Therapeutic Potentials of Hydrogels and Nanogels in CNS Disorders

Abstract

Brain disorders, particularly those that worsen with age, often classified as neurodegenerative disorders constitute a major problem worldwide owing to their complexity and tremendous challenges with getting befitting therapies for them. Biomaterial technology advancements over the past few years are igniting the hope of increased success in drug discovery and development for neurological and neurodegenerative diseases. In this review, we will discuss an overview of biomaterials used in central nervous system (CNS) disorders and their contextual ideal characteristics, the use of hydrogel and nanogel biomaterials that have been explored for the treatment of various CNS disorders, and how these materials have been utilized. We shall also cover discussions on current trends associated with the use of these materials as well as challenges and prospects in this emerging field.

1. Introduction

Central nervous system (CNS) disorder is a term used to describe the diseases and disorders of the brain and spinal cord. Although most of these disorders share some similarities in their etiology and pathogenesis, the presentations and clinical symptoms often vary in many. The complexity of the central nervous system makes it quite difficult and almost impossible to develop drugs that can eliminate the underlying cause of most CNS disorders. Current therapies are usually only effective at reducing pain, ameliorating symptoms and improving function. Progress however has been made in certain areas, especially in CNS infectious diseases such as meningitis, and viral and bacterial encephalitis. Other CNS disorders occur particularly in the older population, albeit it is not so uncommon to find them in the younger population. This group of CNS disorders is referred to as neurodegenerative diseases (neurodegeneration in the sense that there is a progressive loss of neuronal structure and function with aging). Common neurodegenerative disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple Sclerosis (MS), spinal cord injury (SCI) and Amyotrophic Lateral Sclerosis (ALS). Other diseases of the brain that are not necessarily neurodegenerative but affect the neurons are termed neurological disorders. Their pathogenesis may involve the neurons directly or indirectly through other means such as cerebral blood vessels, meninges and immune cells. There are numerous Neurological disorders, common among them are stroke, Epilepsy, Schizophrenia, depression, Obsessive-compulsive disorder (OCD) and Neurodegenerative disorders.

The incidence and prevalence of most neurological disorders vary across the globe. For instance, multiple sclerosis is common in Europe, Canada and other temperate regions while diseases such as cerebral encephalitis are more predominant in Asia, Africa and South America. Others like stroke, AD, PD and epilepsy affect people worldwide, thus requiring global attention. Despite their global burden and negative impact on the world’s economy, only a few drugs are available for their treatment. For instance, there are numerous anticonvulsant agents available for the management of Epilepsy, however, these drugs have drawbacks including high cost, severe side effects and poor or incomplete remission from their use. Management of stroke (the ischaemic type) is achieved with a recombinant tissue plasminogen activator (rTPA) known as alteplase. This drug has a brief time window of fewer than 5 hours and its delayed use has been associated with haemorrhagic transformation. Levodopa is the main drug, in addition to deep brain stimulation, used in the management of PD, it however causes side effects such as bradycardia and tremor and its efficacy diminishes with PD’s progression. Currently, there are no drugs for treating AD – different drugs are only used to manage symptoms. With the emergence of innovative technologies and a better understanding of some novel therapies, there is hope for new drug discovery in this seemingly bleak situation.

Factors such as the complexity of the CNS, the tight regulation of substance movement across the blood–brain barrier and the presence of efflux pumps in the brain preventing therapeutic drug accumulation in the CNS, contribute to the difficulty associated with drug development for neurological diseases. Researchers are constantly innovating new formulations and technologies to circumvent these challenges. Currently, gene therapy with the aid of adeno-associated viruses, cell-based therapy and nanoformulations are being deployed as tools to manage and treat neurological disorders [1, 2]. There are currently four (4) commercially available adeno-associated virus-based gene therapy for CNS diseases [2], whereas the use of bone-marrow-derived stem cells has been employed for ages in the treatment of some types of cancers. Each of these trends led to the discovery of highly efficient drugs for CNS disorders and paved the way for renewed hope of more drug development for neurological diseases. Unfortunately, however, they are not without drawbacks, and current studies are targeted at optimizing the benefits of the new therapeutic approaches whilst eliminating or minimizing their shortfalls. For instance, despite the remarkable success of the use of AAV gene therapy for neurological diseases, this approach is associated with thrombocytopaenia, hepatic and renal toxicity and neuroinflammation of the spinal cord, following high-dose administration [2]. More so, the major routes of administration are highly invasive, making this therapeutic option less convenient and patient-friendly. Vector engineering and the use of immunosuppressive medications are now being considered as ways to bypass these obstacles. With respect to stem-cell therapy, the use of mesenchymal stem cells as a novel therapy for various diseases including neurodegenerative disorders has also met some challenges despite initial enthusiasm. Mesenchymal stem cells (MSCs) are adult stem cells that are capable of proliferation, differentiation and self-renewal. Their use dates to 1956 when leukemia was treated using a bone-marrow transplant [3]. Since then, stem cells have been used to treat other diseases like lymphoma, and autoimmune diseases like MS, restore eyesight following the repair of cornea injury [4], and COVID-19 in 2021 [5]. In contrast, the use of MSC that have proved promising in preclinical experiments for some neurodegenerative diseases has not yielded encouraging results in clinical trials. Challenges such as tumor formation, immunorejection, poor engraftment, incomplete homing and ethical constraint have been identified as factors limiting the clinical applicability of stem cells for neurological disorder [6, 7]. These factors have been attributed to the growth and study of stem cells outside their niche environment [8] and presumably explain why most promising preclinical agents do not replicate their success in clinical trials, leading to a shift in the research approach in this field. In 1999, the stroke therapy academy and industry roundtable (STAIR) put forward some recommendations to optimize the chances of preclinical agents for success in clinical trials. The need to refine preclinical experiments in terms of screening models and methods was a major highlight in the STAIR recommendation and was restated in 2009 [9]. There are various animal models of stroke, but these models often lack features to make them a robust simulation of stroke in humans. It has been proposed that preclinical stroke experiments should be designed in a manner that would enhance the clinical translation of findings. The STAIR recommendations can be extrapolated for other neurodegenerative disorders that have recorded insignificant clinical success. One important way to achieve this is to create a cellular microenvironment inside the laboratory using biomaterial technology. A cell’s niche or microenvironment plays a key role in the way the cell communicates with itself (autocrine) and other cells at varying proximity to it. This microenvironment also influences mesenchymal stem cells’ proliferation, differentiation, self-renewal and aging [10]. Overall, to date, there is no therapy that can halt neuronal degeneration and death, or reconstruct defective brain circuitry following a brain injury caused by trauma or diseases [11, 12].

Biomaterial technology has witnessed remarkable advancement in the last decade, making it suitable to construct, deconstruct and investigate important cellular components in cells’ microenvironments. In addition to mimicking cells’ microenvironment, specific biomaterial construct allows for the prediction of a drug’s pharmacokinetic and pharmacodynamic profiles. This technology uses both natural and synthetic biomaterials formulated singly or in combination to improve their biological, mechanical and physicochemical properties to dub the MSC niche in the laboratory [13, 14]. Examples of natural sources of biomaterials are proteins (such as fibrin, collagen, heparin and gelatin) and polysaccharides (such as alginate, chitin, cellulose, dextran sulphate and pectin). Synthetic sources of polymeric biomaterials include polyethylene glycol (PEG), polylactic-co-glycolic acid (PLGA), polyacrylamide (PAM) [13, 14, 15]. These biomaterials have been used in different forms such as micelles, hydrogels, nanogels, nanoparticles, liposomes and dendrimers to deliver drugs to the CNS. An ideal biomaterial for medical use should be non-toxic during and after use, should be biodegradable, biocompatible, and adaptable, and should not cause inflammation [11]. Hydrogels are prepared by using ninety or more per cent (≥90%) of water, making them incredibly soft [11]. Because of their softness and very minute nano sizes, nanogels and hydrogels have been suitably used to deliver bioactive compounds such as DNA, RNA, recombinant proteins, drugs and trophic factors [16]. Further, hydrogels find use in clinical practice and experimental medicine for disease diagnosis [17], tissue repair and engineering [18], cellular mobilization [19], and as regulators of biological adhesion by serving as barrier materials [20]. Hydrogels, and by extension nanogels, find use in drug delivery because of their unique physical properties that can easily be manipulated for specific drug delivery purposes [21]. This form of drug delivery also helps to circumvent the blood–brain barrier (BBB) restriction and thus, increases the duration of drug action. Hydrogels and nanogels have also been used in delivering cells like MSCs. MSCs can be formulated in a three-dimensional hydrogel and delivered directly into the brain as pregels or administered via other routes for systemic effect. The former provides an avenue to accurately measure the number of cells in a particular brain region as well as promote engraftment of the delivered MSC. Additionally, the porosity of hydrogels can be tuned to allow depot drug formulation, enabling drugs to be eluted slowly [21]. Hydrogels are also biocompatible owing to their high-water content and physicochemical similarities, both mechanically and compositionally, to cell niches. Hydrogels and nanoparticles hydrogel (nanogels) are malleable to biodegradation via exposure internal and external stimuli (e.g., temperature, Ph, light and magnetic fields) [21] thus promoting the control of content release; stable for systemic circulation; enhanced biomedical encapsulation due internal hydrophilic nature. Because hydrogels are deformable – conforming to the shape of their applied surface, this property is exploited for targeted local drug delivery.

In this review, we shall highlight how the different properties of hydrogels are leveraged to discover and develop new diagnostic tools, drugs, and disease models for neurological disorders.

2. Ideal properties of hydrogels CNS disorders

Hydrogels have undoubtedly been employed in different capacities for an array of diseases and disorders. Regardless of the polymer source, hydrogels share some unique properties as mentioned in the introduction. However, an ideal hydrogel should possess properties that make it suitable for use for its intended application and in its target site of action. Hydrogels intended for CNS-related applications should possess specific properties as highlighted below.

2.1 Soft texture

Hydrogels are flexible water-containing matrices made from water-insoluble polymers that are chemically or physically cross-linked. Their porosity and softness make them CNS-friendly since they are unable to cause structural damage to the CNS [22]. Because their physical properties are influenced by changes in pH, osmotic pressure and temperature, hydrogels can easily be personalized for drug delivery in the CNS [23]. Thus, increasing their suitability for neurological disorders.

2.2 Blood: brain barrier permeability

A major challenge in the development of drugs for CNS diseases is the circumvention of the blood-brain barrier by the drugs [24]. Hydrogels have properties that make them similar to the brain’s extracellular matrix, which enables the diffusion of drug-loaded hydrogels through the BBB, leading to effective drug delivery [25]. The deployment of hydrogels in regenerative medicine, especially for neurological disorders is owing to their ability to provide an efficient scaffold to support stem cells prior to being transplanted into the brain. Moreso, the high water content and optimum mechanical properties of hydrogels ensures that they do not cause any harm or disruption to the brain’s physical structure [26].

2.3 Biocompatible and non-inflammatory

The use of stem cells as a promising regenerative tool is limited, in part by the inefficient engraftment following transplantation. Poor engraftment has been attributed to the activation of host cells’ immune response [27]. Hydrogels have been shown continuously to prevent the triggering of severe host immune responses as well as act as a barrier to the activation of the host immune factors, thereby preventing rejection after stem cell transplantation [11, 28, 29]. Moreso, both the polymers and their degradation products should be compatible with the human tissue such that they do not stimulate immunogenic responses in the host. This is a very important consideration for synthetic polymers [30]. The hydrogel should also provide a support structure that favors the cells’ proliferation, differentiation and survival. Biocompatibility can also be expressed as having mechanical properties similar to neural tissues [31] and architectural properties that closely mimic neural extracellular matrix [32].

2.4 Stable and biodegradable

Brain repair and regeneration is a slow process, and as such an ideal hydrogel for CNS-related function should be chemically and physically stable over an extended period [30]. This stability ensures efficient therapeutic and/or diagnostic intervention of the hydrogel. In addition to being stable, the hydrogel and its metabolite should be biodegradable i.e., easily, and completely cleared from the living system after performing their function. A non-biodegradable hydrogel polymer is likely to induce toxicity, rendering it clinically unsafe.

2.5 Scalable

Although not often considered, it is expected that the hydrogels for neurological conditions are made from polymers that can be produced in large amounts for their deployment in clinical practice [30].

3. Application of hydrogels and nanogels in neurological disease

3.1 Stroke

Formerly known as cerebrovascular accident, stroke is one of the leading causes of death and disability globally. It is caused by either occlusion of a cerebral blood vessel or a hemorrhage in the brain leading to the terms ischaemic stroke and hemorrhagic stroke respectively. Ischaemic stroke constitutes the most common of the two types and is mainly treated using thrombolytics and antiplatelets. As mentioned earlier, recombinant tissue plasminogen activator (alteplase®) is the only FDA-approved thrombolytic agent for the treatment of ischaemic stroke. Alteplase® has a short time window of between 3 and 4.5 hrs, and its use must be preceded by a CT or MRI scan for type confirmation. These limitations have led to an increase in the search for more efficacious and universally applicable drugs for ischaemic stroke. Stroke research in the context of drug discovery and development has not recorded significant success. Many promising agents in animal models of stroke have been unable to replicate their preclinical success in humans, and this unfortunate quagmire has led to refinements in the approaches to drug discovery. The use of plant extracts and herbal preparations, drug repurposing and new chemical agents among many other potential agents have been tried with no substantive success. In recent time, regenerative medicine using mesenchymal stem cells have gained some popularity as a promising approach to solving the mystery of drug discovery for stroke. Much research has been conducted using MSC from an array of sources on various animal models of stroke with hopes of clinical reciprocity. The common feature of these experiments is the employment of hydrogels and or nanogels for agent delivery, agent activation, or model creation as discussed in subsequent. Paragraphs.

MSC, along with growth factor, administered via the conventional intravenous or oral routes is reported in many works of literature to aid brain tissue repair and regeneration following a stroke incidence. The clinical applicability of these novel therapies is hampered by their inability to permeate the blood–brain barrier, the low survival rate of transplanted stem cells in the infarct area, inadequate homing into the site of injury and poor integration with the injured brain tissue. Tissue engineering holds a promising approach to addressing these challenges. Stroke therapy discovery is now facing some optimism as biomaterials are being used for drug delivery and model establishment. MSCs are currently formulated as hydrogels and nanoparticles to aid penetration of the BBB, increase homing in the site of injury, and ensure successful engraftment. Studies have revealed the versatility and potential benefits of hydrogels, using different biomaterials, in the management of stroke. A study by Wang and colleagues demonstrated a decrease in infarct volume and enhanced multiplication of neural progenitor stem cells (NPSC) within the MSC microenvironment when cyclosporin was delivered as a PLGA microsphere when compared with minipump-delivered cyclosporin [33]. This finding was corroborated in another study where hyaluronan/methylcellulose (HMAC) hydrogel was used to deliver erythropoietin, leading to the attenuation of tissue inflammation and migration of NPSC and mature neuroblast, and a reduction in apoptosis in mice injured cortical region [34]. Other factors such as brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), which play vital roles in tissue repair via angiogenesis and neurogenesis have also been delivered as extended-release formulations in various hydrogels [28, 35]. The results in primate and rodent species are positive and promising for use in humans.

Hydrogels are also used as models for drug screening because they mimic the cells’ microenvironment. The 3D-bioprinting of hydrogels serves as an in vitro extracellular matrix for conditioning MSC towards successful tissue repair and regeneration in the in vivo cell niche. They provide an environment that aids stem cell homing, engraftment, viability, proliferation and functionality. Fibrin which is an important extracellular matrix protein was used to make a 3D scaffold that allowed the survival and regeneration of neuron-like cells derived from human endometrial stem cells. Compared to the scaffold of fibrin alone, a composite scaffold of fibrin, hyaluronic acid and laminin, enhanced biocompatibility, delayed degradation and helped maintain human NPSC viability and function [36]. Several other studies have proven the importance of growing stem cells (or cells in general) in a niche-like environment. For instance, oxidized alginate hydrogel and injectable and self-healing carboxymethyl chitosan both have elastic moduli-like brain tissue and proved to be viable 3D carriers for the transplantation of neural stem cells [37]. In another study, the hydrogel of injectable self-assembling laminin enhanced vasculature-mediated migration of immature neurons to injured brain lesions via the activation of the β1 integrin pathway [38]. Similarly, the in vivo injection of nerve precursor cells with Matrigel significantly reduced infarct volume, promote neuronal differentiation, and improved behavioral outcomes in rats [39]. Further, hydrogels like the protein hydrogel GSH (Genipin cross-linked sericin hydrogel) provide an efficient environment for the attachment and growth of neurons, whilst sericin permits axonal branching and extension together with the prevention of hypoxia-induced cell death of immature neuroblasts [40]. Thus, serving as a potential 3D carrier for tissue repair and regeneration after ischaemic injury (Figure 1).

Figure 1.

Applications of hydrogels and nanogels in neurological disorders. Hydrogels and nanogels are employed primarily as drug-delivery molecules. However, they have been shown to be relevant in other aspects including, the diagnosis of some neurological conditions, modeling of brain disorders, CNS tissue repair, and regeneration.

3.2 Alzheimer’s disease (AD)

Commonly referred to as the disease of old age, Alzheimer’s disease treatment is currently limited to mainly symptomatic management using drugs from a broad class of drug families. The drugs used in the management of AD symptoms include memantine, galantamine, donepezil, tacrine, and rivastigmine. There is currently no drug to delay or reverse the progression of AD. Research into the use of hydrogels as potential therapeutic agents or aids is gaining momentum, and some experiments conducted to this effect have produced encouraging results. Several routes of hydrogel administration have been tried including intranasal, subcutaneous, and intracranial drug administrations. The use of microneedle patches has also been experimented with. Intranasal drug administration is the most utilized route of hydrogel drug administration owing to its ability to bypass the BBB, cause minimal off-target and toxic side effects, and rapidity of action.

Hydrogel of donepezil formulated by cross-linking hyaluronic acid-dopamine with PLGA with the aid of ferrous sulphate (FeSO₄) was designed as a sustained-release formulation for a single-dose drug administration [41]. This preparation improved the pharmacokinetic properties of donepezil after subcutaneous administration in rats. In another study, the pharmacokinetic properties particularly, the plasma concentration and area under the curve, of donepezil were significantly improved when its liposome was dispersed in chitosan hydrogel and administered intranasally in rabbits, thus buttressing the potential of hydrogels as an effective therapeutic aid for AD [42]. Timosaponin BII, an effective anti-AD agent whose use is limited by its low oral bioavailability was formulated in an in-situ hydrogel that is both ion and temperature sensitive. The formulation was shown to improve spontaneous behavior and spatial memory following intranasal administration in mice [43]. The use of tacrine, an anticholinesterase, in the management of AD is limited by several factors, most importantly its hepatotoxic side-effect. In research by Setya and colleagues in 2019, a nanoemulsion gel of tacrine was formulated, and administered via transdermal patches to rats. The nanogel had a superior pharmacokinetic and stability profile compared to conventional hydrogel and marketed capsules. The nanogel was also found to significantly improve neurobehavioral parameters in amnesic rats and did not cause hepatotoxicity [44].

Some underlying molecular causes of AD are the aggregation of amyloid-β (Aβ) proteins and oxidative stress due to an excess amount of reactive oxygen species (ROS). The search for therapeutic agents for AD is therefore sometimes tailored towards inhibiting Aβ aggregation or scavenging ROS. Some agents that have been found to inhibit this aggregation include curcumin (from Curcuma Longa, turmeric) and epigallocatechin-3-gallate (found in green tea extract). A nanogel formulation of these two compounds using modified hyaluronic acid caused a significant inhibition of Aβ aggregation compared to either agent alone [45]. Further, nanogel formulation of angiopep-2 modified AOC containing oxytocin was able to prevent the production of inflammatory cytokines by inhibiting microglia activation. Consequently, reducing the production of ROS [46].

3.3 Parkinson’s disease (PD)

Being the second most common neurodegenerative disease, Parkinson’s disease is characterized by extreme loss of dopaminergic neurons in the substantia nigra in the nigrostriatal pathway and the formation of Lewy bodies with α-synuclein. This disease faces the challenge of limited therapeutic options. Like Alzheimer’s disease, PD currently has no cure, and treatment is mainly targeted at symptomatic relief using the gold standard drug levodopa. The advancement in biomaterial technology has kindled research into novel therapies for PD, with hydrogels from different sources taking the central stage. Current experiments are designed to either influence one or more of the processes involved in the pathogenesis of PD or to improve the pharmacokinetic properties of PD drugs. In this context, hydrogel and nanogels have been used as carriers to deliver drug molecules, nutrients, and various cells to the brain, employed as a scaffold for cell maturation, serve as a tool to model PD, and used for organ/tissue reconstruction. Some of the studies have also made it to the clinical trial stage.

As a means of drug delivery, thermosensitive hydrogels of poly (N-isopropyl acrylamide) (PNIPAM) were developed to deliver nanocrystals of magnolol, a polyphenolic compound, into the brain through the nasal cavity of mice. This preparation improved the stability of magnolol, prolonged nasal cavity resident time, and enhanced delivery to dopaminergic neurons after effectively bypassing the BBB. These advantages led to the improvement of PD symptoms in the MPTP model of PD [47]. In another study to promote the release of tyrosine, a precursor amino acid for the synthesis of dopamine, from psyllium, psyllium-containing hydrogels of acrylamide and methacrylamide were formulated. The hydrogels caused a significant improvement in the release of tyrosine from psyllium, thus serving as a potential therapy for PD [48]. Nanogel of albiflorin (a potent antioxidant and anti-inflammatory phytochemical from Radix paeoniae Alba) had greater stability and superior efficacy compared to the free drug, thereby offering a prospect for use in PD management [49]. Factors such as glial-derived neurotrophic factor (GDNF), which serve a beneficial purpose in the recovery from PD, have also been formulated in many different types of hydrogels as a therapy for PD in humans. For instance, in a PD human trial, a hydrogel was used for the sustained delivery of GDNF after a dopamine progenitor graft, by significantly enhancing the formation of new dopamine neurons and improving graft plasticity. Consequently, leading to functional motor improvement even after 5 months [50]. To reconstruct the nigrostriatal pathway, a collagen hydrogel housing the ventral mesencephalon and dorsal striatum was loaded with GDNF. A mild growth of tyrosine hydroxylase-positive nerve fiber in the direction of the dorsal striatum was observed after 3 weeks [51]. In a similar study by Moriarty and colleagues (2017), the intra-striatal administration of collagen hydrogel loaded with GDNF caused remarkable improvement in dopaminergic neuron survival, enhanced striatal-innervation capacity, and increased functional efficacy in rats [52].

Dopamine, the primary neurotransmitter that is deficient in PD has also been delivered to the brain in various experimental models of Parkinsonism. It’s logically believed that the availability of functional dopaminergic neurons in the SN is an effective way to treat Parkinson’s disease. To this effect, dopamine-containing nanogels of polyvinylpyrrolidone-polyacrylic acid caused normalization of motor activity with a significant disease-modifying effect following subchronic administration in Parkinsonian rats [53]. Similarly, dopamine-loaded nanoparticles of PLGA caused a sustained release of dopamine in the brain and significantly reversed neurobehavioral deficits after intravenous administration in Parkinsonian rats [54]. In addition to delivering dopamine, hydrogels have also been deployed for the delivery of dopamine agonists, levodopa, and ropinirole in animal models of PD to investigate the possible improvement in their pharmacokinetic and pharmacodynamic features. Ropinirole is given orally with frequent daily dosing due to poor oral bioavailability. In a study by Dudhipala and Gorre (2020), ropinirole-loaded nanogels were administered to haloperidol-induced parkinsonism rats, both orally and transdermally. The results revealed an improvement in the drug’s oral and topical bioavailability, with a marked rise in the levels of catalase, glutathione, and dopamine [55]. Nanogels have been shown to improve the bioavailability of levodopa, a precursor of dopamine. Maximum recovery of levodopa was reported following the intranasal application of levodopa-loaded nanogel of chitosan [56].

The use of stem cells including mesenchymal stem cells from diverse sources to treat PD is also on the rise. The hydrogel of gelatine-PANI loaded with bone marrow-derived mesenchymal stem cells was shown to have superior efficacy when compared to BMSC alone by increasing the expression of BDNF and GDNF in the substantia nigra of mice following stereotactic injection [57]. Similarly, dopaminergic neurons derived from stem cells that were delivered in a 3D hydrogel scaffold showed greater survivability with a corresponding improved motor function in a PD model of mice compared to ordinary dopamine neurons [58].

Generally, biomaterial research in the context of drug discovery and development for Parkinson’s Disease is receiving tremendous attention. Considering the stream of promising preclinical results being obtained, there is no doubt that a breakthrough is almost here.

4. Multiple sclerosis (MS)

Another disease of the CNS where biomaterial technology is finding usefulness is multiple sclerosis (MS). MS is a chronic demyelination disease of the CNS associated with a host of symptoms including loss of sensation, vision, and movements. The treatment of MS is largely achieved with anti-immune and anti-inflammatory agents. The advancement in biomaterial technology with a consequent improvement in neurological research has led to probes into the probable application of hydrogels as therapeutic, diagnostic, and disease-modeling agents for MS. Effective treatment for multiple sclerosis is yet to emerge, and stem cells hold a promising potential for use in this condition. However, as mentioned earlier, the short-lived stay of administered stem cells in the brain and BBB crossing contributes to challenges with stem cell therapy. Hydrogels have been used as a 3D scaffold to deliver differentiated stem cells to promote myelin sheath repair and remodeling in animal models of MS. The formulation of a hyaluronic acid-based hydrogel has been revealed to increase the bioavailability of bone marrow-derived mesenchymal stem cells [59]. Further, the transplantation of interleukin-10-treated dendritic cells (DCs) formulated in polyethylene glycol-based hydrogel through the neck prolonged the lifespan of DCs, prevented disease progression, and modulated the recruitment of immune cells in a preclinical model of MS [60]. The success recorded in these in vivo preclinical studies is a result of findings from previous in vitro preclinical experiments that investigated the effect of hydrogel-based three-dimensional scaffolds on stem cell proliferation and survival in their in vivo niches [61, 62, 63, 64]. Findings from these experiments were able to demonstrate that the hydrogel culture allowed for cell adhesion, development of cell cytoskeleton, cell migration and differentiation, signal transduction, and morphogenesis of the 3D model [65].

Quite unique is the creation of biosensors for the diagnosis of MS and the detection of recovery-related problems, using hydrogels. In addition to serving as a carrier for materials that are responsive to biological signal transduction, hydrogels can in themselves, respond to stimuli thereby potentiating the signaling ability of wearable devices [66]. Biosensors designed to detect the presence of matrix metalloproteinase (MMP)-9, a vital peripheral marker of MS-associated neuroinflammation, have been designed and tried. In 2015, research led by Biela investigated the sensitivity of a hydrogel-based biosensor constructed in their lab using electrodes that were coated with enzyme-sensitive oxidized dextran that has been cross-linked with peptides. This device was able to detect MMP-9 in the presence of MMP-2, at levels between 50 and 400 ng/ml concentrations. The major limitation of the device is the delay of up to 5 minutes before biomarker detection [67]. Some years later, a similar design was constructed using poly (2-oxazoline) cross-linked with specific proteolytic peptides. This device was more able to detect MMP-9 in a lower range of between 0 and 160 nM following hydrogel degradation [68]. Currently, wearable biosensor devices are deployed to monitor balance and mobility with promising use in assessing fatigue, spasm, and tremor [66].

About a decade ago, hydrogels were employed as a tool to aid brain imaging for better diagnosis of multiple sclerosis. The tool, clear lipid-exchanged acrylamide-hybridized rigid imaging-compatible tissue-hydrogel (CLARITY), is an optical cleaning technology capable of making a 3D nanoporous hybrid of hydrogel compounds, from intact brain tissue. Thus, permitting the comprehensive visualization of the whole brain while maintaining natural fluorescence [69, 70]. All these accounts for unprecedented success in the application of hydrogels and nanogels in the diagnosis, prevention, and treatment of multiple sclerosis.

4.1 Brain tumor

Treatment of cancer is generally faced with challenges of poor penetration of anti-tumor agents, systemic/off-target side effects, and a high rate of cancer cells resistance to chemotherapeutic agents. Coupled with these is the additional obstacle of a tight physical barrier, BBB, that must be bypassed by brain-targeted chemotherapeutic agents. A handful number of malignant brain tumors exist with glioblastoma being the commonest and most deadly because of its high metastatic nature which results in recurrence even after triple therapy with resective surgery, radiotherapy, and chemotherapy. Treatment of glioblastoma is primarily achieved with the antineoplastic drug carmustine, available as injectable and implants/wafers. Carmustine administration as an implant is considered superior to the injectable form because it offers a sustained release of the active agent into the tumor cavity over a period of three weeks, and the implants protect against the degradation of carmustine [71]. Yet, wafers are not considered the ideal delivery form due to several important factors including the invasiveness of the implantation procedure, rapid release of carmustine, dislodgement of implant, local side effect of the drug, poor drug penetration, and drug resistance [71, 72, 73].

The biocompatibility and biodegradability properties of hydrogels make them a promising and effective alternative for anti-neoplastic drug delivery in cancers including brain cancers such as glioblastoma. Hydrogels have been utilized to increase drug accumulation at tumor sites leading to enhanced anti-tumor efficacy with reduced systemic and off-target toxicity. They’ve also been employed to enhance tumor death and immunogenicity in cancer therapy [74]. In addition to their use as drug carriers, hydrogels, and nanogels are deployed as in vitro 3D cell models for glioblastoma to aid the understanding of disease behavior as well as provide clarity on the interactions and communications within tumor microenvironment. Further, nanogels are now used, before or after surgery, to deliver anticancer drugs to the brain via intravenous injection and through the nasal cavity [75]. In line with this strategy, temperature-sensitive hydrogel loaded with epirubicin and paclitaxel nanoparticles caused remarkable tumor inhibition and lifespan prolongation when administered to mice bearing human glioma tumor. The hydrogel administration was done after surgical tumor resection [76]. Similarly, microRNA-loaded nanogels of polyglycerol scaffold were designed by Shatsberg and colleagues in 2016 for the treatment of glioblastoma in mice. The nanogels were delivered intratumorally and permitted internalization of the microRNA into the glioblastoma multiforme cells, leading to significant tumor growth inhibition and restoration of the tumor suppressor role of miR-34a in the xenograft mice [77]. In the same vein, etoposide and Olaparib-loaded bioadhesive pectin hydrogel were formulated as nanogel spray that allowed the deep penetration of the two drugs into tumor site and prevented their premature degradation [78].

To aid imaging of cancer cells in the brain, pH- and temperature-sensitive poly (w-isopropylacrylamide-co-acrylic acid) nanogels loaded with nanoparticles of citric acid-coated Fe3O4 were developed. This nanogel serves as a contrast agent for optical imaging and MRI imaging for glioma when it conjugates with Cy 5.5-labeled lactoferrin. More importantly, the contrast nanogel was devoid of any apparent toxic effect and poses no such risk in the future [79]. Research is still ongoing to develop more hydrogel-based therapies for brain tumors and the results obtained so far hold promise for efficient novel approaches.

4.2 Spinal cord injury (SCI)

Traumatic spinal cord injury results from a direct and sudden mechanical insult to the spinal cord resulting in apparent and lifelong autonomic dysfunction, paralysis, sensory impairment, and weakness [80]. Eventually, cystic cavities are formed from a progressive cascade of events including inflammation, neuronal damage, and neuronal death, leading to extracellular matrix (ECM) degeneration. Once formed, the cavities serve as barriers preventing the infiltration of beneficial cellular elements and axonal regeneration, thus constituting a major hindrance to neural regeneration after traumatic SCI. additionally, the cystic cavities also affect the transduction of electrical signals and stimulation of spinal cord tissues, further delaying or preventing axon regeneration and neural stem cell (NSC) differentiation [81, 82]. Biomaterial-based treatments have been experimented with and shown to act as bridges to narrow the cavity spaces.

In a study in 2021, an injectable and self-healing hydrogel of Fmoc-peptide and Fmoc-loaded chitosan carrying curcumin was fabricated and was shown in an in vitro test to cause Schwann cell migration away from the dorsal root ganglia, enhanced neurite growth, and caused remarkable myelination. In an in vivo test, the hydrogel promoted ECM reassembling at the site of the lesion, modified inflammatory cells to an anti-inflammatory population, and significantly improved hind limb mobility [83]. Similarly, in 2022, Luo and co-workers developed a self-healing electroconductive hydrogel ECM using chondroitin sulphate and gelatine biopolymer containing polypyrrole. The hydrogel had comparable conductive and mechanical properties with natural spinal cord tissues. In an in vitro experiment, the hydrogel also enhanced the outgrowth of axons, inhibited astrocyte differentiation, and promoted the differentiation of neurons. Further, the electroconductive ECM hydrogel caused a significant regeneration of myelinated axon into the lesion site, and increased neurogenesis of endogenous NSCs [84].

4.3 Epilepsy

Epilepsy is a brain disease associated with the excessive rapid firing of neurons. To alleviate the continuous electric discharges in the brain, anti-convulsant agents, like other CNS drugs, should be able to cross BBB and bind their receptors in the CNS. Conventional anticonvulsant agents are not able to efficiently circumvent this barrier, leading to higher dosage administration. Consequently, resulting in more off-target effects. The use of hydrogels and nanogels is being considered as an approach to overcome this challenge and the few preclinical experiments conducted so far have been promising. In a study by Ying and colleagues in 2014, an electro-responsive hydrogel was made from four different monomers crosslinked with N, N′-Methylene bisacrylamide. The hydrogel was biphasic in nature – forming a gel at high concentrations above 100 mg/ml and becoming a nanoparticle at low concentrations above 10 mg/ml but below 50 mg/ml. The hydrogel was fabricated to be brain-specific by coupling it to angiopep-2 peptide, which is a ligand of LRP (a low-density lipoprotein receptor-related protein). The specialized delivery hydrogel was used to deliver phenytoin sodium to the brains of amygdala-kindled mice, causing a significant improvement in the anticonvulsant activities of phenytoin [85].

Table 1 shows a list of hydrogels for different CNS conditions that have been approved by the US food and drug agency (FDA) or are currently under investigation in different clinical trial stages.

Hydrogel	Polymer material	Purpose
Stroke
GelMA [86]	Gelatine, methacrylate	Neural repair and regeneration
NeuroGel™ [87]	[N-2-(hydroxypropyl) methacrylamide]	Drug delivery and tissue repair
Alzheimer’s disease
Brain shuttle hydrogel [88]	Gelatine	Drug delivery
NGF Hydrogel [89, 90]	Collagen	Delay disease progression
Parkinson’s Disease
*Duodopa/Duopa [91]	Carboxymethylcellulose and polyacrylamide	Drug delivery
*BrainStem [92]	polyethylene glycol diacrylate	Drug delivery
*Levodopa/Carbidopa Gel (NeuroDerm) [93, 94]	poloxamer 188 and poloxamine 908	Drug delivery
Multiple Sclerosis
Hyaluronic acid hydrogel [95]	Hyaluronic acid	Drug delivery and disease management
Nanoparticles hydrogel [96]	poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) (PEG)	Disease treatment
Brain Tumor (Glioblastoma)
*Gliadel wafer [97, 98, 99]	poly(lactide-co-glycolide) (PLGA) and polyethylene glycol (PEG)	Disease treatment
*Proton-beam delivered polymeric hydrogel brachytherapy device [100]	polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), and Poly (2-hydroxyethyl methacrylate) (PHEMA)	Radiotherapy treatment
*Magtrace and Sentimag [101]	dextran, carboxydextran, and starch.	Disease diagnosis
Fluorescent hydrogel [102]	polyethylene glycol (PEG), polyacrylamide, hyaluronic acid, alginate, polyvinyl alcohol (PVA), and chitosan.	Tumor detection
Spinal cord injury
NeuroScaffold [66, 103]	Poly-lactic-co-glycolic acid and Poly-l-lysine.	Supportive scaffold
Neurogel [104, 105]	Alginate	Repair and regeneration
Silk hydrogel [106]	Sericin and silk proteins derived from silkworms or spiders	Disease treatment
PuraMatrix Hydrogel [107]	RADA16 (L-arginine, L-aspartic acid, and L-alanine.)	Cell growth and tissue regeneration
Epilepsy
Carbamazepine hydrogel [108]	Ethylcellulose, sodium alginate	Drug delivery

Table 1.

Some hydrogels under investigation and those approved for neurological disorders.

*

Represent FDA-approved hydrogels.

Currently, there is a paucity of data on the application of hydrogels and nanogels in other CNS conditions such as amyotrophic lateral sclerosis, depression, and Huntington’s disease. However, the successes recorded in the use of this biomaterial approach in the discussed neurological conditions can easily be extrapolated to other CNS disorders without the need for much caution. Moreover, the challenges that were previously associated with the use of hydrogels such as uncontrolled drug release as a result of poor tunability of shape and geometry, one-time release of administered drugs and limitations with the encapsulation of some drugs such as hydroscopic drugs, antibodies, nucleic acids and proteins [21], are now being circumvented with the aid of 3D printing and the use of nanocarriers. 3D printing allows for the customization of composites of nanocarrier-hydrogel for tissue engineering and drug delivery [109]. Nanocarriers such as liposomes, micelles, dendrimers, and nanotubes that allows surface modification of drugs have also been deployed to improve drug kinetics, aiding targeted delivery [110].

5. Conclusion

Biomaterial technology is unarguably advancing at a rapid pace, and this is occurring in tandem with the increasing search for effective drugs for neurological disorders. So far, preclinical results for experiments involving hydrogels and nanogels have been encouraging and this gives a hint to the anticipation of positive clinical outcomes in a few years to come. However, a lot still needs to be done including finding ways to employ nanogels and hydrogels to improve the intranasal delivery of less potent drugs and reducing the local side effects that follow extended nasal drug delivery.