Natural Polymer-Based Hydrogels for Glaucoma Therapy: History
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Contributor:
KASSAHUN ALULA Akulo
,
Terin Adali
,
MTHABISI TALENT GEORGE MOYO
,
TÜLİN BODAMYALI
Biopolymers have been extensively investigated in a number of medical fields, including tissue engineering and drug delivery. This is largely due to the fact that they are biodegradable within the body, and do not induce an inflammatory reaction. Polynucleotides such as nucleic acids (DNA and RNA), proteins such as polypeptides, and polyesters derived from both plants and animals are also used. When compared to synthetic polymers, naturally occurring biopolymers and their derivatives have acquired preference, and have a comprehensive range of applications in pharmaceutical as well as biomedical research. Natural biopolymers are preferred for medical applications due to their biodegradability, biostability, biocompatibility, and non-toxicity. Additionally, natural polymers have the advantage of being readily available, economically friendly, and ecofriendly. Hydrogels designed from natural polymers exhibit high potential as drug delivery systems for biomaterials to treat ocular impairments.
  • glaucoma
  • natural biopolymers
  • intravitreal injectable hydrogel
  • drug delivery systems

1. Silk Fibroin

Bombyx mori silk is a natural biopolymer obtained from arthropods and lepidopteran insects, particularly silkworms and some spider groups, that produce silk fibers at large. Due to their remarkable mechanophysical and biological properties, silk fibers have attracted the interest of researchers [1], for biomedical and pharmaceutical applications. Silk fibroin is an essential biopolymer used in biomedical applications due to its adaptable properties, with a natural physiology that makes it preferable in the study of tissue reconstruction in age-related ocular disease [2]. Silk fibroin is a fibrous protein that exhibits favorable biocompatibility, bioresorbability, low immunogenicity, and hydrophilicity, promoting its increasing consideration in hydrogel design. It is also rich in β-sheet structures, owing to hydrophobic domains that influence its biodegradability rate [3], as well as its cytological compatibility [4]. Silk fibroin proteins have been used for ocular therapies such as wound healing [5], ocular drug delivery [6], and ocular prostheses [7].

2. Chitosan

Linear-structured chitosan is a natural biopolymer composed of an acetylated unit of N-acetyl-D-glucosamine and β-(1→4)-linked D-glucosamine, a deacetylated unit. It is prepared by treating chitin shrimp shells and various crustacean shells with sodium hydroxide [8].
Due to poly-oxy salt formation, chitosan exhibits basic properties different from those of other polysaccharides [9]. As with other polymers, chitosan can also form hydrogels, films, and particles that can be used for biomedical applications in terms of drug delivery units, tissue engineering, cell culturing, and platforms for cancer diagnosis. Its low toxicity, high biocompatibility, and easy degradability in a natural environment which makes it suitable as natural extracellular matrices [10].
According to surveys carried out by several researchers, the major constraint when working with injectable hydrogel preparations is regulating the time of gelation [11]. However, a chitosan-based formulation of injectable hydrogel was developed that regulates the time of gelation [12].
To be used as a biomaterial, chitosan has important properties that mimic the extracellular matrices of cells, tissues, and organs. Chitosan is prepared and used either in a dried form or in the form of gels, depending on the temperature used and the amount of water present in the structure, which impart properties of flexibility [13].
According to the study conducted by Franca, J.R. et al. [14], chitosan can be widely applied in the treatment of glaucoma-induced intraocular pressure, acting as a basis for controlled drug delivery in the eye. This is because chitosan is polycationic by its very nature, allowing interaction with the polyanionic surface through hydrogen bonding of the ocular mucosa. Chitosan has several biological properties that make it an attractive material for use in ocular formulations [15]. Chitosan has inherent antimicrobial and mucoadhesive properties [16], as well as low toxicity, biodegradability, biocompatibility, and hemocompatibility [17]. Chitosan can disrupt epithelial tight junctions, thus acting as a permeability enhancer [16].

3. Alginic Acid

Brown algae are the main source of the naturally derived polysaccharide alginic acid (Alg), with the molecular formula (C6H11NO6)n. The molecular structure and composition of alginic acid consist of L-guluronic acid and D-mannuronic acid structures connected with alpha-1,4 bonds [18]. As a result of the carboxyl group attached to the C-5 carbon as a chain, it exhibits an acidic nature, and with properties such high hydrophilicity, the capacity for gelation, and pH-dependent viscoelasticity. Furthermore, biocompatibility and biodegradability are some of the physiological properties that make it suitable for use as films and gels developed for medical and food applications [19]. Alginic acid has a biodegradable and biocompatible nature that is favorable for researchers; therefore, its use has been encouraged in ocular treatments [20]. Ocular delivery therapeutics are a current trend in ophthalmology, and alginates have been employed to play an imperative role because of their biocompatibility and immunogenicity [21].

4. Pullulan

Pullulan is a non-ionic polysaccharide extracted from the fermentation of black yeast (Aureobasidium pullulan), and is used broadly in biomedical applications because of its less immunogenic reaction, along with its non-toxic, non-mutagenic, and non-carcinogenic nature [22]. It is utilized in the targeted delivery of drug mechanisms, tissue engineering therapy, and wound-healing activities. Pullulan responds to external stimuli so that it can be used to design hydrogels, which can be used to deliver drugs, nutrients, and (any) other molecules to a targeted area of the host [23]. The biological properties of pullulan include high water retention, biocompatibility, cytocompatibility, protective activity against microbes and biodegradation, and tissue-regenerative characteristics [24].

5. Hyaluronic Acid

A biopolymer regularly found and extracted from the human body, applications of hyaluronic acid as injectable hydrogels have been researched for ocular drug delivery systems, since they can be designed as both stimulus-responsive and static [25]. Anionic hyaluronic acid is incapable of gelation without additive molecules. Hence, hydrogels produced using hyaluronic acid depend on chemical modifications. Egbu et al. formulated two hyaluronic acid gel systems embedded with infliximab for the treatment of blinding infections influencing the elderly population [26]. Hyaluronic acid has been applied in ocular therapeutics because of its favorable biological characteristics, such as biocompatibility, biodegradability, and non-immunogenicity [27]. Due to hyaluronic acid’s biological safety, it has various ophthalmology-related applications, such as treatment for dry eyes, intravitreal drug delivery, and use in contact lenses [27].
The main objective in the development of ophthalmic drug treatment is to extend the therapeutic extent of medications, particularly proteins and antibodies [28].

6. Dextran

Dextran methacrylate and cyclodextrin–dextran are a few examples of dextran hydrogels used in ocular drug delivery [29]. Properties such as stiffness, mechanical strength, and solidness can be adjusted by regulating the monomer in the gel, subsequently improving their significance in drug delivery. Yao et al. [30], designed a drug delivery system for effective in vivo drug release of bevacizumab from a hyaluronic acid/dextran-situated in situ hydrogel for 6 months after intravitreal infusion in hare eyes. The in vivo drug release efficiency results indicated that bevacizumab was delivered at a therapeutically relevant concentration by means of a controlled release mechanism within the vitreous humor [31]. Dextran has been found to exhibit great biocompatibility and low cytotoxicity. Additionally, it has hydrophilic domains, which promote its biodegradability in water and other organic solvents. This biological feature enables its applicability in blended forms with bioactive agents of hydrophobic polymers [32].

7. Methylcellulose

Derived from cellulose, hydroxypropyl methylcellulose (HMPC) is widely used in the pharmaceutical industry because of its solvency in water, rheological properties, and transparency [33]. A group of researchers designed a trans-scleral antisense oligonucleotide-loaded gel for the delivery of drug-loaded macromolecules using methylcellulose and ι-carrageenan dispersions [34]. Periocular injection of the gel resulted in impressive choroid and sclera bioavailability in comparison to the injection of an oligonucleotide solution alone. Methylcellulose has been incorporated into ocular inserts of three types: soluble, insoluble, and bio-erodible, [35]. Methylcellulose has low reactivity with cells. Additionally, interest has been shown in mixing it with biologically active materials such as cytokines and/or the extracellular matrix to control the organization or functions of the cells [36].

8. Gelatin

Gelatin is a collagen-derived biopolymer normally found in scleral and corneal stroma, and its structural networks make it an attractive natural complex for research applications. El-Feky et al. [37] developed an oxidized sucrose-crosslinked gelatin–chitosan hydrogel with the end goal of TM drug conveyance for the treatment and control of ocular hypertension [38]. In vivo and in vitro discoveries indicated that the formulated system maintained favorable release efficacy of the active ingredient, in contrast to the regular eye drops [39]. Gelatin has favorable biological characteristics such as low antigenicity, biocompatibility, and biodegradability, and promotes cell proliferation; therefore, it is widely researched in ophthalmologic therapeutics [40].

9. Collagen

Collagen is biocompatible, biodegradable, and non-toxic for living organisms [41]. Type 1 collagen is an essential biopolymer that has been utilized in hydrogels for tissue engineering applications [42]. Wong et al. [43] designed an injectable composite comprising collagen and alginate for retinal treatment through a drug delivery system loaded with an ocular drug. 

This entry is adapted from the peer-reviewed paper 10.3390/polym14122359

References

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