A Review on: Smart Hydrogel Materials for Local Delivery Drugs

Hydrogels are the drug delivery systems containing cross connected, three-dimensional hydrophilic networks capable of swelling and resistant to dissolving when introduced in water or other biological fluid. Hydrogels can be manufactured in a range of physical forms such as micro particles, nanoparticles, slabs, coatings and films. Hydrogels can absorb high volumes of water or other biological fluids. They are three-dimensional, water-swollen polymeric matrices. They are a smart and ideal material for biomedical use due to their tendency to swell in physiological conditions.¹ The presence of physical or chemical crosslinks, i.e., crystalline and entanglements, makes hydrogels insoluble. These are capable of being prepared to respond to a variety of physiological stimuli present in the body, like temperature, ionic strength, and pH. The presence of hydrophilic functional groups such as -OH, -CONH, -CONH₂, and -SO₃H in polymers that create hydrogel networks is considered to be responsible for the ability of the polymers to absorb water. Depending on the constitution of the polymer and the nature of the aqueous medium, the polymer is therefore hydrated to different extents (frequently greater than 90% of weight) due to the contributions of different groups and domain in the network.²

Properties such as mechanical strength and intracellular and extracellular transport are determined by the chemical structure, shape, and equilibrium swelling of the hydrogel. Hydrogels are most attractive for a range of medical applications, e.g., tissue engineering, release of therapeutic agents (genes, proteins, and drugs), contact lenses, and wound dressings due to their soft nature, biocompatibility, low protein adsorption due to their low surface tension, and comparable to ECM structure.³

Advantages: ⁴

• Hydrogel is tougher and more elastic
• Hydrogel can be readily modified and possesses excellent transparency characteristics.
• They possess a level of flexibility very close to that of living tissue due to their high-water content.
• They can be injected and are biocompatible and biodegradable.
• Hydrogels are able to sense temperature, pH, or metabolite concentration changes and release their payload accordingly.
• Prompt release of nutrients or drugs.

Disadvantages: ⁴

• Costly price.
• Non-adherent; will possibly need supplementary dressing for safety; will also lead to sensation from maggot movement.
• Sterilization is difficult.
• Hypoxia, dehydration, and red eye reactions are less frequent in contact lens deposition.

Properties of hydrogel:

• Swelling properties: The charge and cross-link densities of the polymer network and the concentration of cross-linked polymers during gel formation control the equilibrium swelling extent and the elastic modulus of hydrogels. ⁵
• Mechanical properties: Depending upon the purpose to which the material is to be put, mechanical properties may shift and be tailored. The level of crosslinking can be increased or decreased by heating the material to obtain a gel of higher stiffness. Many factors and reasons are connected with the shifting of mechanical properties, and different analyses have to be carried out based on the material.
• Biocompatible characteristics: The ability of a material to perform in a specific application with an appropriate host response is referred to as biocompatibility. There are fundamentally two elements that constitute biocompatibility: (a) Bio-functionality, or the material's ability to perform the specific function for which it was created. (b) Bio-safety, comprising an appropriate host response that is both systemic and local (the tissue surrounding), the absence of cytotoxicity, and mutagenesis. ⁷

Classification of hydrogel based on the source:

1. Natural hydrogels: Due to their beneficial characteristics such as biocompatibility and biodegradability, natural hydrogels have been used profoundly for the culture and control of stem cells. ⁸ Mostly, they are derived from natural sources such as proteins such as collagen, gelatin, and fibrin, polysaccharides, seaweed, brown algae, and bacterial cultures. ⁹
2. Synthetic hydrogels: Because synthetic hydrogels are composed of man-made polymers, they are less inert compared to hydrogels that are made from biomaterials naturally occurring. ¹⁰ Synthetic hydrogels are easier to modify, have a longer storage life, and can absorb more water compared to natural ones ^11.
3. Hybrid hydrogels: Also referred to as nanocomposite hydrogels, these hydrogels consist of two or more different molecules based on a combination of synthetic and natural components. The physical, electrical, chemical, and biological abilities of a nanocomposite hydrogel can all be amplified by the structure and arrangement of its numerous molecules. ¹²

2. Categorization Hydrogel based on the composition of polymers:

1. Homopolymeric hydrogels: These are networks of polymers made from a single species of monomer, which is the fundamental structural component of all networks of polymers. The kind of monomer and the polymerization process determine whether homopolymers have a cross-linked skeleton.¹³
2. Copolymeric hydrogels: These consist of two or more disparate monomer species and one or more hydrophilic components. They are assembled randomly, in blocks, or alternately within the polymer network's chain. ¹⁴
3. Multipolymeric hydrogels: Also referred to as interpenetrating polymeric hydrogels (IPN), these are an important category of hydrogels that consist of two distinct, network-structured, cross-linked synthetic and/or natural polymer components. One of the components of semi-IPN hydrogel is a crosslinked polymer, and the other is a non-crosslinked polymer. ¹⁵

C. Classification based cross-linking type:

Hydrogels may be divided into two classes based on the physical or chemical nature of the cross-link junctions. Whereas physical networks possess transient junctions resulting from either polymer chain entanglements or physical interactions such as ionic, hydrogen, or hydrophobic contacts, chemically cross-linked networks possess permanent junctions. ¹⁶

D. Physical appearance-based classification:

The process of polymerization employed during the formulation is what makes hydrogels occur in the form of a matrix, film, or microsphere. Based on whether there is an electrical charge on the crosslinked chains or not, hydrogels may be classified into four categories:

a) Neutral (nonionic).

b) Ionic, which includes cationic and anionic materials.

c) An amphoteric (ampholytic) electrolyte bearing basic and acidic groups.

d) Zwitterionic (polybetaines): every structural repeating unit has both cationic and anionic groups.¹⁷

Fig.1 Classification of Hydrogel

Methods Preparation of Hydrogel:

Hydrophilic networks of polymers are referred to as hydrogels. Hydrophobic monomers and hydrophilic monomers are not generally used to produce hydrogels, though occasionally hydrophobic monomers can also be utilized. As a rule, both synthetic and natural polymers are employed to develop hydrogels. Synthetic polymers are more hydrophobic and chemically stronger compared to natural polymers. They only break down at a slow pace owing to mechanical strength, whereas strength is not solely dependent upon durability. Ideal design will strike a balance between these two opposing properties. Moreover, if the natural polymers possess suitable functional groups or are functionalized with radically polymerizable groups, the former can be utilized to build hydrogels based on such polymers. The details of the polymerization methods are explained below:

1. Bulk polymerization: The simplest method, bulk polymerization employs only monomers and initiators that are miscible in monomers. The concentration of the high monomer results in a high rate and extent of polymerization. However, the conversion results in a large increase in the viscosity of the reaction, which generates heat upon polymerization. Through control of the reaction at low conversions, such problems can be avoided. The synthesis of high molecular weight, highly pure polymers is the advantage of bulk polymerization. ¹⁸
2. Free radical polymerization: Acrylates, vinyl lactams, and amides are the main monomers used in this process to form hydrogels. These polymers are functionalized with radically polymerizable groups or possess suitable functional groups. The chemistry of typical free-radical polymerizations, such as the propagation, chain transfer, initiation, and termination processes, is applied in this process. Many thermal, ultraviolet, visible, and redox initiators can be employed to produce radicals in the initiation process. The radicals attack the monomers to convert them into active species. ¹⁹
3. Cross-linking or solution polymerization: In these, the multifunctional crosslinking agent is employed with neutral or ionic monomers. UV radiation or a redox initiator device is employed to thermally initiate the polymerization process. The solvent as a heat sink is the primary advantage of solution polymerization over bulk polymerization. For the removal of the initiator, soluble monomers, oligomers, cross-linking agent, extractable polymer, and other impurities, the resulting hydrogels are washed with distilled water. Solvents employed water–ethanol mixtures, water, ethanol, and benzyl alcohol.²⁰                             

Fig 2 Solution polymerization

4. Suspension polymerization:

The suspension polymerization method is employed to form spherical hydrogel micro-particles measuring between 1 μm to 1 mm in size. The method of suspension distributes the monomer solution within a non-solvent to form a small droplet stabilized by a stabilizer. The polymerization initiated by the thermal decomposition of the free radical. For removal of unreacted monomers, cross-linking reagent, and initiator, the resulting micro-particle rinsed. 18 Grafting onto a support Grafting is polymerization of a monomer on the backbone of a preformed polymer. Chemical reagents or high-energy radiation therapy activate the polymer chains. On the activated macro radicals, growth of functional monomers results in branching, which subsequently results in crosslinking. ²¹                                                          

Fig. 3 Flow chart of Suspension polymerization^.

5. Grafting to a suport:

Hydrogels prepared through bulk polymerization tend to have a weak structure in nature. It is possible to improve the mechanical properties of such a hydrogel by grafting it onto a more robust support with a surface coating. Such a process results in a monomer chain which is covalently attached to a more robust support surface through the process of first creating free radicals on it and then directly polymerizing onto it. Hydrogel has been prepared through grafting processes onto various polymeric supports.                         

Fig.4 Block diagram of grafting method.

6. Physical cross-linking:

Physical or reversible materials have become increasingly popular since they are easy to make and possess the advantage of not needing cross-linking agents. Both their clearance before use and the integrity of the material to be entrapped (e.g., cells, proteins, etc.) are affected by these agents. Many types of gel texture can be created by strategically selecting the type of hydrocolloid, the concentration, and pH. This is a field that is presently in the limelight, particularly within the food industry.

7. Complex coacervation:

Polyanion and polyation can be blended to form complex caoacervate gels. The basic concept in this method is that, based on the concentration and pH of the respective solutions, polymers of opposite charge will bind together and form soluble and insoluble complexes. Coacervation of polyanionic xanthan with polycationic chitosan is one such example. Positive charged proteins below their isoelectric points have a higher tendency to bind with anionic hydrocolloids and form polyion complex hydrogel. ²³  

Fig. 5 Complex coacervation between polyanion and polycation.