http://informahealthcare.com/btyISSN: 0738-8551 (print), 1549-7801 (electronic)

Crit Rev Biotechnol, Early Online: 1–10! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/07388551.2013.794413

REVIEW ARTICLE

Cyclodextrin-based hydrogels toward improved wound dressings

Eva Pinho1,2,3, Martin Grootveld2, Graca Soares3, and Mariana Henriques1

1Institute of Biotechnology and Bioengineering, University of Minho, Campus Gualtar, Braga, Portugal, 2Leicester School of Pharmacy, Faculty of

Health and Life Sciences, De Montfort University, The Gateway, Leicester, UK, and 3Centre for Textile Science and Technology (2C2T), University of

Minho, Campus Azurem, Guimaraes, Portugal

Abstract

Optimal wound dressings should be capable of mechanical wound protection and alsofacilitate the healing process via maintenance of suitable environmental conditions and thecontrolled delivery of bioactive molecules. Hydrogels present suitable properties for wound-dressing applications such as good biocompatibility, together with a high water content, thelatter of which is important for the maintenance of a moist environment and ready removalfrom the wound with a minimal level of associated pain. However, their properties as drugdelivery systems can be improved by the use of cyclodextrins as cross-linking agents.Cyclodextrins have been extensively used as ‘‘carriers’’ on food, textile, cosmetic and, mostespecially, in the pharmaceutical industry in view of their powerful complexation abilities andbiocompatibilities, together with further desirable characteristics. The conjugation ofcyclodextrins with hydrogels may allow the achievement of an optimal wound-dressingmaterial, because the hydrogel component will maintain the moist environment required forthe healing process, and the cyclodextrin moiety has the ability to protect and modulate therelease of bioactive molecules. Therefore, this review aims to gather information regardingcyclodextrin-based hydrogels for possible wound-dressing applications.

Keywords

Bioactive molecules, carriers, cross-link agent,drug delivery, supramolecular structures,

History

Received 23 March 2012Revised 17 January 2013Accepted 6 March 2013Published online 6 August 2013

Introduction

The skin is the largest human organ, and probably the most

heterogeneous, reaching 10% of the total body mass (Metcalfe

& Ferguson, 2007). The main function of the skin is to act as a

protective barrier against the environment, and beyond this

physical protection function, skin is also responsible for:

sensory detection, thermoregulation, fluid homeostasis,

immune surveillance and self-healing (Boucard et al., 2007).

Normally, the human body is able to restore skin integrity after

injury, with a minimal scar, via a complex and interactive

process. However, this healing process can be interrupted by a

series of physical factors such as age, nutritional status or local

factors such as: infections, tissue ischemia, hematomas, foreign

bodies or mechanical pressure. In these situations, medical

treatment is necessary (Guptaa et al., 2010; Jones et al., 2006).

Indeed, in the past few years the number of wounds related to

diseases such as diabetes mellitus, chronic venous disease,

arterial insufficiency and immunological or dermatological

illnesses have increased. Therefore, to improve the life quality

of those affected, a wide range of wound-care products have

been developed (Ather & Hargding, 2009; Harding et al., 2000;

Kokabi et al., 2007; Ovington, 2007).

Wound dressings cover the wound, providing physical

protection against microorganism deposition, wound dehy-

dration and external injuries (Fonder et al., 2008; Purna &

Babu, 2000). Moreover, they can interact with the wound

and accelerate the healing process via the release of

bioactive molecules, and/or by maintaining the moist

environment required for effective wound healing (Kujath

& Michelsen, 2008). New formulations of composite

systems containing synthetic and/or biological agents, such

as gauzes, foams, films, hydrocolloids and hydrogels, have

been developed to maintain the favorable environmental

conditions, and/or to deliver bioactive compounds through

the skin, and hence enhance the healing process (Ather &

Hargding, 2009).

Hydrogels, composed of polymeric networks with a high

water content and biocompatibility status, can be used as

wound-care coverings, drug delivery systems, dental mater-

ials, implants, injectable polymeric systems, ophthalmic

application systems and hybrid-type organs (Guptaa et al.,

2010). Additionally, the presence of CDs on hydrogels as

drug carriers improves the properties of the system and gives

rise to an enhanced level of wound healing (Kanjickal et al.,

2005; Loftsson and Masson, 2001; Santos et al., 2008).

Therefore, this review summarizes the recent advances

made with CD-based hydrogels, based on free access articles

published between 1996 and 2012. A brief description of the

applications of hydrogels for wound-dressing purposes and

CDs incorporations therein is also made.

Address for correspondence: Mariana Henriques, Institute of Biotech-nology and Bioengineering, University of Minho, Campus Gualtar,4710-057 Braga, Portugal. Tel: +351 253 604 401. Fax: +351 253 604429. E-mail: mcrh@deb.uminho.pt

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Hydrogels

Hydrogels are tri-dimensional networks of hydrophilic poly-

mers (Lim et al., 2009), the network confers an insoluble

behavior to the polymeric system and allows the hydrogels to

absorb from 10–20% (an arbitrary lower limit) to up to

thousands of times their equivalent weight in water until the

process reaches an equilibrium state. Therefore, hydrogels

provide the moist environment required for an optimal wound

healing process (Guptaa et al., 2010; Hoare and Kohane,

2008; Hoffman, 2002). They are mainly employed to dry-

to-moderately draining wounds, to promote autolytic debride-

ment in necrotic wounds and in granulating wounds.

The characteristics of hydrogels critically depend on the

polymers employed and on their interactions within the

network. Hydrogels are known as either chemical if their

network is covalently cross-linked (Hoare & Kohane, 2008;

Hoffman, 2002; Yoo & Kim, 2008) or physical if the network

is sustained by molecular entanglements and/or secondary

attractions, including electrostatic interactions, hydrogen

bonding or hydrophobic (Van der Waals) forces (Figure 1).

The reversible character of these hydrogels arises from the

disruption of the above network interactions via modifications

in physical conditions such as ionic strength, pH, temperature,

stress or, alternatively, the addition of specific solutes (Hoare

& Kohane, 2008; Hoffman, 2002; Lee & Mooney, 2001;

Zhang et al., 2005).

Hydrogels can be generated from a wide range of

polymers, and they are characterized according to the

source of these macromolecules: synthetic, natural or a

combination of both (Table 1) (Hoffman, 2002).

Synthetic polymers allow the control, at the molecular

level, of the network structure’s properties and chemical or

biological responses during their design and manufacture

(Hoare & Kohane, 2008; Oh et al., 2008; Peppas et al., 2006).

Within the synthetic category of hydrogels, those most

commonly employed for biomedical applications are neutral

ones. These are derivatives of PHEMA (Jones et al., 2008;

Santos et al., 2008), PVA (Hong & Sun, 2010; Peppas et al.,

2006; Yu et al., 2006) or PEG. PEG is probably the polymer

most investigated and employed for biomaterials purposes in

view of its nontoxicity, non-immunogenicity and also its

approval by the US Food and Drug Administration (FDA)

(Kanjickal et al., 2005; Wu et al., 2009). Immune alterations

on PEG hydrogels, such as surface modification via covalent

bonding with silicone acrylate and thiol linkages, adsorption

and/or ionic attractions or hydrogen bindings, have been

proposed to facilitate their suitabilities for cell contact

(Venugopal et al., 2007).

Furthermore, an increased extent of cell contact can be

achieved by the formation of block of copolymers such as tri-

blocks of PEG with PEO, which confer degradability

potentials to PEG hydrogels, tri-blocks of PEG with PLA or

similar polymers that give rise to or enhance the specific

properties of PEG hydrogels (Peppas et al., 2006).

For example, Molina et al. (2001) prepared a series

of hydrogels from pre-synthesized PLA/PEO/PLA triblock

polymers via a phase separation technique involving the

introduction of low water levels over copolymers present

in a biocompatible organic solvents system, specifically

Table 1. Hydrophilic polymers employed for hydrogelproduction (Hoffman, 2002). See Abbreviations for defin-itions of terms.

Polymer

Synthetic PEG-PLA-PEGPEG-PLGA-PEGPEG-PCL-PEGPLA-PEG-PLAPHBP(PF-co-EG)6acrylate end groupsP(PEG/PBO terephthalate)PEG-bis-(PLA-acrylate)PEG6CDsPEG-g-P(AAm-co-Vamine)PAAmP(NIPAAm-co-AAc)P(NIPAAm-co-EMA)PVAc/PVAPNVPP(MMA-co-HEMA)P(AN-co-allyl sulfonate)P(biscarboxy-phenoxy-phosphazene)P(GEMA-sulfate)

Natural HydroxyapatiteAlginic acidPectinCarrageenanChondroitinSulfateDextran sulfateChitosanPolylysineCollagen (and gelatin)Carboxymethyl chitinFibrinDextranAgarosePullulan

Composites P(PEG-co-peptides)Alginate-g-(PEG-PPO-PEG)P(PLGA-co-serine)Collagen-acrylateAlginate-acrylateP(HPMA-g-peptide)P(HEMA/Matrigel)HA-g-NIPAAm a

Figure 1. Schematic of methods for the formations of the two typesof hydrogels, chemical or permanent and physical or reversible(Hoffman, 2002).

2 E. Pinho et al. Crit Rev Biotechnol, Early Online: 1–10

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poly(ethyleneglycol mono-tetrahydrofurfuryl ether). The

hydrogels generated in this manner exhibited hydrophilic

characteristics which were greater than those of correspond-

ing hydrogels produced via the swelling of dry tablets or films

derived from these copolymers. Indeed, they were sufficiently

soft to permit their trocar injection. Moreover, both BSA and

fibrinogen could be successfully entrapped in these hydrogel

formulations via their pre-mixing with the copolymer solu-

tions prior to gel production. In terms of the time-dependent

release profiles of these unique formulations, these research-

ers’ findings were consistent with gel-protein compatibilities

and incompatibilities with regard to BSA and fibrinogen,

respectively (Molina et al., 2001).

As expected, hydrogels from natural sources are ‘‘friend-

lier’’ to the user because they are nontoxic, biodegradable and

biocompatible, but unfortunately lack some of the mechanical

properties required (Beneke et al., 2009; Satturwar et al.,

2003). The most common natural sources are collagen, HA,

alginate, agarose and chitosan (Boateng et al., 2008; Yoo &

Kim, 2008). The first two sources are components derivatives

of the mammalian extracellular matrix, collagen being its

major protein (Purna & Babu, 2000), and HA which is a

polysaccharide (consisting of linear repeating glucuronate/N-

acetylglucosamine disaccharide units) which has unique

visco-elastic properties and is present in almost all animal

tissues. Agarose, alginate and chitosan are isolatable from

marine sources and have low toxicities and a high level of

biocompatibility (Peppas et al., 2006).

Collagen-based hydrogels can be synthesized without

chemical modifications and, in view of the presence of

many cell-signal domains, they are suitable for cell growth

matrices. In addition, collagen is degraded in vivo by

enzymes, such as collagenase, which is useful for tissue

engineering scaffolds or injectable systems. Nevertheless,

collagen hydrogels have poor mechanical properties, but these

may be improved by chemical cross-linking, cross-linking

with UV light or temperature or by the generation of

admixtures with other polymeric agents (Boateng et al.,

2008; Peppas et al., 2006). HA is a glycosaminoglycan

associated with wound healing, and is present at high levels in

joints. HA hydrogels can be produced via multiple chemical

modifications, and their in vivo degradation is achievable

by enzymes such as hyaluronidase (Boateng et al., 2008;

Luo et al., 2000; Park et al., 2004).

Alginate hydrogels are composed by various polymer

chains, the structural integrity of which is maintained by

ionic bridges and divalent cations. The network cross-link

density depends on the particular monomeric units and

molecular mass of the polymer. The alginate hydrogel degrad-

ation occurs by modifications of its mechanical properties

(Balakrishnan et al., 2005; Mehyar et al., 2008). Chitosan is

composed of linear polysaccharides obtained from the partial

hydrolysis of chitin and is degraded, in vivo, by lysozymes.

Chitosan hydrogels maintain the beneficial bioactive properties

of chitin, in terms of biodegradability and bioactivity, and

provides improvements in water retention capacity over that of

chitin (Kirker et al., 2002; Peppas et al., 2006; Tran et al., 2011).

Composite hydrogels arise from the incorporation of

natural and synthetic polymers into the same network. The

‘‘natural’’ component of the hydrogel contributes to the high

affinity and specificity for the cell binding activities of the

matrix, and the synthetic part allows control of the mechan-

ical and physical properties of these systems. For example,

bioactive molecules can be ‘‘entrapped’’ into the synthetic

network and be released by environmental stimuli, act as

degradable ‘‘triggers’’ or improve the biocompatibility of the

system (Peppas et al., 2006).

Currently, there are a number of hydrogels brands available

for wound-dressing purposes already commercialized, espe-

cially in the case of skin substitutes, as reviewed by Boateng

and co-workers and Shai and Maibach (Boateng et al., 2008;

Shai & Maibach, 2005). These skin substitutes involve

scaffolds capable of releasing drugs which improve the cell

growth and promote tissue regeneration. The attractive

scaffolding properties of bioactive synthetic hydrogels have

arisen their exact molecularly customized biofunctions and

attenuatable mechanical properties, together with the provi-

sion of microenvironments with functional properties similar

to those of ECMs, which promote cell growth and tissue

generation. Indeed, a range of design strategies have been

examined to generate synthetic hydrogels with novel bioactive

ECM-mimetic attributes, including cell adhesion, binding of

growth factors and proteolytic degradation (Zhu & Marchant,

2011).

Moreover, essential knowledge regarding these materials

can be employed for the development of new wound-dressing

materials.

Hydrogels are also cheap and effective wound-dressing

agents in view of their high-level biocompatibilities, perme-

ability to oxygen, powerful water absorption and moisture

retention properties (Figure 2). Their removal from the wound

sites can be made with minimal pain or trauma (Juris et al.,

Figure 2. Representation of the most important features of the hydrogelas a wound dressing.

DOI: 10.3109/07388551.2013.794413 Cyclodextrin-based hydrogels 3

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2011; Roy et al., 2010). Moreover, they are semi-transparent,

allowing visual observation of the wound state without

removal of the dressing. Because these hydrogels have

soothing and absorption characteristics, they are suitable for

partial-thickness wounds such as superficial thermal burns,

friction blisters, chemical peels, derma-abrasion, facial laser

resurfacing and ulcers (Figure 3) (Blanco-Fernandez et al.,

2011; Yoo & Kim, 2008).

However, with regard to the bioactive agent delivery

systems, hydrogels have a number of limitations. Indeed, the

capacity of hydrogels to load hydrophobic drugs is restricted,

and the release of those molecules usually occurs via a rapid

nonlinear diffusion to the surrounding environment

(Thatiparti et al., 2010). Furthermore, the drug’s biological

activity may be lost via its interactions with solvents, or by

phenomena imposed by the environmental conditions

required for hydrogel production, such as pH and temperature

(Kanjickal et al., 2005).

Hydrogels already commercialized included synthetic,

natural and composite materials (Boateng, et al., 2008; Shai

& Maibach, 2005). However, to the best of the authors’

knowledge, there are little or no publications available regard-

ing CD-based hydrogels, in which the CD species is acting as a

cross-linking agent for wound-dressing applications.

Cyclodextrins

CDs are a group of structurally related cyclic oligosaccharides

described for the first time by Schardinger (Buschmann &

Schollmeyer, 2002; Loftsson & Duchene, 2007). They are

produced by the bacterial enzymatic degradation of starch

(Del Valle, 2004; Jug et al., 2008; Loftsson & Duchene, 2007;

Manakker et al., 2009).

CDs have the shape of a truncated cone, mainly in view of

the chair conformation of the glucopyranoside units (Liu &

Fan, 2005; Szejtli, 2004). Because their hydroxyl groups are

oriented to the outer molecular surface, CDs have a micro-

heterogeneous environment, the outside having hydrophilic

characteristics and the inner cavity being a hydrophobic

environment (Jug et al., 2008; Manakker et al., 2009).

Therefore, CDs are able to accommodate lipophilic molecules

or even polymers to form IC in aqueous solutions (Manakker

et al., 2009; Szejtli, 2004).

The naturally occurring CDs are a-CD with 6 units, b-CD

with 7 units and g-CD with 8 units (Buschmann &

Schollmeyer, 2002; Cal & Centkowska, 2008; Matsuda &

Arima, 1999). These three CDs have the same cavity height;

however, their cavity volume and diameter varies, which

determines the classes of molecules (‘‘guest’’ molecules) that

will fit better in each CD cavity. b-CD is more accessible,

with a lower cost price, and is also the most commonly

employed one for commercial proposes (Del Valle, 2004).

CD derivatives can be manufactured by aminations,

esterifications or etherifications of the primary or secondary

hydroxyl groups of naturally occurring CDs (Loftsson &

Duchene, 2007). The CD derivatives may help to control the

chemical activity of the ‘‘guest’’ molecule, and chemical

modifications of CDs enlarge the applications of such

molecules. For example, functional groups that act on

molecular recognition can be added to CDs, enabling their

use in enzyme mimetization, targeted drug delivery or

analytical chemistry applications (Del Valle, 2004; Duan

et al., 2005).

Inclusion complex

IC formation represents a dimensional fit between the CD and

the ‘‘guest’’ molecule, and depends, besides the guest’ size,

on the specific local of interaction between the CD’s surface

atoms and those of the ‘‘guest’’ molecule (Buschmann &

Schollmeyer, 2002; Del Valle, 2004; Arun et al., 2008). The

process of the ‘‘guest’’ inclusion into the CD occurs at the

molecular level, with the substitution of enthalpy-rich water

molecules from the central cavity by the lipophilic ‘‘guest’’ or

moiety (Del Valle, 2004; Jug et al., 2008; Manakker et al.,

2009; Marques, 2010; Szejtli, 2004).

The inclusion process is dynamic and the ‘‘guest’’

molecule-CD interactions are required to reach equilibrium

to stabilize the IC (Jug et al., 2008; Liu & Guo, 2002). The IC

is very stable, and possesses a long shelf life at ambient

temperature and under dry conditions. However, it can be

disrupted by increases in temperature, or by exposure of the

Figure 3. Comparison of wound healing between (a) gauze and (b) a typical waterborne polyurethane (WBPU) hydrogel (HG-78 sample) dressings(Yoo & Kim, 2008).

4 E. Pinho et al. Crit Rev Biotechnol, Early Online: 1–10

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complex to water, which can replace the ‘‘guest’’ molecule

within the CD cavity (Jug et al., 2008). However, this may be

helpful when the goal is to achieve a controlled release of the

‘‘guest’’, for example a drug.

Applications

CDs are capable of encapsulating a wide range of molecules

such as straight or branched aliphatic chains, aldehydes,

ketones, alcohols, organic acids, fatty acids, aromatics, gases

and polar compounds such as halogens, oxyacids and amines

(Del Valle, 2004). In addition, CDs are safe for use in

humans; indeed, they may only be harmful at extremely high

concentrations (Buschmann & Schollmeyer, 2002; Irie &

Uekama, 1997; Matsuda & Arima, 1999).

The main interest in CDs lies in their ability to encapsulate

‘‘guest’’ molecules and hence modify their physiochemical

characteristics (Del Valle, 2004; Jug et al., 2008). In fact, CDs

can enhance the solubility of lipophilic ‘‘guests’’; stabilize

the ‘‘guest’’ molecule against potentially damaging agents

(such as oxygen, visible or ultra-violet light and heat); control

their volatilities and sublimation properties; allow the phys-

ical isolation of incompatible compounds (via chromato-

graphic separation); permit taste modifications by ‘‘masking’’

flavors; control odors; and attenuate the release of bioactive

compounds (Buschmann & Schollmeyer, 2002; Duan et al.,

2005; Manakker et al., 2009).

Besides the improvement of some characteristics of the

‘‘guest’’ molecule, ICs have low cost and good availability,

which make them useful for pharmaceutical applications,

analytical sciences, separation processes and catalysis. They

are also of much value to the cosmetic, textile, food and

packaging industries (Buschmann & Schollmeyer, 2002;

Manakker et al., 2009; Szejtli, 2003).

The food industry has used CDs to form ICs with lipids,

flavors and colorings. They are very helpful for flavor

protection and delivery, and also have the ability to remove

some unhealthy compounds (e.g. cholesterol), and also

improve the textural properties of some foods (Loftsson &

Duchene, 2007).

CDs are widely used in cosmetic, personal care products

and toiletries, such as toothpastes, skin creams, softeners and

tissues. Additionally, antimicrobial agents can be added to

toothpastes as ICs (Buschmann & Schollmeyer, 2002; Del

Valle, 2004; Loftsson & Duchene, 2007). Moreover, ICs are

used as chemical stabilizers to prolong the action of active

compounds, to decrease local irritation or, alternatively, to

mask unpleasant odors (Ishihara et al., 2002). CDs are used

to improve perfume fragrance, enhance the effect of room

fresheners by suppressing the volatilities of their odor

molecules and also to control the release of fragrances in

detergent formulations.

The pharmaceutical industry possesses a wide range of

products with CDs, where they are used as active ‘‘carriers.’’

Usually, the drugs involved must be able to reach the cellular

membrane without a corresponding loss of integrity, and also

be hydrophobic enough to cross it. Therefore, CDs can be

used to facilitate drug delivery processes by the maintenance

of hydrophobic drugs in solution, and deliver them into cell

membranes, enhancing their level of penetration via

substitution of the drug by blood serum or tissue biomol-

ecules in the cavity (Del Valle, 2004; Duchene et al., 2003;

Matsuda & Arima, 1999). Moreover, CDs are used as

solubilizers and stabilizers, and are able to reduce local

irritation, a phenomenon attributable to their high level of

biocompatibility (Del Valle, 2004; Loftsson and Duchene,

2007; Manakker et al., 2009; Matsuda & Arima, 1999; Arun

et al., 2008; Zhao et al., 2010).

Supramolecular structures of CDs for drug deliverypurposes

CDs and their derivatives have been employed and studied

for molecular recognition, drug delivery systems, and also as

building blocks for nano-structured functional materials.

Molecular architectures, including oligomers, polypseudor-

otaxanes, polytotaxanes, nanoparticles, nanocages and

hydrogels, have been constructed based on the ability of

CDs to specifically link (covalently or non-covalently)

to other CDs or polymers (Del Valle, 2004; Li, 2010;

Manakker et al., 2009).

These nanosize architectures are composed by CD aggre-

gates with numerous functional groups, resulting in multiple

cavities with the capability to interact with various ‘‘guest’’

molecules. This promotes the connection between the

‘‘guest’’ and the CDs by co-operative binding, which

facilitates interactions between CDs and the guest’s functional

groups, and/or the ‘‘guest’’ itself. Hence, SM-CD mimic the

co-operative multimode, multipoint binding often found in

biological systems. Therefore, SM structures improve the

capacities of CDs to encapsulate drugs, a process which

enhances drug bioavailability and bioactivity (Chen & Liu,

2010; Li & Loh, 2008).

SM-CDs can be produced by covalently linking several CD

cavities on a polymer, or by grafting them on a polymer

through nucleophilic displacement, condensation or acylation

reactions. They may also be constructed by the contribution of

several covalent interactions which give rise to well-organized

structures (Harada et al., 2009).

Bioactive CD-oligomers (O-CD) are composed of CD

cavities linked by functional bridges that provide additional

interactions with the ‘‘guest’’ molecules, together with the co-

operative binding of several CD units to improve the

encapsulation of important bioactive ‘‘guests’’ (Chen &

Liu, 2010; Harada et al., 2009; Leung, 2000; Liu et al., 2003,

2004).

Polypseudorotaxane and polyrotaxane structures consist of

a long-chain molecule (axle component) and several CDs

(wheel components) (Li & Loh, 2008; Loethen et al., 2007).

Harada et al. (2009) described a method to generate both

classes of these structures. The production of polypseudor-

otaxanes (Figure 4a) involves the entrapment of CDs on

polymers or polyelectrolytes, and then stabilizing them

through the use of hydrogen bonds between adjacent CD

cavities and further noncovalent interactions between the

long-chain molecule and the threaded cavities. The poly-

rotaxanes (Figure 4b) are obtained from polypseudorotaxanes

to which bulk terminals (organic or organometallic groupings)

were added at the chain ends to prevent the CD’s detachment

(Chen & Liu, 2010; Harada et al., 2009).

DOI: 10.3109/07388551.2013.794413 Cyclodextrin-based hydrogels 5

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The bioactive two- or three-dimensional supramolecular

assemblies are composed by: (1) an improvement of

polypseudorotaxanes with added side chains, giving the

structure a two-dimensional configuration that enables inter-

actions between SM molecules and the bioactive agent; (2)

nanostructures of modified CDs with three-dimensional

configurations that are constructed via covalent and non-

covalent linkages with gold; and (3) hydrogels that arise from

the combination of long polymers and CDs (Chen & Liu,

2010; Ke et al., 2007). The first two structures have their

major applications in the DNA field, and because it is outside

of the scope of this article, only hydrogels will be discussed in

the next section.

Cyclodextrin-based hydrogels

As noted above, hydrogels possess novel properties, enabling

them to be employed as drug delivery systems with the ability

to improve wound healing, since, they have effective

biocompatibilities and a sufficient water content. However,

predominantly, such hydrogels require covalent cross-linking

or severe environmental conditions to achieve a ‘‘gel’’ state

which limits their applicability, and hence the sorption of

drugs is very time-consuming with these systems and impairs

drug integrity (Hoare & Kohane, 2008; Li, 2010).

Therefore, the main goal of this research area is the

development of a hydrogel capable of delivering a drug

without an associated cross-linking agent (i.e. one that is

integral and has an effective level of activity), as well as a

requirement to be generated at a suitable temperature and pH

value for in vivo use.

The further utilization of CDs as cross-linking agents

improve the ‘‘swelling’’ properties of the hydrogels and

further assist in protecting the drug trapped inside the cavity

(Figure 5) (Li, 2010; Li & Loh, 2008). Consequently, SM

systems composed by polymers and cyclodextrin have been

investigated for possible wound-dressing applications,

because this system has the capacity to form spontaneous

tri-dimensional physical cross-linking macromolecular net-

works that correspond to a hydrogel (Hoare and Kohane,

2008; Huh et al., 2001).

To date, there are little or no documented reports available

concerning the actions and efficacies of CD-based hydrogels

for wound-dressing purposes. However, Lee and co-workers

(2012) investigated the therapeutic capacity of a hydrogel

composed of b-CD, PEI and SF, and containing CAE and

HCA in the healing of pressure sores. In view of its

hydrophobic nature, HCA’s release was influenced by its

partitioning between the b-CD cavity and the bulk water

phase, and not by the hydrogel’s swelling capacity. Results

acquired revealed that the pressure sores treated with this

hydrogel system healed within a period of 6 days, compared

to a 10-day length for control (untreated) pressure sores, and

the researchers concluded that the b-CD/PEI/SF hydrogel

containing CAE and HCA diminished the healing time

required for these sores.

Figure 5. Schematic representation of theCD-based hydrogel, where CD may have twoutilities: (1) cross-linker and (2) a drugcarrier. This system improves the capacity ofthe hydrogel to carrier hydrophobic drugs andavoids the drug aggregation (adapted fromPeng et al., 2010).

Figure 4. Schematic representation of (a) a-CD PEG polypseudorotaxanes and (b) aCD PEG polyrotaxanes (Li et al., 2011).

6 E. Pinho et al. Crit Rev Biotechnol, Early Online: 1–10

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CD-based hydrogels result from the ‘‘threading’’ of CDs

onto parts of long polymers or copolymers with high

molecular masses. The CD–drug complex may be added to

the polymer (1) after or during gel cross-linking, (2) via

grafting or (3) by direct cross-linking with diglycidyl-ethers.

The first method is easier to perform but may induce an early

liberation of the complex from the hydrogel, alleviating the

extent of control over the release kinetics. On the other hand,

the other two strategies permit a better level of modulation of

drug release from the system (Hoare & Kohane, 2008).

Chemical supramolecular hydrogels

Chemical supramolecular hydrogels are typically formed

from polypseudorotaxanes or polyrotaxanes with CDs cova-

lently linked by cross-linking agents or by modifications

of the polymeric backbone. For example, biodegradable

polymers with hydrolyzable threadings have been developed

for drug or gene delivery applications (Chen, 2011).

The first published work with CD-containing polymeric

hydrogels described a procedure to build a network from the

chemical cross-linking of a-, b- or g-CDs with EPH, as a

biofunctional cross-linking agent. The first studies proved that

this network was able to form a complex with a variety of

poorly water-soluble drugs. To enhance the swelling capabil-

ity, increase the drug loading capacity and reduce the toxicity

of EPH, the cross-linking was performed in the presence

of cationic or anionic compounds. For example, Li and

co-workers (2004) described a positively charged network

by cross-linking b-CD with EPH in the presence of choline

chloride, and this resulted in an effective encapsulation and

release of the anti-inflammatory drug naproxen and had a

lower toxicity when compared with networks without CDs.

Negatively charged EPH cross-linking b-CD networks con-

taining carboxymethyl groups were also reported. In this case,

the hydrogels could be loaded with cationic drugs such as

those with microbicidal properties, a phenomenon rendering

them useful for wound-dressing and chewing gum formula-

tions of value against mucosal infections. Other cross-linking

agents were also described for CD-containing polymeric

hydrogels, such as diepoxides, alkyleneglycoldi (epoxypro-

pyl) ethers, the diisocyanate hexamethylene diisocyanate and

anhydrides. The use of CD derivatives, such as methyl-bCD,

sulfobutylether-bCD or 2-hydroxypropyl-b-CD, has been a

helpful strategy, because they are capable of improving the

capacity of these hydrogel materials to absorb water

(Manakker et al., 2009).

To tailor the mechanical properties of covalently linked

networks, this cross-linking has been employed to incorporate

water-soluble polymers such as PVA or hydroxypropyl

methycellulose. Nozaki et al. (1997) described a procedure

to couple pNIPAAm-, (with terminal carboxyl acid groups) to

amine-functionalized EPH pre-cross-linked by b-CD.

However, the material obtained exhibited a temperature-

dependent behavior.

Although polymerization of CDs with low-molecular-mass

cross-linking agents demonstrate appropriate properties, the

coupling of preexisting networks to modified or unmodified

CDs achieves an improvement in these properties. For

example, CDs can be used as cross-linking agents as

described by Bibby (1999). His work reported an esterifica-

tion of CD’s hydroxyl groups with PAA’s carboxylic acid

groups, and generation of an anhydride between PAA chains

in this manner led to the formation of a network inducible

with temperature. Paradossi et al. (1997) suggested the

production of a heterogeneous biocatalyst gel system loaded

with copper(II) ions by cross-linking chitosan with an

oxidized (aldehyde-containing) CD via reductive amination.

A recent work used a highly selective copper(I)-catalyzed

1,3-dipolar cyclo addition (click chemistry) between an

alkyne-modified CD and an azide-functionalized

poly(NIPAAm-co-HEMA) during hydrogel generation. The

improvements offered by this process were an effective

control of the gelation rate and the reaction conditions

(Rostovtsev et al., 2002; Tornøe et al., 2002).

Copolymerizations and chemical- or radiation-mediated

inductions are also widely used for the production of CD/

polymer networks. The most common polymers used are

vinyl- or (meth)acryloyl-modified CD monomers with further

vinyl monomers (acrylic acid, 2- HEMA, and NIPPAm).

g-CD-PAA systems with pH-dependent swelling properties

(Siemoneit et al., 2006), and b-CD-maleic anhydride hydro-

gels with both temperature- and pH-dependent behavior (Liu

& Fan, 2003) have been described for drug-release materials.

Moreover, vinyl-substituted polymeric macromers, such as

MAH and PLA, the MAH-substituted block copolymer of

Pluronic F68 and PCL have been employed for the develop-

ment of hydrogels with controlled characteristics via radical

polymerization with CD derivatives (Chen & Jiang, 2011).

Covalently linked polymer/CD adducts can also be

developed by cross-linking CD to reactive polymer end-

groups, for example end-modified PEG, and these agents have

swelling properties which depend on the network composition

(i.e. the ratio of polymer:CD). Desirable PEG characteristics

(biocompatibility, non-immunogenicity and an effective

loading capacity for hydrophobic drugs) render these hydro-

gels valuable candidates for biomaterials (Cesteros et al.,

2007; Salmaso et al., 2007).

Supramolecular physical hydrogels

To avoid the adverse effects of using cross-linking agents for

hydrogel formation, selected systems have been developed

in which gelation is induced via complexation between CDs

and polymer chains (Li, 2010; Manakker et al., 2009).

Physical supramolecular hydrogels arise from noncovalent

interactions, such as (1) electrostatic interactions, (2) hydro-

phobic interactions between amphiphilic polymers, (3) hydro-

gen bonding or (4) stereocomplex formation between

polymers with opposite chiralities, which confer reversibility

behavior to the network systems. This cross-linking can be

performed in aqueous environments, while the drug is loaded,

a process which improves the properties of the network

(Manakker et al., 2008; 2009).

In this case, network generation is a consequence of the

CD inclusion of ‘‘guest’’ molecules, for example linear

polymers. The polymers predominantly used are PEG, PPO

and PCL (Manakker et al., 2008). PEG is probably the most

widely employed for physical CD-based hydrogels in view of

its biocompatibility, biodegradability and hydrophilicity,

DOI: 10.3109/07388551.2013.794413 Cyclodextrin-based hydrogels 7

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properties which render the network suitable for biomedical

applications (Li, 2010).

Hydrogels based on a-CD-PEG and its copolymers have

been designed, and modifications to these materials have been

made to improve their physico-chemical properties, and also

their biocompatibilities. The triblock of PEG and PPO (PEG-

PPO-PEG) has weak physical interactions between chains in

aqueous environments, an observation ascribable to the

hydrophilic behavior of PEG, which renders this copolymer

unsuitable for long-term drug release applications. However,

this can be overcome by using a-CD as a ‘‘trap’’ to the PEG

segments, a process which changes the hydrophobicity of the

copolymer, hence reduces the effective polymer concentration

required for gelatinization, and also confers thermo-reversi-

bility behavior to the copolymer (Li, 2010). Moreover, the

PEG-PPO-PEG copolymer is not biodegradable, and therefore

the use of PHB, a natural, optically active and biodegradable

polyester with high crystallinity and hydrophobic properties

(instead of PEG only on its triblocks), gives rise to a

polypseudorotaxane with a high self-assembly tendency in

aqueous environments. The stability of the copolymer PEG-

PHB-PEG is attributable to complementation of the com-

plexation between the a-CD and PEG, with hydrophobic

interactions between the mid-placed PHB blocks. For these

reasons, PEG-PHB-PEG is a thyrotrophic and reversible

supramolecular hydrogel, and can be employed for the long-

term release of macromolecular drugs without a requirement

for post-application removal (Chen, 2011; Li, 2010).

Additionally, a-CD-PEG-PCL (where PCL is an amphi-

philic biodegradable copolymer) presented a similar behavior

to a-CD- PEG-PHB-PEG. This is specifically the case for

competition between complexation of PEG by CD versus

hydrophobic PCL, as well as for the reversibility behavior of

the hydrogel and its thyrotrophic properties. This shows that it

is possible to develop supramolecular hydrogels by IC

formation with other amphiphilic biopolymers for the purpose

of drug delivery with a minimal level of adversity to the user

(Chen, 2011; Li, 2010).

The reversible properties of these physical hydrogels result

from the entropically unfavorable inclusion of the polymer

and the CD via complexation linkages. Therefore, changes

in the environment, such as temperature and pH values,

can induce dissociation of the polymer from the CDs

(Chen, 2011).

Conclusions

Hydrogels provide major benefits for wound-dressing appli-

cations because they can retain a moist environment (crucial

for wound healing purposes) and are biocompatible. However,

with regard to drug delivery applications, the trapping of low-

to-moderately hydrophobic bioactive molecules is not very

efficient, and their release is rapid and nonlinear with time.

CDs are capable of forming inclusion complexes with a

wide range of bioactive molecules and also with polymers.

CDs can act, simultaneously, as therapeutic agent carriers and

as enhancers favorable hydrogel properties in biosystems.

Therefore, cyclodextrin-based hydrogels may provide a

solution to the achievement of a wound-dressing material

capable of maintaining appropriate conditions for wound

healing, in addition to improving the healing process itself via

the release of bioactive molecules.

Declaration of interest

The authors thank the Foundation for Science and Technology

(Portugal) for financial support to the CEB research center

and E. Pinho grant (SFRH/BD/62665/2009) and also to

FEDER through Programa Operacional Factores de

Competitividade – COMPETE and by national funds by

FCT – Fundacao para a Ciencia e a Tecnologia in the context

of project PEst-C/CTM/UI0264/2011.

The authors report no declarations of interest.

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