.4 mg/ml Col. + 10 μg/ml FN,	≃ 165 μm	10 Pa>
0.4 mg/ml Col. + 100 μg/ml FN	≃ 155 μm	10 Pa>
0.6 mg/ml Col. + 0 μg/ml FN,	≃ 200 μm	10 Pa>
0.6 mg/ml Col. + 1 μg/ml FN,	≃ 187 μm	10 Pa>
0.6 mg/ml Col. + 10 μg/ml FN,	≃ 185 μm	10 Pa>
0.6 mg/ml Col. + 100 μg/ml FN	≃ 155 μm	10 Pa>
0.8 mg/ml Col. + 0 μg/ml FN,	≃ 168 μm	10 Pa>
0.8 mg/ml Col. + 1 μg/ml FN,	≃ 180 μm	10 Pa>
0.8 mg/ml Col. + 10 μg/ml FN,	≃ 190 μm	10 Pa>
0.8 mg/ml Col. + 100 μg/ml FN	≃ 165 μm	10 Pa>
1 mg/ml Col. + 0 μg/ml FN,	≃ 160 μm	10 Pa>
1 mg/ml Col. + 1 μg/ml FN,	≃ 168 μm	10 Pa>
1 mg/ml Col. + 10 μg/ml FN,	≃ 195 μm	10 Pa>
1 mg/ml Col. + 100 μg/ml FN,	≃ 185 μm	10 Pa>
1.25 mg/ml Col. + 0 μg/ml FN,	≃ 160 μm	≃ 10 Pa
1.25 mg/ml Col. + 1 μg/ml FN,	≃ 185 μm	10 Pa>
1.25 mg/ml Col. + 10 μg/ml FN,	≃ 178 μm	10 Pa>
1.25 mg/ml Col. + 100 μg/ml FN,	≃ 180 μm	10 Pa>
1.5 mg/ml Col. + 0 μg/ml FN,	≃ 180 μm	10^{^2} Pa>
1.5 mg/ml Col. + 1 μg/ml FN,	≃ 188 μm	10^{^2} Pa>
1.5 mg/ml Col. + 10 μg/ml FN,	≃ 185 μm	10^{^2} Pa>
1.5 mg/ml Col. + 100 μg/ml FN,	≃ 188 μm	10^{^2} Pa>
2 mg/ml Col. + 0 μg/ml FN,	≃ 155 μm	10^{^2} Pa>
2 mg/ml Col. + 1 μg/ml FN,	≃ 175 μm	10^{^2} Pa>
2 mg/ml Col. + 10 μg/ml FN,	≃ 175 μm	10^{^2} Pa>
2 mg/ml Col. + 100 μg/ml FN,	≃ 158 μm	10^{^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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48. Abu-Rub MT, et al.: Nano-textured self-assembled aligned collagen hydrogels promote directional neurite guidance and overcome inhibition by myelin associated glycoprotein. Soft Matter. 2011; 7(6): 2770–2781. Publisher Full Text
49. Page MJ, McKenzie JE, Bossuyt PM, et al.: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. Publisher Full Text
50. Rahimi-Movaghar V, et al.: Epidemiology of traumatic spinal cord injury in developing countries: a systematic review. Neuroepidemiology. 2013; 41(2): 65–85. PubMed Abstract | Publisher Full Text
51. Zhou W, Blewitt M, Hobgood A, et al.: Comparison of neurite growth in three dimensional natural and synthetic hydrogels. J. Biomater. Sci. Polym. Ed. 2013; 24(3): 301–314. PubMed Abstract | Publisher Full Text
52. Assunção-Silva RC, et al.: Hydrogels and cell-based therapies in spinal cord injury regeneration. Stem Cells Int. 2015; 2015: 1–24. PubMed Abstract | Publisher Full Text
53. Xing H, Yin H, Sun C, et al.: Preparation of an acellular spinal cord scaffold to improve its biological properties. Mol. Med. Rep. 2019; 20(2): 1075–1084. PubMed Abstract | Publisher Full Text
54. Zhang N, Yan H, Wen X: Tissue-engineering approaches for axonal guidance. Brain Res. Rev. 2005; 49(1): 48–64. PubMed Abstract | Publisher Full Text
55. Little L, Healy KE, Schaffer D: Engineering biomaterials for synthetic neural stem cell microenvironments. Chem. Rev. 2008; 108(5): 1787–1796. PubMed Abstract | Publisher Full Text
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57. Malafaya PB, Silva GA, Reis RL: Natural–origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv. Drug Deliv. Rev. 2007; 59(4-5): 207–233. Publisher Full Text
58. Han Q, Sun W, Lin H, et al.: Linear Ordered Collagen Scaffolds Loaded with Collagen-Binding Brain-Derived Neurotrophic Factor Improve the Recovery of Spinal Cord Injury in Rats. Tissue Eng. Part A. Oct 2009; 15: 2927–2935. PubMed Abstract | Publisher Full Text
59. Shoichet MS: Polymer scaffolds for biomaterials applications. Macromolecules. 2010; 43(2): 581–591. Publisher Full Text

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Author details Author details

¹ Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences,, Tehran, Iran
² Cellular and Molecular Research Center & Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
³ Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular‑Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
⁴ Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
⁵ Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
⁶ Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
⁷ Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
⁸ Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
⁹ School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
¹⁰ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
¹¹ Department of Orthopedics and Neurosurgery, Thomas Jefferson University and the Rothman Institute, Philadelphia, Pennsylvania, USA
¹² Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
¹³ Universal Scientific Education and Research Network (USERN), Tehran, Iran
¹⁴ Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
¹⁵ Spine Program, University of Toronto, Toronto, Canada

Kurosh Mojtabavi
Roles: Formal Analysis, Investigation, Validation, Writing – Original Draft Preparation

Morteza Gholami
Roles: Methodology, Writing – Review & Editing

Zahra Ghodsi
Roles: Project Administration, Supervision

Narges Mahmoodi
Roles: Validation, Writing – Review & Editing

Sina Shool
Roles: Data Curation

Saeed Kargar-Soleimanabad
Roles: Data Curation

Niloufar Yazdanpanah
Roles: Data Curation

Alexander R. Vaccaro
Roles: Writing – Review & Editing

Vafa Rahimi-Movaghar
Roles: Conceptualization, Supervision, Validation

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.

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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: 1 not approved]. F1000Research 2022, 11:16 (https://doi.org/10.12688/f1000research.74087.1)

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Reviewer Report 11 Oct 2024

Isabella Drew, School of Human Sciences, The University of Western Australia School of Biological Sciences, Perth, Western Australia, Australia

Stuart I. Hodgetts, Perron Institute for Neurological and Translational Science, Perth, WA, Australia; School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia

Not Approved

https://doi.org/10.5256/f1000research.77802.r321115

Review of Mojtabavi et al – 2024

Stuart Hodgetts and Isabella Drew (PhD student)

“SYSTEMATIC REVIEW Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review.”

1) ... Continue reading

Review of Mojtabavi et al – 2024

Stuart Hodgetts and Isabella Drew (PhD student)

“SYSTEMATIC REVIEW Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review.”

1) Review by Stuart Hodgetts
The systematic review was first received in January 2022. Its original aims were “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”. After applying the inclusion and exclusion criteria, only one paper was considered for analysis. The result is therefore NOT a systematic review of these hydrogels in the treatment SCI, because the single paper was in fact only an in vitro study – and is not applicable to any in vivo comparison, since no animal models of SCI were used to test the scaffolds. This single paper effectively was a comparison of neurite outgrowth in varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels. This manuscript does very little than offer a very superficial precis of a single published study that by itself provides more information than the review offered here. It is therefore unclear what benefit or contribution this review makes to the field.
There appears to be no attempt to include, or at the very least make mention of, any updates the total number of manuscripts that might be included since 2022. Therefore, its relevance nearly 3 years on comes under question. A recent systematic review El Husseiny et al 2024 [Ref - 1] appears to hold more relevance in terms of final comparisons (El-Husseiny et al 2024 - International Journal of Biological Macromolecules 260 (2024) 129323). Additionally, the senior author Rahimi-Movaghar also published in 2022 a systematic review and meta-analysis comparing the “Efficacy of hydrogels for repair of traumatic spinal cord” [Ref - 2] in Biomed Mater Res, which was an informative and timely publication. The Mojtabavi et al submission does little to promote the field forward, and would benefit from waiting until future studies that fit the selection criteria provide a more informative narrative.

Specific comments:
Introduction
“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”. Specify biological treatments? What about exoskeletons? Electrical spinal stimulation to bridge circuitry?

“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.” Relevance? Why was cell culture the directive here?

Methods
I was unable to find a statement regarding updates since 2022.
I would suggest the authors to add information or statement whether the criteria included searches for both pre clinal and clinical studies (i.e. https://clinicaltrials.gov/), or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.

Results
“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.” How many studies compare these types of hydrogels simply in vitro....with no SCI requirements? How does the single paper in this review make the comparison relevant (inclusive) for SCI?

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”. Why? What is your evidence for this? “sufficient environment”…This seems a bit vague. Can the authors please clarify what do they wish to convey exactly here. Hydrogels alter the local environment but the vast majority of studies show little if any benefit to substantive regeneration and/or regrowth, and very few if any link them to specific functional improvements/outcomes.

“Also, these scaffolds help with the need for a physical matrix to which neurons and endogenous repairing cells can adhere.” What are these “types of endogenous” cells - Kindly describe here.

“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” It was stated above that you believe they should “remain for a long time” - what is the optimum time for this (e.g. rodent vs human SCI...? acute vs chronic?)

“Still, there might be some inadequate shreds of evidence to report that one of these types has an advantage over the other.” The highlighted term again seems a bit vague. Can the authors please clarify specifically what do they mean exactly here.

In summary, this systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Whether this warrants indexing as a peer reviewed manuscript is questionable.
Please also see highlighted pdf document with highlighted concerns/changes by clicking on this link -

https://f1000research.s3.amazonaws.com/linked/682333.Mojtabavi_et_al_2024_Comparing_natural_hydrogels_to_self_assembling_peptides_in_SCI_treatment_a_systematic_review_highlighted_suggestions.pdf

Recommendation: Not approved

2) Supplementary Review (invited) by PhD student Isabella Drew:

Not approved (Maybe approved with reservations)

The systematic review aims to highlight the lack of studies comparing natural and synthetic hydrogel material for spinal cord injuries. Through their inclusion and exclusion criteria, only one paper was approved for analysis, which explored how varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels influenced neurite outgrowth. While it is important to address the lack of studies on this topic, I believe it is difficult to answer their research question from one article, and this manuscript may benefit from the following suggestions.

Minor improvements
It is important that every sentence is referenced, and to ensure that each source at the end is included in the text, as reference 55 is not cited. To improve the flow of the review, I recommend the following:

Ensure that you are consistent with your acronyms as you interchange between “spinal cord injuries” and “SCI”
The way some sentences are written interrupt with the flow and readability of the review
Some paragraphs are a sentence in length, and could be joined to the previous or subsequent paragraph

Methods
The inclusion and exclusion criteria may benefit from including more detail, such as whether the authors searched for both pre clinal and clinical studies, or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.

Major improvements
Since only one paper was included in the systematic analysis, the following suggests may aid in strengthening the overall message.

Introduction
While the authors explain that a permissive growth substrate is critical for regeneration at the injury site, and state the beneficial characteristics of both natural and synthetic hydrogels, an elaboration on this would provide sufficient context for the review. Specifically, instead of stating they “have gained tremendous recognition”, explain why this is the case and specific outcomes in relation to your data collection criteria i.e. axonal regeneration, revascularisation, invasion/elongation of astrocytes. I believe this is pertinent to strengthen your argument that more comparative studies need to be conducted to progress this therapy, if the audience understands their therapeutic potential that has been supported by primary articles. If the authors are limited by word count, then removing the second last paragraph could address this concern.

Results
The authors only address one of 6 data items stated in their methods: axonal regeneration. If the paper approved for analysis only contained information on a 6^th of the data collection criteria, then it raises questions as to whether the methods (search and analysis criteria) need alteration. Additionally, this section seems a bit vague and would benefit from more elaboration such as “specific interactions in collagen” and “more expectable behaviour” in the third paragraph.

Discussion
The synthesis of the included article reads more like a summary. The fact that only one paper has conducted a comparative analysis can be utilised to strengthen the argument if the authors refrain from utilising the current passive tone. There needs to be more analysis on the included paper.

In conclusion, the systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Although, since only one article was included in the results section, if the authors haven't provide a more in-depth analysis, it may be best written as a narrative review.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

References

1. El-Husseiny H, Mady E, Doghish A, Zewail M, et al.: Smart/stimuli-responsive chitosan/gelatin and other polymeric macromolecules natural hydrogels vs. synthetic hydrogels systems for brain tissue engineering: A state-of-the-art review. International Journal of Biological Macromolecules. 2024; 260. Publisher Full Text
2. Ayar Z, Hassannejad Z, Shokraneh F, Saderi N, et al.: Efficacy of hydrogels for repair of traumatic spinal cord injuries: A systematic review and meta‐analysis. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2022; 110 (6): 1460-1478 Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Spinal Cord Injury repair (including hydrogels and SAPs)

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Isabella Drew, The University of Western Australia School of Biological Sciences, Perth, Australia

Stuart I. Hodgetts, Perron Institute for Neurological and Translational Science, Perth, Australia; The University of Western Australia, Perth, Australia

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Reviewer Report

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11 Oct 2024 | for Version 1

Isabella Drew, School of Human Sciences, The University of Western Australia School of Biological Sciences, Perth, Western Australia, Australia

Stuart I. Hodgetts, Perron Institute for Neurological and Translational Science, Perth, WA, Australia; School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia

3 Views Cite this report Responses(0)

Not Approved

Review of Mojtabavi et al – 2024

Stuart Hodgetts and Isabella Drew (PhD student)

“SYSTEMATIC REVIEW Comparing natural hydrogels to self-assembling peptides in spinal cord injury treatment: a systematic review.”

1) Review by Stuart Hodgetts
The systematic review was first received in January 2022. Its original aims were “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”. After applying the inclusion and exclusion criteria, only one paper was considered for analysis. The result is therefore NOT a systematic review of these hydrogels in the treatment SCI, because the single paper was in fact only an in vitro study – and is not applicable to any in vivo comparison, since no animal models of SCI were used to test the scaffolds. This single paper effectively was a comparison of neurite outgrowth in varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels. This manuscript does very little than offer a very superficial precis of a single published study that by itself provides more information than the review offered here. It is therefore unclear what benefit or contribution this review makes to the field.
There appears to be no attempt to include, or at the very least make mention of, any updates the total number of manuscripts that might be included since 2022. Therefore, its relevance nearly 3 years on comes under question. A recent systematic review El Husseiny et al 2024 [Ref - 1] appears to hold more relevance in terms of final comparisons (El-Husseiny et al 2024 - International Journal of Biological Macromolecules 260 (2024) 129323). Additionally, the senior author Rahimi-Movaghar also published in 2022 a systematic review and meta-analysis comparing the “Efficacy of hydrogels for repair of traumatic spinal cord” [Ref - 2] in Biomed Mater Res, which was an informative and timely publication. The Mojtabavi et al submission does little to promote the field forward, and would benefit from waiting until future studies that fit the selection criteria provide a more informative narrative.

Specific comments:
Introduction
“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”. Specify biological treatments? What about exoskeletons? Electrical spinal stimulation to bridge circuitry?

“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.” Relevance? Why was cell culture the directive here?

Methods
I was unable to find a statement regarding updates since 2022.
I would suggest the authors to add information or statement whether the criteria included searches for both pre clinal and clinical studies (i.e. https://clinicaltrials.gov/), or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.

Results
“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.” How many studies compare these types of hydrogels simply in vitro....with no SCI requirements? How does the single paper in this review make the comparison relevant (inclusive) for SCI?

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”. Why? What is your evidence for this? “sufficient environment”…This seems a bit vague. Can the authors please clarify what do they wish to convey exactly here. Hydrogels alter the local environment but the vast majority of studies show little if any benefit to substantive regeneration and/or regrowth, and very few if any link them to specific functional improvements/outcomes.

“Also, these scaffolds help with the need for a physical matrix to which neurons and endogenous repairing cells can adhere.” What are these “types of endogenous” cells - Kindly describe here.

“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” It was stated above that you believe they should “remain for a long time” - what is the optimum time for this (e.g. rodent vs human SCI...? acute vs chronic?)

“Still, there might be some inadequate shreds of evidence to report that one of these types has an advantage over the other.” The highlighted term again seems a bit vague. Can the authors please clarify specifically what do they mean exactly here.

In summary, this systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Whether this warrants indexing as a peer reviewed manuscript is questionable.
Please also see highlighted pdf document with highlighted concerns/changes by clicking on this link -

https://f1000research.s3.amazonaws.com/linked/682333.Mojtabavi_et_al_2024_Comparing_natural_hydrogels_to_self_assembling_peptides_in_SCI_treatment_a_systematic_review_highlighted_suggestions.pdf

Recommendation: Not approved

2) Supplementary Review (invited) by PhD student Isabella Drew:

Not approved (Maybe approved with reservations)

The systematic review aims to highlight the lack of studies comparing natural and synthetic hydrogel material for spinal cord injuries. Through their inclusion and exclusion criteria, only one paper was approved for analysis, which explored how varying concentrations of fibronectin added to different concentrations of PEG or collagen-based gels influenced neurite outgrowth. While it is important to address the lack of studies on this topic, I believe it is difficult to answer their research question from one article, and this manuscript may benefit from the following suggestions.

Minor improvements
It is important that every sentence is referenced, and to ensure that each source at the end is included in the text, as reference 55 is not cited. To improve the flow of the review, I recommend the following:

Ensure that you are consistent with your acronyms as you interchange between “spinal cord injuries” and “SCI”
The way some sentences are written interrupt with the flow and readability of the review
Some paragraphs are a sentence in length, and could be joined to the previous or subsequent paragraph

Methods
The inclusion and exclusion criteria may benefit from including more detail, such as whether the authors searched for both pre clinal and clinical studies, or a specific stage of spinal cord injuries: immediate, acute, subacute, chronic.

Major improvements
Since only one paper was included in the systematic analysis, the following suggests may aid in strengthening the overall message.

Introduction
While the authors explain that a permissive growth substrate is critical for regeneration at the injury site, and state the beneficial characteristics of both natural and synthetic hydrogels, an elaboration on this would provide sufficient context for the review. Specifically, instead of stating they “have gained tremendous recognition”, explain why this is the case and specific outcomes in relation to your data collection criteria i.e. axonal regeneration, revascularisation, invasion/elongation of astrocytes. I believe this is pertinent to strengthen your argument that more comparative studies need to be conducted to progress this therapy, if the audience understands their therapeutic potential that has been supported by primary articles. If the authors are limited by word count, then removing the second last paragraph could address this concern.

Results
The authors only address one of 6 data items stated in their methods: axonal regeneration. If the paper approved for analysis only contained information on a 6^th of the data collection criteria, then it raises questions as to whether the methods (search and analysis criteria) need alteration. Additionally, this section seems a bit vague and would benefit from more elaboration such as “specific interactions in collagen” and “more expectable behaviour” in the third paragraph.

Discussion
The synthesis of the included article reads more like a summary. The fact that only one paper has conducted a comparative analysis can be utilised to strengthen the argument if the authors refrain from utilising the current passive tone. There needs to be more analysis on the included paper.

In conclusion, the systematic review effectively highlights the lack of literature comparing natural and synthetic hydrogels for spinal cord injury repair. Although, since only one article was included in the results section, if the authors haven't provide a more in-depth analysis, it may be best written as a narrative review.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Partly
Is the statistical analysis and its interpretation appropriate?

Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?

Yes
If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.)

Not applicable

References

1. El-Husseiny H, Mady E, Doghish A, Zewail M, et al.: Smart/stimuli-responsive chitosan/gelatin and other polymeric macromolecules natural hydrogels vs. synthetic hydrogels systems for brain tissue engineering: A state-of-the-art review. International Journal of Biological Macromolecules. 2024; 260. Publisher Full Text
2. Ayar Z, Hassannejad Z, Shokraneh F, Saderi N, et al.: Efficacy of hydrogels for repair of traumatic spinal cord injuries: A systematic review and meta‐analysis. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2022; 110 (6): 1460-1478 Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Spinal Cord Injury repair (including hydrogels and SAPs)

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

Responses (0)

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

Abstract

Keywords

Introduction

Method

Ethical considerations

Eligibility criteria

Electronic searches

Selection and data collection process

Data items

Results

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

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

Table 2. Axonal regeneration and elasticity of scaffold.

Discussion

Conclusion

Data availability

Underlying data

Extended data

Reporting guidelines

Grant information

References

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