Hydrogel Biomaterials for Drug Delivery: Mechanisms, Design, and Drugs

Abstract

Due to their unique physical and chemical properties, hydrogels have attracted significant attention in several medical fields, specifically, drug delivery applications in which gel-based nanocarriers deliver drug molecules to the region of interest in biological organs. For different drug delivery applications, hydrogel systems can be manipulated to provide passive and/or active delivery. Thus, several drug targeting, loading, and releasing mechanisms have been devised and reported in the literature. This chapter discusses these mechanisms and their efficacy with respect to different drug delivery applications. Furthermore, the drug dosage is dependent on the design and shape of the hydrogel systems, which in turn depend on the route of the drug administration. This chapter covers the types of hydrogel-based products applied via different routes of drug administration. Lastly, this chapter addresses different classifications of delivered drugs including small molecular weight drugs; therapeutic proteins and peptides; and vaccines.

1. Introduction

Hydrogels are three-dimensional polymeric networks that are utilized in various medical applications due to their unique properties: hydrophilicity, biodegradability, non-toxicity, and their controllable mechanical properties to mimic the mechanics of biological tissues [1, 2]. Furthermore, their structural properties exhibit similarities with biological extracellular matrix components which makes them ideal for cell culture and growth [3].

From the mechanical perspective, the concentration of the polymer network in hydrogels controls, to large extent, their mechanical strength allowing them to mimic the mechanics of physiologically loaded tissues [4]. Consequently, due to their availability and relatively low cost, hydrogels have become an attractive option when developing quantitative techniques that measure the mechanics of biological tissues [5, 6, 7, 8].

On structural level, hydrogels can be produced by chemical or physical cross-linking. In chemical (permanent) hydrogels, the network is crosslinked with strong covalent bonds that connect the molecular chains [9]. In physical (reversable) hydrogels, the gel’s molecular chains are connected with weaker forces such as hydrogen-bonding and ionic forces, thus, they can be easily dissolved by altering their environmental conditions (e.g., temperature, ionic strength, or pH of the gels [10]). These crosslinking methods allow the synthesis of multi-network hydrogels. For instance, hydrogels can be fabricated to have highly crosslinked rigid chains that are entangled with weakly crosslinked chains to provide a functional network system used in synthesizing biomaterials for several medical applications [11, 12].

One of the medical applications the hydrogels used in is contact lenses, mainly due to their unique physical properties and ease of processing; for example, Bauman et al. [13] developed Silicone Hydrogel lenses with nano-textured surface that mimics the surface of human cornea. Hydrogel lenses are also known for their wettability, a property necessary to avoid tear deposits [10], thanks to plasma treatment during the synthesis process [14]. Gas permeability is also a key characteristic of contact lenses to provide the cornea with efficient supply of oxygen at sufficient rates. Hydrogel lenses can be designed to meet this requirement thanks to their hydrated polymer matrix [10]. Hydrogels are also commonly used in wound dressing; they have been used in combination with other materials to form composite products efficient for different dressing applications; for example, a gauze impregnated with thermoplastic hydrogels allows for absorbing wound exudate while maintaining relative slimy consistency, as a result, it prevents adherence to the wound that normally results in pain during gauze changes [15]. Moreover, flexibility and transparency of hydrogels also made them an attractive option in wound dressing. While flexibility facilitates easy removal of the dressing products, transparency allows for continuous observation of the wound healing process [16].

Nowadays, delivery and release of drug molecules is receiving significant attention in many fields of medicine in which therapeutic drugs are loaded in polymer-based-carriers. These carriers transport the drugs to the targeted location [17, 18]. The efficacy of gels as drug-carriers relies in their adjustable porosity through controlling the crosslinking density of their matrix. Their porous structure allows for drug loading and releasing with high efficiency [19, 20]. Numerous studies have been published on the potential applications of hydrogels in drug delivery focusing on their mechanism, shape of the gel-carriers, and types of transported drugs. Therefore, this chapter, will discuss different drug loading and releasing mechanisms with respect to their corresponding medical application. Furthermore, the drug dosage is dependent on the design of the hydrogel systems, which in turn depend on the route of the drug administration (e.g., rectal, ocular, peroral, etc.), thus, this chapter will shed the light on the types of hydrogel-based carriers applied via different routes of drug administration. Lastly, this chapter will cover different classifications of the delivered drugs using gel-based delivery systems including small molecular weight drugs; therapeutic proteins and peptides; and vaccines.

2. Drug loading, targeting and releasing

2.1 Drug loading

Drug loading is an important property of a drug delivery system, and it is defined as the process of incorporating a drug into a carrier. The therapeutic agents can be introduced into gel-carriers by ionic interaction, dipole interaction, hydrogen bonding, physical encapsulation, covalent bonding, precipitation, or surface absorption. It’s common that more than a loading mechanism is used in drug delivery systems, and the ideal loading strategies are determined based on the compatibility between the physicochemical properties of the drug and the carrier.

The drug-loading process can take place during the formation of the carriers, or by incubating carriers into a concentrated drug solution to allow the loading through adsorption on their surface area [21]. However, this method has limited loading capacity, and the incubation time can influence the drug loading efficacy [22, 23]. In general, the entrapment and loading of drug molecules into polymer carriers depend on several characteristics: polymer and crosslinker concentrations, molecular weight of the polymer, and drug-polymer interactions [24, 25, 26]. The higher the polymer concentration the more efficient the drug entrapment is; at a high concentration, the polymer viscosity is increased, which delays the drug diffusion within the polymer particles [27]. Similarly, the high concentration of the crosslinker yields tangible increase in the loading efficiency [28]. Conversely, Fu et al., 2004 reported that the encapsulation efficiency decreases when the molecular weight of the polymer increases [29]. In protein based drugs, the interaction between the polymer and the drug molecules contribute to the entrapment efficiency; it increases if the protein molecules are entrapped into hydrophobic polymers, moreover, ionic interaction between the molecules and the polymer particles increase the efficiency of encapsulation, specifically, in polymers that belongs to carboxylic end groups [30].

2.2 Targeting

The delivery of therapeutics by nanocarriers can be passive: transport of drug-carrying nanoparticles through permeable vessels due to the enhanced permeability and retention (EPR) effect; or active: based on molecular recognition in which peripherally targeting moieties that interact with specific cell receptors [31].

In localized cancer therapy, the mechanism of passive targeting relies heavily on the tumor characteristics; tumor hypoxia causes rapid growth of leaky vessels, which increases the permeation of nano-delivery systems into the tumor, the lack of lymphatic filtration allows for the retention of these systems on the tumor’s interstitial space [32]. Moreover, this targeting strategy also depends on the carriers’ size; delivery systems larger than 50 kDa permeate through leaky vessels and retained in the tumor, smaller molecules are washed out quickly (very short circulation time) from the tumor [33]. The charge and the surface chemistry affect the circulation time of carriers; mononuclear phagocyte system (MPS) cells tend to opsonize largely hydrophobic and charged systems. Thus, water-soluble and neutral (or slightly anionic) compounds (e.g., Polyethylene Glycol) are used to coat the nanocarriers surface [31, 32, 34]. Active targeting also depends on the EPR effect to accumulate the delivery nanocarriers in the tumor region, however, the efficacy of this strategy capitalize on equipping the nanocarriers’ surface with ligands that bind to specific receptors of cancer cells, thus, enhancing the penetration and efficiency of the chemical therapeutics. Figure 1 illustrates passive and active targeting strategies.

Figure 1.

Schematic illustration of active and passive delivery of drug molecules.

2.3 Drug releasing

Biodegradation of the nanocarriers is essential for the release of the drug molecules over extended periods of time (days or weeks). It is also crucial for the removal of delivery systems from the body [35]. The carrier size has an effect on the efficacy of the releasing process; drug molecules loaded at or in proximity to the surface of small particles are released at a fast rate due to the large surface-to-volume ratio. On the other hand, slower release rates are associated with larger particles, nevertheless, more drug molecules can be loaded. Modulation of the drug release can also be controlled by the molecular weight of the gel composition; higher molecular weight tends to exhibit slower release rates [36, 37]. In general, the mechanism of releasing drugs is dependent on three main parameters: drug diffusion and dissolution, gel matrix design, and interaction between the drug and the gel matrix.

The transport of the therapeutic molecules out of the gel matrix is a complex process that depends on the dissolution and diffusion of the drug [38]. Several studies have been conducted to develop mathematical models that describe this process [39, 40, 41]. The basic equation of the dissolution rate as a function of diffusion can be described as [42].

$$\frac{dM}{dt}=\frac{DA}{\mathrm{h}}\left({\mathrm{C}}_{\mathrm{s}}-\mathrm{C}\right)$$E1

Where dM/dt is the rate of dissolution, A is the surface area of solid in contact with the dissolution milieu, D is the diffusion coefficient, ${\mathrm{C}}_{\mathrm{s}}$is the drug solubility, and C is the drug concentration at time t, and h is the diffusion boundary layer thickness at the solid’s surface. This equation shows that the dissolution rate is directly dependent on the surface area of the particle and the solubility of the drug. Conversely, larger thickness of the diffusion boundary layer reduces the dissolution rate. When the size of the nanocarriers is reduced from the micro-domain to nano-domain, the surface area increases resulting in a higher rate of dissolution as reported in [43].

There are several mechanisms to release the drug, most common strategies are diffusion and swelling controlled. In diffusion-controlled delivery systems, drug molecules diffuse from a region of high drug concentration (reservoir) through the gel matrix or membrane. The design of these systems is commonly available as spheres, cylinders, slabs, or capsules. These systems can have a constant rate of release as described by Eq. (1), or their release rate can be proportional to the square root of time. In the latter case, the drug is usually dispersed or dissolved uniformly through the matrix of the hydrogel [10]. In swelling controlled systems, the drug is dispersed within carriers made of a glassy gel, and upon contact with biofluids, they swell beyond their boundary which results in the diffusion of the drug during the relaxation of the gel chains, this process is known as anomalous transport [10, 44]. Illustrations of the two releasing mechanisms provided in Figure 2. The structure of the nanocarriers’ controls the release of the drugs; using hydrogels alone in synthesizing the nanocarriers can result into fast premature release of drugs and poor tunability [45]. Therefore, using additives can enhance the control of the drug delivery process; using Polydopamine (PDA) as an additive to the hydrogel materials in making the nanocarriers provides an on-demand capability to release the drug. In high glutathione (GSH) and acidic condition, the bond between the drugs and PDA experience weakening. This is a useful property to release the drugs in inflammatory areas or tumor cites where pH levels are low. While at neutral pH levels such as in normal tissues, the bond between the PDA and the therapeutic dugs is not affected [46, 47, 48, 49, 50]. Furthermore, PDA generates heat upon exposure to near infrared (NIR) laser, which makes it ideal for NIR triggered drug delivery [51].

Figure 2.

Schemes of drug release systems: (a) from a reservoir system; (b) from a matrix system.

3. Hydrogel administration

Besides long-term stability and release properties, passing the toxicity screening is essential for hydrogel formulations to be used in drug delivery. This is mainly due to the rise of inflammatory reactions that occur as a result of the degradation of synthetic polymers [52]. Therefore, achieving biocompatibility is necessary to use hydrogels in an environment of living organisms. Most in-vivo tests are conducted on animal models to provide reliable biomedical mimicry. As a result, several hydrogel-based drug delivery systems have been developed and approved for clinical use through different administration routes. Currently, the common accessible routes of these systems are Oral [53], rectal [54], subcutaneous [55], transdermal [56], ocular [57], and intraperitoneal [58]. These administration routes are illustrated in Figure 3. Table 1 provides examples of gel-based products used in drug delivery through different administration routes.

Figure 3.

In-vivo hydrogel-based drug delivery in most common routes of administration. The schematic illustration is reproduced from [59].

Route of administration	Shape	Typical dimensions	References
Oral	Spherical beads; Discs; Nanoparticles	1 μm–1 mm; Diameters of 8 mm and thickness of 1 mm; 10–1000 nm	[35, 60, 61]
Rectal	Suppositories	Conventional adult suppositories dimensions (32 mm in length) with central cavity of 7 mm and wall thickness of 1.5 mm	[62]
Transdermal	Dressing	Variable	[63]
Subcutaneous	Injection (hydrogel spacers in prostate cancer therapy)	N/A	[64, 65]
Intraperitoneal	Injection (hyaluronic acid hydrogel loaded with chemotherapeutics)	N/A	[66]

Table 1.

Types of hydrogel-based products applied via different routes of drug administration [10, 59].

3.1 Oral route

Oral administration currently is the most common and convenient for hydrogel drug delivery systems, thanks to their bioavailability and nontoxicity they provide [67, 68]. However, such systems have limitations due to the metabolic effect these systems have on the living organism including but not limited to denaturation and reduction of epithelial membrane permeability [52]. Delivery systems in this strategy are usually made from caprolactone, MPEG, itaconic acid pH-sensitive hydrogels as they were reported to have no signs of toxicity [68].

3.2 Rectal route

This route provides an alternative to intravenous and subcutaneous medication delivery. It has faster absorption of the medication through rectum’s blood vessels, which makes it ideal for therapeutics that have high bioavailability and shorter duration [69, 70]. Moreover, it provides a stable environment in which the drugs are released since this administration strategy bypasses the gastrointestinal tract. As a result, minimal alterations occur to the drug concentration when it reaches the circulation system [71]. Hydrogel-based delivery systems such as catechol-chitosan gels have shown excellent biocompatibility and were reported to have no toxicity in-vitro and in-vivo [54, 72].

3.3 Subcutaneous route

This route is very common in studies that involve animal models when developing gel-based injectable biomaterials such as alginate [73], gelatin [74], poly-acrylamide [75], ellagic acid [76], and pectin [77]. While these biomaterials have shown no toxic response when deployed in-vivo into the animal model, the majority of the studies have reported inflammatory effect due to the vascularized nature of the subcutaneous region that is associated with reactions against foreign moieties [78].

3.4 Transdermal route

In topical delivery, the therapeutics reach the circulation system through penetrating the skin layers; the drug passes through the startum corneum to deeper epidermis and dermis until it is absorbed by the dermal microcirculation [79, 80]. The hydrophilic nature of hydrogels allows them to hold considerable amounts of fluid content that ranges between 10% to 1000 times gels’ dry weight [81], which makes them ideal for carrying drugs such as insulin, theophylline, sodium fluoride, and progesterone and heparin. Transdermal hydrogel patches can provide a controlled rate of drug delivery in addition to providing a cooling effect at the location where they are applied [81]. Hydrogels can also be combined with bio-adhesives to prolong the therapeutic effect of the delivered drug when applied topically [82].

3.5 Intraperitoneal route

Intraperitoneal injections of hydrogel systems are considered a successful delivery strategy for various therapeutic agents. The injected hydrogels compounds can achieve efficient drug delivery while exhibiting anti-adhesiveness properties on the peritoneum [83]. Although intraperitoneal hydrogels were reported to be non-toxic [84], their hydrophilicity can compromise the concentration of the delivered pharmaceutical agents [58].

4. Types of therapeutics delivered using hydrogels-based delivery systems

4.1 Small molecular weight drugs

Budhian et al. [85] categorized the release of this class of drugs into three stages; (i) initial burst, during which the drugs immediately released into the medium; (ii) induction, in which the release of drugs is gradual; and (iii) slow release, in which the release reaches a steady slow rate [85]. These stages are controlled by three unique properties of the gel in use to synthesize the delivery systems: hydrophobicity, surface coating, and particle size [35]. The lower the hydrophobicity the higher the release of drugs during the burst stage; for example, the percentage of released drugs after 1 day is 45% for 220 nm strongly hydrophobic PLA particles, on the other hand, the release percentage is 70% for the same size of the moderately hydrophobic PLGA particles. The release stages are also affected by the surface coating of the nanoparticles; coating PLGA particles reduces the number of drugs released by 40%. The rate of release and the initial burst are affected by the size of the particles; increasing the size decreases the total surface area which reduces the burst period, furthermore, the larger the size, the longer the pathways the drug molecules take during the diffusion which increases the induction period [85].

4.2 Therapeutic peptides and proteins

Among several peptides- and proteins-based therapeutics that are used in drug delivery, enzymes are the most studied class of drugs [86]; examples of such enzymes include L-asparaginase, cysteine desulfatase, cysteine oxidase, arginase, and arginine decarboxylase [87]. Currently, only a few protein- and peptide-based drugs have been used in medicinal setting. The clinical use of this class of drugs is hindered by several factors: enzymatic degradation, renal filtration, inefficient cell entry, accumulation in nontargeted organs, immune system response that causes allergic reaction, and protein inactivation due to intrinsic properties such as low stability in an environment of physiological pH and temperature [88].

A simple approach to overcome the elimination of this class of drugs is introducing it via injection to the targeted organ. However, this strategy has its own limitations such as difficulty or delocation of the targeted site, drug toxicity, and long-term hospital setting administration [88]. Other delivery strategies were proposed such as microfabricated chips and implantable devices [89, 90]. While these strategies have shown promising results, their deployment and extraction require surgical intervention. To overcome these challenges and to stabilize the therapeutic proteins and peptides in the physiological environment, they are encapsulated into nanocarriers. This technique protects the enzymes from the degradation parameters imposed by the physiological environment while delivering different types of protein-based drugs [88].

Shimizu et al. [91] developed nanocarriers that efficiently encapsulates bone morphogenic proteins (BMPs), which have significant capability to convince bone formation. When BMPs are encapsulated by the developed nanocarriers, they provided sustained delivery of the BMPs over a time period of 14 days. In cancer therapy, polymersomes are used to deliver therapeutics; Danafar et al., 2016 investigated the delivery of drug molecules encapsulated into mPEG-PCL hydrogel nanocarriers in treating breast cancer. Their mPEG-PCL carriers provided suitable pH-dependent delivery of therapeutics to breast cancer cells [92].

4.3 Vaccines

Establishing an immunological memory and provoking sufficient immune response are the two primary factors that determine the efficacy of a vaccine delivery system [93, 94]. The main administration routes of vaccine delivery systems are parenteral and non-parenteral. The first is administered using hypodermic needles inserted through subcutaneous, intramuscular, and intradermal routes [95, 96]. On the other hand, non-parenteral delivery systems capitalize on needle-free devices such as jet injectors, liquid, powder, and polymeric (including hydrogel) systems [97]. In hydrogel-based systems, gel particles encapsulate the vaccine molecules and deliver it through intramuscular, oral, and transcutaneous routes [98, 99]. In recent years, different hydrogel delivery systems were developed to increase the efficiency of the vaccine delivery, Table 2 summarizes these systems and their applications.

Hydrogel based system	Applications	References
Thermo-sensitive	H5N1 Influenza vaccination; Ebolavirus glycoprotein antigen; prevention of ovine brucellosis	[100, 101, 102]
Capsules	Oligopeptide antigen delivery	[103]
Bio bullets	Bacterial vaccines (Brucella Abortus strain RB51 live vaccine)	[104]
Injections	Swine H1N1 influenza killed vaccine; fibroblast growth factor (bFGF); codelivery of immune check point inhibitor and tumor vaccine	[105, 106, 107]
Nanogels and peptides	Adjuvant for the vaccine delivery systems for West Nile and respiratory syndrome viruses	[108, 109]
Micro-scale particles	Oral delivery of bovine serum protein; intramuscular delivery of “transmission blocking malaria” vaccine	[110, 111]
Gel patches	Tetanus and diphtheria vaccination	[112, 113]
Micro-needles	Influenza vaccine; DNA vaccine against hepatitis B; Japanese encephalitis vaccine; and rabies vaccine	[114, 115]

Table 2.

Hydrogel-based delivery systems and their applications.

5. Conclusion

Drug carriers are revolutionary delivery systems in the field of medicine. While there have been several studies that reported different types of polymers that has been used to synthesize the carriers, hydrogel-based systems seem to be very promising due to their affordability, production simplicity, and their unique ability to load different types of drugs. Although several gel-based systems have been investigated, designed and IP-protected, it seems only limited number of these product has actually reached the market, which indicates the need for further investigations on improving the performance of current products and develop new ones. This chapter addressed different hydrogel-based drug delivery systems from different perspectives including mechanisms (loading, releasing, and targeting), design (shape and route of administration), and the classes of delivery drugs. These elements are essential when designing and investigating state-of-the-art hydrogel-based delivery systems.

Acknowledgments

The author acknowledges the support of BK21 FOUR Program through the National Research Foundation of Korea (NRF), the Ministry of Education.