International Journal of Pharmaceutics 573 (2020) 118803

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Hydrogel-based commercial products for biomedical applications: A review T

Sara Cascone , Gaetano Lamberti
⁎

Department of Industrial Engineering, University of Salerno, 84084 Fisciano, SA, Italy

ARTICLE INFO ABSTRACT

Keywords: Hydrogels are hydrophilic polymer networks, able to absorb large amount of water, increasing their volume and
Hydrogels showing a plethora of different material behaviors. Since their first practical application, dating from sixties of
Commercial products last century, they have been employed in several fields of biomedical sciences. After more than half a century of
Biomedical applications industrial uses, nowadays a lot of hydrogels are currently on the market for different purposes, and offering a
Drug delivery
wide spectra of features. In this review, even if it is virtually impossible to list all the commercial products based
on hydrogels for biomedical applications, an extensive analysis of those materials that have reached the market
has been carried out. The hydrogel-based materials used for drug delivery, wound dressing, tissue engineering,
the building of contact lens, and hygiene products are enlisted and briefly described. A detailed snapshot of the
set of these products that have reached the commercial maturity has been then obtained and presented. For each
class of application, the basics of requirements are described, and then the materials are listed and classified on
the basis of their chemical nature. For each product the commercial name, the producer, the chemical nature and
the main characteristics are reported.

1. Introduction (Rizwan et al., 2017).

The first generation of hydrogels was obtained mainly by the me-
The origin of the term hydrogel goes back to 1894, when it was used chanism of chain addition reaction, usually involving vinyl monomers
to indicate colloidal gels of certain inorganic salts (Rizwan et al., 2017). and an initiating free radical specie. The free radical polymerization
Nowadays, the term hydrogel is used to identify a class of material proceeds until the recombination of two radical species or dis-
completely different from the beginning: hydrogels are three dimen- proportionation takes place. One of the main hydrogel-forming polymer
sional cross-linked networks of polymer chains that can absorb and hold in this category was polyacrylamide (PAM), which found its place in
large amounts of water in the interstitial spaces between chains. The industrial applications as an agricultural gel. Another important
first appearance of a hydrogel on the market is dated in 1949 with the polymer is poly(hydroxy-alkyl methacrylate) (pHEMA) that, despite its
poly(vinyl alcohol) cross-linked with formaldehyde and it was mar- discovery is dated 50 years ago, is still one of the key materials in the
keted with the trade name Ivalon, used for biomedical implant. How- development of contact lens. Hydrophilic polymers covalently cross-
ever, the real turning point for the production and the use of hydrogels linked constitute the second major category of the first generation hy-
was the synthesis of poly(2-hydroxyethyl methacrylate) (pHEMA) gels drogels. Among them, polyvinyl alcohol (PVA) and polyethylene glycol
for contact lens application in 1960, which represented the starting (PEG) still play a major role in tissue engineering. Finally, another
point for the spread and flourishing hydrogel market. category in the first generation hydrogels is the cellulose-based hy-
On the basis of an historical classification, hydrogels can be con- drogels, which are used extensively in drug delivery application as
sidered belonging to different eras: (i) first generation hydrogels (sixties matrix for drug dispersion (Sharma et al., 2018).
onwards), which are cross-linked hydrogels with relatively high swel- During the 1960s, the scientists’ attention was attracted by the
ling and good mechanical strength; (ii) second generation hydrogels possibility to transfer chemical energy into mechanical work. Moved by
(start of seventies), which are stimuli-responsive, meaning that they are this aim, during the 1970s the second generation of hydrogels was in-
able to respond to specific stimuli such as pH, temperature, or biolo- troduced on the market: the stimuli responsive hydrogels (Buwalda
gical molecules adapting their behavior; and (iii) third generation hy- et al., 2014). The use of these hydrogels allowed the triggering of a
drogels comprising of stereo-complexed materials (e.g., poly(ethylene specific event (such as the drug release or the erosion of the polymer) as
glycol)-poly(lactic acid), PEG-PLA cross-linked by cyclodextrin) a response to a change of the external environment (i.e. temperature or

⁎
Corresponding author.
E-mail address: [email protected] (S. Cascone).

https://doi.org/10.1016/j.ijpharm.2019.118803
Received 30 May 2019; Received in revised form 14 October 2019; Accepted 15 October 2019
Available online 01 November 2019
0378-5173/ © 2019 Elsevier B.V. All rights reserved.
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

Fig. 1. Some examples of methods to crosslink hydrogels and their biomedical applications.

pH). Belonging to this generation of hydrogels, PEG-polyester block initial polymers. One of the main application of stereocomplexation to
copolymers have to be mentioned, which are commonly known under produce hydrogels concerns the employing of PLLA and PDLA (en-
the tradename of Pluronics (by BASF) or Poloxamers (by ICI). These antiomers of poly-lactic acid) blocks in amphiphilic copolymers for the
polymers exhibit a phase transition from the sol to the gel state at low preparation of injectable pharmaceutical forms. Hydrogels can be
temperatures and from the gel to the sol state at higher temperatures, produced using the crosslinking by hydrophobic interactions, as in the
feature that has been widely used in sustained and controlled release for case of cyclodextrins, which have a hydrophobic cavity that can host
applications in human body. The second major type of stimuli-re- different molecules. Only a few reports on metallohydrogels, in which
sponsive polymers are the pH – sensitive hydrogels. These polymers the reversible bonds between macromonomers are based on metal–li-
usually contain acidic or basic moieties that are hydrolyzed at low or gand coordination, have been published: PEG, Pluronics and PEG–PLA
high pH, respectively. Thus, using the pH variation in different zones of end-functionalized with ligands such as terpyridine or bipyridine were
the body, controlled release from hydrogel can be achieved. Biomole- employed as well to prepare hydrogels in the presence of transition
cule – sensitive hydrogels respond to a variation of the concentration of metal ions such as Mn(II) and Ni(II) (Buwalda et al., 2014). Belonging
a certain biomolecule with a conformational change. Among these to the third generation of hydrogels are the natural building blocks that
biomolecules, glucose is undoubtedly the most famous one. One ap- are able to naturally self-assembling in ordered structures, such as
plication involving hydrogels is based on the release of insulin in- peptides. These macromolecules that assemble into hydrogels are
corporated in a matrix containing glucose oxidase and pH sensitive usually designed according two different criteria: using genetically
moieties. When the glucose diffuses inside the matrix, it is converted in engineered copolymers or hybrid systems composed by a synthetic
gluconic acid, which causes a lowering of the pH and a subsequent polymer and a peptide (or protein).
swelling increase due e.g. protonation of amine functionalities. In these In spite of their classification or nature, it has to be highlighted that
conditions, insulin can be released from the matrix, which can be hydrogel market size nowadays is valued at USD 10.87 Billion (in 2016)
considered a self-regulating system (Buwalda et al., 2014). Usually, the and is projected to reach USD 15.33 Billion by 2022, at a CAGR
second generation of hydrogels is characterized by the crosslinking via (Compound Annual Growth Rate) of 6.04% from 2017 to 2022. The
hydrophobic or ionic interactions. increase in consumption of personal care & hygiene products is one of
On the contrary, the third generation of hydrogels is characterized the most significant factors driving the growth of the hydrogel market
by crosslinking methods that allow to tune the thermal, mechanical, during the forecast period (Hydrogel Market by Raw Material Type,
and degradation properties of the hydrogels: stereocomplexation, in- 2017).
clusion complex formation, metal–ligand coordination, and peptide This review is aimed to explore the different hydrogels’ applications
interactions. The first example of stereocomplexation was reported in in biomedical field, with particular attention to the hydrogels that are
1953 by Pauling and Corey for a polypeptide. A polymer stereocomplex used in commercial products. A list of the marketed products, their
is defined as a stereoselective interaction between two complementing main constituent, and their producer is appended at the end of each
stereoregular polymers, with final properties different compared to the paragraph.

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

2. Applications of these is affected of leakage into the gastrointestinal tract. Thus, in

order to allow the release only across the buccal mucosa, mucoadhesive
Hydrogels are a unique class of materials: they are hydrophilic, self- patches or tablets can be used (Hoogstraate and Wertz, 1998). The ideal
supporting, three-dimensional viscoelastic networks, which allow the characteristics of the polymer used for these formulations are: good
diffusion and the attachment of molecules and cells. These networks spreadability, wetting, swelling, viscoelasticity, good adherence to the
can be composed of homopolymers or copolymers, and their structural buccal mucosa and mechanical properties (Caccavo et al., 2015),
and physical integrity is due to the presence of crosslinks, which can be bioadhesive properties both in dry and liquid state, low cost, biode-
of physical (such as entanglements or crystallites) or chemical (junc- gradability properties, non-toxic degradation products, and it has not to
tions or tie-points) nature. Based on the nature and on the stability of be a vehicle of secondary infection such as dental caries (Sudhakar
the crosslinking, which can be achieved by different methods (i.e. using et al., 2006). Hydrogel-based bioadhesive tablets can control the release
temperature, ions, or UV radiation), the final hydrogel results in a rate of the drug depending on the hydration of the device, which is the
polymer with specific and peculiar characteristics. driving force determining its swelling ability. Hydrogels commonly
Due the wide spectrum of both chemical and physical character- used in these applications are: hydroxypropyl cellulose (HPC), hydro-
istics, hydrogels have been extensively used in pharmaceutical and xyethyl cellulose (HEC), polyacrylic (PA) resins, carboxymethyl cellu-
biomedical applications. In Fig. 1 the main methods to achieve the lose (CMC), polyvinyl alcohol (PVA), hydroxypropylmethyl cellulose
hydrogel’s crosslinking are listed and some of the application fields (HPMC), chitosan (Hoogstraate and Wertz, 1998; Nagai and Machida,
covered by this review are depicted. 1993; Shojaei, 1998; Patel et al., 2018). The use of cellulosic or acrylic
polymers generally offers almost immediate, high adhesion perfor-
2.1. Drug delivery mance for prolonged times, even with high drug content.
Concerning the commercial product that can be found on the
Hydrogels are extensively used in drug delivery and play a major market, they range from hydrogels for mouth care and hydration to
role as drug vehicle. In this paragraph the commercial products for drug sustained drug delivery systems to prevent angina. Some of them are
delivery based on hydrogels are listened on the basis of the adminis- listed below, the main features and web address where find more in-
tration route. formation for each product are given in Table 1:

2.1.1. Buccal delivery • Lubrajel™ BA (by Ashland) oral moisturizing hydrogel is a solution
The oral cavity is covered with mucous membranes with a total for mouth moisturization and it is used in mouthwashes, oral gels
surface area of 100 cm2, consisting essentially of multilayered epithe- and sprays.
lium covered with mucus. The oral cavity can be divided in three areas: • Hydrogel 15% (by Honest O3) is an oral gel with ozone infused
the floor of the mouth, the inside of the cheeks, and the gums. Each of sunflower seed oil. This mucoadhesive hydrogel is uniquely for-
these parts is suitable as site of drug administration: the sublingual mulated to clean and nourish the mouth for optimal health.
route uses the floor of the mouth, the buccal route the cheeks, and the • Biotène® product line (by GlaxoSmithKline) has been formulated to
gingival route uses the gums (Hoogstraate and Wertz, 1998). The oral manage a dry mouth and relieve the symptoms.
cavity can be considered an attractive site for drug delivery because of • SCHALI® Dental Care Hydrogel (by SchaliProduct) is a highly-ef-
the ease of administration, the avoiding of drug degradation in the fective universal product for everyday dental and gums care, in-
gastrointestinal tract, and the avoiding of the first-pass metabolism tended to promote complete oral hygiene and regeneration. The
effect (Hao and Heng, 2003). The main advantages of the buccal ad- product contributes to better oral microflora, fresher breath, and
ministration route, besides that previously mentioned, are the patient helps in healing different gingival conditions. SCHALI® Dental Care
compliance, due to the fact that it is not painful, the rapid onset of Hydrogel may be successfully used for treatment and prevention of
action, the very low risk of irritation or undesired side effects, the ex- infectious (bacterial and viral) diseases in oral cavity and larynx.
cellent accessibility, the ease of removal in emergency, the higher Active phyto- and mineral ingredients of the product are capable of
permeability than the skin, the fact that buccal mucosa is well vascu- eliminating bacterial plaque on teeth surface, which causes in-
larized (Hoogstraate and Wertz, 1998; Nagai and Machida, 1993). flammation and smell.
In general, to deliver a drug from the oral cavity, a series of re- • Gengigel® (by Oraldent Ltd.) is a biological mouth and gum-care gel
sistance have to be passed: the drug has to leave the pharmaceutical based on hyaluronan, which helps to accelerate the healing process
form, to diffuse through the mucosa into the local blood circulation of ulcers within the mouth.
systems, and to reach the systemic blood circulation. Substances can be • Nicorette® (by Johnson&Johnson) or Nicotinell® (by
transported across the mucosal membrane by passive diffusion, carrier- GlaxoSmithKline) chewing gums or spray are used to deliver nico-
mediated active transport or endocytosis (Campisi et al., 2010). tine in order to quit smoking gradually.
From the viewpoint of permeability, the sublingual mucosa is more • Buccastem® M buccal tablets (by Alliance) are prochlorperazine
permeable than the buccal mucosa, making it particularly suitable in tablets for nausea and vomiting in previously diagnosed migraine.
applications in which a rapid onset is desired, such as in cases of acute Once placed, Buccastem M tablet dissolves slowly, letting the
disorders. However, this advantage of the sublingual mucosa is lessened medication enter in blood stream without necessity of swallowing.
by the fact that a dosage form put on the sublingual site is affected by • Zilactin-B Gel® (by Zila Pharmaceuticals) is a buccal film used to
the movement of the tongue during speaking. On the other hand, a relieve pain from minor mouth problems (such as toothache, sores)
dosage form inserted onto the buccal mucosa receives less stress, but delivering a local anesthetic (benzocaine) numbing the painful area.
absorption of a drug from the gingiva does not seem promising and it is • Imdur® (by Key Pharmaceuticals) is used to prevent angina by de-
usually preferred for treatments of chronic disorders. Despite many livering isosorbide mononitrate and it can be absorbed by sublingual
dosage forms are suitable for delivery into the buccal mucosa, such as route.
tablets, patches, sprays, chewing gums, or lollypop systems, a large part

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

Table 1
Hydrogel-based commercial products used in buccal drug delivery.
Product Company Main constituent URL

Biotène® GlaxoSmithKline Carbomer and hydroxyethyl cellulose 2txQDwE

Buccastem® M Alliance Xanthan gum 2Itqf1f
Gengigel® Oraldent Ltd. Hyaluronan 2q8cblk
Hydrogel 15% Honest O3 Carbomer 2BM3Cze
Imdur® Key Pharmaceuticals Hydroxypropylcellulose and hydroxypropyl methylcellulose 2Kd6IAJ
Lubrajel™ BA Ashland Glyceryl acrylate and glyceryl polyacrylate 2NktRS1
Nicorette® Johnson&Johnson hydroxypropyl methylcellulose 2NmKKeP
Nicotinell® GlaxoSmithKline Xanthan gum and gelatin 2XhRGP6
SCHALI® SchaliProduct Cellulose gum and hydrogenated starch 2U3P990
Zilactin-B Gel® Zila Pharmaceuticals hydroxypropylcellulose 370JkjQ

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table. Example: "2txQDwE" became "https://bit.ly/2txQDwE".

2.1.2. Oral delivery release can be classified into three categories, depending on the release
The oral administration has been ever considered the simplest and rate limiting step: (i) diffusion controlled, which depends on the drug
the most comfortable administration route, which improves patient diffusivity across the polymeric matrix; (ii) swelling controlled, which
compliance and reduces costs if compared with the injection-based depends on the time necessary to the solvent to penetrate inside the
delivery. Thus, this seems the ideal administration route for therapeutic polymeric matrix and form the gel layer; and iii) chemically controlled,
molecules, in particular for the treatment of chronic disease; however, which depends on reactions happening inside the polymeric matrix
the oral delivery is limited to small molecules. The main challenge in such as hydrolytic or enzymatic degradation of the matrix, usually
the oral drug delivery is to transport drugs into the intestine safely, called generically “erosion” of the matrix (Lin and Metters, 2006).
since most of the drugs orally taken are absorbed in the gastrointestinal Two kinds of conventional formulations based on hydrogels are
(GI) tract. Moreover, they have to face other obstacles such as the poor widely used in oral drug delivery: the matrix systems and the reservoir
permeability across the GI mucosa, the acid catalyzed or proteolytic systems. Concerning the matrix systems, the drug is completely dis-
degradation of drugs, which is particularly relevant in the delivery of persed into the polymeric bulk, usually this result is obtained by me-
molecules such as peptides or proteins (Rizwan et al., 2017). The oral chanical mixing of dry powders. When these matrices enter in contact
delivery of these drugs is in fact seriously limited by low bioavailability with biological fluids, the solvent diffuses into the matrix and causes
due to enzymatic degradation and poor penetration of the intestinal the glass-rubber transition, the gel formation, and the polymer swelling.
membrane into the bloodstream. Beside the proteolytic degradation, a Through the gel layer, the dissolved drug can easily diffuse to be re-
great problem in the oral delivery of macromolecules is constituted by leased into the dissolution medium. Meanwhile, the polymer chains
the low bioavailability of macromolecules, since it decreases sharply dissolve causing the erosion of the matrix. The reservoir systems are
when the molecular mass exceeds 500–700 Da. Moreover, the mole- composed by a drug core which is surrounded by a polymer shell. In
cules need a minimum level of lipophilicity to be absorbed transcellu- these systems the drug release rate is controlled by the hydrogel
larly through passive diffusion and, unfortunately, most interesting properties (its composition and molecular weight), the shell thickness,
macromolecules are hydrophilic (Goldberg and Gomez-Orellana, 2003). the physicochemical properties of the drug (its solubility, particle size,
Thus, since from the discovery of insulin and heparin (Goldberg and or molecular weight) (Yang and Pierstorff, 2012; Caccavo et al., 2017a).
Gomez-Orellana, 2003), one of the greatest challenges is to deliver Some of the commercial products based on hydrogels for oral drug
macromolecules orally (Langer, 1998). The looking for a solution to delivery available on the market are listed below, the main features and
overcome these limitations has focused the attention of scientists for web address where find more information for each product are given in
long time (Peppas et al., 2004). Successful delivery of these molecules Table 2.
requires innovative techniques, such as protection by hydrogel net-
works (Sharpe et al., 2014; Dalmoro et al., 2017). In example, in order • Suprax® (by Sanofi Aventis) is an antibiotic useful to treat a number
to avoid the degradation of proteins or peptides, which takes place in of bacterial infections. It was patented in 1979 and approved for
the acidic environment of the stomach, they can be encapsulated in a medical use in the United States in 1989. It exerts its bactericidal
hydrogel that remains shrunk in the acidic environment avoiding the effect by attaching to penicillin-binding proteins and inhibiting
release of the drug. To reach this goal, natural polymers with anionic peptidoglycan synthesis, thus causing damage to the bacterial cell
pendant groups are usually used since they remain protonated in acidic wall.
environment (Gao et al., 2014; Barba et al., 2009). The most common • Lopid® (by Pfizer Inc.) is a lipid regulating agent, which decreases
practice is to graft natural polymers with acrylic acid derivatives in serum triglycerides and very low density lipoprotein (VLDL) cho-
order to achieve a pH sensitivity to the final polymer (Rizwan et al., lesterol, and increases high density lipoprotein (HDL) cholesterol.
2017; Cascone et al., 2016; Zheng et al., 2019; Mutalabisin et al., 2018). • Advil® Film-Coated (by Pfizer Inc.) is designed for fast pain relief, in
These kind of hydrogels are called “stimuli-responsive hydrogels”, the whole Advil® products family the active ingredient is ibuprofen.
which are able to adapt their network structure, swelling behavior, • Kaletra® (by AbbVie Ltd) is a prescription medicine that is used with
permeability, or mechanical strength depending on the environmental other antiviral medicines to treat human immunodeficiency virus-1
changes, enabling the control of the drug release (Caccavo et al., 2018). (HIV-1) infection.
The external stimuli can be of physical (temperature, electric field, • Vicoprofen® (by AbbVie Ltd) combines the opioid analgesic agent,
light) or chemical (pH, ionic strength, and molecular recognition hydrocodone bitartrate, with the nonsteroidal anti-inflammatory
events) nature (Sharpe et al., 2014). A review on the polymeric network (NSAID) agent, ibuprofen.
design of hydrogels to address responsive and mechanical properties • Gaviscon® (by Reckitt Benckiser Group) is a sodium alginate-based
has been published by Liu et al (2018). pharmaceutical form used for the treatment of symptoms resulting
The drug release mechanisms from hydrogels can vary significantly from the reflux of acid, bile and pepsin into the esophagus such as
depending on a series of factors, which can be related to solute char- acid regurgitation, heartburn, indigestion.
acteristics, formulation composition, or polymer properties (Caccavo, • Toviaz® (by Pfizer Inc) is indicated in adults for treatment of the
et al., 2016; Zarzycki et al., 2010; Cascone, 2017). In general, drug symptoms (increased urinary frequency and/or urgency and/or

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

urgency incontinence) that may occur with overactive bladder gastrointestinal tract, vaginal delivery offers some advantages respect
syndrome. to the oral delivery. Moreover, it has also great potentiality for systemic
• Belviq XR® (by Eisai Inc.) extended-release tablets of lorcaserin delivery due to its large surface area, highly perfusion of tissues, and
hydrochloride is a serotonin 2C receptor agonist for oral adminis- high permeability to a wide range of compounds, including peptides
tration used for chronic weight management. and proteins. On the other side, vaginal delivery as administration route
• Ranexa® (Gilead Sciences) is a prescription medicine used to treat is underestimated because of gender specificity and cyclic variations. In
angina that keeps coming back (chronic angina). In 2016, it was the fact, the permeability of vaginal membrane is influenced by estrogen
276th most prescribed medication in the United States, with more concentration, which of course affects the pharmacokinetics of an ad-
than a million prescriptions. ministered drug, and by the vaginal fluid amount, which changes de-
• Xartemis XR® (Mallinckrodt Pharmaceuticals) is an extended-release pending from the period and the age, and can lead to the detachment of
tablet for oral administration containing both immediate- and ex- a pharmaceutical form. However, a large variety of pharmaceutical
tended-release components. Xartemis XR® is formulated to im- forms are currently used for vaginal delivery, they include: tablets and
mediately release a portion of its oxycodone and acetaminophen capsules, liquid preparations, gels, foams, vaginal films or rings, and
doses and it is designed to swell in gastric fluid and gradually release tampons.
the remainder of oxycodone and acetaminophen to the upper gas- Thus, one of the main drawbacks of this administration route is its
trointestinal (GI) tract. physiological removal mechanism, which is responsible of reduced re-
• Aplenzin® is bupropion hydrobromide extended-release tablet, in- sidence times of the administered forms, that limits considerably the
dicated for the treatment of major depressive disorder (MDD). potentiality of this route. Two main approaches have been proposed to
• Voltaren® is available as enteric-coated tablets for oral administra- overcome this limitation: the use of mucoadhesive formulations to
tion of diclofenac sodium. It is indicated for relief of the symptoms prolong the residence times onto the vaginal mucosa, and the external
of osteoarthritis or rheumatoid arthritis. stimuli-sensitive gelling systems, which undergoes a sol-gel transition
• Levora® and Portia® are oral contraceptive that delivers levo- in the vaginal environment (Caramella et al., 2015).
norgestrel and ethinyl estradiol, hormones that are commonly used The formulations having mucoadhesive properties allow better
in birth control systems. The hormones release is regulated by contact with the vagina surface and longer residence times. The me-
croscarmellose sodium, which is an internally cross-linked sodium chanism of adhesion involves a contact stage, in which three phe-
carboxymethylcellulose, used as a disintegrant and hypromellose, nomena take place simultaneously: hydration, wetting, and diffusion
respectively. (Caccavo et al., 2015). Then, a consolidation stage, which involves the
• Osmotic drug-delivery systems suitable for oral administration ty- strengthening of polymer–mucin joints due to the interactions between
pically consist of a compressed tablet core that is coated with a the polymer chains and the mucus layer, mainly due to van der Waals
semipermeable membrane coating. Some examples are Concerta® forces, hydrogen bonds, or electrostatic interactions (Caramella et al.,
(by Alza Corporation), extended-release tablets approved for the 2015). Usually, these properties are conferred to a formulation by ex-
treatment of attention deficit hyperactivity disorder (ADHD), cipients or polymers. The most used polymers in vaginal formulation
Jurnista® (by Janssen), prolonged release tablets with a semi- are hydrogels: polyacrylates, which are the most investigated bioad-
permeable cellulose acetate coating, both produced using the hesive polymers for vaginal applications, chitosan, which is a natural
OROS® technology, properties of Alza Corporation. polymer easily processable, cellulose derivatives, in particular carbox-

Table 2
Hydrogel-based commercial products used in oral drug delivery.
Product Company Excipients URL

Advil® Pfizer Inc hydroxypropyl methylcellulose 2EWtWb0

Aplenzin® Valeant Pharmaceuticals International, Inc. Ethylcellulose and polyvinyl alcohol 2Cet1ln
Belviq XR® Eisai Inc. Polyvinyl alcohol, hydroxypropyl methylcellulose, polyethylene glycol 2VK8o82
Concerta® Alza Corporation hydroxypropyl methylcellulose (Hypromellose) and polyethylene oxide 2XRKLfy
Jurnista® 2TIrJsV
Gaviscon® Reckitt Benckiser Healthcare Ltd. Sodium alginate and carbomer 974P 2F4Vyfd
Kaletra® AbbVie Ltd Polyvinyl alcohol 2CdCwSa
Levora® Mayne Pharma Inc. Croscarmellose sodium 2LMq159
Lopid® Pfizer Inc hydroxypropyl methylcellulose 2UvsT8n
Portia® Teva Pharmaceutical Industries Ltd. Hypromellose 2nl1Z7U
Ranexa® Gilead Sciences Polyvinyl alcohol and hydroxypropyl methylcellulose 2NYIhYn
Suprax® Sanofi Aventis hydroxypropyl methylcellulose 2J7dZnv
Toviaz® Pfizer Inc Polyvinyl alcohol and hydroxypropyl methylcellulose 2O05Kso
Vicoprofen® AbbVie Ltd hydroxypropyl methylcellulose 2Tvt7ja
Voltaren® GlaxoSmithKline hydroxypropyl methylcellulose and polyethylene glycol 2XRTA9e
Xartemis XR® Mallinckrodt Pharmaceuticals hydroxypropyl cellulose and polyvinyl alcohol 2ERRnC1

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table. Example: "2txQDwE" became "https://bit.ly/2txQDwE".

2.1.3. Vaginal delivery ymethyl cellulose (CMC), hydroxypropylmethylcellulose (HPMC) and

Bacteria, fungi, or viruses can easily colonize the vaginal lumen, their mixtures, Carbopol, and hyaluronic acid, a natural polymer em-
causing various pathologies, among them the most diffused is the va- ployed for its high hydration properties (Valenta, 2005). Among the
ginitis. Thus the vagina has been traditionally employed as route of others, alginate and gelatin can be used in the preparation of vaginal
administration for the delivery of antimicrobial and antiviral drugs. The delivery formulations due to their properties of moisture retention and
vagina constitutes an alternative to the parental route for the admin- biocompatibility.
istration of propranolol (which is more available if the hepatic first-pass Environmentally-sensitive gels are able to undergo a sol-gel transi-
effect is avoided), human growth hormone, insulin, and steroids (which tion in the vaginal environment and, among them, the most used are
show reduced side effects if taken by vaginal route). Since a lack of drug undoubtedly the thermo-sensitive hydrogels. These gels change their
interactions has been observed in vagina compared to the characteristics gelling when the temperature changes from ambient to

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

the physiological one. Thermo-gelation is a reversible mechanism that HPV-induced epithelial micturition and dryness as a complementary
includes partial crystallization, coil-to-helix transition, hydrophobic therapy.
association, and micelle packing, which serves as reversible physical • RepHresh™ Vaginal Gel promotes the maintaining of natural pH
cross-linking points to form a gel (Das Neves and Bahia, 2006). using bioadhesive ingredients (Carbopol), staying in place for up to
The most used products already available on the market are the 3 days.
vaginal odor control products, which are used to contain odor origi- • pHemme revive Natural moisturizer using aloe vera extract and
nating from the vaginal area, including odor during menstruation, ur- other natural ingredients, which help to maintain the natural
inary incontinence, or odor due to imbalance of bacteria. It has been moisture of the vagina such as sodium HA that penetrates the skin
estimated that only the global vaginal odor control product market will and gives immediate moisturizing relief.
grow at a CAGR of 5.32% during the period 2018–2022. • Vagisil® is one of the most diffused vaginal products. It works as a
Some of the commercial products based on hydrogels for vaginal fast acting and long lasting treatment for the symptoms of dryness
applications available on the market are listed below, the main features and helps to re-establish the natural moisture.
and web address where find more information for each product are • Cervidil® (dinoprostone, 10 mg) is a vaginal insert approved to start
given in Table 3. and/or continue the ripening of the cervix in pregnant women who
are at or near the time of delivery. Cervidil® should only be inserted
• Replens® Long-Lasting Moisturizer contains a bioadhesive that al- by a trained healthcare professional in a hospital setting appropriate
lows it to attach to dry cells and deliver continuous moisture until for childbirth.
those cells are naturally regenerated. • Metrogel Vagina® is the intravaginal dosage form of the synthetic
• Hyalo gyn® acts as a moisturizer due to the strong hydrating prop- antibacterial agent, metronidazole, at a concentration of 0.75%.
erties of HA derivative, Hydeal-D®. It adheres to the vaginal mucosa, • Crinone® is a hormone delivery system to administer progesterone
enhancing the residence time, thus hydrating and protecting the usually during fertility assisted procedures. When the gel is inserted
tissue. into vagina, the progesterone is slowly released into the blood-
• ProHydrate® Complex is exclusive to Vagisil. This formulation stream throughout the day.
contains a blend of moisturizers, including Hyaluronic Acid. • Encare® is a vaginal contraceptive that releases nonoxynol-9 as
• Zestica Moisture™ is formulated utilizing two different lengths of HA spermicide directly in vagina.
molecules: (i) shorter molecules of HA, which release water im- • Conceptrol and Gynol II are two hormones-free contraceptives. They
mediately for instant relief and (ii) longer HA molecules, which are based on the use of spermicides that act directly in the vagina.

Table 3
Hydrogel-based commercial products used in vaginal drug delivery.
Product Company Excipients URL

Canesbalance BV Gel Bayer AG Methylhydroxypropyl cellulose 2ZhCaGG

Cervidil® Ferring Pharmaceuticals Inc. PolyEthylene Oxide 33OnJt0
Conceptrol® Caldwell Consumer Health Sodium CarboxyMethyl Cellulose 2M6gG8p
Gynol II 2B1NokV
Crinone® Serono Carbopol 2KO6dOo
Deligyn Dermofarm S.A. Carbomer 2YZYeGH
Elanee Intimate Hydrogel Grünspecht Naturprodukte GMBH Hydroxyethylcellulose 2KNyqDq
Encare® Blairex Laboratories Inc. Polyethylene glycol 2M7PIgA
Hyalo gyn® Fidia pharma USA Inc. Hyaluronic acid 2ZdTZSM
K-Y® jelly Johnson&Johnson hydroxyethyl cellulose 2KX6Gws
Metrogel Vaginal® 3 M Pharmaceuticals Carbopol 2Z9uffd
Miphil® Sandoz Hydroxyethylcellulose 2TLIjFW
pHemme® Revive Aurium Pharma Inc. Hydroxyethylcellulose 2KWULi9
RepHresh™ Vaginal Gel Church & Dwight Co., Inc. Carbopol 2ZcC5A0
Replens® Church & Dwight Co., Inc. Hydroxyethylcellulose 30mviVI
Vagisil® Combe Inc. Hyaluronic acid 2KGdteQ
Zestica Moisture™ Searchlight Pharma Inc. Hyaluronic acid 2TIid6O

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table.
Example: "2txQDwE" became "https://bit.ly/2txQDwE".

gradually break down to deliver a second wave of moisture. 2.1.4. Transdermal delivery
• Canesbalance Bacterial Vaginosis Gel is a triple benefit, 7-day During the last years, transdermal delivery has represented an at-
treatment that relieves the symptoms of bacterial vaginosis infec- tractive alternative to oral drug delivery. For a certain kind of drugs,
tion: it helps to regulate the pH balance, which effectively relieves transdermal delivery offers many advantages with respect to the most
unpleasant odor and abnormal discharge, restricts growth of bad common oral administration. This route can be used when an oral ad-
bacteria, and supports good bacteria (lactobacillus). ministration is not feasible due to a poor absorption of the drug, or to a
• Deligyn is indicated to combat the symptoms of irritation, dryness high first-pass effect, or enzymatic degradation in the gastrointestinal
and itching of the vaginal mucosa with a special adhering for- tract or liver, or when injections using hypodermic needles is not tol-
mulation that guarantees the efficacy of the treatment. erated by the patients (Prausnitz, 2004). However, only a minority of
• Elanee Intimate Hydrogel is a medical water-based lubricant with drugs can be delivered by passive penetration into the skin. The skin is a
panthenol as additive. It moisturizes the skin and avoids the vagina very heterogeneous membrane, which has the role to impede the flux of
drying out. toxins into the body and minimize the water loss. This results in a very
• SILOffGyn is a medical product in the form of a vaginal cream gel for low permeability to the penetration of foreign substance, and the
the treatment of human papillomaviruses (HPV) or dryness. stratum corneum, which is the external skin layer, is the main controller
SILOffGyn creates a protective vaginal mucosa film that acts as a of the absorption. This layer, although it has a thickness of only
defense barrier and provides optimal conditions for the healing of 20–25 μm, is a very effective barrier toward the penetration of drugs

6
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

and it constitutes the major problem to overcome in order to make this structure (Azagury et al., 2014);
administration route effective (Valenta and Auner, 2004). Thus, the • electroporation: it uses short, high-voltage pulses to reversibly
number of drugs that can be administrated by conventional patches is disrupt lipid bilayer of the skin, providing also an electrophoretic
limited to those having a low molecular mass, high lipophilicity, and driving force that can persist for hours (Denet et al., 2004; Prausnitz
small required doses (Prausnitz et al., 2004). Even if the transdermal et al., 1993);
route of administration has been traditionally considered only for to- • cavitational ultrasound: in this case the ultrasounds generate ca-
pical use to treat skin diseases, in recent years it has been considered vitation, which is the formation, oscillation and, in some cases,
also for systemic delivery of drugs (Peppas et al., 2000). In 1979 in the collapse of bubbles in an ultrasonic pressure field. The bubbles os-
United States the first transdermal system for systemic deliver was cillate and collapse at the skin surface generating localized shock
approved. It consisted in a three-day patch for the delivery of scopo- waves and liquid micro-jets at the stratum corneum surface en-
lamine to treat sickness connected to motion. A decade later, the ni- hancing the skin permeability (Polat et al., 2011);
cotine patches were launched on the market and became the first • microneedles and microneedle arrays: they are minimally-in-
transdermal blockbuster, enhancing the visibility and the compliance of vasive devices that painlessly by-pass the skin’s stratum corneum.
patients toward the transdermal patches. Since then, it was estimated Microneedles pierce across the epidermis and increase the skin
that a new patch was approved on average every 2.2 years (Prausnitz permeability creating micron-scale pathways into the skin and they
and Langer, 2008). The most important events and dates associated to can actively drive drugs into the skin using i.e. hollow microneedles
the transdermal drug delivery are reported in Prausnitz et al. (2004) (Courtenay et al., 2018; Migdadi et al., 2018).
and Prausnitz and Langer (2008).
The conventional transdermal patches that have been marketed Hydrogels are being used for transdermal delivery in various forms
during the years can be divided into two main categories: the reservoir- such as patches or creams. They facilitate the skin permeation of drugs
type and the matrix type patches. The first kind are characterized by a via skin hydration by a moisturizing effect and are suitable for topical
complex design which provides the holding of the drug into a solution applications. Furthermore, they have been studied as a means for sta-
or a gel from which the deliver can be controlled by a membrane lo- bilizing and improving transdermal delivery of other systems such as
cated between the drug reservoir and the skin. The latter kind is liposomes, micelles, and nanoparticles (Kong et al., 2016).
characterized by a simpler design in which the adhesive and mechan- Some of the commercial products based on hydrogels for trans-
ical properties of the formulation are combined and usually the rate of dermal delivery available on the market are listed below, the main
drug delivery is governed only by the skin permeability. The main features and web address where find more information for each product
advantage of the reservoir-type patches on the matrix-type is the flex- are given in Table 4.
ibility of the formulation and the better control of the delivery rates
(Prausnitz et al., 2004). After the success of patches on the market, it • Clean & Clear® Persa-Gel® 10 Acne Medication is a unique formula
was realized that the skin enhancement permeability was necessary to that goes to work immediately, releasing the medicine deep into the
enlarge the applications of transdermal delivery. This goal can be pores where pimples start.
achieved by (i) increasing the skin permeability by the rupture of the • Neutrogena® family (by Johnson & Johnson) are used to deliver
stratum corneum structure, or (ii) providing an additional driving force several active ingredient in a cosmetic line containing hydrogels to
for the transport across the skin, and this has to be realized avoiding control the delivery through the skin.
injury to the deeper living tissue (Prausnitz and Langer, 2008). These • Collagen Hydrogel Mask (by Skin Republic) is a serum mask that
techniques can provide the use of (Mitragotri, 2000): instantly restores moisture, elasticity and a healthy glow to the skin.
The formula contains nutrient-packed sea minerals to nourish and
• chemical enhancers: they disrupt the highly ordered bilayer hydrate.
structures of the intracellular lipids in stratum corneum by inserting • Astero® (by Gensco Pharma) is a FDA-cleared hydrogel plus topical
amphiphilic molecules or by extracting lipids using solvents and anesthetic (containing Lidocaine HCl 4%) indicated for painful
surfactants (Benson, 2005; Pathan and Setty, 2009; Finnin and wounds such as ulcerations, pressure wounds, first and second de-
Morgan, 1999); gree burns, post-surgical incisions, cuts and abrasions.
• biochemical enhancers: peptides have been examined as en- • Voltaren Gel® and Voltadol® (by GlaxoSmithKline) and Flector®
hancers of skin permeability (magainin) (Kim et al., 2008) or en- Patch (by IBSA Farmaceutici Italia) contain diclofenac, a non-
zymes (trypsin) (Li et al., 2008); steroidal anti-inflammatory drug to reduce pain and inflammation.
• iontophoresis: it applies a continuous low-voltage current that • Lidoderm® (by Teikoku Pharma USA) was the first prescription,
provides an electrical driving force for transport (Kanikkannan, topical, hydrogel patch approved in the United States for post-her-
2002; Barry, 2001); petic neuralgia (PHN) in 1999. Lidoderm provides analgesia
• noncavitational ultrasounds: they apply an oscillating pressure (without anesthesia) directly to the affected nerves delivering lido-
wave at high frequency that disrupt the stratum corneum lipid caine.

Table 4
Hydrogel-based commercial products used in transdermal drug delivery.
Product Company Main constituent URL

Astero® Gensco Pharma Polyethylene Glycol(PEG) 400 2GV67U8

Collagen Hydrogel Mask Skin Republic Collagen and Sodium Hyaluronate 2GVGoex
Flector® Patch IBSA Farmaceutici Italia Gelatine and carboxymethylcellulose 2NHPThJ
Lidoderm® Teikoku Pharma USA sodium carboxymethylcellulose 2EtPdbM
Neutrogena® Johnson & Johnson Hyaluronic Acid 2UjIwzH
Persa-Gel® 10 Clean & Clear Carbomer, HPMC 2n9BfUk
Voltaren Gel®, Voltadol® GlaxoSmithKline Polyethylene Glycol(PEG) 2TqC8cJ

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table. Example: "2txQDwE" became "https://bit.ly/2txQDwE".

7
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

2.1.5. Ocular delivery release systems are perfect candidates for sustained intravitreal protein
The eye is a very particular organ both from the anatomical and delivery, especially if they are designed to be biocompatible, injectable
physiological point of view, since it contains several different struc- or rapidly in-situ forming, bioresorbable or biodegradable, and trans-
tures, each with a highly specific function. For this reason, the design parent (Delplace et al., 2019). Hydrogels have been approved for sev-
and the optimization of the ocular drug delivery systems have always eral ophthalmic applications since they offer several advantages com-
been a very challenging task for scientists (Srivastava and Pathak, pared to the traditional materials such as colloidal drug delivery
2011). The main obstacle that these formulations have to overcome is systems or polymeric implants. Among these advantages, the mild
to bypass the protective barrier of the eye without causing permanent preparation conditions and the high water content are important fea-
tissue damage (Kumar et al., 2013). The first problem to be solved is the tures to preserve the activity of molecules such as peptides, nucleic
drug loss from the ocular surface that is due to two main causes: the acids, and proteins. Moreover, some kinds of hydrogels can be ad-
flow of lacrimal fluid, which removes the administered compounds ministered using less invasive methods compared to the use of long-
from the eye surface, and the systemic absorption instead of ocular term delivery implants, such as the temperature responsive or in situ
absorption, which takes place both in the conjunctival sac (due to local crosslinked hydrogels (Kirchhof et al., 2015). These hydrogels can be
blood capillaries) or after the solution flow to the nasal cavity (Urtti, administered in the sol-state into the human body and the gelation
2006). Corneal epithelium limits drug absorption from the lacrimal happens in situ.
fluid into the eye since the most apical corneal epithelial cells form Concerning the market of biopharmaceuticals for ophthalmic pre-
junctions that limit the drug permeation. However, trans-corneal per- scriptions, the global sales exceeded $8 billion in 2016 and is expected
meation is the main mechanism of drug transport from lacrimal fluid to to reach $35.7 billion by 2025, with a strong growth in the next five
aqueous humor. Moreover, the blood ocular barriers have to be taken years (Mandal et al., 2018). The global ocular drug delivery technology
into account, both the anterior one, which is composed of the en- market was valued at 15 Billion of US dollars in 2016, and is expected
dothelial cells in the uvea that limit the transport of hydrophilic drugs to reach 25 Billion of US dollars by 2025, expanding at a CAGR of
into the aqueous humor, and the posterior one, between blood stream 5.81% from 2017 to 2025 (Newswire, 2019).
and eye that comprises the retinal pigment epithelium. An overview of Some of the commercial products available on the market are listed
the ocular barriers to anterior segment delivery and the methods to below, the main features and web address where find more information
overcome these barriers using nanocarrier systems can be found in for each product are given in Table 5.
Bachu et al. (2018). Thus, factors affecting ocular bioavailability are:
inflow and outflow of lacrimal fluids, absorption or interaction of drugs • Hylo® Gel (by Candorpharm Inc.) ensures an intensive and lasting
into lacrimal tissues, dilution with tears, and corneal barriers. Due to all lubrication of the ocular surface to treat severe, chronic dry eyes.
these obstacles, topical application of a drug to the eye normally entails These highly viscous eye drops remain for considerably long times
a loss of approximately 95% of the administered dose, which results in on the ocular surface.
poor ophthalmic bioavailability (El-Feky et al., 2018; Battaglia et al., • SYSTANE® Gel Drops provide lasting relief from dry eye irritation.
2018; Gulsen and Chauhan, 2005). Ideal properties of ophthalmic de- They are a thicker eye drops formulation that creates a protective
livery systems are: good corneal penetration with prolonged contact shield over the eyes.
time with corneal tissues, appropriate rheological properties, comfort • Clinitas Hydrate Eye Gel (by Altacor) is another formulation in-
and easiness of installation for the patient, and stability. tended to relief the dry eye syndrome. The eye gel works to enhance
There are several possible routes of drug delivery into the ocular the layer of your tear film, providing longer-lasting moisture
tissues depending on the target tissue. Usually, topical ocular and throughout the day.
subconjunctival administrations are used for anterior targets and intra- • Ocular Therapeutix™ is a versatile platform used to encapsulate
vitreal administrations for posterior targets (Urtti, 2006). Topical ophthalmic pharmaceuticals within hydrogels to deliver sustained
ocular delivery is usually accomplished by eye drops or ointments, and therapeutic level of drugs to targeted ocular tissues (https://
which account for approximately 90% of currently marketed oph- www.ocutx.com/about/hydrogel-technology/).
thalmic pharmaceuticals due to their low costs, rapid drug action, ease • Retisert® (by Bausch and Lomb) is a sterile implant designed to re-
of administration, and high acceptance by patients because they are not lease fluocinolone acetonide locally to the posterior segment of the
invasive (Bertens et al., 2018). Among their disadvantages, in addition eye for approximately 2.5 years.
to the scarce bioavailability, there is the short contact time on the eye • In 2014, The US Food and Drug Administration approved Iluvien®
surface that usually implies repeated administrations that can weaken (by Alimera Sciences) for the treatment of diabetic macular edema
the patient compliance (Shen et al., 2018). The contact times can be to deliver 36 months of continuous, low-dose corticosteroid with a
prolonged by formulations design such as gels, gelifying formulations, single injection.
hydrogels, nanoparticles, liposomes, and micelles (Jeon et al., 2018). • Restasis® (by Allergan) ophthalmic emulsion is indicated to increase
Using the subconjunctival administration, the drug can bypass the tear production in patients whose tear production is limited due to
conjunctiva–cornea barrier, giving direct access to the trans-scleral ocular inflammation.
route (Burgalassi et al., 2018). Due to this, this route of administration • Ocusert®, a pilocarpine ocular therapeutic system, is the first pro-
has been often used clinically despite it is very invasive due to the re- duct marketed by Alza Corporation. It is used for glaucoma treat-
peated injections (Shen et al., 2018). One of the most used devices for ment and it is composed by a copolymer membrane in which the
drug delivery into the conjunctival sac are the resorbable ones, which core is a drug reservoir dispersed into an alginic acid matrix.
dissolve over the time releasing their drug content. These devices have • Lacrisert® and Vitrasert® (by Bausch and Lomb) are a prescription
the main advantage that they have not to be removed, even if usually lubricant that is inserted into the eye to provide up to 24-hour relief
they have a limited time of action (typically less than 24 h), requiring from moderate to severe dry eye symptoms and the first intravitreal
frequent administrations (Bertens et al., 2018). Concerning the drug implant for the treatment of cytomegalovirus (CMV) retinitis in
delivery into the vitreous humor, this has the advantage to offer a direct AIDS patients, respectively.
access to the vitreous and retina, determining an immediate and in- • Ozurdex® (By Allergan) is a tiny implant for ophthalmic intravitreal
creased therapeutic effect at the intended tissue. This delivery tech- injection that slowly releases corticosteroid medication over time,
nique has been long used in therapeutics: since 1911 intravitreal in- without the need for monthly injections. It dissolves naturally and
jections were described to employ an intravitreal air bubble does not need to be removed.
tamponading a retinal tear (Meyer et al., 2016). Moreover, being the • Dexycu and Yutiq™ employ Verisome® technology (property of
humor itself a gel, primarily composed by hyaluronan, hydrogel-based EyePoint Pharmaceuticals) to dispense a sustained-release of drugs

8
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

using biodegradable formulations. attractive for patients. One of the main drawbacks in the use of hy-
• I-vation intravitreal implant and sustained drug delivery system (by drogels as wound dressing is that exudate accumulation can cause
Surmodics, Inc.) have been proven to provide controlled long-term maceration and bacterial proliferation in the wound. Moreover, the low
drug delivery into the posterior chamber of the eye. mechanical strength of hydrogels leads to a difficulty in handling
(Dhivya et al., 2015). When a new material is proposed to be used as
wound dressing, the testing of its mechanical properties is of a funda-
Table 5 mental relevance. It has to possess good tensile properties (tensile
Hydrogel-based commercial products used in ocular drug delivery.
strength), since it has to bear the elongational stresses applied on the
Product Company Main constituent URL human skin. Tensile strength, which is defined as the ratio between the
force necessary to break the sample and its cross-sectional area, and
Clinitas Altacor Carbomer 2GIlmz9
Hydrate®
elongation at break, which is defined as the ratio between the length at
Hylo® Gel Candorpharm Inc. Sodium hyaluronate 2Gzopta breaking point and the initial one, can be easily measured using a
Iluvien® Alimera Sciences Polyvinyl alcohol and silicone 2DwpyyJ texture analyzer. The polymer sample is held between two clamps po-
adhesives sitioned to a certain distance between them. Once the test is started, one
I-vation Surmodics, Inc.) Poly(methyl methacrylate) (PMMA) 2GGDyc7
of the clamps begins to move pulling the sample towards the top. The
Ocusert® Alza Corporation Alginic acid 2E6y4FP
Ozurdex® Allergan poly (D,L-lactide-co-glycolide) 2GKGzbk force and the elongation are measured at film broke (Khan et al., 2000).
(PLGA) In the wound care and healing, it is crucial to identify the correct
Restasis® Allergan Carbomer 2GAf44u needs of the injured part in order identify the material that most ap-
Retisert® Bausch and Lomb Silicone elastomer and polyvinyl 2X4sNGy propriately has to be used. Some examples of materials that are com-
alcohol membrane
Lacrisert® Hydroxypropyl cellulose 2GHVqU3
monly used in wound care and commercial products available on the
Vitrasert® Polyvinyl alcohol coating 2UUZKmL market are listed below (Inc, 2018), the main features and web address
Systane® Alcon Polyethylene Glycol 400 2StjFfZ where find more information for each product are given in Table 6.
Yutiq™ EyePoint polyvinyl alcohol 2Bz0xT3 Hydrocolloids: it is a wide class of materials, and they are usually
Pharmaceuticals
used on burns, necrotic wounds, or under compression wraps. They can
The URL for each product webpage is: "https://bit.ly/" + the seven-character
be used as powders or pastes of gelatin, pectine, or carbox-
string reported in the table. Example: "2txQDwE" became "https://bit.ly/ ymethylcellulose.
2txQDwE".
• 3 M™ Tegaderm™ Hydrocolloid Dressing (3 M Health Care) is a self-
adhering product used on superficial wounds and abrasions, super-
2.2. Wound dressing ficial and partial-thickness burns.
• Gentell CMC Fiber Dressing (Gentell Corp.) is a carbox-
Wound healing is a complex process that includes the replacing of ymethylcellulose absorptive dressing for wounds with moderate to
devitalized or missing cellular structure and tissue layers and it is heavy exudate since gel-like substances support the moist healing
strongly dynamic, since it involves several cell populations, the extra- process and minimize the risk of leakage and maceration.
cellular matrix, and the intervention of mediators (i.e. growth factors) • Comfeel® Plus Contour Dressing (Coloplast Corp.) is a butterfly-
(Velnar et al., 2009). It is a continuous process, which involves co- shaped hydrocolloid (mainly composed by carboxymethylcellulose)
ordinated actions between different immunological and biological sys- dressing for better conformity and adhesion, specially designed for
tems: the fact that different parts of a wound may be at different healing difficult-to-dress areas.
stage makes the wound treatment an interesting and challenging topic. • CovaWound™ Hydrocolloid dressing (Covalon Technologies, Ltd.)
Since a complete and detailed description of the phases of wound maintains an optimal moist wound environment and provides a high
healing and the factors affecting the process is beyond the scope of this rate of moisture vapor transmission. Composed of an absorbent
work, the reader can refer to more specific literature (Guo and DiPietro, hydrocolloid matrix that has a hydrocolloid border laminated onto a
2010; Janis and Attinger, 2006; Martin, 1997). Despite that, it is worth breathable polyurethane film backing. It is indicated for the man-
to mention properties that, if owned by the dressing used to treat the agement of lightly exuding wounds such as: pressure, leg and foot
wound, can help during the healing process. First of all, keeping a ulcers, superficial partial-thickness burns.
wound moist rather than dry allows to heal more rapidly and with less • DermaFilm® (DermaRite Industries, LLC) is a hydrocolloid protec-
chance of scarfs. Keeping away the wounds from mechanical stresses, tive wound dressing for minor abrasions, closed surgical wounds,
which can cause the opening of the wound, and from the external en- superficial pressure ulcers, and skin grafts.
vironment, minimizing the danger of contaminations due to pathogens
or foreign bodies is a common practice. Of fundamental relevance is to Alginate: this type of dressings are used for moderate to high
keep high level of oxygen tension on wound’s surface, since oxygen is amounts of wound drainage, venous ulcers, packing wounds and pres-
not only a key element in the reparative processes such as cell pro- sure ulcers in stage III or IV.
liferation and synthesis of collagen, but even because it aids the gen-
eration of leukocytes, which are essential to kill bacteria (Tandara and • Ca-alginate dressing (Gentell Corp.) is a sterile, comfortable, ad-
Mustoe, 2004). An ideal wound dressing should contribute to maintain vanced fiber-structured alginate with a highly absorbent capacity.
an appropriate temperature to promote the blood flow to the wound Alginate dressings absorb, collect and contain exudate while pro-
bed, it must be sterile, non-toxic, and non-allergic (Dhivya et al., 2015). viding a moist healing environment. It is intended for application in
Due to the hydrogels’ properties of maintaining a high moisture dry form on shallow wounds including leg, pressure, and diabetic
content at the wound site and simultaneously allowing the gas ex- foot ulcers and surgical wounds. May also be used for minor con-
change between the wound and the external environment, of bio- ditions such as lacerations, abrasions, skin tears and minor burns.
compatibility, of fast biological fluids absorption (i.e. of wound exu- • Kaltostat® (Convatec) is a soft, sterile, alginate dressing that con-
date), and of providing a cooling effect decreasing the temperature of verts to a firm gel on contact with fluid. It may be used on moderate
the wound site, their applications in wound management have attracted to heavily exuding wounds chronic and acute wounds.
both the academic and the industrial interests (Sharma et al., 2018). • Algisite M (Smith & Nephew) is a calcium-alginate dressing which
Moreover, due to hydrogels’ softness and elasticity, they are easy to be forms a soft gel that absorbs when it comes into contact with wound
applied and removed, making the dressing more comfortable and then exudate. Algisite M may be used for the management of minor

9
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

conditions such as lacerations, abrasions, skin tears, minor burns. burns. It is characterized by a glycerin formulation which not dry
Alginate fibers create a moist wound environment at the wound out.
surface. This helps to prevent eschar formation and promotes an • Sofargel (Sofar) is used in the healing of abrasions, grazes, cut, first-
optimal moist wound environment. The dressing allows wound and second-degree burns. It is mainly composed by a hydrogel
contraction to occur, which may help to reduce scarring and also (Carbopol 974P) and allows to maintain the moisture content to
allows gaseous exchange necessary for a healthy wound bed. simplify tissue regeneration.
• NU-GEL™ Hydrogel (Systagenix) helps to create a moist wound • Inadine™ (Systagenix) is PVP medication dunked in Polyethylene
healing environment and is indicated for debridement and de- Glycol (PEG). It is indicated for the treatment of ulcers, minor burns,
sloughing of wounds together with the management of chronic and chronic wounds.
wounds throughout all stages of the healing process. The gel can be • Finally, it has to be mentioned in this compound class
used to soften and hydrate eschar by facilitating rehydration of the Amniomatrix®4 (Derma Sciences Inc.), which is a cryopreserved li-
wound. quid allograft derived from the components of the amniotic mem-
• Finally, it has to be mentioned Medihoney® Adhesive Dressings brane and amniotic fluid that provides structural tissue to advance
(Derma Sciences Inc.), which is composed of a Calcium Alginate soft tissue repair, replacement and reconstruction.

Table 6
Hydrogel-based commercial products used in wound dressing.
Product Company Main constituent URL

Algisite M Smith & Nephew Alginate 2D59yU6

Condress Collagen 2Spi0Hn
Amniomatrix®4 Derma Sciences Inc. Amniotic membrane and fluid constituents 1Y5LrJw
Medihoney® Adhesive Dressings Alginate 2DS648T
Comfeel® Plus Contour Dressing Coloplast Corp. Carboxymethylcellulose 2MM74yn
CovaWound™ Hydrocolloid dressing Covalon Technologies, Ltd. Hydrocolloids 2MPPRnB
Cutimed® Gel Bsn Medical Gmbh Carbomer 940 2G6kTXK
DermaFilm® DermaRite Industries, LLC Hydrocolloids 2WFfb4d
Gentell CMC Fiber Dressing Gentell Corp. Carboxymethylcellulose 2ScM6OX
Ca-alginate dressing Alginate 2BmLjAB
Helix3-cm® Amerx Health Care Corp. Collagen 2HQ0fwP
Inadine™ Systagenix Polyethylene Glycol 2S5YrEJ
NU-Derm™ Hydrogel Alginate 2HZ5mem
Kaltostat® Convatec Alginate 2RDyrey
Kendall™ Hydrogel Dressing Cardinal Health Glycerin formulation 2GqY7tf
Sofargel Sofar Carbopol 974P 2BhPSMu
Tegaderm™ Hydrocolloid Dressing 3 M Health Care Hydrocolloids 2StNlIU

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table. Example: "2txQDwE" became "https://bit.ly/2txQDwE".

dressing impregnated with 100% Leptospermum or Manuka Honey. 2.3. Tissue engineering & scaffolds
This dressing provides wound fluid absorption capabilities and
continuous donation of honey to the wound bed, which has an an- Tissue engineering is a relatively new field that combines the use of
timicrobial effect. This dressing is for partial to full thickness living cells, biocompatible materials, and growth factors to create
wounds and burns that are moderately to heavily draining. tissue-like structures. It is aimed to restore or improve tissue functions
that are defective or that have been lost because of pathological con-
Collagen: this dressings can be used for chronic or stalled wounds, ditions. The methods used by tissue engineering can be divided into
ulcers, bed sores, transplant sites, surgical wounds, second degree or three categories: (i) implantation of isolated cells or cell substitutes into
higher burns and wounds with large surface areas. Collagen is a fibrous the organism, (ii) delivering of tissue-inducing substances (such as
protein that constitutes the extracellular matrix of human tissues, growth factors), and (iii) placing cells on or within different matrices
among them skin, tendons, and bones and it constitutes about 25% of (Dhandayuthapani et al., 2011). The last strategy is based on the im-
the total body proteins. plantation of living cells on a natural or synthetic extracellular sub-
strate, or scaffold, in order to be implanted in living bodies. Scaffolds
• Helix3-cm® (Amerx Health Care Corp.) is composed by 100% of are three-dimensional porous solid biomaterials that are designed to
bovine collagen and it is a thin, semi-transparent dressing used to fulfill one or more function, such as: (i) to promote cell attachment,
maintain a moist wound environment allowing a better observation migration, and cell-biomaterial interactions; (ii) to allow, through
of the wound healing process. adequate porosity and interconnected channels, sufficient transport of
• Condress (Smith & Nephew) is a dressing composed by pure equine gases, nutrients, and wastes (Caccavo et al., 2017b) in order to guar-
collagen extract from horse tendons and contributes to speed up the antee cell survival, proliferation, and differentiation; (iii) to biodegrade
healing process of chronic skin wounds, even acute wounds. at a controlled rate that usually is the same of tissue regeneration at
predetermined conditions; (iv) to ensure the desired mechanical char-
Miscellaneous: this type of dressing is intended for painful wounds, acteristics; (v) protect cells from possible damages via external factors;
necrotic wounds, pressure ulcers, donor sites, second degree or higher and (vi) to have a minimal degree of inflammation and toxicity
burns and infected wounds. (Dhandayuthapani et al., 2011; Berthiaume et al., 2011; Ovsianikov
et al., 2018). A scaffold is ideally expected to function as a temporary
• Cutimed® Gel (Bsn Medical Gmbh) is a clear, amorphous hydrogel extracellular matrix (ECM), capable of fulfilling various biomechanical
(Carbomer 940) for the treatment of necrotic and sloughy tissues in requirements, whilst being gradually resorbed and eventually replaced
chronic wounds. by host bone (Deb et al., 2010). The first successful tissue-engineered
• Kendall™ Hydrogel Dressing (Cardinal Health) is indicated for use skin products were produced in early 1980s but most scientists agree
on light- to moderate-draining wounds, first- and second-degree that modern tissue engineering started around 1987. Some historical

10
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

highlights related to tissue engineering and its development are re- in mind that not all the tissue engineering applications require a com-
ported in Berthiaume et al. (2011). Nowadays, approximately 500 plete degradation of the scaffold but in some cases, such as articular
different companies are involved in tissue engineering field worldwide cartilage or corneal replacement, a permanent scaffold may be the
and the global scaffold technology market has been evaluated in 879 better choice. Hydrogels have unique characteristics, such as hydro-
million of US dollars in 2018 and the prevision is 1063 in 2020 (Lee philicity, biocompatibility, and the ability to modify the drug release
et al., 2014). Among the companies related to three-dimensional cell rate by controlling the swelling and degradation rate with external
culture consumables and instruments, BD Biosciences is the largest with stimuli, which make them perfect candidates to act as carriers for
a 27% of the market share, followed by Life Technologies (16%), controlled release of bioactive molecules or drug depots. For this
Corning (11%), Sigma-Aldrich (8%), Lonza (6%), Insphero (4%), 3D reason, to mimic the function of ECM as reservoir of growth factors, a
Biotek (4%), and Global Cell Solutions (3%) (Lee et al., 2014). The class of proteins or polypeptides that contributes to cell functions such
eventual pathway from a new scaffold idea to the final clinical appli- as differentiation, migration, proliferation and gene expression, they
cation is long and expensive, often taking up to 10 years with a cost have been incorporated in hydrogel based scaffolds (Zhu and Marchant,
ranging from 10 to over 200 million of dollars (Hollister, 2009). 2011). Using the combining of tissue engineering and drug delivery
The most important characteristics that the materials chosen as functions, the same system may be able to regulate cell response and
scaffold must have is the biocompatibility, in order to avoid undesired tissue formation.
body reaction to the implant, such as reject, and to facilitate the cell Hydrogels commonly used for scaffold production can be (i) natural,
attachment, and the biodegradability, in order to disappear after a such as proteins, polysaccharides; (ii) synthetic, both non-biodegrad-
certain time by degradation into nontoxic products (Yang et al., 2001). able (PHEMA, PVA) and biodegradable (PEG, synthetic peptides); or
Another fundamental issue that have to be considered is the micro- and (iii) hybrids (complex hydrogels deriving from a combination of poly-
macro-structure of the materials. Highly porous materials are desirable mers) (Zhu and Marchant, 2011; Rahmani Del Bakhshayesh et al.,
because large surface area promotes cell attachment and growth, be- 2018).
cause the diffusion of nutrients and wastes is facilitated, as well as the Alginate. Alginate is a brown-algae-derived polysaccharide com-
vascularization, which is particularly important in tissues and organs posed of β-D-mannuronic acid and R-L-guluronic acid units. By the
with metabolic functions. Of course, the pore size and the pore size addition of divalent cations, alginate solutions rapidly form iono-
distribution have a fundamental role in tissue engineering (Chen et al., tropical gels that have been found extremely interesting for applications
2018) and they have to be adapted depending of the scaffold applica- in biomedical field. It is commonly used as microcarriers for cell en-
tion (Jeon et al., 2018; Yang et al., 2001), in order to facilitate the re- capsulation (Gonzalez-Pujana et al., 2018; Cañibano-Hernández et al.,
vascularization of tissues. Concerning the structure of a scaffold, not 2018). Since alginate does not have cell-interactive properties and does
only the dimensions are a critical factor, but even the continuity of not mimic the natural ECM, it can be found combined with other hy-
pores within the matrix. In fact, if the structure is highly porous but the drogels, cell-interactive peptides, or growth factors that can be attached
channels are not interconnected, the mass transport (of nutrients, to the alginate backbone (Van Vlierberghe et al., 2011). Moreover, al-
wastes, and cells) is inhibited, failing the scaffold role (Wang et al., ginate semi-interpenetrating polymer networks can be successfully used
2018). Moreover, scaffolds necessitate to have the mechanical strength in biomedical applications, mainly due to the combination of the
necessary to maintain its structure after the implantation, especially for properties of the constituting materials that allows to overcome the
application in tissues such as bones or cartilages and they have to disadvantages of a single polymer network, providing better thermal
guarantee a good processability, particularly when the final shape of stability, mechanical and chemical resistance (Zoratto and Matricardi,
the implanted scaffold has an influence on its activity (Yang et al., 2018; Kumar et al., 2018). Thus, alginate can be found combined with
2001). Three different categories of scaffold applications can be iden- elastine and angiogenic factors for reconstruction of blood vessel, with
tified: (i) space filling agents; (ii) bioactive molecule delivery; and III) agarose, hyaluronic acid, and growth factor for cartilage repair appli-
cell/tissue delivery (Drury and Mooney, 2003). cations, with chitosan for liver repair applications (Van Vlierberghe
Hydrogels are materials commonly used in tissue engineering field et al., 2011). A review of the use of alginate hydrogels in culturing 3D
because of their biocompatibility, degradability, processability under cells can be found in (Andersen et al., 2015), one of the most used
mild conditions (which facilitate the entrapment of viable cells), their alginate-based commercial product for 3D cell culture is AlgiMatrix®
mechanical and structural properties comparable with many tissues and (by Thermo Fisher Scientific).
ECM, and the possibility to be delivered in a low-invasive way (Drury Hyaluronic Acid. Hyaluronic acid (HA) is naturally occurring as
and Mooney, 2003). Different applications of hydrogels can be found in glycosaminoglycan (GAG) and it is present in all the vertebrates. It is a
literature related to regenerative medicine, such as scaffold for cellular major constituent of the ECM, in example it can be found in the vitreous
organization, tissue barrier against restenosis, bioadhesives, drug re- humor of the human eye, in skin, in cartilage, in synovial joint fluid,
servoir, matrix to deliver bioactive agents encouraging the natural re- and in the matrix produced by the cumulus cells around the oocyte
parative process, or to encapsulate and deliver cells (Slaughter et al., prior to ovulation (Collins and Birkinshaw, 2013). However, high mo-
2009; El-Sherbiny and Yacoub, 2013; Chung et al., 2018; Dash et al., lecular weight HA is a natural barrier for angiogenesis and prolifera-
2018; Badylak and Gilbert, 2008). The ECM is a complex network tion, thus, to allow cellular infiltration and remodeling of the material
structure surrounding and supporting cells of natural tissues and it by cells, HA can be crosslinked with protease-degradable peptides and
constitutes also a bioactive and dynamic environment that mediates modified with cell adhesion ligands (Lam et al., 2014). HA-based
cellular functions (Zhu and Marchant, 2011). Thus, it is highly desirable polymers has been used as cell carriers for tissue engineered repair of
to produce scaffolds that mimic both the structure and the bio-functions bone and cartilage or their regeneration, in central neural tissues en-
of the natural ECM. One of the prerequisites necessary for the cell gineering for nerve and brain repair, in soft tissue repair and smooth
growth process is the cell attachment to the ECM to allow cells pro- muscles engineering (Collins and Birkinshaw, 2013).
liferation and migration. It has to be considered that these functions last
until the degradation of the polymer is complete. Thus, if the biode- • Hyalograft® (Anika Therapeutics, Inc.) is a minimally invasive tissue
gradation is faster than the tissue regeneration, the scaffolds will lose engineering approach, consisting in the implantation of expanded
their carrier function for cell growth; on the other hand, if the biode- autologous chondrocytes grown on a three-dimensional HA-based
gradation is too slow compared with tissue regeneration, the scaffolds scaffold, useful in treatment of acute cartilage lesions (Menaa et al.,
will impede tissue regeneration. Therefore, scaffolds’ critical design 2011). This technology has been recently resumed to produce solid
factors are the degradation rate of the polymer and the transition of the HA-based treatments, including Hyaloglide®, a transparent, highly
functions between the scaffold and the emerging tissue. It has to be kept viscous barrier gel used to prevent or reduce adhesions after various

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

surgical procedures; Hyalonect®, a bio-resorbable knitted mesh used • TissueMend™ Soft Tissue Repair Matrix (by Stryker Orthopaedics) is
in orthopedic and trauma reconstructive surgeries composed of an acellular, collagen membrane used to repair and reinforce soft
Hyaff® (HA crosslinked by esterification with benzyl alcohol); and tissues where weakness exists. It is composed of native collagen,
Orthovisc-T®, an ultra-pure, high molecular weight injectable hya- non-denatured, from fetal bovine dermis.
luronic acid (HA) designed to relieve pain and restore function to • The OrthADAPT™ Bioimplant is a biocompatible, stabilized, term-
tendons damaged by chronic tennis elbow. inally sterilized collagen scaffold launched from Pegasus Biologics,
• Gel-One® Hyaluronate (by Zimmer Biomet) is an injectable hyalur- Inc., in order to improve the repair and reconstruction of soft tissue
onate gel approved for the treatment of osteoarthritis of the knee. in musculoskeletal procedures.
• Alloderm® Regenerative Tissue Matrix (RTM) (by BioHorizons) is an
Collagen. Collagen is the most abundant protein in the human acellular dermal matrix for soft tissue applications, containing un-
body, nearly 30% of all proteins. During tendons and ligaments healing, damaged collagen and elastin matrices.
cells that usually produce collagen of normal intact tissues are induced • Apligraf® (by Organogenesis) consists of living cells and structural
to synthesize different types of collagen at the repair site (Liu et al., proteins. The lower dermal layer combines bovine type 1 collagen
1995). Since the role of collagen is of fundamental relevance during the and human fibroblasts (dermal cells), which produce additional
natural healing processes, this has been extensively used as support matrix proteins.
material, particularly for tendon and ligament repair (Chen et al.,
2009). Concerning the commercial products used in this area, the most Other polymers commonly used as scaffolds are:
famous are:
• poly(glycolic acid) (PGA) that can be used in applications such as
• Graftjacket™ (by Wright Medical), which is derived from human synthetic suture (Dexon™ by Medtronic) or bone internal fixation
dermal collagen matrix and it is freeze-dried with a proprietary devices due to its good mechanical properties.
process that prevents the formation of ice crystals to preserve the • Poly(lactic acid) (PLLA) is used in orthopedic fixation device, such
intact matrix including vascular channels. as SmartPin® and Bio Mini-Revo® (by Conmed), which are resorb-
• The Restore™ Orthobiologic Soft Tissue Implant (by DePuy, Inc.) is a able orthopedic pin and screw-in implants, respectively, Bio-
round device, manufactured from 10 layers of Small Intestine Anchor® (by Conmed) for shoulder repair intervention; Biocryl® and
Submucosa (SIS), a biomaterial derived from porcine small intestine Milagro Advance Interference screw (by De Puy) used in cruciate
and it is composed mainly of water and collagen. ligament reconstruction.
• The Zimmer® Collagen Repair Patch (by Zimmer) is a biological • Poly(lactide-co-glycolide) (PLGA) is used for resorbable sutures
implant consisting of an acellular scaffold of collagen and elastin, (Vicryl® by Ethicon Inc.) due to its high degradation kinetics.
derived from porcine dermal tissue. In tensile tests, the Zimmer • Polyethylene glycol (PEG) can be used in surgical procedures, such
Collagen Repair Patch was shown to withstand a significantly larger as Veriset™ Hemostatic patch by Medtronic; a PEG ester solution and
load than SIS patches. a trilysine amine solution are constituent of DuraSeal®, a synthetic
• Permacol™ (by Tissue Science Laboratories) surgical implant is a absorbable surgical sealant by Integra.
porcine dermal collagen implant from which cells, cell debris, DNA
and RNA are removed in a gentle process that is not damaging to the The main features and web address where find more information for
3D collagen matrix. The resulting acellular collagen matrix is then each product listed in this section are given in Table 7.
cross-linked for enhanced durability.

Table 7
Hydrogel-based commercial products used in tissue engineering applications.
Product Company Main constituent Application URL

AlgiMatrix® Thermo Fisher Scientific Alginate Cell culture 2UF71Hg

Alloderm® Regenerative Tissue Matrix BioHorizons Collagen and elastine soft tissue applications 2SqFPhP
Apligraf® Organogenesis Collagen and fibroblast Living cells and structural proteins to produce 2TuaHvd
matrices
Biocryl® De Puy Poly(lactic acid) cruciate ligament reconstruction 2HZbUts
Milagro Advance 2t6Icbw
Dexon™ Medtronic poly(glycolic acid) synthetic suture 2t6KJTc
or bone internal fixation devices
Veriset™ Hemostatic patch Polyethylene glycol Hemostatic patch 2RAH7lX
DuraSeal® Polyethylene glycol absorbable surgical sealant 2MQFOhX
Gel-One® Hyaluronate Zimmer Biomet Hyaluronic acid Osteoarthritis of the knee 2Sq79Nm
Graftjacket™ Wright Medical Collagen preserve the intact matrix including vascular 2HRXvyT
channels
Hyaloglide® Anika Therapeutics, Inc. Hyaluronic acid Cartilage lesions 2G9pEQy
Hyalonect® Reduce adhesions after surgery 2GbWAaQ
Orthovisc-T® Restore function of tendons 2DUkmGh
OrthADAPT™ Bioimplant Pegasus Biologics, Inc. Collagen Repair of soft tissue in musculoskeletal procedures 2SmtVWv
Permacol™ Tissue Science Collagen 2GlxPbD
Laboratories
Restore™ Orthobiologic Soft Tissue Implant DePuy, Inc. Collagen and water Orthopedic tissue 2SpE7gJ
SmartPin® Conmed Poly(lactic acid) resorbable orthopedic pins 2BfIO2Y
Mini-Revo® shoulder repair intervention 2BjFfIW
Bio-Anchor® 2t0YBye
TissueMend™ Stryker Orthopaedics Collagen Soft Tissue Repair Matrix 2UGETDQ
Vicryl® Ethicon Inc. Poly(lactide-co- resorbable sutures 2MOh4Hl
glycolide)
Zimmer® Collagen Repair Patch Zimmer Collagen and elastine Rotator Cuff Tendon Repair 2HM0LMe

The URL for each product webpage is: "https://bit.ly/" + the seven-character string reported in the table. Example: "2txQDwE" became "https://bit.ly/2txQDwE".

12
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

2.4. Contact lens preferred by patients in terms of comfort (Orsborn et al., 2018; Ozark and
Kunzler, 1999; Steffen et al., 2008); even if it has to be considered that in
The first time that a corneal lens (or rigid lens) was developed dates vivo hydration levels can be influenced by lens thickness, osmolarity, size
back to 1948, when, starting from a laboratory error, an optical techni- of the palpebral aperture, or environmental conditions (Fonn, 2007).
cian tried to wear in his own eye only the corneal portion of a PMMA Thus these properties are fundamental, since the first reason leading pa-
scleral lens and he found that the lens could be tolerated by his eye. This tients to the discontinuation of the use of contact lens is discomfort (about
discovery led to the first patent in the same year (Efron, 2016). The at- 50%), followed by vision problems (about 10%) and difficulty of handling
tempts to improve the wearability and the performances of contact lenses (about 5%) (Sulley et al., 2017). In order to combine the characteristics of
grew during the years, but the turning point was achieved by Otto softness, wettability, and comfort of the conventional hydrogels with the
Wichterle, who produced, although discouraged by his superiors, soft high oxygen transmission of siloxanes and fluorosiloxane, a new class of
lenses composed of hydroxyethyl methacrylate (HEMA). The patent (Otto materials, called siloxane hydrogels, have been introduced (Nicolson and
and Drahoslav, 1965) to produce commercially soft contact lenses was Vogt, 2001; Lin et al., 2014).
acquired by Bausch&Lomb in 1972. Since then, the market of contact Concerning the commercial products currently available on the
lenses started to proliferate. Since the first uses of contact lenses, it ap- market, they have been proliferated during the years (see Table 8).
peared evident that the physiological response of the eye would have Among them, it can be found:
been improved by using materials more permeable to oxygen and with a
reduced absorption of proteins, lipids, or other teats’ constituents. The • Avaira® and Biofinity® (Coopervision Inc.) are both composed of N-
following turning point in the improvement of contact lenses was the vinylpyrrolidone (NPV) with viscosity modifying admixture (VMA)
incorporation of silicone into the basic PMMA structure, which led to the in order to increase comfort and stability to the lens.
birth of a new family of polymers for contact lens applications, the so • Coopervison launched in the market the MyDay® contact lenses,
called silicone acrylates (1974). Actually, the most significant advance in with the Smart Silicone™ technology, which allows to deliver
contact lenses development since the introduction of HEMA has been oxygen to the eyes much more efficiently using less silicone. This
attributed to the launch on the market of two spherical-design silicone results in softer lens and allows more room in the lenses for other
hydrogel lenses by CIBA Vision (with the product Focus Night & Day®) components to improve the hydration of eyes.
and Baush & Lomb (with the product Purevision®) in 1998. In 2001 lenses • Based on the use of silicone hydrogel are the PremiO lenses (by
manufactured from silicone hydrogel materials were introduced into the Menicon), product of Japanese research to optimize the delivery of
US market and, since then, their prescribing has reached a peak of 73% of oxygen to the eye using very permeable materials.
all soft lenses, remaining at this level up to 2014 (Efron et al., 2015).
Being the ocular environment very sensitive to the external stimuli, As mentioned above, the siloxane-based materials are extensively
the hydrogel based biomaterials used to produce contact lenses must have used to produce contact lenses, some examples are:
specific properties, such as: be permeable to oxygen and to ions, in order
to ensure the corneal metabolism and the on-eye movement, respectively, • Dailies Total1 (by Alcon), having a water content that ranges from
be comfortable, hydrolytically stable, biologically inert, and allow a clear 33% at the core to over 80% at the surface, and at the outer surface
and stable vision maintaining a continuous tear film on the eye (Deichert reaches almost 100%, nearly the same as the surface of the cornea.
et al., 1979). In order to obtain a high visual performance, the hydrogel Moreover these lenses allow oxygen to freely flow resulting in the
selected as contact lens material needs to be transparent. This char- highest oxygen transmissibility of any daily contact lens on the
acteristic is usually expressed as the percentage of transmission of the market.
visible electromagnetic spectrum. Thus, hydrogels suitable to be used as • Moreover, Alcon produces Air Optix® Aqua contact lenses, char-
contact lens materials have to transmit at least 90% of visible light. The acterized by SmartShield Technology, which is a surface technology
loss of transparency of a hydrogel is usually due to a phase separation of for moisture retention and consistent comfort, based on plasma
water that can be caused in example by temperature, thus the storage and iconicity modification. This allows to retain moisture and to limit
handling of these products should be accurate. The mechanical properties cholesterol sorption and deposits to increase the lenses comfort.
of contact lens materials are fundamental since they determine the • Finally, it has to be mentioned the first selling contact lenses brand
comfort, the durability, and the handleability of the product. It has to be in the world: Acuvue Oasys®, produced by Johnson & Johnson. It is
highlighted that the mechanical properties of hydrogels are not easy to be characterized by the wetting technology called Hydraclear® Plus
measured, due to the hydrophilic nature of the polymers and to the large technology, which stabilizes the tear film promoting comfortable
amount of water contained in their network (Caccavo et al., 2018). In wear.
fact, any deformation applied to a hydrogel involves the redistribution of
water inside the network affecting the characteristics of the sample,
Table 8
which could result different from those of the material used during the
Hydrogel-based commercial contact lens.
final application (Tranoudis and Efron, 2004). In general, the strength of a
hydrogel is measured in order to evaluate its resistance during handling Product Company Main constituent URL
and the elastic modulus in order to evaluate the deformability of lenses
Acuvue Oasys® Johnson & siloxane-based materials 2UIEBMs
and their fitting characteristics in human eyes. Surface characteristics of Johnson
contact lens materials directly affect the interaction with eyes and the Avaira® Coopervision Inc. N-vinylpyrrolidone and 2GcYgkq
surrounding tear films, which means that affect the biocompatibility with Biofinity® viscosity modifying 2tFtsDy
the ocular environment. Surface properties include friction, wettability, MyDay® admixture 2GwSnOi
silicone hydrogel
and surface water contact. Friction happens when two surfaces slide Dailies Total1 Alcon siloxane-based materials 2HV9UlN
against each other, and this sliding causes the wear of one or both the Air Optix® Aqua 2GeAlRA
surfaces. In order to prevent the wear of the surfaces, it can be provided a Focus Night & CIBA Vision silicone hydrogel 2HYUZqK
lubrification process. Wettability is a characteristic of a fluid that is spread Day®
PremiO lenses Menicon silicone hydrogel 2SwGxKC
on a solid surface. To enhance the comfort of contact lens, materials have
Purevision® Baush & Lomb silicone hydrogel 2t6ArCx
been modified in order to reduce friction by increasing lubricity of the
surface (i.e. adding wetting agents) (Stapleton and Tan, 2017). Studies The URL for each product webpage is: "https://bit.ly/" + the seven-character
suggested that hydrogels having lower modulus, higher oxygen trans- string reported in the table. Example: "2txQDwE" became "https://bit.ly/
missibility to the cornea, and higher equilibrium water content were 2txQDwE".

13
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

2.5. Hygiene retain the water even under pressure. It is composed mainly of so-
dium polyacrylate with high content of COO− and Na+ ions. The
Hygiene products based on hydrogels include disposable diapers, difference between the ionic content inside the polymer and the
sanitary pads, and adult protective underwear for incontinence. Among external environment determines the intensity of the osmotic pres-
the different products, disposable diaper is the largest consumer of sure and, consequently, of the amount of water absorbable.
superabsorbent polymers (SAP), which are extensively used to absorb • HySorb® (Basf) portfolio offers different kinds of products, among them
fluids. Superabsorbent materials are three-dimensional cross-linked it has to be mentioned HySorb® Biomass Balanced, superabsorbent
polymers (linear or branched) able to absorb and retain heavy amounts obtained from renewable feedstock like biogas or bio-naphtha that can
of liquids due to their excellent hydrophilic properties. They are char- be derived from organic waste or vegetable oils, and Saviva®, obtained
acterized by a high swelling capacity, and they are capable to absorb by a new technology of droplet polymerization, which forms a
water (or biological fluids) up to 1000 times their weight (Alam and pathway for a quick liquid distribution thanks to a system of fine ca-
Christopher, 2018). The main advantages in the use of these polymers pillaries that allows an homogeneous swelling behavior.
are that they are able to hold moisture away from the skin, promoting • Ultrasorbs™ AP Premium Drypad (Medline Industries Inc.) are air-
its health, preventing diaper rush and colonization of germs, and re- permeable drypads that feature a patented, SuperCore® absorbent
ducing the risk of fecal contaminations and potential spread of gas- that draws in moisture, locks it away from the skin and feels dry to
trointestinal infections (Feksa et al., 2018). the touch in just minutes.
Since the 1970s, diaper technology has been of great commercial • Sanwet (Sanyo Chemical Industries Ltd.) is the evolution of the first
interest, and about 1000 patents have been published for last 25 years SAP appeared on the Japanese market for hygiene applications and
on the construction and design of diapers. Japan started the first it is characterized by two features: the controlled absorption speed
commercial production of hydrogels in 1978 for use in feminine nap- and the improved-permeability of swollen gel.
kins, and later in 1980, Germany and France started using them in baby • HI-SWELL™ (Songwon Industrial Co. Ltd) exhibits quick and high
diaper (Haque and Mondal, 2018). The use of SAP in diaper industry water absorbency and an excellent stability to heat and light.
was proposed in 1982 in Japan reducing the size of diapers (of about
50%) and improving the retention performances, reducing the leakage The main features and web address where find more information for
values below 2% (Caló and Khutoryanskiy, 2015). Nowadays, the most each product are given in Table 9.
common polymers used as superabsorbent materials are based on cross-
linked synthetic polymers, such as acrylic acid and its copolymers with Table 9
acrylamide. On the market of the hygiene products cellulose-derived Hydrogel-based commercial products used in hygiene applications.
materials containing polymeric particles, which can be synthetic, such Product Company Main constituent URL
as polyacrylates, sulfonated polystyrene, poly(vinyl alcohol, or natural,
such as carboxy-alkyl cellulose, gum, carboxy-alkyl starch, or cellulose Aqua Keep Sumimoto Seika sodium polyacrylate 2t7tAJ1
Chemicals Co. LTD.
sulfate, are very common. The final characteristics of the super-
HI-SWELL™ Songwon Industrial Co. SAPs 2Ge9S6K
absorbent polymer can vary significantly depending on its composition: Ltd
i.e. the maximum absorbency of natural materials (such as cellulose or Huggies Kimberly–Clark SAPs 2DbtVPe
protein based materials (Panahi and Baghban-Salehi, 2018; Sannino HySorb® Basf superabsorbent 2BkN3u8
et al., 2009) ranges from 10 to 100 g water /g material, which is far less Saviva® obtained from 2WHlVyF
renewable feedstock
than that of commercial synthetic polymers (~1000 g/g) (Alam and
Pampers Procter&Gamble SAPs 2MRYsGs
Christopher, 2018). Sanwet Sanyo Chemical SAPs 2SyWX5b
One of the major drawbacks in the use of diapers is the production of Industries Ltd.
solid wastes. In fact, it has been reported (Haque and Mondal, 2018) that Ultrasorbs™ AP Medline Industries Inc. SAPs 2UNXxtr
Premium Drypad
a child till the age of 30 months using disposable diaper creates about
SuperCore®
1092 m3 of garbage per year. Disposable diapers are the third largest
single consumer item in landfills, and represent about 4% of solid waste. The URL for each product webpage is: "https://bit.ly/" + the seven-character
In a house with a child in diapers, disposables make up 50% of household string reported in the table. Example: "2txQDwE" became "https://bit.ly/
waste (Ajmeri and Ajmeri, 2016). Thus, many attempts have been taken 2txQDwE".
to make reuse of the items like disposable diapers, napkins, hospital
bedsheets, sanitary towels, and other similar products. The recycling of
such complex products is performed separating ingredients for further 2.6. Fillers
uses, in fact the cellulosic part is recyclable and biodegradable. This
process is tedious and not efficient, thus it made scientists to think al- Although the concept of filler injections to adjust facial soft tissue
ternatively, using ingredients completely biodegradable. Novel types of defects has been introduced since the 19th century (Neuber in 1893 was
hydrogels, containing sodium carboxymethylcellulose (NaCMC) and the first physician who transplanted fat from arms into facial defects
hydroxyethyl cellulose (HEC) cross-linked with divinyl sulfone (DVS), (Baumann et al., 2006), it has been only 30 years since the introduction
can swell like SAPs, and exhibit high water retention as a result of the of the first Food and Drug Administration-approved filler material, the
capillary effects (Pérez-Álvarez et al., 2018). bovine collagen (Pak et al., 2014). After that, the researches and studies
Concerning the commercial products containing SAPs, it has to be in this field have been proliferated and, nowadays, there are over 35
considered that Pampers (owned by Procter&Gamble) and Huggies major filler producer companies worldwide. It has been evaluated that
(from Kimberly–Clark) are the two most widely used disposable diaper global dermal filler market will surpass USD 8.5 billion by 2024 and is
brands, with about 35% and 22% global market share, respectively set to 5.8% of CAGR in 2017 according to a new research report by
(Caló and Khutoryanskiy, 2015). Moreover, the global feminine hy- Global Market Insights Inc., probably due to world population aging
giene products market, forecasted to be worth 38,000 million of US looking for anti-aging and wrinkle treatments (Ugalmugale and Size,
dollars by 2026 end, is expected to increase at a CAGR of 6.9% during 2018). According to the International Society of Aesthetic Plastic Sur-
the period 2018–2026. gery (ISAPS), the number of non-surgical cosmetic procedures has in-
creased by around 9% annually in 2017. Biodegradable fillers segment
• Aqua Keep (Sumimoto Seika Chemicals Co. LTD.) is a super- held largest market part (around 88%) in 2017 due to safety offered by
absorbent polymer which holds water within molecular chains and this type of fillers and to the fact that complications related with their

14
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

use disappears spontaneously, since they are biodegradable substances • Cross-linked porcine collagen is on the market under the name of
that are eventually metabolized by the body, usually in a period ranging Evolence® and Evolence Breeze® (by Johnson & Johnson). These
from months up to one year. Biodegradable fillers can be divided into were used in the treatment of acne scars but the manufacturer
two main classes, according with their duration into the human body: company announced the products’ retirement.
the nonpermanent fillers, such as collagen or hyaluronic acid, and the • CosmoDerm® and CosmoPlast® (by Allergan) are both human-de-
semipermanent fillers, such as polylactic acid and calcium hydro- rived collagen products, and they are used for the treatments for
xylapatite (Cheng et al., 2016). Among hydrogels, the most used as smoothing wrinkles, filling furrows (deep wrinkles) and restoring
filler in cosmetic industry are, undoubtedly, bovine collagen and hya- the border of the lip.
luronic acid, both belonging to the biodegradable fillers category, and • Isolagen® (by Isolagen Europe Ltd.) is an autologous cell therapy
polyacrylamide hydrogel filler, which is a non-biodegradable filler with that uses the patient's own fibroblasts to correct defects, including
long lasting effects. The physical properties of fillers determine their wrinkles and scarring.
unique characteristics and, then, they define the potential application • Autologen® (by Autogenous Technologies) is made of human dermis
in cosmetic soft tissue and dermal correction. Among these properties, from skin using a laborious process for harvesting.
it has to be evaluated the gel hardness or, in general, the rheological • To avoid complex procedures, Dermologen® (by Collagenessis Inc.)
behavior of the filler since this property affects the flow of the gel was developed. This is identical in structure and substance to the
passing through a syringe and, when it is released and restored, it gains previous one, but it is obtained, rather than using autologous skin,
its viscoelastic state. Thus, the gel hardness influences both the struc- from a cadaveric source (Yen, 2011).
ture and the stiffness of the filler. Gels with higher stiffness can provide
a better support in facial muscles and they better resist to the dynamic Obtained from a cadaveric source are:
forces acting during their movements. On the other side, gel with low
modulus better suits the use in areas with static and superficial wrin- • Cymetra® (AlloDerm, LifeCell Corporation), composed by micro-
kles, where the mechanical resistance is not a critical factor. The par- nized human cadaveric dermis,
ticle size within the gel determines the volume filling once it is injected, • Fascian® (by Biosystem), composed by human cadaveric fascia
which means, from a clinical point of view, the degree of correction that (Guthoff and Katowitz, 2009).
can be realized. Moreover, this parameter has to be checked after the
production because the particles size has to be able to pass through the An hybrid product, Artefill® (known in Europe as Artecoll®), is a
syringe’s needle during the intervention avoiding pain, bleeding, or mixture of bovine collagen and homogeneous polymethylmethacrylate
edemas. The hydrogel concentration in the filler determines the long- microspheres, which not only help to maintain the desired results much
evity and the stability of the correction intervention (Monheit and longer, but also to stimulate natural collagen production.
Coleman, 2006). Usually, the filler concentration provided by the Hyaluronic acid. Hyaluronic acid (HA) segment accounted over
manufactures includes both cross-linked gels and a fluid component of USD 4.5 billion in 2017. It is commonly adopted by elderly people to
the hydrogel. This latter one is easily metabolized by the human body correct facial lines and reduce wrinkling. After Botox, hyaluronic acid is
and does not contribute to the duration and effectiveness of the product the most common non-surgical cosmetic procedure in the U.S. because
(Kablik et al., 2009). The swelling degree of a filler depends on whether of the large number of approved products and the low risk of compli-
the filler has reached the equilibrium state for bound water, and this cations. Moreover, HA fillers have the advantage over collagen of being
depends on the gel characteristics. Thus, hydrated and equilibrium gels instantly reversible by the application of hyaluronidase. HA was dis-
have already reached their hydration capacity and they do not swell covered by Karl Meyer and his assistant John Palmer in 1934 (Beasley
when injected, non-equilibrium gels, on the contrary, tends to swell et al., 2009).It is a glycosaminoglycan disaccharide, which exists
post injection, thus this behavior has to be considered before the ap- naturally in the body. HA fillers can be derived both from animal or
plication. bacteria sources. HA products differ from the collagen products since
Collagen. Bovine collagen was the first kind of filler approved by they do not contain local anesthetic. This, combined with their in-
FDA for the use in aesthetic treatments. Bovine collagen is resorbable, creased viscosity compared to collagen, can result in more discomfort
and it has been used in soft tissue augmentation with a duration effect with injection (Johl and Burgett, 2006). Although its properties well fit
of less than 6 months. It has to be considered that collagen is the major the necessities of a dermal filler, at the beginning its use was seriously
structural component of the dermis and it has a fundamental role in limited because of its rapid degradation in biological tissues. Later, its
providing strength and support to human skin (Baumann et al., 2006). performances have been highly improved by the cross-linking proce-
However, the possibility to develop an allergic reaction to the use of dure that stabilizes and prolongs its duration over the time, making HA
collagen involves many people, since the injected collagen material can competitive on the market. Each company uses different cross-linking
be detected by body as a foreign substance and degraded by col- chemicals to obtain its product but all of them have in common the fact
lagenases and inflammatory cells (Johl and Burgett, 2006). In 2003, that they can be irritating or toxic for the skin, thus one of the funda-
FDA approved human-derived bioengineered collagen implants mental step of the filler production process is the purification (Beasley
(Rostan, 2007). These implants are composed by collagen derived from et al., 2009).
bioengineered human fibroblasts cultured in a bioreactor simulating the
human body and screened for viral and bacterial pathogens. Thus, since • Restylane® and Perlane® products (by Q-Med and distributed by
the collagen source is human and does not contain animal-derived Medicis Aesthetics) are non-animal stabilized hyaluronic acids
products, allergy test before using these implants are not necessary. (NASHAs), or rather, of bacterial origin (they are derived from
Other two types of collagen have to be considered: the collagen fibers cultures of Streptococcus equi). Both of them are cross-linked with
(and extracellular matrix) derived from human cadaveric tissues and butanediol diglycidyl ether (BDDE). Restylane® was the first non-
the autologous collagen, which is produced from a patient’s own skin. animal stabilized HA approved in the United States in 2003
These products have lost interest in the market once the bioengineered (Monheit and Coleman, 2006), Perlane® was approved later, in
collagen was launched. 2007. The only difference between these two products is the particle
The most famous collagen types available are: size: the largest fraction of gel particles for Perlane is between 940
and 1090 μm, whereas the largest fraction for Restylane® is between
• Zyderm® I and II (by Collagen Corporation), and Zyplast®, both of 250 and 500 μm (Beasley et al., 2009).
bovine-origin, are usually the less expensive but the risk of allergic • Juvéderm™ family products are manufactured by Corneal and dis-
reaction is higher. tributed by Allergan. They are non-particulate forms of NASHAs,

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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

Table 10 incorporates 0.3% lidocaine and the concentration of HA in this

Hydrogel-based commercial fillers. product is the highest available on the market.
Product Company Main constituent URL • Captique™, Prevelle Silk®, and the Hylaform® family are all manu-
factured by Genzyme and use divinyl sulfone (DVS) as cross-linking
Artefill® Suneva Medical bovine collagen and 2WNkMWb agent. Hylaform® was the first HA developed for dermal filling: re-
homogeneous
leased in Europe in 1996, it was FDA approved in the United States
polymethylmethacrylate
microspheres
in 2004. Despite Captique™ and Prevelle Silk® are bacterial-based
Autologen® Autogenous Collagen from human dermis 2TAYTaN HA, Hylaform® and Hylaform Plus® are avian-derived, from the
Technologies body of rooster combs. The duration is estimated to be 4–5 months
Captique™ Genzyme bacterial-based hyaluronic 2GcZ4Wx (Yen, 2011).
Prevelle Silk® acids 2DXsQw0
Hylaform® avian-derived hyaluronic 2BonGHU
Hylaform Plus® acids 2DiTjTl Since the market demonstrated repulsion towards the animal-based
CosmoDerm® Allergan human-derived collagen 2GtwY8T products, NASHAs are currently the most used as fillers worldwide (see
CosmoPlast® Table 10). Most products are cross-linked with single ether bonds, only
Juvéderm™ non-animal stabilized 2jCYoxw
Puragen™ family (by Mentor Corporation) subjects a two-stage double
hyaluronic acids
Cymetra® AlloDerm, LifeCell micronized human cadaveric 2taBtxq
cross-linking process with 1,2,7,8-diepoxyoctane (DEO) using a pro-
Corporation dermis prietary DXL™ technology, which increases stability and duration over
Dermologen® Collagenessis Inc. Collagen from cadaveric 2RM5gpM time.
source
Elevess® Anika Therapeutics chemically modified non- 2BqYAbg
animal hyaluronic acids
Evolence® Johnson & Johnson Cross-linked porcine collagen 2Bmhgcs 3. Conclusions
Evolence
Breeze® Despite hydrogels have existed for more than half century, their
Fascian® Biosystem Collagen from human 2I71bwK charm is still unquestioned. Due to their fascinating properties, hy-
cadaveric fascia
Isolagen® Isolagen Europe Ltd. Collagen with autologous cell 2StKQGJ
drogels have attracted the attention of both scientific and industrial
therapy communities but, even if the studies concerning their potentiality are
Restylane® Q-Med non-animal stabilized 2mnOgJu spread diffused, not all the formulations developed have reached the
Perlane® hyaluronic acids 2Rqsl1g market. Focusing only on the biomedical applications, hydrogels have
Zyderm® Collagen bovine-origin collagen 2GrRNS5
been used in different forms and amounts, in several fields, such as the
Zyplast® Corporation 2Ge7ahQ
drug delivery, wound healing, or tissue engineering.
The URL for each product webpage is: "https://bit.ly/" + the seven-character The studies devolved to the development of new hydrogels’ for-
string reported in the table. Example: "2txQDwE" became "https://bit.ly/ mulations or to the improvement of their properties are still attracting a
2txQDwE". lot of attention from scientists, but only a small part of them will result
in the invention of a new product for people’s daily life.
cross-linked with BDDE and they were approved by FDA in 2006. The main intent of this review is to give to the readers an overview
According to the producer, these products feature a crosslinking of the hydrogels that have reached the market over the time, listing
process called Hylacross®, which produces a softer, more viscous gel same of the commercial products that have been launched. However,
which is intended to enhance durability, in fact is has been de- the authors are aware that a complete and comprehensive review of all
monstrated that this fillers last up to 12 months (Cheng et al., 2016). the commercial products is not possible, thus in the following Table 11
• Elevess® (by Anika Therapeutics) is cross-linked with biscarbodii- a list of the main hydrogels that have resulted in a commercial product
mide (BCDI) and was approved by FDA in 2006. It is based on and the properties that characterize their use in specific application
chemically modified non-animal HA proprietary technology which fields is reported.

Table 11
Chemical structure and properties of the main hydrogels used in biomedical applications.
Hydrogel Chemical structure Main properties Applications

Alginate Natural water-soluble polymer; Wound healing, drug delivery, and

Biocompatible and structured as extracellular tissue engineering applications.
matrix;
Crosslinkable ionically or covalently.

Carbomer Weak anionic polyelectrolyte; Disposable diapers, buccal delivery, gels

Degree of ionization depends on solution pH; for skin care.
(Poly(acrylic acid)) Mucoadhesive properties.

Carboxymethyl Ionic cellulose-derivative; Matrix for transdermal delivery and

Solubility pH-dependent; wound dressing, constituent of SAPs for
cellulose Viscosity-increasing properties; hygienic applications.
Mucoadhesive properties.

Collagen Main structural protein in the extracellular space; Cardiac applications, cosmetic surgery,
Biodegradable, biocompatible, and weak antigenic; filler, bone graft, tissue engineering,
Obtainable from different sources (animal and wound healing.
human);
Cell attachment capability;
Adhesive properties.
(continued on next page)
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S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

Table 11 (continued)

Hydrogel Chemical structure Main properties Applications

Gelatin Film forming properties; Suspending agent, encapsulating agent,

Foam stabilizer; and tablet binder in pharmaceuticals
Adhesive properties as warm solution;
Gelling properties.
Glycerin Smoothness improver and lubricant; Rectal administrations, jellies and
Humectant properties; creams for topical uses, wound dressing.
Plasticizer;
High solvent power.
Hyaluronic Acid Natural water-soluble polymer; Wound and skin healing, filler,
Biocompatible and structured as extracellular cosmetics, tissue engineering, injectable
matrix. gel.

Hydroxyethyl cellulose Non-ionic cellulose derivative; Excipient in pharmaceutical

Gelling and thickening agent; formulations, cream for topical
Bubble-forming; medications, ointments, eye drops.
High hydrophilicity and maximum erodibility.

Hydroxypropyl methylcellulose Non-ionic cellulose derivative; Excipient in pharmaceutical

Thermal gelation properties; formulations, matrix for controlled
Film-forming properties; delivery tablets, emulsifier, eye drops.
High hydrophilicity.

Hydroxypropyl Non-ionic cellulose derivative; Topical ophthalmic protectant and

Fully soluble in water and polar organic solvents; lubricant, excipient for controlled
cellulose Solubility in water temperature-dependent. delivery tablets.

poly (D,L-lactide-co-glycolide) Biodegradable and biocompatible copolymer; Optical delivery, resorbable sutures,
FDA approved; carrier for controlled delivery, tissue
Soluble in a wide range of organic solvents; engineering applications.
Crystallinity and melting point tunable with the
molecular weight.
Poly(lactic acid) Biocompatibility and biodegradability; Tissue engineering, wound healing,
Good mechanical properties: matrix for drug delivery systems.
Thermal plasticity.

Poly(methyl methacrylate) Non-degradable polyacrylate; Intraocular lenses, orthopedic surgery,

Excellent optical properties; screws in bone fixation, cosmetic
Mechanical p[roperties are tunable depending on surgery, dentistry.
the ratio of monomer and initiator during the
polymerization

Polyethylene glycol Water-soluble linear polymer; Parenteral, topical, ophthalmic, oral and
Absorbing and binding properties; rectal preparations, base of ointments,
Do not readily penetrate the skin. wound dressing.
Polyvinyl alcohol Water-soluble synthetic polymer; Excipient in sustained-release
Film-forming, emulsifying, and adhesive formulations, matrix for capsules,
properties; coating material for eye drops.
High oxygen barrier properties.
siloxane Siloxane-hydrogels improve gas permeability of Ocular drug delivery and contact lenses.
contact lenses, comfort of lenses and easiness of
implantation.

Xanthan gum Natural polysaccharide; Creams and suspensions as emulsion

Highly soluble in hot and cold water; stabilizer, in cosmetics as thickener and
Stable in acidic and alkaline environments; stabilizer, buccal delivery.
Approved by FDA and compatible with foods.

17
S. Cascone and G. Lamberti International Journal of Pharmaceutics 573 (2020) 118803

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