Hydrogels have been widely used in drug delivery, wound dressings, tissue engineering, and hygiene products. This article introduces hydrogels in terms of their history, structural forms, and applications in drug delivery.

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Hydrogels: History & Application in Drug
Delivery
Hydrogels are composed of hydrophilic polymers with a three-dimensional network
structure that can absorb large amounts of water as well as be used to carry drugs.
Hydrogels prepared with suitable materials are biocompatible and have controlled
mechanical and viscoelastic properties. Since the coining of the term "hydrogel" in the late
19th century, hydrogels have been widely used in drug delivery, wound dressings, tissue
engineering, and hygiene products. This article introduces hydrogels in terms of their
history, structural forms, and applications in drug delivery.
Figure 1. Structure of hydrogel at the molecular level.
History of Hydrogels
The term hydrogel can be traced back to 1894 and was first used to describe a colloid of
some inorganic salts. Today, hydrogel has a completely different meaning than it had at
the beginning. The first ever hydrogel reported in 1949 for biomedical implant was Ivalon,
poly(vinyl alcohol) cross-linked with formaldehyde. And in 1960, PHEMA
(Polyhydroxyethylmethacrylate) was introduced which bring the market of hydrogel to
boom. Looking back at the history of hydrogel, it can be roughly divided into three
generations.
First-genaration Hydrogels
The first-generation hydrogels are divided into three main categories. The first category is
polymers of alkene monomers subjected to radical-induced chain addition reactions,

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mainly represented by polyacrylamide (PAM) and polyhydroxyethyl methacrylate
(pHEMA), which remain an important biomaterial despite having been invented more than
70 years ago. The second category is covalently cross-linked hydrophilic polymers, mainly
represented by polyvinyl alcohol (PVA) and polyethylene glycol (PEG), which are mainly
used in tissue engineering. The third category is cellulose based hydrogels, which are
mainly used as drug dispersion matrices in drug delivery.
Second-generation Hydrogels
The second generation of hydrogels is mainly PEG/polyester block copolymers, which are
characterized by the ability to convert the chemical energy of the hydrogel into the
mechanical energy of the hydrogel to achieve the specified function.
This category of stimuli-responsive hydrogels, which can respond to external
environmental changes (such as temperature or pH), appeared on the market in the
1970s. Stimulus-responsive hydrogels can be broadly classified into three categories.
 ▶ Temperature-sensitive hydrogels. They exhibit a phase transition from gel to
sol state from low to high temperatures, mainly represented by Pluronics from BASF or
Poloxamers from Imperial Chemical Industries, UK.
 ▶ pH-sensitive hydrogels. These polymers are hydrolyzed at high or low pH
environments, respectively.
 ▶ Biomolecule-sensitive hydrogels. These hydrogels can respond to changes
in the concentration of specific biomolecules through conformational changes. For
example, glucose oxidase-incorporated hydrogels can be used for insulin delivery. As
glucose diffuses in the hydrogel matrix, it is converted to gluconic acid by glucose oxidase
in the hydrogel, which causes a decrease in the pH of the environment. The subsequent
increase in lysis due to protonation of the amine functional group of the hydrogel allows
insulin to be released from the matrix, forming a system of self-regulated insulin release.
Third-genaration Hydrogels
The main feature of third-generation hydrogels is "cross-linking", which modulates the
mechanical and degradation properties of hydrogels mainly through stereoconjugation,
inclusion, metal-ligand coordination and synthesis of peptide chains. For example, one of
the main applications of stereoconjugation is the preparation of injectable hydrogels by
blocking two amphiphilic copolymers, poly(L-lactic acid) (PLLA) and poly(D-lactic acid)
(PDLA). There are also studies on the use of cyclodextrin inclusion compounds to
construct hydrogels with hydrophobic cavities that can accommodate different molecules.
In addition, there are also studies on synthetic peptide (or protein) hydrogels constructed
by using the folding structure of peptides in genetic engineering, but such hydrogels are
mainly embodied in research.
Hydrogels for Drug Delivery

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There is increased interest in hydrogels for drug delivery due to their stimuli-responsive
properties, which can change its properties (such as mechanical properties, swelling
capacity, hydrophilicity, or permeability of bioactive molecules) under the effect of
surroundings, including temperature, pH, electromagnetic radiation, magnetic field, and
biological factors. Here, we will focus on hydrogel-based delivery of drugs.
Buccal Drug Delivery
Buccal or oral mucosal routes have various advantages for the administration of drugs
which undergo severe first-pass metabolism. Hydrogel seemed an appropriate material
for the buccal delivery systems because of its mucoadhesiveness, sustained-release
property, good feel in the mouth, and safety.
The oral cavity is lined by a mucous membrane consisting of stratified squamous
epithelium and an underlying connective tissue layer. The drug delivery process in the oral
cavity mainly goes through: drug dissolution, drug diffusion through the mucosa by
passive or active means to the local blood circulation system and finally to the systemic
blood circulation. Therefore, the permeability of different sites brings different drug
delivery modes.
The sublingual mucosa is more permeable than the buccal mucosa and is suitable for
drugs that require a rapid onset of action, but drug delivery through the sublingual mucosa
can interfere with tongue movement during speech. In contrast, drug delivery through the
buccal mucosa has less impact on tongue movement and is preferred for the treatment of
chronic diseases, whereas drug delivery through the gingiva is often limited to local action.
Mucosal drug delivery results in a large portion of the drug entering the gastrointestinal
tract, therefore hydrogels with mucoadhesive properties are considered in the dosage
form design. Hydrogel-based bioadhesive tablets can be used to control the rate of drug
release using water cooperation. Common matrices used in these hydrogel applications
are hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyacrylic acid (PA),
carboxymethyl cellulose (CMC), polyvinyl alcohol (PVA), hydroxypropyl methylcellulose
(HPMC), chitosan, etc.
The hydrogel drugs currently on the market for buccal delivery, mainly for oral care and
rehydration or for continuous delivery systems for angina prevention, are listed in the table
below.
Table 1. Hydrogels for buccal drug delivery
Intravaginal Drug Delivery

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The vagina has been traditionally used as a route of administration for delivering
anti-microbial and anti-viral drugs, as bacteria, fungi or viruses can easily multiply in the
vagina and cause a variety of lesions that induce vaginitis. In addition, vaginal delivery is
also an alternative to parenteral routes of administration of propranolol, human growth
hormone, insulin, and steroids due to its large surface area, high perfusion of tissues, and
high permeability to peptides and proteins, etc. The main obstacle to vaginal
administration is the change in vaginal fluid content and permeability of the vaginal
mucosa caused by changes in age and hormone levels, which in turn affects drug release
and pharmacokinetics.
Currently, two approaches are used to overcome this limitation: the use of mucosal
adhesives to prolong the residence time of the drug on the vaginal mucosa, and the use of
stimuli-sensitive hydrogels with a sol-gel transition in the vaginal environment. Both
solutions, in turn, rely heavily on matrix excipients. The most commonly used polymers in
vaginal preparations are hydrogels: polyacrylates, chitosan, cellulose derivatives such as
carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC) and hyaluronic
acid, alginate and gelatin. The main drugs currently on the market, mainly care products
and gynecological drugs, are listed in the table below.
Table 2. Hydrogels for intravaginal drug delivery
Transdermal Drug Delivery
Transdermal administration is a specific route of administration suitable for poorly
absorbed oral drugs with high first-pass effects and for patients who are intolerant to
injections. The skin is an inhomogeneous membrane with very low permeability
characteristics that reduce water loss and stop the flow of toxins into the body.
The outermost layer of the skin is the stratum corneum, which is only 20-25 μm thick and
prevents the penetration of foreign substances, but is also the greatest obstacle to
transdermal drug delivery. Conventional transdermal patch delivery requires drugs with
low molecular weight, high lipophilicity, and small doses. In 1979, the first transdermal
system for systemic drug delivery, scopolamine transdermal patch, was approved in the
United States. Ten years later, nicotine patches were marketed, which not only featured

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high patient compliance but also greatly increased the visibility of transdermal
formulations among patients.
Conventional transdermal patches marketed in recent years can be divided into two main
categories: reservoir-based patches and matrix-based patches. The first type is
characterized by keeping the drug in a solution or gel and controlling drug delivery through
a membrane located between the drug reservoir and the skin. The latter combines the
adhesive and mechanical properties of the formulation, and the drug delivery rate is
controlled solely by skin permeability. Overcoming skin permeability is thus the key to the
problem, as hydrogels promote skin penetration of the drug through skin hydration for
both topical and systemic effects. Listed below are some of the commercial products
based on transdermal drug delivery hydrogels available in the market, which cover a
relatively wide range of drug delivery from dermatological conditions to systemic drug
delivery.
Table 3. Hydrogels for transdermal drug delivery
Ocular Drug Delivery
With the proper formulation design of hydrogels, contact time can be extended, especially
with subconjunctival administration, where the drug can bypass the conjunctival-corneal
barrier and enter directly into the transscleral pathway to the posterior part of the eye.
Hydrogel formulations have been used in a variety of ophthalmic applications because
they offer several advantages over conventional materials, such as mild preparation
conditions, high water content, and important features that maintain the activity of
molecules such as proteins. Moreover, certain temperature-sensitive and in situ hydrogels
can be administered in a less invasive manner for long-term implantation purposes. Some
of the commercially available hydrogel-based products on the market for ocular drug
delivery are listed below.

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Table 3. Hydrogels for ocular drug delivery
Conclusion
Hydrogels have been receiving a lot of attention due to their unique properties. Although
relevant theoretical studies have been conducted to dig deeper into it, there are still many
prescriptions that have failed to enter the market, and hydrogels are still promising in the
field of drug delivery.
At present, PEG has been widely used as hydrogels, and it is expected that future
application prospects will also be quite broad. Biopharma PEG provides multi-arm PEG
derivatives, including 4-arm and 8-arm PEG products, as well as some other PEG
products with special structures, which can be used to crosslink into degradable PEG
hydrogels.
4arm PEG Succinimidyl Carboxymethyl Ester Hydrogel
4arm PEG Amine Hydrogel
4arm PEG Thiol Hydrogel
8arm PEG Amine (tripentaerythritol), HCl Salt Hydrogel
8arm PEG Amine, HCl Salt Hydrogel
8arm PEG Thiol (hexaglycerol) Hydrogel
Acrylate PEG NHS Ester Hydrogel
Methoxy PEG Amine Hydrogel
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transdermal drug delivery[J]. Nature Reviews Drug Discovery, 2004,3(2):115.
[3]Cascone S, Lamberti G. Hydrogel-based commercial products for biomedical

7. Biopharma PEG https://www.biochempeg.com
applications: A review[J]. International Journal of Pharmaceutics, 2019,573:118803.
[4]Bertens, Christian, J., et al. Topical drug delivery devices: A review[J]. Experimental
Eye Research, 2018.
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