Next-generation biopolymer gels: innovations in drug delivery and theranostics

Abstract

Biopolymers or natural polymers like chitosan, cellulose, alginate, collagen, etc. have gained significant interest recently due to their remarkable tunable properties that make them appropriate for a variety of applications & play a crucial role in everyday life. The features of biopolymers which include biodegradability, biocompatibility, sustainability, affordability, & availability are vital for creating products for use in biomedical fields. Apart from these characteristics, smart or stimuli-responsive biopolymers also show a distinctive property of being susceptible to various factors like pH, temperature, light intensity, & electrical or magnetic fields. The current review would present a brief idea about smart biopolymer gels along with their biomedical applications. The use of smart biopolymers gels as theranostic agents are also discussed in the present review. This review also focuses on the application of biopolymers in the fields of drug delivery, cancer treatment, tissue engineering & wound healing. These areas demonstrate the development and utilization of different types of biopolymers in current biomedical applications.

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1. Introduction

The term “biopolymers” describes polymeric materials entirely or partially synthesized by living organisms by chemical synthesis of biological ingredients from natural resources.¹ Similar to other polymers, biopolymers consist of interconnected repeating units, called monomers.² The primary benefit of biological polymers is their capacity to degrade in the presence of living microorganisms.³ Through the enzymatic action of microbes, biopolymers disintegrate into CO₂, CH₄, H₂O, inorganic chemicals, etc.⁴ The benefits of biopolymers include reduced carbon emission, biocompatibility, renewability, & affordability.⁵ Additionally, biopolymers have the extremely significant benefit of being ecologically friendly. Biopolymers have been shown to be risk-free, non-thrombogenic, non-carcinogenic, and easy to extract.^6,7Fig. 1 summarizes the main characteristics of biopolymers. Biopolymers are being widely employed in medical, pharmaceutical & industrial fields.³

Fig. 1 Essential features of biopolymers.

In the pharmaceutical sector, polymeric gels are acknowledged as possibly useful delivery techniques for handling medication delivery issues. Gels are usually homogeneous, semi-solid formulations that include a medication dispersion in a three-dimensional (3D) network that is either hydrophilic or hydrophobic.^8,9 The simplicity of preparation has led to the popularity of these formulations. Additionally, they provide a close connection between the therapeutic component & the site of action, along with controlled delivery via several pathways. Gels are commonly divided into two categories: hydrogels (a) & organogels (b). Large quantities of biological fluids or water may bond to hydrogels, a form of hydrophilic three-dimensional polymeric network, without the polymer dissolving.¹⁰ As a cross-linked network of hydrophilic polymers, hydrogels may swell when they come into contact with biological fluids or aqueous fluids and contract (de-swell) when the water is released.^11–13 Hydrogel possesses the capacity to hold a large amount of water by virtue of capillary action & osmotic pressure. Because of these properties, hydrogels mimic real tissues' extracellular matrix.¹⁴ The hydrogels which are sensitive to external stimuli contain functional groups that are ionizable. The sensitivity of these hydrogels is determined by the type, content, and quantity of functional groups on the polymer backbone.^15,16 Organogels or oleogels are the result of immobilizing gelator fibers with an organic liquid phase and then creating a three-dimensional network.¹⁷

Hydrogel particles with a submicron size range are called microgels, or nanogels.^18,19 In aqueous solutions, hydrophilic, hydrophobic, or amphiphilic polymers are combined chemically or physically to create nanogels.^20–22 Synthetic, natural, or an amalgam of the two types of polymers can be used to generate nanogels. Depending on the synthesis techniques used, nanogels can take on a variety of morphologies, including spherical particles, core–shell structures, & core–shell–corona structures.²³ In the biomedical field, nanogels are particularly advantageous over other types of nanomaterials because of their ability to react rapidly to changes in temperature, ionic strength, light, & pH.^22,24 Because of its beneficial features, which merge those of hydrogels & nanoparticles, nanogels are considered as a promising drug delivery system. Many bioactive molecules, such as proteins, drugs, & vaccines, have been extensively studied and delivered via nanogels.^21,25,26

Environmentally-sensitive or intelligent gels are other names for smart polymer gels. Researchers are becoming more and more interested in stimuli-responsive gel systems, especially in delivery systems that are controlled or self-regulated. In reaction to slight variations in their surroundings, such as pH, temperature, light, magnetic field, & ionic components, stimuli-responsive or “smart” gels exhibit an exceptional physiochemical change. Since these are reversible alterations, when the signal or trigger is withdrawn, the system may go back to its original state.^27,28 Polymer gels' response to external stimuli is governed by several factors, including the material's shape or dimensional change (strain), its force-exerting capability, response speed, shape recovery, and viscoelastic loss resulting from heat dissipation.²⁹ These days, stimuli-responsive polymers may sense two or more stimulating events in addition to a single one because of their unique design.³⁰ Hydrogels that respond to changes in temperature or pH are most widely used.^31–33 Targeting cells or tissues with controlled drug release, biopolymer gels may be engineered to react to environmental signals therefore augmenting therapeutic effects. Research has demonstrated that these gels are a flexible and efficient drug delivery platform because they can be tailored to increase drug characteristics, release mechanisms, and targeting abilities in addition to being strengthened mechanically for tissue regeneration.⁵

Biopolymers can be modified using a range of chemical and physical methods to greatly improve their performance and qualities, opening up a larger range of uses. Among other qualities, these changes can enhance biodegradability, thermal stability, and mechanical strength. The various physiochemical medications include mechanical processing, thermal treatment, crosslinking, grafting, etc. Biopolymers' mechanical qualities can be improved by changing their physical structure through processes like extrusion and molding. Biopolymers become stronger and more flexible as a result, which makes them appropriate for a range of applications in construction and packaging. Biopolymers can also be heated to enhance their processing properties and thermal stability. Applications like automobile parts, where heat resistance is essential, may benefit from this alteration. Crosslinking leads to the formation of bonds among polymer chains, which improve the thermal stability and mechanical strength of the biopolymer. These biopolymers are frequently utilized in coatings and adhesives, besides other applications that call for long-lasting materials. Another modification is grafting, grafting is the technique of adding various groups of chemicals to the core of a biopolymer, which could enhance its lipophilicity or hydrophilicity and increase its compatibility with various other substances. These biopolymers are used in medication delivery systems (bio medical field). Modified biopolymers have a wide range of significant biomedical uses, from tissue engineering & wound healing to drug delivery systems. They are a potential area for medical research and development because of their capacity to be customized for certain purposes.^34–36Fig. 2 demonstrates statistics about the number of publications in PubMed since 2000 until 2024 regarding this subject. These data explain the urgent need to explore the enigma of favorable biopolymer gels for biomedical applications.

Fig. 2 Comparative statistical data about the number of publications in PubMed since 2000 till 2024: comparative general data about the number of publications in PubMed when searching for keywords/phrases: (1) biopolymers and hydrogels (blue column); (2) biopolymers and hydrogels in biomedical applications (orange column). Linear trend lines show the importance and urgent need for research concerning biopolymer gels for biomedical applications.

2. Properties of gels

2.1 Swelling

When the gelling agent and solubilizing solvent come into contact, the gelling agent absorbs a lot of solvent and increases in volume. This process is referred to as swelling. The process is brought about by a substantial amount of solvent penetrating the matrix. The strength, number, and kind of links among the individual molecules of the gelling agent often determine the degree of swelling.³⁷ Hydrogels' ability to swell when exposed to H₂O or physiological fluids relies on the osmotic pressure created by the hydrophilicity of the constituent polymers, the static charges on the polymer, and the counter ions in the hydrogel matrix. Three stages are involved in the swelling of hydrogels: the diffusion of liquid into the hydrogel, the relaxation of the chains of polymers upon hydration, & the enlargement of the network as the chains relax.³⁸ Absorption resulting from the hydrophilic & polar groups' attraction to water molecules is known as primary bound water. Consequently, the hydrogels expand, and the hydrophobic components that are exposed bind with water molecules, resulting in secondary bound water.³⁹ Hydrogels' water capacity is often determined by the equilibrium swelling ratio (SR) or swelling degree (SD), which may be computed using the following equation.
where M is mass of hydrogel.

The swelling index (SD) of some biopolymer based hydrogels is indicated in Table 1.

Table 1 SD of different biopolymer-based hydrogels

Biopolymer	Swelling degree (g g^−1) in H2O	Ref.
Alginate	1.65 to 3.85	40
Carboxymethyl cellulose	50 to 200	41
Guar gum	125 to 220	42
Starch	500 to 1200%	43
Chitosan	More than 100%	44
Cellulose	200 to 1000	45

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2.2 Syneresis

Certain gels instantly release a certain amount of fluid as they contract upon standing. This phenomenon is called syneresis. This process shows that the polymeric gel was unstable from a thermodynamic perspective. Decreasing the gelling agent concentration in a gel increases the degree of syneresis. The process of contraction arises from the relaxation of elastic stress that is created during the gels' settling.³⁷ Syneresis is generally linked to the stiffness of the gel and has been ascribed to disproportion within the forces on each side of the gel–fluid interface.⁴⁶ Additionally, aging-related chemical changes to the polymer can also cause syneresis. For example, at elevated temperatures, the acrylamide-based polymers employed in H₂O cutoff treatments are almost susceptible to hydrolysis. The carboxylate moieties created by the hydrolysis of the polymer's acrylamide groups can additionally combine with divalent cations, resulting in gel syneresis. Another explanation for this syneresis is that divalent ions & carboxylates are over-crosslinked.⁴⁷

2.3 Aging

Colloidal systems often exhibit slow aggregation. This phenomenon is called ageing. Aging in gels results in the steady development of a denser structure of the gelling agent.³⁷ Aging has a major effect on the biopolymer composites. Aging affects performance under many circumstances. Composites can deteriorate chemically, thermally, mechanically, organically, or by photo-oxidation as they undergo aging. Additionally, the bio composites' ability to efficiently absorb oxygen at high temperatures speeds up the biopolymer composites' degradation.⁴⁸

2.4 Structure

The network that is created when the particles of the gelling agents bind together is what gives a gel its stiffness. Particle characteristics and stress straighten them & thus reduce flow resistance.³⁷ It is believed that the type of force and the nature of the gelling component or components are accountable for the interactions that define the gel characteristics and networking structure.⁴⁹

2.5 Rheology

Gelling agent solutions and flocculated solid dispersions have a pseudoplastic nature, meaning that they obey non-Newtonian law and exhibit a viscosity decrease as shear rate increases.³⁷ A commercial fluorosilicone gel (Dow Corning DC4-8022) serves as an example to illustrate several facets of gel rheology. Despite its softness, this gel is nonetheless regarded as strong due to the persistent chemical crosslinks. These soft gels' viscoelastic nature is easily noticeable and adds to their rich dynamic responsiveness.⁵⁰ Viscosity and shear-thinning behavior are important rheological characteristics in the setting of hydrogels for 3D printing. Proper extrusion via the printer nozzle is ensured by an appropriate viscosity, and shear-thinning behavior enables the hydrogel to decrease viscosity under shear stress throughout printing, promoting layer deposition & smooth flow.⁵¹ Kim et al.⁵² focused on using carrageenan to improve the rheological properties of alginate hydrogels, particularly for extrusion-based bioprinting techniques.

3. Biopolymers employed in smart drug delivery

3.1 Chitosan

Chitosan is an extensively researched harmless biopolymer that is widely used for a range of medical uses.^53,54 This cationic polymer is made from the naturally existing polymer chitin and is made up of N-acetyl & D-glucosamine. Chitosan is naturally present within the exoskeletons of fungi,⁵⁵ insects, mollusks, annelids, and crustaceans. Moreover, chitosan has hemostatic, mucoadhesive, adhesive, and biocompatible properties.^56,57

Chitosan has been included in DDSs in a variety of forms, including oral tablets, gels, films, beads, and microspheres for transdermal, ocular, nasal, and oral routes.^58,59 Chenite et al.⁶⁰ documented the application of chitosan-β-glycerophosphate (C-β-GP) water-based solutions as pH-sensitive and thermoresponsive gelling systems. The ammonium groups in chitosan are neutralized by the phosphates in the glycerophosphate salt, which increases the hydrophobic & hydrogen bonding within the chitosan chains at higher temperatures and forms a more cohesive gel compared to that formed at lower temperatures. The same gel was examined for the in vitro administration of drugs⁶¹ and the in vivo distribution of physiologically active growth factors.⁶⁰ Dang et al.⁶² examined the process of conjugating hydroxybutyl groups to chitosan, with the aim of producing a polymer that is both thermoresponsive as well as soluble in water. Another method that has been investigated is the modification of chitosan using synthetic polymers to produce thermoresponsive materials.^63–65 Carrageenan and chitosan together create a pH-sensitive system where the SO₄ groups of carrageenan & the NH₂ groups of chitosan interact electrostatically in order to control drug release in an alkaline environment.⁶⁶

3.2 Hyaluronic acid

HA is a linear anionic polysaccharide that occurs naturally. Its natural chemical structure is composed of 2 disaccharide units, N-acetyl-D-glucosamine and D-glucuronic acid, which polymerize into large macromolecules (approx 30 000 repeating units). HA is neither immunogenic, thrombogenic, inflammatory or poisonous, but biodegradable in nature. Because of its innately advantageous natural properties, HA is utilized in various pharmaceutical and biomedical applications. Efficiency is enhanced by the amount of hydroxyl and carboxylic acid groups. These functional groups may be helpful to form new functional groups by crosslinking conjugation, and chemical bonding. A simple method for producing the beneficial microgel or nanogel from HA biopolymers is to use a functional crosslinker.^67–70 Liang et al.⁷¹ synthesized a novel nanogel via self-assembly of granzyme B (GzmB) linear polyethylenimine (PEI), and hyaluronic acid–epigallocatechin gallate conjugates (HA–EGCG), in order to introduce GzmB into cancerous cells. Studies demonstrated that epigallocatechin gallate (EGCG) moieties improved the binding of proteins through physical bonds, resulting in strong nanogels. The use of HA–EGCG as an effective intracellular protein carrier for specific cancer therapy is underlined by this study.⁷² Nitric oxide (NO) & antimicrobial peptide (AMP) can be delivered simultaneously via a nanogel that was created by Fasiku et al. to fight microbial or biofilm associated infections. The NO-releasing nanogel was made by crosslinking a hyaluronic acid solution with divinyl sulfone. The resultant nitric oxide (NO)-antimicrobial peptide (AMP) showed great anti-bacterial or anti biofilm activity in in vitro release studies.^73,74 The properties of hyaluronic acid are highly intriguing, and its applications in biomedicine seem endless. Because of its great swelling capacity, elasticity, and viscosity, it is being used as an injectable hydrogel to improve human soft tissue in regenerative medicine and cosmetology. Its poor mechanical qualities and quick deterioration after injection underneath living tissue are its drawbacks. Various modifications were done in order to improve its hydrogel quality such as photopolymerization, crosslinking with epihalohydrin, divinyl sulfone, epoxides, etc.⁷⁵

3.3 Alginate

Alginate is an established linear anionic polyelectrolyte polysaccharide composed of α-L-guluronic acid (G units) & β-D-mannuronic acid (M units) (linked via 1–4 glycosidic bond) and is being widely used in the synthetic hydrogel in artificial ECM (extracellular matrix).⁷⁶ The monosaccharide sequences of alginate can be organized through blocks of repeating M regions (MM blocks), repeating G regions (GG blocks), or hybrid M & G regions (MG blocks). Gels made from alginates with a larger percentage of G blocks are notably stronger than those made from alginates having a higher percentage of M blocks. This is owing to the fact that G residues are more suitable than M residues to bind divalent ions. Therefore, the primary factors influencing the physiochemical properties of alginate include the M/G ratio & the order of monosaccharide repetitions.^77,78 As soon as counter ions are added, alginic acid or its derivatives begin to form a polymeric network, which results in the hydrogel delivery system. An alginate reaction can be initiated by any type of cationic species, although studies have shown that CaCO₃ and alginate reactions are the most effective and desirable.⁷⁹ Initially, the food industry employed alginate as a component and adjuvant, owing to its qualities such as biocompatibility, elasticity, nontoxicity, biodegradability, affordability, etc. it is being widely employed as a major biomaterial in numerous cutting-edge uses in the pharmaceutical, medical, & cosmetics sectors. Like various other naturally occurring polymers, alginate has several drawbacks, like poor dimensional stability, limited biocompatibility, and poor mechanical properties.

In order to produce biodegradable colloidal structures like nanoparticles, gels, biofilms, microcapsules, & beads, alginate is used. These biodegradable structures are used in regenerative medicine, orthodontic use, drug delivery, wound healing, etc.⁷⁵ Valentino et al. demonstrated the formation of nanogels via ionotropic gelation between the cationic spermidine (SP) and the anionic alginate.⁸⁰ In light of the results, the formulation containing 0.017% (w/w) SP & 0.17% (w/w) alginate (less viscous) was determined to be the most suitable sample. The antioxidant and anti-inflammatory qualities of the formulation, as well as its biocompatibility, were confirmed by the in vitro study conducted on Schwann cells. The element that contributes to the work's uniqueness is the application of SP as both a crosslinker and a neuroprotective agent.⁷³

3.4 Cellulose

Cellulose is the most common polymer occurring naturally on Earth, and it may be found in a broad variety of sources, such as plants (such as wood, cotton, etc.), microorganisms (including amoeba, algae and fungi), and marine life (like tunicates). Cellulose is a polysaccharide composed of anhydro D-glucopyranose units linked with each other via glycosidic linkage (β-1–4 linkage). The fundamental component of many biological compounds is cellulose. Cellulose's hydroxyl groups give it the natural tendency to organize itself and form extensive networks by connecting individual molecules with hydrogen bonds.

Cellulose and its derived substances are now being thoroughly investigated for possible use in medicine,⁸¹ biomedicine,⁸² the pharmaceutical field,^83,84etc., due to its cost effectiveness, extensive availability, good mechanical properties, biocompatibility, biodegradability, and low cytotoxicity.⁸¹ A lot of study has been done on cellulose-based nano gels; just as it has been done with different polysaccharides. A study conducted recently produced responsive and functional nanosilver by in situ reduction of AgNO₃ using oxidized carboxymethyl cellulose (OCMC). Nanosilver is confined inside the OCMC gel system. The oxidized carboxymethyl cellulose (OCMC) polymer chain stabilizes nanoparticles in addition to the reduction process. The potent antibacterial property of the silver nanogels effectively eliminated Gram-positive as well as Gram-negative bacteria. The produced Nanogels destroyed the bacterial cell wall & generated ROS within the cell, resulting in bacterial cell death.⁷³

Hydrogels made from cellulose have widespread use in various applications such as biosensors, heavy metal adsorbers, wastewater treatment dyes, and more.⁷⁵ The hydrogels derived from cellulose and its related substances showcase benefits in structure and morphology, such as pore diameters and swelling ratio increment, owing to the repellent effects of intramolecular carboxyl groups.⁸⁵ For instance, novel hydrogels made from carboxymethyl cellulose that were physically cross-linked using phytic acid (an uncommon crosslinking agent) showed antibacterial activity.⁸⁶

3.5 Gelatin

Gelatin refers to a protein that is produced by hydrolyzing collagen in a regulated, partial, and irreversible manner. The collagen comes from animal tissues (such as bone, skin, & cartilage)—typically from fish, bovine or pigs. Two varieties of gelatin are often produced, notably type A (by acid hydrolysis) & type B (by alkaline hydrolysis), based on the method employed as well as the types of animals.⁷⁵ Gelatin is composed of peptide sequences and is soluble in water (warm). It retains the ability to form basic gel structures through hydrophobic crosslinking at cold temperatures. Due to its distinct physical and chemical properties, gelatin is a biocompatible and non-immunogenic protein that is used as a medication and cell carrier. Gelatin can only be applied at body temperature or higher because of its melting point, which is between 30 and 35 °C. Because of this restriction, it is typically chemically altered in a variety of creative ways, such as by further crosslinking procedures.^87,88 Hydrogels based on gelatin are soluble in water, non-immunogenic and non-toxic substances. They were used for a variety of biomedical applications, including cell encapsulation, bone repair,⁸⁹ nerve regeneration,⁹⁰ 3D bioprinting⁹¹ and wound healing due to their remarkable biodegradability and biological compatibility properties.^92,93 Gelatin's availability and wide range of commercial applications have made it an important component for the formation of nanogels, for example fish gelatin methacryloyl (GelMA)-based nanogels were created using a water-in-oil nanoemulsion.⁷³ The main drawbacks of hydrogels based on a gelatin are their low melting point and weak mechanical strength.⁷⁵

3.6 Collagen

Collagen is an extracellular structural protein that occurs primarily in mammalian connective tissues and essentially gives the body its mechanical strength. Fibroblast cells are the primary producers of collagen, which is mostly found in tendons, skin and ligaments. The triple-helix structure of collagen contains hydrogen bonds, which give it extraordinary tensile strength. Its cationic flexible polymer structure is made up mostly of peptide sequences that are hydrophobic. Collagen finds widespread application in various areas of delivering drugs, tissue engineering, biomedical engineering, and nowadays it is used as a carrier for nucleic acids, proteins, and genes. In cell cultures and biomedical research, collagen serves as one of the most widely utilized biopolymers. The primary benefits of collagen include its strong cell adhesion substrate, low immunogenicity and chemostatic properties. The limitations of collagen's use can be seen in its drawbacks, which include a significant shrinkage, rapid rate of disintegration, poor mechanical strength, and opacity. Collagen's use can be increased by modifying it.^73,75Table 2 summarizes the characteristics of different biopolymers.

Table 2 Comparison of characteristics among different biopolymers

Biopolymer	Source	Characteristics	Application	Ref.
Chitosan	Fungi, crustaceans, etc.	Polysaccharide, moderate mechanical strength	Wound dressings, drug delivery	55 and 94
Hyaluronic acid	Animal connective tissue	Polysaccharide, excellent mechanical properties	Biomedical field and cosmetic field	95
Alginate	Brown algae and some bacterial species	Polysaccharide, outstanding mechanical qualities	wound dressings, agricultural industry (seed coating)	96 and 97
Cellulose	Plant, microorganisms, marine life	Polysaccharide, good mechanical properties	Drug delivery, packaging, textiles	94 and 98
Gelatin	Animal tissues (collagen)	Protein, weak mechanical qualities	Tissue engineering, 3D bioprinting	99–101
Collagen	Animal (mammalian connective tissues)	Protein, extraordinary mechanical strength	Biomedical research, cell culture, gene carrier	99 and 102

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4. Classification of smart biopolymers

The last two decades have seen a sharp increase in the application of functional polymers. These polymers react to variations in pH, electric or magnetic fields, temperature and other factors in a desirable manner (Fig. 3).¹⁰³ The literature extensively documents the methods by which these stimuli induce structural modifications in the polymer chain and subsequently modulate drug release.¹¹ External stimuli are generated using various stimuli generating devices, while internal stimulus is created inside the body to regulate the structural modifications in the polymer network and achieve the required medication release.¹⁰⁴Table 3 highlights the various hydrogel types, their responses to various stimuli, and possible uses in the biomedical industry.

Fig. 3 Stimuli responsive swelling of the hydrogel.

Table 3 Different hydrogel types, their responses to various stimuli, and possible uses

Gel type	Stimulus	Application	Ref.
pH responsive	Acid or base environment	Delivery of drugs. Delivery of cells.	105 and 106
Thermo-responsive	Heating or cooling, possible electromagnetic waves, including infrared.	Tissue engineering, drug administration, wound care, and imaging methods.	107 and 108
Electro-responsive	Electrical	Regulated release of drugs	109
Light-responsive	Electromagnetic waves	Regulation of biological materials, biosensors, and stimulating factors	110
Ultrasound responsive	Sound or US	Imaging, drug delivery and cancer therapy	111
Glucose-responsive	Glucose	Insulin release, blood glucose monitoring,	112
Enzyme responsive	Enzyme	Delivery of drugs	113

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4.1 pH responsive biopolymers

The ability of naturally occurring polymers to respond smartly to pH variations has been widely researched. Because of the variations in pH that might occur naturally or as a result of physiological or pathological conditions in the body, pH-responsive materials have become particularly interesting.¹¹⁴ For example, variations in pH are seen in several physiological locations, including the gastrointestinal system, vagina, and blood arteries. These variations may provide as a good foundation for medication release that responds to changes in pH.¹³ Since tumor tissues have been found to have a significantly more acidic environment (pH range of 5–6) than healthy tissues (pH 7.4), pH-sensitive hydrogels are also being considered in the treatment of cancer targeting.

Any polymer that is pH-sensitive must possess an ionizable basic or acidic functional group that reacts when the pH of the surrounding environment changes.¹⁰⁵ Since these polymers have basic groups (amino salts) or acidic groups (carboxylic or sulphonic) in their structure, they may accept or release protons in reaction to pH variations.¹⁰⁷ Depending on their degree of (de)protonation, these polymers respond to pH changes by self-assembling into vesicles, micelles, gels, unimers, swelling/deswelling phenomena, etc.¹¹⁵ Examples of pH-sensitive biopolymers are gum-tragacanth, chitosan, dextran, hyaluronic acid, alginate & xanthan (Table 4).^116,117

Table 4 pH-sensitive biopolymers along with their advantages

Biopolymer	Source	Ionic nature	Advantages	Ref.
Chitosan	Exoskeleton of fungi	Cationic	Minimal levels of toxicity, biologically active, biodegradability, hemostatic action, and mucoadhesive properties.	55, 118 and 119
Alginate	Brown seaweeds	Anionic	Produces a gel with varying swelling properties when divalent cations like Ca^2+, Ba^2+, Sr^2+, and Zn^2+ are present.	120–122
Hyaluronic acid	Connective tissue, skin and synovial fluid.	Anionic	Non-toxic, biodegradable, non-immunogenic and biocompatible.	123 and 124
Gelatin	Animal tissues	Cationic	Water soluble, non-toxic, cell adhesion capacity, low immunogenic.	125 and 126

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Polymers having basic functional groups are called polycations, and those with acidic functional groups are called polyanions. When the pH of the medium is higher than the pK_a, polyanions exhibit an enlarged state; when the pH is less than pK_a, they disintegrate. Similarly, for a polybase, polymer chain disintegration takes place when pH > pK_b; as a result, they expand when pH < pK_b. Chitosan (cationic polymer) expands in pH environments below pK_b because of the protonation of the amine or imine functional groups. Sodium alginate (anionic polymer) expands in a basic environment due to the ionization of the acidic functional group. Fig. 4 shows a schematic representation of the pH-responsive hydrogel's drug delivery mechanism.

Fig. 4 Schematic illustration of the drug delivery mechanism of pH-sensitive hydrogels.

4.2 Thermo-sensitive biopolymers

The thermo-sensitive smart polymers adjust their microstructural characteristics in reaction to temperature changes. These polymers are the most researched, widely utilized, and safest in biomaterials and drug delivery systems.^127,128 Hydrogels make up the majority of thermo-responsive biopolymers; in these materials, changes in external temperature can control the gelation, swelling, & water affinity.¹²⁹ The two primary categories of these hydrogels are as follows: (1) hydrogels with an upper critical solution temperature (UCST) and (2) hydrogels with a lower critical solution temperature (LCST). The primary constituents of UCST hydrogels are hydrophilic groups, and as the temperature rises, so does their capacity to expand into an appropriate solvent. Below a certain temperature, called the critical temperature, the polymer matrix contracts & collapses (Fig. 5a). Consequently, at temperatures under the UCST, they're in a gel form. Gelatin and agarose are examples of natural polymers in this category.^129–131

Fig. 5 Thermo-sensitive gels: sol–gel transition occurs in UCST hydrogels whenever the temperature drops; sol–gel transition occurs in LCST hydrogels whenever the temperature increases. The phase separation border is shown by the black lines.

The LCST type of hydrogels, on the other hand, also experience temperature-dependent sol–gel transitions and are made up of hydrophobic as well as hydrophilic groups. The gel turns into a very viscous liquid as the temperature drops beyond the LCST (Fig. 5b). Certain cellulose derivatives are typical examples of biopolymers that show LCST.^129–134 The most commonly used polymers in drug delivery systems are those with LCST. In order to treat an injury or subcutaneous layer, the polymer may be merged with therapeutic agents like medicines, proteins, or cells and injected into the body. As a result, a gel depot develops at the injection site when the temperature is raised.¹³⁵ Human C-peptide mixed with a biopolymer resembling elastin may be injected subcutaneously to form a hydrogel depot, which would enable the release of human C-protein into the circulation gradually over a 19-day period, according to the study by Lee et al.¹³² In order to produce a hybrid scaffold, Dong et al.¹³⁶ created an injectable thermo-responsive chitosan hydrogel and integrated it into a 3D-printed poly(ε-caprolactone). The resulting materials retained their long-lasting compressive strength & offered a favorable microenvironment beneficial for osteogenesis & cell proliferation. Xiao et al.¹³⁷ created a biodegradable hydrogel using thermoresponsive PNIPAAm, cleavable lactic acid, & dextran groups. In order to create hydrogels, Merten et al.¹³⁵ modified xyloglucan polymers & reported that this might modify the polymer's LCST by eliminating galactose, which would increase its hydrophobicity.

Temperature-responsive polymeric systems have the following benefits: they can deliver both lipophilic & hydrophilic drugs; they can target particular sites for drug delivery; they help in avoiding the use of hazardous organic solvents; and they have sustained release qualities with fewer adverse effects. However, they also have a number of drawbacks, including rapid drug release, a polymeric system that is not biocompatible, and an abrupt decrease in pH as a result of acidic degradation.^134,138Table 5 summarizes common thermo-sensitive biopolymers employed in medical applications.

Table 5 Typical thermo-sensitive biopolymers and their medical uses

Biopolymer	Hydrogel type	Characteristics	Application	Ref.
Collagen	UCST	It is non-toxic, biodegradable, and cytocompatible.	Drug administration wound healing tissue engineering	114 and 139
Gelatin	UCST	Biodegradable, biocompatible, less expensive and easy functionalization.	Tissue engineering bio-sensing drug delivery wound healing	114, 139 and 140
Cellulose	—	Easily accessible, mild cytotoxic, biodegradable, & biocompatible.	Drug delivery	139
Agarose	UCST	Biocompatible, biodegradable, non-toxic.	Drug administration, tissue engineering.	141

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4.3 Stimuli-responsive biopolymers

4.3.1 Light responsive biopolymers. When exposed to a certain wavelength, light-responsive gels can alter their characteristics. These changes, which might involve the gel expanding or contracting, are usually accomplished making use of chromophores, which are light-sensitive functional groups.¹¹⁰ The capacity of light responsive polymers to regulate the release timing and location makes them very desirable for inducing drug release.¹⁰³ Light sensitive polymers can be ultraviolet or visible light sensitive. However, as visible light-responsive polymers are safe, affordable, widely accessible and clean, they are more advantageous.¹⁰⁷ Light-responsive drug carriers are made of polymers containing various photo-sensitizers, including triphenylmethane, stilbene, & azobenzene.

Light-sensitive hydrogels are synthesized by adding photosensitive groups to the polymeric structure. The response might be either reversible or irreversible depending on the nature of the photosensitizer used.¹⁴² In addition to causing partial or total decrosslinking, degradation, swelling, and/or shrinking of the hydrogel structure, light can also cause photosensitive moieties of the hydrogels to cleave, isomerize, or dimerize.¹⁴³ Three main types of light-responsive drug delivery systems are: drug release platforms based on photoisomerization, photochemical reactions, and photothermal reactions. When hydrogels are exposed to light, photoisomerization usually results in a conformational shift from trans to cis. Drugs can diffuse out of hydrogels' matrixes during this period due to the opening of the pores of the hydrogels.¹⁴⁴ Drug release can be induced via photochemical reactions that alter the hydrogel's network structure & configuration.¹⁴⁵ By using materials that can transform light energy into heat energy, the photothermal reaction causes a disruption in a drug carrier that is sensitive to heat.^146,147 Anugrah et al.'s¹⁴⁶ NIR-sensitive polymer hydrogel, which is made of alginate cross-linked with tetrazine through the Diels–Alder process, serves as a regulated drug carrier. To the polymer hydrogel matrix, doxorubicin and an NIR-responsive indocyanine green were introduced by gelation. The resulting hydrogels showed a fast release pattern for doxorubicin upon NIR irradiation & a regulated release pattern under physiologically simulated settings.

4.3.2 Electro-responsive biopolymers. Electrically sensitive polymers are those that alter their physical characteristics in reaction to slight variations in electric current. Electro-responsive hydrogels (ERH) have the ability to expand or contract in reaction to an electric current.¹⁴⁸ These polymers are widely used in the fields of controlled drug administration, artificial muscle actuations, energy transductions, & sound attenuation. They convert electric energy into mechanical energy. The backbone structure of these polymers has a comparatively high proportion of ionizable groups.¹⁰³ Most of the time, polymers that are electro-responsive also show pH responsiveness. The hydrogel shrinks and swells locally at the anode and cathode when it is subjected to electric fields because opposing ions & immobile charged groups are created in the polymer network. This results in bending of the hydrogel, the degree of which relies on the hydrogel's structure, the strength & direction of the applied electric field, and the duration of the application.^109,149 This bending ends with the release of a drug. Polyaniline, polypyrrole, sulfonated styrene, polythiophene, and PVA are examples of synthetic electrically conductive polymers, whereas chitosan, alginate, and hyaluronic acid are examples of biopolymers.¹⁵⁰ Smart muscle-based devices that are biocompatible and electro-sensitive have been developed using hydrogels containing derivatives of acrylamide & carboxylic acid.¹⁵¹ An important factor in this kind of drug delivery technique is the deliberate choice of an electric current that can release the medicine without stimulating the nerve endings in the surrounding tissue.¹⁵² Technologies like infusion pumps, iontophoresis, & sonophoresis are examples of electrically regulated delivery systems.¹⁵³

4.3.3 Magnetic-responsive biopolymers. Magnetic micro- & nanoparticles are drawn to an external source of magnetic field, which is the basic idea of magnetic targeting. Several factors need to be considered while building a magnetic-responsive delivery system, like magnetic properties of the carrier particles, field strength, & field geometry. According to the principle, the particle/drug combination will experience a translational force when there is a magnetic field gradient. This pushes the complex in the direction of the magnet by successfully trapping it in the field at the desired location.^154,155 The magnetic-sensitive systems are composed of magnetic cores that incorporate Fe₂O₃ or Fe₃O₄, exhibiting considerable magnetic responsiveness to external magnetic fields.^156–158

Three common synthesis methods—grafting, blending, and co-precipitation or embedding—are used to create magnetic-sensitive hydrogels. Magnetic nanoparticles vibrate and the temperature rises in the presence of an alternating magnetic field (AMF). This accelerates the drug's particle motion and the polymer's breakdown, which facilitates drug release.¹⁵⁹ Moreover, the magnetic-sensitive hydrogel experiences a magnetocaloric effect when exposed to a magnetic field, which might cause alteration in the diffraction peaks & the hydrogel's discolouration.¹⁶⁰ Zhang and colleagues synthesised hydrogels by mixing PEG and hyaluronic acid, then adding type II collagen and magnetic nanoparticles to the gel. This hydrogel might move to the sites of tissue defects in physiological fluids under magnetic direction by reacting to an applied magnetic field.¹⁶¹ Emulsion polymerization techniques may be used to trap harmless, biocompatible iron oxide nanoparticles in nanogels, which makes them suitable for the delivery of pharmaceuticals. Magnetic-sensitive nanogels allow for remote management of the medication distribution.^162,163 In order to achieve multiresponsive characteristics, using Fe₃O₄ nanosystems modified with oleic acid, Li et al. polymerized NIPAM and chitosan. These magnetically sensitive chitosan-based devices might potentially guide the delivery of medication via magnetic means.¹⁶⁴ In a nutshell, minimal invasiveness, excellent tissue permeability, quick reaction, and outstanding controllability are some benefits of these hydrogels. However, there are certain drawbacks as well, including limited mechanical strength, material toxicity, & poor biocompatibility.^165,166

4.3.4 Bio-responsive biopolymers. Since bioresponsive hydrogels may change their structural composition in reaction to a particular biomolecule, like glucose, proteins, nucleic acids, or polypeptides, these hydrogels have attained a lot of interest recently.¹⁶⁷ One of the major issues in materials science & modern medicine is the fabrication of materials allowing diabetic patients to self-monitor their blood glucose levels in order to control their blood sugar levels.¹⁶⁸ In the discipline of drug administration, glucose-responsive hydrogels (GRHs) have garnered a lot of interest as a means of combating diabetes-induced chronic inflammation.^168,169 When glucose diffuses into the membrane and changes into gluconic acid, it is the primary mechanism by which GRHs release their contents. Insulin is released as a result of this action, which also lowers the hydrogel's pH and induces swelling.¹⁷⁰

Another class of bioresponsive hydrogels is enzyme-responsive hydrogels. They may be utilized to create hydrogels that respond to enzymes and serve as a natural trigger.^171,172 An enzyme-catalyzed reaction is one of the most widely used processes to generate enzyme-responsive hydrogels.¹⁷² These systems differ from conventional catalyzed or noncatalyzed chemical processes due to their great selectivity along with enzyme specificity. Because of these exceptional properties, these hydrogels may be employed as extremely beneficial systems for tumor tissue-targeted administration & site-specific triggered release, which are strenuous to accomplish with standard stimuli polymers that are sensitive to light, pH, or temperature.^173–175 The extremely selective and precise association of an antibody with its antigen results in an antigen-responsive hydrogel.¹⁶⁷ The non-covalent interaction between the antigen and the antibody causes certain kinds of hydrogels to crosslink reversibly. Antigens present in the surrounding environment that are free of charge might compete with the hydrogel's antigens (Fig. 6). As a result, the contact between the antibody & antigen becomes weaker and the hydrogel's crosslinking density is decreased, leading to swelling or osmosis.¹⁷⁶ These responsive materials have practical applications in the fields of clinical diagnostics, remote-regulated vaccination depots, and drug administration.¹⁶⁷

Fig. 6 Diagram demonstrating the hydrogels that respond to antigens. The hydrogel swells as a result of the unbound antigens present in the surroundings competing with the hydrogel's binding antigens to reduce crosslinking density.¹⁵⁹

4.3.5 Ultrasound-responsive biopolymers. Using ultrasonic waves to target the hydrogel matrix or polymers directly is one of the innovative methods for using ultrasound in drug delivery.¹⁷⁷ For a long time, researchers have devoted a great deal of interest on ultrasound-responsive polymeric materials. These intelligent materials are more suitable than other stimuli-responsive materials since they allow more effective medication administration & targeted therapy using largely non-invasive techniques.¹⁷⁸ The production of heat energy, disruption of cell membranes due to micro-convection or inertia cavitation, & increased blood capillary permeability are the primary biological mechanisms of ultrasonic activity.¹⁷⁹ This drug delivery system may be utilized for carrying a variety of drugs, including tiny drug molecules, proteins,¹⁸⁰ & DNA.¹⁸¹ A cross-linked hydrogel that may self-heal and release medication when stimulated by ultrasound was described by Mooney et al.¹¹¹ These hydrogels were created by cross-linking alginate with Ca²⁺ ions. It has been demonstrated that ultrasound permits the release of drugs without impairing the structure of the hydrogel.

5. Significance of biopolymer gels as theranostic systems

A noteworthy development in the world of medical technology is theranostic gels. They are a particular kind of hydrogel that integrates diagnostic and therapeutic features into one unit. These gels have the capacity to give real-time monitoring or imaging of the treatment's success in addition to delivering therapeutic chemicals to specific areas within the body. So theranostic agents are nanoparticles that can function as both a diagnostic and a therapeutic agent on the same platform.¹⁸² The following favorable attributes of this system are well known: (a) thermo-sensitivity; (b) injectability, because of a reversible sol-to-gel phase transition at or near body temperature; (c) localizability through quick gelation; (d) extremely low cytotoxicity of dissolved elements; (e) biodegradability with adjustable biodegradation periods; and (f) sustainability and long-term drug release.¹⁸³ These kinds of small-sized molecules have a number of disadvantages, including inadequate blood circulation times, cytotoxicity, poor biodistribution, etc. It is crucial to use nanotechnology and create novel approaches for concurrent diagnosis as well as treatment systems because of this.¹⁸⁴

An interesting advancement in biomedicine, theranostic gels have important ramifications for diagnosis and treatment. Since a single nanocarrier can combine both therapeutic and imaging modalities, the field of theranostics has drawn a lot of attention as combined therapy and diagnosis,¹⁸⁵ creating methods based on precision medicine to increase the effectiveness of cancer,^186,187 targeted delivery,^188,189 responsive properties (like stimuli of pH change, temperature or light),^190,191 imagining compatibilities,^192,193etc.

5.1 Integration of diagnostics and theranostics

This exciting field of study, which focuses on the fusion of therapeutic drug delivery vehicles with diagnostic detecting agents, has given rise to the word theranostics.¹⁹⁴ In order to improve results, theranostics fundamentally combines diagnostic and therapeutic methods that are linked to the same exact molecular targets. This allows for more precise patient selection, treatment response & tissue toxicity prediction, and response evaluation.¹⁹⁵ Theranostics and diagnostics combined constitute a major breakthrough in customized medicine. The process of diagnosing includes determining whether an illness or condition exists using a variety of tests, imaging methods, or other strategies. The goal of traditional diagnostics is to identify the ailment or condition that a patient has and theranostics combines medicine and diagnostics. In addition to providing a diagnosis, theranostics also advises on the best course of action for a given patient based on their individual biology. It entails adjusting the course of treatment to the unique features of each patient's illness. The materials used to create theranostic gels are usually those that have the ability to encapsulate medications or imaging agents and react to external stimuli to release them in a controlled manner. Both chemical and biological medications (i.e., proteins and peptides) are considered therapeutic agents, while radionuclides, heavy elements like iodine, superparamagnetic iron oxides, fluorescent dyes or quantum dots, etc. are frequently used as diagnostic agents^196,197 and the polymers used are both natural and synthetic like poly(N-isopropylacrylamide),¹⁹⁸ PAA–PEG poly(aspartic acid)–poly(ethylene glycol); polyglutamic acid; HPMA N-(2-hydroxypropyl) methacrylamide; PLA–PEG poly(lactic acid)–poly(ethylene glycol); PLGA–PEG poly(lactic-co-glycolic acid)–poly(ethylene glycol); and PAMAM poly(amido amine).¹⁹⁹

5.2 Biomedical applications of theranostic biopolymer gels

5.2.1 Cancer treatment. Localized cancer therapy may be achieved by the use of theranostic gels. By adding imaging agents into the gel, they can simultaneously monitor the patient's response to treatment and deliver anti-cancer medications to targeted locations. This makes it possible to track the growth or regression of tumors in real time.^{184,186,200,201}

5.2.2 Wound healing. Theranostic gels can be applied as bandages for wounds. They can provide real-time monitoring of the healing process, infection status, and tissue regeneration in addition to delivering therapeutic medicines like growth factors or antibacterial agents to aid in the healing process; for example, in one case antimicrobial peptide ε-polylysine (ePL) and polydopamine (PDA) nanoparticles were used to create injectable theranostic hydrogels that might be used for on-demand bacterial debris removal, imaging-guided antibacterial photodynamic treatment (PDT), and real-time wound diagnostics.^202,203

5.2.3 Drug delivery systems. By providing controlled release of therapeutic agents and permitting real-time monitoring of drug distribution and pharmacokinetics, theranostic gels can improve the efficacy and safety of drug delivery systems. This is especially helpful for diseases like diabetes or chronic pain management, when precise medication dosage is essential.²⁰⁴

5.2.4 Regenerative medicine. Theranostic gels can be used in tissue engineering & regenerative medicine to administer scaffolds, growth factors, or stem cells to encourage tissue regeneration while enabling non-invasive monitoring of tissue integration and functionality; for example, theranostic gels' functions in repairing heart tissue, urethral muscle tissue, arteries, regenerative corneal implants, etc.^205,206

5.2.5 Neural interface technologies. Theranostic gels have the potential to be utilized as neural interfaces in neuroscience to observe and regulate brain activity. They enable the simultaneous imaging of neural activity and the delivery of neuroactive medications or therapeutic substances to certain brain areas.²⁰⁷

5.2.6 Dental applications. During dental operations, theranostic gels can be used to treat periodontal disorders, promote tissue regeneration, and provide antimicrobial medicines to cure or prevent oral infections. Evaluating patient outcomes and treatment efficacy can be made easier with real-time monitoring.²⁰⁸

6. Applications of smart biopolymer gels

Considering their unique patterns and their capacity to be used and function in a variety of situations, polymer hydrogels have many uses. Polymer hydrogels' water content makes them sufficiently versatile for use in a wide range of biological, pharmacological, & industrial applications.²⁰⁹ The various applications of smart hydrogels are depicted in Fig. 7.

Fig. 7 Applications of smart hydrogels.

6.1 Drug delivery

Owing of the observed regulated or pulsatile drug release pattern, which resembles biological demand, the use of intelligent polymers for drug delivery holds immense promise.²¹⁰ Polymer hydrogels must possess the following characteristics in order to be used as drug delivery systems: (i) a porous structure,²¹¹ (ii) a sufficient release rate,²¹² (iii) the capacity to safeguard the drug,²¹² & (iv) be biodegradable & biocompatible.^11,213,214 Polymeric compounds are generally a great option for application as a medication delivery agent. On the other hand, bio-polymers along with their derivatives demonstrate superior characteristics, including water solubility, non-hazardous, biodegradability, & biocompatibility.^215,216 Additionally, with regulated drug release, these biopolymers can lessen drug toxicity. Furthermore, they lessen any enzymatic breakdown prior to a therapeutic substance being released at the target areas. Many stimuli, including physical, chemical, environmental, or a combination of many stimuli, can cause the release of a therapeutic drug.²¹⁷

Biodegradable hybrid hydrogels were created using chitosan, a natural polymer, & polyurethane, a synthetic polymer containing azomethine, for the regulated release of medications such as 5-fluorouracil. These hydrogels demonstrated favorable drug release characteristics of 50% 5-fluorouracil, indicating their suitability for this usage.²¹⁸ Hydrogels based on guar chitosan di-aldehyde that were cross-linked in situ for double drug release were created for use in colorectal cancer treatment. These were intended to treat colorectal cancer while simultaneously providing chemotherapy and pain relief.²¹⁹

6.2 Wound repair

There are four steps in the healing process of wounds (Fig. 8).²²⁰ An excellent wound dressing needs a few characteristics in order to function well and be effective: (a) to shield the wound against microbial infection; (b) to have biocompatibility; (c) to possess the ability to retain moisture; (d) to possess gas permeability; and (e) to supply a moist atmosphere in order to lessen the development of scars.²²¹ By virtue of their outstanding hydrophilicity, biological compatibility, and 3D porous frameworks that mimic the extracellular matrix, hydrogels have specific advantages in wound healing.²²²

Fig. 8 Figure illustrating the phases involved in healing of a wound.

Stimulus-sensitive hydrogels, which are created depending on changes in surface pH & temperature, can significantly speed up wound healing. Temperature and pH are significant physicochemical parameters in the human body. Aiming to produce a highly ROS-responsive hydrogel, Hu et al.²²³ added boronic acid moieties upon alginate polymer chains, resulting in a smart injectable hydrogel exhibiting self-healing capabilities. The hydrogel became both antibacterial along with anti-inflammatory when micelles of the antibiotic amikacin & the anti-inflammatory drug naphthalene propylamine were assembled into it at the same time. In addition to retaining the hydrogels' outstanding rheological qualities & structural integrity, this formulation allowed for controlled medication release at inflammatory areas, which successfully aided in wound healing. A wound dressing based on dynamic imine bonding was created by Ding et al. using collagen, chitosan, & di-aldehyde terminated PEG.²²⁴ The resulting hydrogels have demonstrated excellent injectability, remarkable hemostatic capacity, antibacterial activity, thermal stability, & healing potential. Yu et al.²²⁵ created an injectable hydrogel consisting of carboxymethyl chitosan, γ-polyglutamic acid, & polydopamine hydrogel, intended for antimicrobial purposes and preventing tumor recurrence. This hydrogel demonstrated an excellent biocompatibility.

6.3 Tissue engineering

Tissue engineering is another field where smart biopolymers have been utilized. In order to heal organs & tissues injured by illness or trauma, tissue engineering has emerged as an emerging area. It works to repair or regenerate wounded or diseased biological tissue or produce replacement organs for a variety of illnesses, including diabetes, heart disease, cirrhosis, osteoarthritis & spinal cord injury.²²⁶ The method of creating a scaffold structure with the correct mechanical, chemical, & physical characteristics to allow for cell penetration & three-dimensional tissue growth is the essence of tissue engineering. The primary goal is the development of new tissue within the scaffold to merge with the tissue of the host. Conversely, the scaffold acts as a transient route for regeneration & will disintegrate either during or after healing, obviating the necessity for eliminating the material later and eradicating possible adverse effects linked to the body's retention of materials.²¹⁰ In the area of tissue engineering, thermoresponsive polymers are frequently utilized in two situations: first, as substrates that support cell growth and proliferation and second, as injectable gels for in situ scaffolding.²¹⁰ Owing to hydrogels special qualities—such as hydrophilicity, transparency, adjustable mechanical strength, and biocompatibility—hydrogels are becoming essential materials in corneal tissue engineering. Because of these properties, hydrogels can be used to simulate the corneal environment and promote tissue healing. Negin Khoshnood et al. show how hydrogels that can be customized for certain ocular medication delivery applications can be made via 3D bioprinting. The use of betamethasone-loaded gellan gum (GG) and polyethyleneimine (PEI) composite hydrogel shows how sophisticated production techniques might improve hydrogels' performance in corneal applications. Furthermore, the hydrogel demonstrated appropriate mechanical strength, transparency (80%), and rates of deterioration, indicating its potential as a corneal repair material.²²⁷ Hydrogels—more especially, polyethyleneglycol (PEG)-cyclodextrin polyrotaxane microgels—are used in ocular tissue engineering because of their moldable and injectable qualities, which promote corneal tissue regeneration and increase the efficiency of tissue engineering techniques.²²⁸ As scaffolds, eye drops and films, hydrogels derived from protein-polysaccharide bio materials are used in corneal tissue engineering. Their promotion of ocular permeability, cell adhesion, and proliferation helps heal corneal lesions and associated conditions.²²⁹ Therapeutic hydrogels improve tissue repair by acting as vehicles for therapeutic genes that surpass cellular barriers. Because of its slow-release nature, gene therapy in tissue engineering is more effective.²³⁰ Injectable hydrogels in cardiac tissue engineering give cardiomyocytes and stem cells a supporting matrix, which is essential for healing injured heart muscle. They facilitate the repair of cardiac wall stress and preserve cell viability.²³¹

6.4 Cancer treatment

Currently, surgery, radiation, chemotherapy, immunotherapy, & targeted molecular therapy are used to treat cancer at different stages.²³² Owing to the adverse effects linked to the high cytotoxicity of chemotherapy drugs, there has been considerable interest in the development and production of novel, efficient cancer treatment methods. Polymer hydrogels are the most suitable drug delivery mechanism for cancer therapy among a wide range of different formulations, such as films, suspensions, etc. Hydrogels that are sensitive to pH, temperature, & ions are effective drug release systems.²³³ Thermo-sensitive hydrogel systems have been proven to be effective as they alter states at various temperatures to aid in the loading & releasing of cancer medications.²³⁴ Hydrogel loaded with chitosan/disulfiram that released the anticancer medication disulfiram is a good example of a thermo-sensitive hydrogel. Compared to the disulfiram drug alone, this system exhibited more cellular uptake and sustained administration, which may aid in cancer therapy.²³⁵ A hybrid, injectable, thermo-responsive hydrogel was created by Gao et al.²³⁶ for concurrent administration of doxorubicin & co-encapsulated norcantharidin NPs to patients with hepatocellular carcinoma through intratumoral injection. Tumor growth along with angiogenesis were suppressed during in vivo testing using a mice tumor model.

6.5 Antimicrobial applications

Current medical care relies on antimicrobial medications, such as antibiotics, to prevent infections since they can either work to kill or stop the development of pathogens. The emergence of multiresistant microorganisms in chronic non-healing wounds sometimes renders antibiotic therapy completely useless in eliminating infections.^237,238 Gupta et al.²³⁹ generated Ag nanoparticles encapsulated in a bio-synthetic bacterial cellulose hydrogel in order to create a wound hydrogel dressing. The acquired hydrogel dressing exhibited a wide range of antibacterial effects towards three pathogenic microorganisms that are commonly found in wounds: Staphylococcus aureus, Candida auris, & Pseudomonas aeruginosa. Vaishali et al.²⁴⁰ created a chitosan hydrogel system in which the antimicrobial drug cefuroxime was covalently conjugated with chitosan polymers through ester bonds, giving the hydrogel matrix a long-lasting antibiotic action at localized areas. The obtained hydrogels demonstrated strong cell & hemocompatibility, which may increase the options for treating wound infections.

6.6 Bio-sensing applications

Bio-sensing is an emerging analytical discipline for the detection of biological markers by employing transducing systems.²⁴¹ Polymer hydrogel-based biosensors have drawn a lot of interest recently because of their high sensitivity, simplicity of fabrication, and versatility in a variety of domains (drug detection, disease diagnosis, and environmental contamination detection). Because of their similarity to biological tissue & biocompatibility, they are used in the biomedical field.²⁴² For electrochemical bio-sensing, it has been reported that hydrogels in the shape of porous, cell-like films were created by merging nanoparticles of Prussian blue & several enzymes on electrode surfaces. They were created by drop casting composite hydrogels onto the surface of SPE-type screen printed flexible electrodes. The two amperometric bio-sensors that were created using hydrogel composites that included alcohol dehydrogenase & glucose oxidase demonstrated excellent sensitivity for the quick detection of ethanol & glucose in serum. Hydrogels have the potential to serve as electrochemical bio-sensing systems since their matrix may effectively immobilize certain enzymes & nanomaterials for the identification of an array of analytes.²⁴³ A novel, extremely sensitive, and affordable DNA hydrogel sensor has been developed by Wang et al. for the quantitative visual detection of miRNAs, with possible applications in the bio-sensing of nucleic acids.²⁴⁴

7. Conclusion and future perspectives

Research on bio-responsive polymers has grown rapidly in recent decades and has a major impact on materials science, molecular pharmaceutics, and nanobiotechnology. The majority of stimulus-responsive systems are engineered for controlled delivery of drugs in order to accomplish programmed release and overcome the drawbacks of systemic drug administration, and new materials for tissue engineering and diagnostics are receiving more and more attention.²⁴⁵ This review addresses the vast array of beneficial natural polymers that are utilized to create various smart biopolymer gel formulations that entrap active ingredients and are intended for use in biological applications. The most prominent characteristics, such as biocompatibility & biodegradability, allow their use in biological, biomedical, & pharmaceutical applications. It's also imperative to conduct more research on the identification & development of novel biopolymers. In the realm of drug delivery, smart biopolymer gels represent an important breakthrough. Biopolymers can be employed to synthesize hydrogels for specific benefits & unique characteristics. Biopolymer gels sensitive to external stimuli (pH, temperature, ultrasound, enzymes, etc.) are currently used for targeted drug delivery, which has proved to be important in the treatment of diseases like cancer, diabetes, brain injury, etc. To increase the response efficiency even more, bio-responsive systems that are triggered by several stimuli have been developed. By altering the physic-chemical properties of hydrogels, these systems can become very specific for targeted delivery of drugs. In addition to drug delivery and various applications, these hydrogels hold potential for the development of ultrasensitive fluorescent & electrically conductive variants, which can be utilized in wearable, implantable, and disposable biosensors for quantitative measurements. The theranostic use of these smart gels has drawn significant attention since it can allow precise treatment and drug delivery. With further developments in biomedical engineering, materials science, and imaging technologies, biopolymer gels have a promising future in theranostic applications. These developments might enhance imaging sensitivity and resolution, improve clinical application and regulatory concerns, and assist biopolymer gels in reaching their full potential in biocompatibility along with stability difficulties generally. Although theranostic uses of nanoparticles coated with biopolymers have been studied, further study is required to determine their long-term safety and toxicity.²⁴⁶ The present study on smart biopolymer gels has advanced significantly, but there are still several drawbacks, including limited mechanical strength, UV carcinogenesis, thermal denaturation, & material toxicity. Hydrogels exhibit fragility and present difficulties in the handling process during the loading of therapeutic agents. They often exhibit spatial heterogeneity as well as an inhomogeneous distribution of crosslink density. The mechanical characteristics of hydrogels are diminished by the unwanted spatial heterogeneities. Over time, hydrogels undergo hydrolytic and enzymatic biodegradation, and hydrogels composed of biopolymers are often biodegradable.^247,248 Numerous smart hydrogels have been created & introduced thus far, but their commercialization as drug delivery systems remains unconvincing; just a small number of them have been used in clinical settings.²⁴⁹ In fact, there are currently no precise legal guidelines or criteria for the application of smart drug-loaded hydrogels in therapeutic activities, even with recent developments in the pharmaceutical sector. Furthermore, before they are commercialized, the release characteristics must be modeled in order to make significant advances in in vivo release.²⁵⁰ Therefore, it is crucial to improve the features of these gels in order to ensure the safety as well as efficacy of these formulations. In a nutshell, biopolymers hold great promise for developing novel disease models, creating innovative formulations, and producing medical devices that are safe and effective for the general public.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

The authors acknowledge Department of Pharmaceutical Sciences, University of Kashmir for providing the necessary facilities to carry out this work.

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