Biomaterials as regenerative therapies for traumatic brain injury: a narrative review

Wang Hui; Su Zhi; Ling Ziao

doi:10.4103/2773-2398.356521

REVIEW

Year : 2022 | Volume : 1 | Issue : 3 | Page : 122-127

Biomaterials as regenerative therapies for traumatic brain injury: a narrative review

Wang Hui¹, Su Zhi², Ling Ziao³
¹ Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Institute of Rehabilitation Medicine, School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
² School of Kinesiology, Shanghai University of Sport, Shanghai, China
³ School of Life Science and Technology, Shanghai Tech University, Shanghai, China

Date of Submission	18-May-2022
Date of Decision	09-Jun-2022
Date of Acceptance	28-Jun-2022
Date of Web Publication	29-Sep-2022

Correspondence Address:
Wang Hui
Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Institute of Rehabilitation Medicine, School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.356521

Abstract

Over recent years, the events associated with traumatic brain injury (TBI) have become critical health problems. TBI involves various functional deficits that are caused by neuronal loss and is a common feature in various neuropathologies. Patients with TBI have a very high degree of disability and impairment at both the physical and psychological levels, thus creating a significant burden on the quality of life. Although stem cell therapy has achieved some success in the reconstruction of neural circuits for TBI therapies, there are several limitations that need to be overcome, such as the stem cell transplantation pathways and time to transplantation are challenges for clinical application. Recently, bioactive materials from the tissue engineering field have become promising candidates for TBI therapies. Herein, we briefly summarize and discuss the advantages and disadvantages of TBI-related biomaterials (such as hydrogels, nanofibers, and nanomaterials) for the regeneration of neural tissue and functional recovery at the lesion sites of TBI. Finally, we describe the desirable characteristics of bioactive materials for neural repair in TBI. Because the development of therapeutic strategies with biomaterials is still in its infancy, biomaterials deserve high priority and further development as a treatment for TBI.

Keywords: biomaterials; functional reconstruction; tissue repair; traumatic brain injury

How to cite this article:
Hui W, Zhi S, Ziao L. Biomaterials as regenerative therapies for traumatic brain injury: a narrative review. Brain Netw Modulation 2022;1:122-7

How to cite this URL:
Hui W, Zhi S, Ziao L. Biomaterials as regenerative therapies for traumatic brain injury: a narrative review. Brain Netw Modulation [serial online] 2022 [cited 2023 Sep 22];1:122-7. Available from: http://www.bnmjournal.com/text.asp?2022/1/3/122/356521

Introduction

Traumatic brain injury (TBI) is usually caused by external trauma or mechanical force resulting in tissue deformation and most commonly occurs in young adults. During the primary stages of TBI, the blood–brain barrier (BBB) is compromised; this is often accompanied by contusions, hematomas, and diffuse axonal injury; which involves the irreversible and immediate death of some neuronal cells or tissues (Tan et al., 2020). Furthermore, secondary cascades of damage develop over an extended period and may include a range of physiological processes such as necrosis, excitotoxicity, oxidative stress, vascular disruption, and inflammation (Rocha et al., 2020). Trauma activates the resident microglia which then occupies the gap in the BBB left by damaged astrocytes, thus helping to maintain the integrity of the BBB. Concomitantly, the microglia phagocytose and remove residual dead neurons and glial cells to help reduce the level of damage incurred by brain tissue. However, these processes also lead to the formation of glial scars that hinder the growth of new tissue (Rosenfeld et al., 2012).

TBI also results in the initiation of many different pathophysiological mechanisms, including the release of certain neurotransmitters, the generation of some free-radicals, calcium-mediated injury, apoptosis, inflammatory gene activation and induces respiratory and energy dysfunction in mitochondria (Lozano et al., 2015). Some neurotransmitters, such as glutamate, exacerbate the leakage of ion channels, activate astrocytes, and further exacerbate the condition; this is accompanied by the swelling of brain tissue, thus reducing cerebral blood flow and increasing brain pressure (Dorsett et al., 2017). However, there is still a lack of effective clinical treatment methods for TBI; thus, patients suffering from TBI are associated with a very poor prognosis. In addition, existing clinical measures such as neuroprotective compounds, hypothermia therapy, and decompressive craniectomy are largely ineffective and can sometimes even be harmful due to the fact that they can exacerbate neuronal damage (Clifton et al., 2001; Maas et al., 2008). Another option is to utilize exogenous or endogenous stem cells to rebuild neural circuits at the lesion site, thereby promoting the repair of damaged tissue and the recovery of neural function in the brain. In addition to alleviating the death of brain tissue or neuronal cells, another approach involves the application of exogenous or endogenous stem cells to rebuild the neural circuits for TBI. Recently the emergence of some biomaterials has offered new perspectives and more opportunities for TBI therapies (Lindvall et al., 2004; Chang et al., 2013).

As regenerative medicine strategies advance (Lozano et al., 2015), specific technologies from various fields (including biology, physics, chemistry, and biomaterials) are increasingly being combined in an effort to repair or regenerate damaged tissues. Some bioactive materials can induce or trigger a multitude of effects on cells or tissues and respond to various external stimuli, eventually leading to the regeneration of tissue (Chang et al., 2013). Although the application of bioactive materials in the central nervous system is not a novel concept (Chen and Liu, 2016), the application of such materials has been seriously limited due to the complexity of the brain and the high risk associated with clinical interventions. Over recent years, research has suggested that bioactive materials may exhibit the potential to promote nervous tissue repair by offering support and biochemical metabolic events that are beneficial for both cell migration and survival. Bioactive materials, arising from natural materials or synthetic polymers, can efficiently integrate with host tissues by mimicking the local cellular microenvironment and providing mechanical and nutrition resources for cell migration and survival (Chen and Liu, 2016). Apart from physical support, biomaterials can also serve as drug carriers and control the release of drugs or exogenous stem cells to the lesion site. After intravenous administration, the first-pass effect traps the donor cells in the lungs; thus, the number of cells reaching the lesions in the brain is significantly reduced (Fischer et al., 2009). However, strategies based on biomaterials are not suitable for the treatment of mild TBI because of the risk of widespread degeneration in the white matter; furthermore, the deposition of bioactive matrices may cause further damage to cells or tissues in the brain (Guan et al., 2013). We reviewed the development and application of several common materials in the repair of TBI to provide ideas and suggestions for TBI. We have searched through the Web of Science database for biomaterial and TBI topics and listed around 50 classic articles.

Biomaterials

Previous preclinical studies (Hoffman, 2001; Hennink and van Nostrum, 2002; McDermott et al., 2004; Kurisawa et al., 2005; Lee et al., 2008; Shi et al., 2016; Winter et al., 2016; Zhang et al., 2018; Alegret et al., 2019; Wang et al., 2022) have shown that the biomaterials relevant for neural tissue engineering can be divided into three different categories: (1) hydrogels, which have been extensively used for neural tissue regeneration and functional recovery because of their excellent mechanical properties and bio-compatibility; (2) micro-nanoparticles, which are mainly used for targeted or sustained release; and (3) fibers and conduits, in which specific topographical characteristics can induce or guide axonal growth.

Generally, hydrogels are three-dimensional networks formed by the mutual cross-linking of hydrophilic polymers. Due to their high-water content, hydrogels are very soft and particularly suitable for the repair of soft tissue, such as the brain, spinal cord, and skin. Because hydrogels can physically and chemically mimic the natural neural extracellular matrix, various forms of injectable or implantable hydrogel materials have been developed for the repair of nervous tissue (Shi et al., 2016; Winter et al., 2016; Zhang et al., 2018). Hydrogels can be prepared from a range of natural materials, including hyaluronic acid, chitosan, fibrin, methylcellulose, agarose, collagen and alginate. Synthetic materials, such as poly(ethylene glycol), poly(methacrylic acid), 2-hydroxyethyl ester, poly[N-(2-hydroxypropyl) methacrylamide] and poloxamers are also common raw materials for the development of hydrogels (Alegret et al., 2019). However, there are still some key problems to solve when considering cell-directed hydrogels as a topical application for TBI. For example, implanted material can potentially cause an increase in intracranial pressure. It is important to consider the rheological characteristics of any implanted biomaterial as these must be adapted to the environmental and treatment conditions of the damaged area. Furthermore, the application of hydrogels requires the lesion to be completely sealed. Therefore, for TBI, it is necessary to respect the supple nature of the surrounding tissue and provide physical support while preventing the inflammatory response and further aggravation. In addition, numerous macroscopic factors of the hydrogel can affect tissue regeneration at lesion sites, including pore size, porosity, swelling, and viscoelasticity. At the microscopic level, it is also important to consider the pore opening, swelling, and viscoelasticity of a hydrogel as these factors will all affect tissue regeneration properties at the lesion site (Wang et al., 2022).

Hydrogels have attracted significant attention from researchers due to the fact that they do not require surgical implantation or removal and because of their excellent injectability and biodegradability. Hydrogels can be prepared by both physical and chemical cross-linking. Reversible physical interactions between polymer chains are the main mechanisms by which physical crosslinks are formed in hydrogels; these include ionic, substrate-ligand, and hydrophobic interactions (Lee et al., 2008). The in vivo stability of hydrogels is weak because physical crosslinking does not involve chemical reactions. Consequently, the materials being implanted are often damaged following interaction with physiological molecules within the microenvironment or by mechanical stress in vivo. Michael-type addition reactions (Hoffman, 2001), disulfide bond formation (Kurisawa et al., 2005), and aldehyde-mediated cross-linking (McDermott et al., 2004) are relatively common forms of chemical cross-linking that is involved in the formation of hydrogels. Chemically cross-linked hydrogels often possess better levels of physical stability and mechanical strength than those formed by physical cross-links. The density of crosslinking and the biodegradability of a hydrogel are crucial factors to consider because these both play a role in the control of drug release, adhesion, cell proliferation, and tissue regeneration. Therefore, the ability to fine-tune the density of crosslinking is essential in regulating the degradability of hydrogels (Hennink and van Nostrum, 2002).

Hydrogels

One key hydrogel is gelatin; this is a derivative of collagen, a major component of the extracellular matrix found in most connective tissues (Elias and Spector, 2012). Due to its excellent biocompatibility and superior adhesion properties, gelatin can effectively increase the level of interaction between cells and biomaterials. Thus, collagen or gelatin-based bioactive materials have been wildly applied in many fields of tissue engineering, including bone, cartilage, blood vessels, brain, and spinal cord (Klotz et al., 2016; Derakhshanfar et al., 2018; Dhand et al., 2021). In addition, polysaccharides and self-assembling co-polypeptide hydrogels have been used for the construction of tissue (Mukherjee et al., 2020; Wang et al., 2022). However, these two hydrogels are mainly formed by physical interactions between polymers, especially hydrophobic interactions, rather than chemical cross-linking; this leads to low levels of stability. For example, the versatility of xyloglucan gels is limited by the fact that their mechanical properties are rarely modulated (Mukherjee et al., 2020); moreover, these gels are not easily degraded in the brain.

Certain properties can be achieved by adjusting the composition of a gel by applying self-assembling polypeptide hydrogels. However, some researchers have found that this type of hydrogel is less effective with regard to neurite infiltration. Over recent years, researchers have developed a novel and injectable porous gelatin hydrogel which incorporates modified gelatin and modified carboxymethyl cellulose (Unagolla and Jayasuriya, 2020). Research has also shown that the use of glialcellline-derived neurotrophic factor drugs and increased porosity can effectively prevent glial scarring; furthermore, such modified materials can exhibit better integration with peripheral nerve tissue (Fon et al., 2014). Certain types of materials have shown excellent performance in promoting the regeneration of axons. Of these, hyaluronic acid (HA) has performed in an excellent manner. The main reason for this is that HA is the main component of soft connective tissues in living organisms. Furthermore, HA is distributed widely in many organs, particularly in the central nervous system (Graça et al., 2020; Amorim et al., 2021). In addition, HA has shown beneficial effects on wound repair due to its excellent biocompatibility (Graça et al., 2020).

Finally, some researchers have found that HA can significantly reduce glial scar formation during central nervous system repair. However, cells do not adhere to the surface of HA; thus HA and its derivatives have limited value for application in tissue engineering (Li et al., 2020). Therefore, HA hydrogels need to be combined with other materials so that they can be endowed with cell adhesion ability; this strategy will facilitate the further use of HA and its derivatives for the regeneration of tissue (Wang et al., 2012).

Nanofibers

Over recent years, electrospinning fiber, ranging from nanometers to micrometers, has been obtained with electrostatic force (Miller et al., 2018). Because electrospinning scaffolds can mimic the layered structure of laminin and collagen in the extracellular matrix, these scaffolds possess significant potential to facilitate cellular adhesion and axonal penetration, guide neurite extension, and enhance integrative action between implants and tissues. Hence, electrospinning scaffolds have significant potential for application in central nervous system repair (Miller et al., 2018; Qiang et al., 2021). Furthermore, self-assembly can be used to fabricate nanofibers. Self-assembly nanofibers are often assembled via hydrophobic interactions in oligopeptides or amphiphilic peptides, with the hydrophobic groups as the central core and the hydrophilic groups as the outer sheath (Sahab Negah et al., 2018; Sarkar et al., 2021). Eventually, a self-assembled peptide nanofiber scaffold can be fabricated.

Researchers have designed a functionalized self-assembling peptide known as RADA16 hydrogel; this is formed by efficient electrostatic self-assembly via hydrophobic interaction between charged aspartic acid (D), arginine (R), and hydrophobic alanine (A) (Guo et al., 2009). The β-sheet secondary structure of this peptide, along with the three-dimensional network structure of the hydrogel and its mechanical properties, can be regulated by environmental conditions including pH and ionic concentration. The RADA16 hydrogel can sustain the survival and multiplication of neural stem cells and has demonstrated high angiogenic potential and biocompatibility (Wang et al., 2017).

Nanoparticles

Due to the unique physical and chemical properties of nanomaterials, nanotechnology has provided a promising platform for the treatment of TBI. Nanomaterials possess a large surface area and special nanostructures and properties that can be developed for drug delivery and tissue repair. Therefore, a variety of nanomaterials, such as exosomes, liposomes, and silica nanoparticles (NPs) have been developed for the repair of TBI (Rocha et al., 2020). Following TBI, the permeability of the BBB changes; this allows the uncontrolled infiltration of inflammatory cells which in turn affects the transfer and exchange of nutrients and oxygen for tissues and cells. However, the increased permeability of the endothelium offers opportunities for NPs to deliver drugs for TBI therapy (Kwon et al., 2016; Alam Bony and Kievit, 2019). Nevertheless, the severity of trauma inevitably affects the uptake and retention of NPs. To effectively increase the retention of NPs at the injury site, methods have been developed to control the size of the NPs or graft-targeted molecules (such as peptides or antibodies) onto the surface of material (Cruz et al., 2016; Bharadwaj et al., 2018). In addition, in the field of TBI, NPs can also be used to modulate reactive oxygen species (ROS) in order to regenerate injured tissues and improve tissue repair and functional reconstruction (Cruz et al., 2016). Brain injury often results in the oxidation of cells and tissues. These changes in the cellular microenvironment can exacerbate the permeability of the BBB. Furthermore, the infiltration of inflammatory cells can further amplify the damage incurred by cells and tissues. The development of novel nanomaterials that can act as antioxidants would enhance our ability to destroy free radicals (Dhall and Self, 2018) while avoiding potential side effects and providing key protective effects (Bitner et al., 2012).

Xu et al. (2016) developed a nanocomposite NP featuring an oxygen-reactive polymer formed from polyethylene glycol and thioether. The thioether-containing unit of the material is responsible for scavenging ROS. In addition, this modified material also contains gadolinium that can be applied for magnetic resonance imaging. An animal study of TBI has shown that the intravenous delivery of this nanomaterial can clear ROS very effectively (Xu et al., 2016). Other research has shown that the valency and oxygen deficiency of ceria NPs suggest that these could serve as self-regenerating radical scavengers. For example, van der Horn et al. (2016) found that nanoceramics ceria NPs were well tolerated in mice and could be incorporated perfectly into cellular tissues. Furthermore, this material was effective in reducing the production of ROS under inflammatory conditions. van der Horn et al. (2016) also injected cerium NPs into a model of mild TBI injury and observed a significant reduction in the damage caused by free radicals; in addition, they found a significant improvement in memory function.

Conclusion

Although stem cell transplantation has been investigated extensively, after nerve injury in the brain, the underlying endogenous repair mechanisms and ability to promote functional healing are unclear. In this paper, we evaluate the properties of biomaterials, investigate the specific relationship between materials and tissues, and analyze their potential application for TBI repair [Figure 1]. Research and development of new implantable biomaterials can provide new opportunities for the regeneration and repair of endogenous nucleus pulposus stem cells in the brain. To maximize the therapeutic potential of biomaterials, new materials need to possess excellent biocompatibility, specific stability, and biodegradability and provide options for chemical modification. Herein, we discuss recent advances and current challenges in the use of biomaterial-based therapies for TBI regeneration [Table 1]. Future studies should aim to elucidate the mechanisms by which endogenous stem cells can promote neural recovery and how the fate of transplanted stem cells can be regulated. The temporary transplantation of biomaterials is currently an effective and promising therapeutic strategy. New materials may serve as an adjunct to cell therapy by using exogenous stem cells. Two important factors need to be considered in future research: (1) the biocompatibility of biomaterials with brain tissue and (2) the differences and efficacies of treatments between animals and humans. It is vital that we develop an in vitro model to determine the effect of specific biomaterials on TBI tissue repair.

Figure 1: Biomaterials used for traumatic brain injury.
Note: Figure created with BioRender.com.

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Table 1: The major types of materialsand their characteristics for the repair of traumatic brain injury.

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Author contributions

HW and ZL conceived the idea; HW wrote the manuscript; ZS edited the manuscript. All authors have read and approved the published version of the manuscript.

Conflicts of interest

The authors declare no competing financial interests.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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