Biomedical Application of Hydrogels and Their Importance

Introduction

Hydrogels are made up of polymers that can expand and swell but don't dissolve aqueous solutions (up to a certain limit) [1]. It is observed as colloidal suspension with water along with a dispersal medium [1, 2]. It retains water because these are made up of monomers with hydrophilic functional groups. However, it does not dissolve in water because of cross-links between the network chains [2]. Further, these networks maintain stability with the surrounding media and temperature for shape and strength [1, 2]. Hydrogels may be natural or may be synthetically synthesized in

FIGURE 6.1 Importance of hydrogels in the biomedical arena.

the laboratories. The structure of hydrogels change if we alters the basic structure of monomers, cross-linker(s), and concentration. [3]. Hydrogels can be used in different fields including biomedical science (Figure 6.1).

Properties of Hydrogels

• 1) Swelling: Swelling is the most important characteristic of a hydrogel. These structures support free diffusion of solute molecules in aqueous media while the polymer network of hydrogel functions as a vessel to hold the solvent jointly together. They can absorb up to thousands of times their dry weight in liquid media [4].
• 2) Permeation: The permeation process is done via pores. Pores are made in hydrogels through phase separation during synthesis. The average size of the pore, the size distribution, and interconnections among them are the key factors of a unique hydrogel [5, 6].

Classification of Hydrogels

Hydrogels may be classified into different types:

A. Based on source

Hydrogels can be made up of either natural or synthetic or the combination together.

• 1) Natural. Examples includes pectin, agarose, collagen, fibrin, etc.
• 2) Synthetic. Examples include PEG-PLA-PEG, PEG-PLGA-PEG. etc.
• 3) Combination of both : An example is collagen-PEG.

B. Based on the method of polymeric composition

Hydrogels can be prepared from the cross-linking of a single monomer unit or a combination of more than one type of monomer.

• 1) Homopolymer gel: In these hydrogels, only one type of hydrophilic monomer is used for preparation and possesses a cross-linked backbone structure. Examples are polyvinyl pyrrolidone (PVP) and poly (acrylic acid) gels.
• 2) Co-polymer gel: These types of hydrogels are composed of a minimum of two co-monomers species in which at least one is hydrophilic. These types of gels can be prepared to be sensitive to certain stimuli such as pH, light, etc. An example is co-polymerization of itaconic acid with N-vinyl- 2-pyrrolidone (NVP) as a monomer and N,N-methylene-bisacrylamide (MBAAm), which gives a pH-sensitive gel.
• 3) Interpenetrating polymer network (IPN): These hydrogels are made up of two polymers formed w'ithout covalent bonds but cross-linked among similar molecules. In IPN, the bulk of the matrix, i.e., polymer, acts as a reservoir for the active agent and releases it in a long-term manner. An example is an IFN blend of chitosan and hydroxyethyl cellulose.

C. Based on ionic charges

Hydrogels can be classified into four types based on their ionic charges:

• 1) Neutral hydrogel (nonionic): These hydrogels do not have any charges. Examples are dextran and agarose.
• 2) Anionic hydrogels: These hydrogels are negatively charged. Examples are pectin and hyaluronic acid.
• 3) Cationic hydrogels: These have positive charges. Examples are polylysine and chitosan.
• 4) Ampholytic hydrogels: These hydrogels have both positive and negative characters. Examples are collagen and fibrin.

Applications

Highly adsorbent diapers have the characteristics of being waterless or dry even after substantial adsorption of water. Here, the property of hydrogel for water adsorption is being used by multinational companies. These hydrogel-loaded diapers hold water at maximum extent; most of them are fabricated with different concentrations of sodium polyacrylate, which reduces the dermatological problems related to prolonged contact with wet tissues [11, 12].

6.4.2 Watering Beads for Plants

These hydrogels are fabricated not for retaining water but to sustain releasing water. The release of water into plant species is the attractive feature of hydrogels in the market, from horticulture to plant genetic engineering [13].

6.4.3 Tissue Engineering

Hydrogels can represent the physiochemical and biological properties of most human native tissues and therefore can be applied in tissue engineering as tissue replacements [14, 15]. pH-sensitive gels have been applied to deliver macromolecules into the cellular system and release drugs due to acidic conditions [16]. Such gels change themselves according to the tissues environment.

• 6.4.4 Biomedical Applications
• 6.4.4.1 Drug Delivery

Before administration of the hydrogel into the body, it first has to be incorporated with the desired drug or therapeutic agent [17]. This can be done by the two following methods:

• 1) In the first method, the hydrogel and drug are mixed together, and the polymer is allowed to cross-link. If necessary, initiators and cross-linkers are added. The drug is present within the matrix of the polymerized gel.
• 2) In the second method, an already polymerized gel is allowed to sit in the drug solution. The drug solution is absorbed into the gel until equilibrium is achieved [18].

After loading the drug, the gel is dried and ready for use.

6.4.4.2 Drug Release Mechanism Using Hydrogels

The hydrophilic nature of hydrogels to imbibe water makes hydrogels an excellent tool in drug delivery systems. Hydrogels have capacity to absorb a huge quantity of water, sometimes even greater than 90% of their own weight. For purposes of drug release using hydrogels, pharmaceutically active agents are encapsulated within hydrogels, and this can be done by physical entrapment, covalent conjugation, or controlled self-assembly. Owed to their rapid and controllable diffusion rate, hydrogels have been considered a promising vehicle for drug delivery systems for diseases such as diabetes, osteoarthritis, cancer therapy, etc. The main advantage of using hydrogels is their drug delivery in a controlled manner for a longer duration, rending the drug active for a longer time [19-21].

• 6.4.4.3 Delivery of Drug through Hydrogel Occurs Mainly through Three Mechanisms [19, 22]
• 6.4.4.3.1 Diffusion Controlled Mechanism

This is the most accepted and popular mechanism model for release of drug from hydrogels. This type of diffusion depends on the structure and morphology of the polymer and is based on the concentration gradient of the drug. An example is the release of doxorubicin from pluronic-based hydrogels composed of polyethylene glycol) and polyxamer in response to increasing temperature and increasing hydro- phobicity [19, 23].

It can be of two types:

• 6.4.4.3.7.7 Reservoir Device System In this model, the drug remains at the core of the gel, encapsulated by the polymeric membrane. Drug release via polymeric membrane follows Fick’s law of diffusion down the concentration gradient, i.e., from the core of the gel to the surrounding media. To extended drug release at constant rate, the drug is incorporated at a very high concentration at the core [24].
• 6.4.4.3.1.2 Matrix Device System In this method, the drug is homogeneously distributed all over the gel and is released through the macromolecular pores in the polymeric hydrogel rather than from the core as in a reservoir device. The release rate is proportional to the square root of time [25].
• 6.4.4.3.2 Chemically Controlled Mechanism

In this mechanism, drug molecules are released by reversible or irreversible enzymatic and hydrolytic reactions within the matrix, and the amount of drug release at a particular time is dependent on the rate of degradation of bonds. In cases of erodible polymers, the rate depends on the rate of degradation and dissolution of the hydrogel. In hydrophilic polymers, erosion occurs all over the polymeric matrix whereas it takes place only on the polymeric surface in hydrophobic polymers [26]. An example is the release of doxorubicin from degradation of disulfide cross-links in the presence of glutathione tripeptide in cases of poly (oligo(ethylene oxide)-methyl methacrylate) gel.

6.4.4.3.3 Swelling Controlled Mechanism

As the hydrophilic matrix absorbs solvent molecules, the gel swells up and the volume increases, which results in the increase in the size of the pores. As the pore size increases, the drug molecules are released from the polymer. In this case, drug diffusion is faster than hydrogel expansion. An example is the release of hydrophilic doxorubicin molecules from a thermosensitive nanogel during its swelling process. Thermosensitive nanogel undergoes a reversible phase transition changing from hydrophilic (swelling) to hydrophobic (shrinking) as a function of temperature change [27].

• 6.4.5 Advantages of Hydrogels
• • Hydrogels have a high degree of plasticity or flexibility and are a close resemblance to natural tissue due to their significant liquid content.

• • The features of hydrogels are controlled by external factors that have the ability to sense changes in pH, temperature, or concentration of metabolite and release drugs accordingly.
• • Hydrogels are more patient compliant than injections as they can be taken through parenteral routes.
• • Hydrogels are readily transforming.
• • Controlled drug release can be achieved using hydrogels to achieve a target delivery with the desired release rate and site.
• • They are biocompatible, non-immunogenic, and biodegradable and show minimal toxicity.
• 6.4.6 Disadvantages of Hydrogels
• • Hydrogels are expensive.
• • Hydrogels are non-adherent in nature; they may need to be protected by a secondary dressing.
• • Hydrogels have low mechanical strength (in many reports).
• • They can be hard to load with drugs/nutrients (in some cases).