International Journal of Biological Macromolecules 51 (2012) 681689

Contents lists available at SciVerse ScienceDirect

International Journal of Biological Macromolecules

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

Review

Advances in biomedical applications of pectin gels

F. Munarin , M.C. Tanzi, P. Petrini
Biomatlab, Bioengineering Department, Politecnico di Milano, P.zza Leonardo da Vinci 32, 20133 Milan, Italy

a r t i c l e

i n f o

Article history:
Received 28 May 2012
Received in revised form 19 June 2012
Accepted 1 July 2012
Available online 7 July 2012
Keywords:
Pectin
Natural polymers
Polysaccharides
Biomaterials
Drug delivery
Tissue engineering

a b s t r a c t
Pectin, due to its simple and cytocompatible gelling mechanism, has been recently exploited for different
biomedical applications including drug delivery, gene delivery, wound healing and tissue engineering.
Recent studies involving pectin for the biomedical eld are reviewed, with the aim to capture the state
of art on current research about pectin gels for biomedical applications, moving outside the traditional
elds of application such as the food industry or pharmaceutics.
Pectin structure, sources and extraction procedures have been discussed focussing on the properties
of the polysaccharide that can be tuned to optimize the gels for a desired application and possess a
fundamental role in application of pectin in the biomedical eld.
2012 Elsevier B.V. All rights reserved.

Contents
1.
2.
3.

4.
5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pectin structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pectin sources and extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Hot water extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Extraction with chelating compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Enzymatic extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Formation of gels and polyelectrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pectin for biomedical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Pectin for drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1.
Nasal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2.
Oral drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.3.
Ocular drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.4.
Cancer-targeted drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Pectin polyplexes for gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Pectin gels for tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Pectin gels as wound healing patches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Pectin is a natural polymer constituting the cell walls of most
plants, and it is extensively employed in food industry, as a

Corresponding author. Tel.: +39 0223999511; fax: +39 0223993360.

E-mail address: fabiola.munarin@mail.polimi.it (F. Munarin).
0141-8130/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijbiomac.2012.07.002

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thickener or stabilizing agent. It is usually extracted from several

types of fruits, with chemical or enzymatic methods.
Pectin is a branched macromolecule with high molecular
weight, which can be converted into hydrogels, intended as exible network of polymer chains that can swell but do not dissolve in
water. Highly concentrated pectin solutions and low pH facilitate
the formation of coil entanglements, resulting in the obtainment
of physical gels. Moreover, water-insoluble gels may be obtained

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F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

with the use of divalent or trivalent cations. This simple gelling

mechanism has raised interest for the preparation of hydrogels
for biomedical applications, namely: drug delivery, gene delivery,
tissue engineering and wound healing.
Pectin structure deeply affects the properties of the gels: the
monosaccharidic content, branching and spatial disposition of the
crosslinking blocks need to be carefully considered when designing
pectin gels for specic biomedical applications.
As for many other naturally occurring polymers, pectin molecular weight, degree of esterication (DE) and acetyl-esterication are
heterogeneous, depending upon the source and the conditions of
extraction. Therefore, pectins extracted from different sources and
with different methods may be more or less suitable in a desired
biomedical application, due to differences in gelling and mechanical properties, stability and responses to chemical and physical
conditions. Here, pectin sources and extraction methodologies are
reviewed, in view of the nal properties determining the gelling
mechanisms and the possible biomedical applications.
Pectin for food technology or pharmaceutical elds, especially
for colon treatments, were extensively reviewed [14]. However, a
review including all the biomedical elds of application of pectin
gels is, at the best of our knowledge, still missing. Our purpose is to
highlight how this natural polysaccharide has recently raised interest for applications such as tissue engineering, cancer treatments
and gene delivery.

2. Pectin structure
Pectin is composed of at least three polysaccharide domains:
homogalacturonan (HGA), rhamnogalacturonan-I (RG-I) and

rhamnogalacturonan-II (RG-II) [57]. HGA is the major component

of pectic polysaccharides, and contains -(1 4)-d-linked galacturonic acids (1,4--d-GalpA) that are partially methyl-esteried
and sometimes partially acetyl-esteried.
The ratio of methyl-esteried residues (6-O-methyl--d-GalpA)
of the HGA backbone to the total carboxylic acid units in the salt
form is named degree of esterication (DE) [8]. Depending on the
degree of esterication, pectins are classied as low methoxyl (LM,
DE < 50%) or high methoxyl (HM, DE > 50%), showing dissimilar
properties. These characteristics were found to affect in depth the
properties of the formed gels, and therefore they should be carefully
controlled to address the desired biomedical application [9].
RG-I is composed of the disaccharide unit galacturonic
acidrhamnose [1,4--d-GalpA-1,2--l-Rhap-]n , 2080% of the
Rhap residues being substituted with neutral oligosaccharides, mainly arabinofuranose and galactose (-l-Araf and
-d-Galp). Furthermore, fucose, glucopyranose and 4-O-methylglucopyranose (-l-Fucp, -d-GlcpA, and 4-O-methyl--d-GlcpA)
may be found as terminal residues of the side chains (Fig. 1). The
branched RG-I domain is the so called hairy region.
RG-II has a more complex structure: it presents a small backbone
consisting of 1,4--d-GalpA residues, and side chains of different
sugars such as rhamnose, galacturonic acid, galactose, arabinofuranose, fucose, apiofuranose (-l-Rhap, -d-GalpA, - or -d-Galp,
-l-Araf, -l-Fucp, -d-Apif) and many others.
How the three domains are assembled is still in debate. Typical hypotesis refers to a model in which the HG, RG-I, and RG-II
backbones are covalently crosslinked to form block co-polymers
(Fig. 1), but the relative position of the three main domains is still
not fully known. The alternate smooth regionshairy regions is
actually the traditional model proposed to describe the disposition

Fig. 1. Schematic representation of pectin structure with the model of the smooth regionshairy regions: main domains and monosaccharidic composition, according to
Refs. [5,7,128,129].

F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

of the domains: it consists in a linear backbone of unbranched

HGA residues alternately linked to branched RG-I residues [7,10].
However, recent studies on pectin composition reported other
plausible models for pectin structure: the RG-I backbone model,
in which HGA is positioned as a RG-I side chain [11] and the living
thing model, in which unsubstituted HGA is connected to the RGI but with not-linear congurations. In this model, the backbone
of pectin is alternately composed of two linear HGA residues and
one RG-I core, where the HGA blocks can take horizontal as well as
vertical positions [5].
In a biomedical perspective, the understanding of the organization of pectin domains may be fundamental to tailor cell adhesion
and the mucoadhesive or anti-methastatic properties of pectin gels
and for the formation of mechanically stable gels.
3. Pectin sources and extraction
Pectin constitutes about the 30% of the primary cell walls of
plants [12]. However, only few plants are processed as sources
for commercial pectins, depending on the yield, time and cost of
the extraction procedures, the desired properties of the extracted
pectins and the availability of the raw materials [13]. The pectic
substances extracted from fresh tissues or dry matter of fruits and
vegetables vary from 0.1% to 30%, and, according to source and
methods of extraction, a wide range of pectin degrees of esterication may be obtained (Table 1).
Up untill now, pectin is mainly produced from waste materials
from the juice, apples and cider industries, whereas sugar beet roots
and sunowers are sources of minor importance [22]. The industrial
extraction is usually carried out by acid treatments (pH 13) at
high temperature (7090 C). After extraction, standardization is
usually required to obtain samples with consistent properties. In
this process, different extracts are blended, diluted and added with
sugars (i.e. sucrose or dextrose) to achieve pectins with standard
properties.
Pectin chemical structure undergoes important structural
changes during the extraction procedures. Compared to native
pectin, the extracts present lower amount of methylester groups,
thus increasing the charge density of the macromolecule [4244].
In some cases, depending on the type of extraction, the degree
of acetylation of native pectins can be modied after extraction
[45,46].
Pectin extraction, and especially enzymatic extraction [47,48],
is also known to induce depolymerisation of the pectin chains,
resulting in shorter branched chains [49,50].
Table 1
Yield and degree of esterication of pectins extracted from different sources.
Pectin source

Yeld (%)

DE (%)

References

Aloe
Apple
Banana
Cacao pod husks
Carrots
Chickpea
Chicory roots
Citrus fruits
Durian
Grape fruit
Mango
Passion fruit
Peach
Potatoes
Pumpkin
Red dragon fruit
Soy hull
Sugar beet pulp
Sunower

5
219
215
411
719
8
35
626
210
1332
929
470
418
510
722
415
1828
416
1011

3
2280
4980
57
3458
67
3556
5680
>50
7576
4986
10
2084
11
5368
5175
5360
1448
3439

[14,15]
[1618]
[19]
[20]
[21,22]
[23]
[24]
[2527]
[28]
[29]
[30,31]
[32,33]
[34,35]
[36]
[37]
[38]
[39]
[40]
[41]

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Extraction procedures other than the industrial ones have been

proposed to increase the yield, to lower cost and time of extraction and to obtain controlled structures and chemical properties.
Even though these methods might be not suitable for the industrial production, they acquire great importance for the biomedical
research where higher cost products can be accepted to some
extent to obtain specic properties. Therefore, the production of
a variety of pectins with tailored structure and chemical properties
may be exploited for the fabrication of biomaterials with tunable
gelling mechanisms, mechanical and stability properties, adaptable
to the requirements of the biomedical applications. As an example, a pectin gel for bone tissue engineering would have higher
mechanical properties and stability than the one intended for drug
delivery.
Different extraction procedures are here described, with a particular focus on which conditions make them more or less suitable
for the extraction of pectins for biomedical applications.

3.1. Hot water extraction

The hot water extraction is the traditional method used to
extract pectin from the primary cell walls of fruits or vegetables
[51,52]. With this method, the extraction is performed by mixing
the raw materials with acids: citric, nitric, hydrochloric, sulphuric
or phosphoric acids [19,5355] or alkali, mainly NaOH [56] in different concentrations, the pH of the aqueous solutions varying from
1 to 10.
The main disadvantages in the use of hot water extraction consist in the long period of heating, which can lead to the rupture of
pectin chains with a decrease of the degree of polymerization, and
the difculty of separating pectin from the other plant residues. The
depolymerisation of pectin chains may induce a reduced ability to
form entangled systems, which results in gels with low mechanical
properties, particularly appropriate for drug delivery or for soft tissue regeneration but inappropriate for the regeneration of tissues
where the mechanical stimuli transmission has a key role in the
regenerative process (i.e. bone or cartilage regeneration).
Acid treatments may also induce corrosion of the extraction
equipment and lead to problems of water pollution, whereas the
alkaline extraction could decrease the methyl and the acetyl content and the length of the main chain of galacturonic acid by
-elimination [57].
To overcome these drawbacks, Fishman et al. proposed two different strategies to shorten the time of extraction. The heating time
was reduced by coupling the hot water extraction with microwave
pre-treatments or by use of steam injection heating under pressure
[55,58,59].

3.2. Extraction with chelating compounds

Besides being prevalent in the primary cell walls, pectin can be
found also in the middle lamella (the layer connecting adjacent cells
in the plant cell walls) bonded with calcium ions, in the form of calcium pectate. To extract pectin from the middle lamella, cold and
hot aqueous solutions of calcium chelating compounds, as ethylene
diamine tetraacetateEDTA [60], cyclohexane diamine tetraacetate
CDTA [61,62], imidazole buffer [45,62], sodium hexametaphosphate [40] or ammonium oxalate [63,64] remove calcium ions from
calcium pectate without damaging the pectin galacturonic chains.
However, the complete removal of the reagents is difcult to obtain
upon purication, and the residual chelating agents may deeply
affect the gelling properties of pectin, reducing the ability to form
stable gels.

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F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

3.3. Enzymatic extraction

The specic extraction of pectin through enzymes has also
been exploited. Pectinase is a general term used to identify different enzymes, mainly extracted from microorganisms and fungi
[6569], which catalyze the extraction of pectin from the plant cell
walls. The enzymatic treatments lead to the rupture of the internal links of pectin, thus decreasing the viscosity of the solutions,
and permitting easier ltration and centrifugation. Furthermore,
enzymatic treatments allow the reduction of water pollution and
less environmentally damaging waste is produced. The major disadvantage found in the use of enzymes is their complex production
processes and high cost. Furthermore, if the extraction process
is not well controlled, pectin may be degraded by the enzymes,
causing its gelling properties to be lost. Overall these disadvantages make this extraction the least preferable to extract pectins
for biomedical applications.

4. Formation of gels and polyelectrolytes

Pectin molecular weight, degree of esterication and esterication patterns along the polysaccharide chains determine whether
gelling can occur or not, and affect in depth the properties of the
gels. Other parameters, such as temperature, pH, presence of cosolutes or cations, need to be further considered for pectin gel
fabrication [70]. Furthermore, the esterication patterns of pectin
chains vary according to the chemical or physical agents used
during the extraction: acidic de-esterication causes random distribution, whereas pectinesterase enzymatic degradation results in
blockwise distribution of the methyl ester groups [70].
HM pectins, with more than 50% of the methyl esteried carboxyl groups, form physical gels at pH < 3.5 and in the presence of
more than 55% (w/v) co-solutes, as sucrose, mainly due to the formation of entanglements, hydrophobic interactions and hydrogen
bonds [71]. Thus, an increased DE results in a more rapid gel formation, as several hydrophobic bonds may be formed among pectin
methyl ester groups [70].
Water-insoluble gel formation from LM pectin occurs in the
presence of positive divalent ions over a wide range of pH values,
either with or without co-solutes.
The interactions of the carboxyl groups of LM pectin backbone
with Ca2+ ions induce the formation of the so-called egg box

Table 2
Polycations investigated to form pectin gels.
Cation

Gel strenght

Divalent ions

Ca2+
Cu2+
Sr2+
Ni2+
Zn2+
Cd2+
Pb2+
Mg2+

+++
++
+++
++
++
++
++

Trivalent ions

Al3+
La3+
Fe3+

++
+
+

structure, even though it slightly differs from the egg box model
originally dened for alginates [72,73].
According to the egg box model originally hypothesized for
LM pectins [74], there is an initial dimerization step of two homogalacturonic chains by cooperative bridging of parallel facing chains
through Ca2+ ions. Cooperativity is possible because homogalacturonic chains are relatively rigid [75] and the binding of a rst
calcium cation by two pectin chains facilitates their alignment with
respect to each other, which in turn allows the easier binding of a
next calcium ion, and so on along the sequence [76]. The antiparallel orientation of the two chains seems to be the most favorable
arrangement, and this initial dimer association is strongly stabilized
by hydrogen bonding, in addition to electrostatic interactions [77].
Subsequent Ca2+ -induced aggregation of the preformed egg box
dimers in tetramers, hexamers, etc. can occur, but these subsequent
associations of dimers have no particular specicity and seem to be
merely governed by electrostatic interactions (Fig. 2). These multimers are therefore easily disrupted by competing monovalent ions
while the initially formed chain dimers are not.
The minimum number of successive non-methyl esteried
residues needed to obtain the divalent ion chelation has been estimated to be in a range of 620 [78].
Besides calcium ions, other divalent or trivalent cations may
be used for the formation of LM pectin gels. Some studies [79,80]
investigated the formation of pectin gels with divalent and trivalent
ions, by comparing the strength of the resulting gels (Table 2).
Nevertheless, the positive charges needed to form pectin gels
may be obtained from other polycationic polysaccharides, such as

Fig. 2. Egg box gelation mechanism of pectin: the carboxyl groups of pectin backbone form polyelectrolyte complexes with polyvalent cations (i.e. calcium ions). The gelation
can be quickly reversed by monovalent cations (i.e. sodium or potassium ions).

F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

chitosan [8183]. The electrostatic interactions among the oppositely charged polysaccharides provide the formation of physical
hydrogels with controlled properties. Blends of pectin and chitosan
form polyelectrolyte complexes (PECs) in a pH range 36, with both
polysaccharides in the ionized form. PEC of pectin and chitosan may
also be obtained at pH < 2, when the suppression of the electrostatic
charges is replaced by the favored formation of hydrogen bonds
[70].
Overall, pectin gels have been obtained in numerous physical
forms, including micro- and nano-particles [8487], lms and coatings, injectable gels or solid scaffolds [81], by varying the type and
concentrations of the crosslinkers.
5. Pectin for biomedical applications
The promising aspects of pectin gels for biomedical applications are related to easily tunable physical properties (as previously
discussed in the structure and sources and extractions sections)
high water content and ability to homogeneously immobilize cells,
genes, proteins, drugs or growth factors [8487]. There are many
different biomedical applications suitable for such gels, which can
be generally divided in drug delivery, gene delivery tissue engineering and wound healing [88]. The properties of pectin gels used
for biomedical applications are summarized in Table 3.
5.1. Pectin for drug delivery
Safety and efcacy of pharmaceutical agents can be greatly
improved by the immobilization or covalent attachment of the
drug on a biomaterial carrier. Such drug delivery systems improve
the conventional drug administration as they provide in situ controlled and sustained release of active biomolecules. The pattern of
drug release may be constant, oscillating, declining continuously,

685

or even pulsatile. For most drug delivery systems, natural polymers

are employed as inert, biocompatible carriers [89,90]. But nowadays, natural polymers are increasingly considered for targeting or
pathology-responsive functions [91].
Among natural polymers, pectin has interesting properties for
drug delivery applications, such as the muco-adhesiveness, the ease
of dissolution in basic environments and the ability to form gels in
acid environments. Muco-adhesiveness can be exploited to target
and control the drug delivery in the nasal or gastric environment,
while the ease of dissolution in basic environments, associated to
its resistance to proteases and amylases, is making pectin suitable
to release drugs in the colon. The possibility of forming gels in acid
conditions, instead, enhances the contact time of drugs for gastric
or ocular treatments [92,93].
Furthermore, pectin has been found to recognize galectin
molecules, which are involved in different stages of cancer
pathologies, being particularly appealing to target tumor cells for
chemiotherapic treatments [94].
5.1.1. Nasal drug delivery
Conventionally, nasal drug delivery is employed for the treatment of local diseases such as nasal allergy, nasal congestion and
nasal infections. Recent studies have shown that the nasal route
can be exploited for systemic delivery of low molecular weight
drugs, peptides and proteins that are not easily administered by
injection, or when a rapid release is required. The extensively vascularized nasal cavity ensures the systemic availability of drugs or
molecules of interest, avoiding the hepatic rst-pass metabolism.
Nasal administration is suitable for patients who may have difculty in swallowing tablets or for those refusing intramuscular
therapies.
Generally, conventional nasal formulations such as liquid drops
or sprays are rapidly cleared from the nose, with residence times

Table 3
Sources and chemical properties of the commercial pectin extracts used for biomedical applications. The molecular weight of the extracts, though a critical parameter for gel
formation, is often not specied.
Biomedical application

Commercial source

Molecular
weight [kDa]

Degree of
esterication [%]

Cross-linker

References

Nasal drug delivery

Pectin type E440

Pectin type FPA
Fluka
N.A.a
CP Kelko GENU (type B, LM101 AS
and LM104 AS-FS)
HiMedia Laboratories Ltd., India
Cargill, Unipectine OF305C
CP Kelko GENU (type LM101 AS
and LM104 AS-FS)
Herbstreith & Fox KG
CP Kelko, GENU (type LM104
AS-FS)
Otto Kemi, Mumbai, India
East-Asiatic Company, type 7210

20400
N.A.a
30-100
N.A.a
N.A.

<50
<50
60
N.A.a
72, 36, 28

Ca2+
Ca2+
Chitosan
Na+ , K+ , Mg2+ , Ca2+
Not crosslinked (tablets)

[9698]
[99]
[100]
[101]
[9]

N.A.
N.A.
N.A.

N.A.
25
36, 28

Not crosslinked (emulsion dehydration)

Ca2+ , Zn2+
Ca2+ , Ca2+ and chitosan

[103]
[104]
[105]

100
N.A.

70
28

Not crosslinked (spry dry)

Zn2+ and chitosan

[106]
[107]

N.A.
N.A.

N.A.
<50

Not crosslinked (emulsion dehydration)

Dicalcium phosphate

[108]
[109]

N.A.a
Cesap, Cesapectin LM 32
N.A.
N.A.

>4
N.A.
N.A.
N.A.

<30
32
<50
<50

Na+
Not crosslinked (spry dry)
Not crosslinked (solutions)
Not crosslinked (solutions)

[110]
[111]
[94]
[112]

Gene delivery

Herbstreith & Fox KG, type CU701

Sigma Aldrich
Herbstreith & Fox KG

261
80
150

42
<50
2732

Ca2+
Amidated pectin crosslinked with DNA
Ca2+ , Mg2+ , Mn2+

[120]
[121]
[122]

Tissue engineering

Sigma Aldrich
Herbstreith & Fox KG, type CU701
Herbstreith & Fox KG, type CU701
Herbstreith & Fox KG, type CU701
Pectin extracted from cactus

N.A.
261
261
261
N.A.

42
42
42
42
N.A.

Chitosan
Ca2+
Ca2+
Ca2+
Not crosslinked (blends with PVA)

[81]
[85]
[86]
[87]
[126]

Oral drug delivery

Ocular drug delivery

Cancer-targeted drug
delivery

Wound healing
a

Data not available as protected by patents.

Products described in Table 4a

686

F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

in man of 1215 min [95]. On the other hand, viscous solutions are
difcult to administer as drops or sprays, and powder formulations
require sophisticated delivery devices for deposition and accurate
dosing.
Hence, mucoadhesive polymers have been proposed for the
preparation of carriers to achieve a controlled release of the active
principle, according to hydration/diffusion mechanisms of the
mucosal tissue. Recent studies have shown a mucoadhesive potential for LM pectin, which was demonstrated to be due to hydrogen
bonding between pectin free acid groups and mucin [92]: under
appropriated conditions, pectin reverts from an aqueous solution
into a gel when applied to mucosal surfaces. Pectin has been investigated either for sustained, rapid or pulse nasal delivery. Among
the applications, fentanyl (an opioid painkiller) pectin nasal spray
was proven to improve the analgesic onset, treatment efcacy and
acceptability to treat breakthrough cancer pain [9698], where
a rapid drug release is requested. Alternatively, pectin has been
used in combination with peptides [99] or with chlorpromazine
hydrochloride [100] in the treatment of psychotic symptoms showing interesting absorption properties and a sustained systemic
release. Nasal pectin sprays containing nicotine have been further
suggested as an alternative approach for smoking cessation [101].
Two different systems have been proposed: a pulse delivery of
nicotine for rapid absorption and a controlled release of nicotine
for sustained absorption. The controlled release has been achieved
by preparing a polyelectrolyte complex from pectin and nicotine,
whereas the pulse release can be obtained by overloading the complex with nicotine, so that the composition contains some excess
nicotine for immediate release and absorption.
5.1.2. Oral drug delivery
Oral delivery is still the preferred route of drug administration,
especially for chronic pathologies where repeated administration
is required. However, drugs are transported over a long distance
and experience different environmental conditions, such as low pH
and mechanical pressure in the stomach, protease attack in the
small intestine, and microora digestion in the colon [102]. For
these reasons, oral drug delivery is not suitable for the administration of most proteins and polypeptide drugs due to their high
susceptibility to digestive enzymes in the gastrointestinal tract,
poor absorption and limited ability to be transported across the
intestinal barriers [4]. To protect drugs from degradation, and to
obtain target release in specic organs, drugs are encapsulated into
micro- or nano-capsules. Pectins were considered in the preparation of capsules for sustained drug delivery and for taste-masking.
The ability of pectins to be resistant to proteases and amylases,
which are active in the gastrointestinal tract, and to be degraded
by the intestinal microora make them suitable for colon drugs,
proteins or polypeptide delivery [103]. As a drawback, pectin gels
swell in aqueous media, and a small amount of drug may be
released in the gastrointestinal tract. To overcome this problem,
divalent ions, such as Ca2 , Zn2+ or other polymers, such as chitosan,
ethylcellulose or hydroxypropylmethyl cellulose [4,9,104108],
were used to form strong pectin gels, for drug delivery in the
colon.
The ability of pectin gels to swell in acid conditions may be considered an advantage if these systems are considered for weight
reduction and obesity treatments. In fact, when pectin gels reach
the aqueous environment of the gastric uids, the gels begin to
swell to ll the stomach and to adhere to the stomach walls for a
long time before digestion, which leads to a prolonged non-appetite
sensation [109].
5.1.3. Ocular drug delivery
Topical application of drugs into the eye is the most popular
and well-accepted route of administration for the treatment of

various eye disorders. The bioavailability of ophthalmic drugs is,

however, very poor due to efcient protective mechanisms of the
eye. Blinking, baseline and reex lachrymation remove rapidly foreign substances, including drugs, from the surface of the eye. The
use of water-soluble polymers able to form hydrogels in physiological conditions, such as pectins, has been evaluated as a new
strategy to enahance the contact time and the drug penetration
[93]. An alternative approach was the application of pectin systems
for an in situ gel formation [110], where pectin is applied in a liquid
form and then gels in the eye. The gelation is mainly triggered by
the pH of the tears and by the presence of electrolytes in the tear
lm.
Preliminary studies were assessed on pectin microspheres as
an ocular delivery system for piroxicam (a non-steroidal antiinamatory drug) and, possibly, for other drugs [111]. This system,
while ensuring a high bioavailability, has been shown to reduce
some disadvantages of other ophthalmic delivery systems, such
as vision blurring, need for insertion and removal, and stability
problems.
5.1.4. Cancer-targeted drug delivery
Pectin appears to be able to inhibit cancer metastasis and primary tumor growth in multiple types of cancer in animals [94,112].
The inhibitory effect was suggested to be due to the recognition of
galactan components of pectin by galectin-3 (Gal3). Gal3 is involved
in several stages of cancer progression and metastasis, angiogenesis and neoplastic cell response to cytotoxic drugs [113,114] and it
is highly expressed in a variety of metastatic cancer cells [115].
Citrus pectin obtained from the peel and pulp of citrus fruits
and modied by means of high pH and temperature treatments
[94,116] have been used to target Gal3 and successfully inhibited
its metastatic functions. Thus, modied pectins, possibly loaded
with cytotoxic drugs to induce neoplastic cell apoptosis, hold the
potential to dramatically increase the efciency of a conventional
chemotherapy.
5.2. Pectin polyplexes for gene delivery
A possible approach to the treatment of genetic disorders is gene
therapy. The main objective in gene therapy consists in replacing
defective genes, substituting missing genes or silencing unwanted
gene expression to consequently eliminate the root cause of the
disease. Many studies focus on the transfer of the genetic materials
to the targeted tissues, either with viral or non-viral transfection
vectors. The efciencies of viral transfection vectors are, in general,
superior to their non-viral counterparts, however the potentially
adverse immunogenic response associated with the use of viral
vectors are increasingly making the non-viral gene carriers as the
vectors of choice. Among non-viral vectors, polycationic polymers
as branched polyethylenimine (b-PEI) [117] or chitosan [118] have
shown high transfection efciency both in vitro and in vivo. As a
drawback, the positive charge of the polycations may cause high
cytotoxicity and instability in the presence of serum or extracellular
matrix (ECM) components. To overcome this limit, different anionic
polymers have been employed to decrease the surface charge of the
polyelectrolyte complexes [119].
Pectin was found to be suitable for coating b-PEI polyplexes to
form pectin-coated polyplexes with a reduced surface charge that,
in turn, led to decreased transfection with a concomitant lower
cytotoxicity and higher stability [120].
With a different approach, Katav et al. [121] suggested a chemical modication to pectin to make the anionic polymer applicable
for DNA delivery: pectin structure was modied with amine groups,
and the modied compound formed complexes with plasmid DNA
while exhibiting high stability. Other studies have investigated the

F. Munarin et al. / International Journal of Biological Macromolecules 51 (2012) 681689

formation of pectin nanoparticles with different cations to entrap

the DNA for transfection [122].

Table 4
Pectin-containing hydrocolloid wound dressings.
Type of dressing

5.3. Pectin gels for tissue engineering

Natural polymers have been employed as scaffolds to stimulate specic cell functions and to direct cell-cell interactions both
in implants that are initially cell-free, possibly loaded with growth
factors to promote tissue regeneration [123,124], and in implants
to support cell growth. These materials have been patterned in
two-and three-dimensions, to generate multicellular tissue architectures which may regenerate healty tissues in a pathological site.
Few studies report the use of pectin for tissue regeneration, probably taking into account the non-adhesiveness of this polysaccharide
for cells. However, pectin hydrogels were found to have a great
potential for bone tissue engineering applications, as they promote
the nucleation of a mineral phase if immersed in adequate physiological solutions [85], with the formation of biomimetic constructs
better mimicking the natural architecture of the bone. Unmodied and chemically modied pectin gel, microspheres and coatings
were studied for the 2- and 3-dimensional culture of bone cells,
showing interesting properties for cell viability, metabolic activity
and differentiation [81,86,87]. Concerning the chemical modications, pectin oxidation was assessed to accelerate the degradation
of the gels so as to increase the release of immobilized cells; enzymatic treatments were proven to release the homogalacturonan
part of the pectins producing hairy regions, which are proved to
induce a favorable interactions with different cell types [125] and
RGD (arginineglycineaspartic acid) sequence was coupled on
pectin backbone, to enhance cell adhesion, thus stimulating cell
growth and proliferation [86]. Furthermore, composite hydrogels
prepared with pectin and polyvinylalcohol were evaluated as prosthetic nucleus pulposus substitutes, showing good biocompatibility
with broblasts and no evidence of degradation or displacement
after implantation in the animal model [126].
5.4. Pectin gels as wound healing patches
Generally, the application of hydrogel lms on wounds or ulcers
was aimed to prevent bacterial infection, support the autolytic
debridement and maintain a moist healing environment. However,
further evidence suggested the suitability of hydrogels as localized drug or growth factors delivery systems, barriers to prevent
post-surgical adhesions and matrices for skin regeneration. Hence,
hydrogel lms should participate actively in the wound healing
process rather than simply being passive barriers against desiccation. The natural properties of pectin impart several advantages
to the wound dressings, such as hydrophilicity, which permits
removal of exudates, the retention of an acid environment, which
may act as barrier against bacteria and the ability for binding active
molecules as drugs or growth factors to heal the wounds.
As a wound heals, the cells around it are stimulated by growth
factors to proliferate and grow into the wound [127]. When pectin
is added to the wound, it serves as a binding agent, protecting
growth factors from degradation. A wide variety of hydrocolloid
pectin-based wound dressings has been patented and is nowadays
commercially available (Table 4). They are mainly composed of
adhesive, absorbent polymers, pectin gelling agents and sodium
carboxy-methylcellulose. The hydrophilic pectin particles react
within the dressing with the wound uid to form a soft gel over
the wound bed, thus removing or controlling exudates in wounds.
The acid environment obtained with pectin solubilization may
further act as a bacterial or viral barrier. In addition, pectin hydrogels provide improved systems of loading and releasing drugs, i.e.
antibiotics, pain relievers and/or tissue repair factors at the site of
action.

687

Composition

Hydrocolloid sheets, uses: cavity or at shallow wounds with low to medium

exudates; absorbent; conformable; suitable for problematic areas: heel,
elbow, sacrum
CombiDERM (ConvaTec Ltd.)
Cellulose, pectin, Salsorb90 (acrylic
polymer)
Carboxymethylcellulose, pectin,
DuoDERM (ConvaTec Ltd.)
propylene glycol
Polyurethane foam sheet coated
Granuex (ConvaTec Ltd.)
with pectin, gelatin and
carboxymethylcellulose
Hydrocoll
(Hartmann)
Pectin, gelatin and
carboxymethylcellulose
Hydrocolloid paste, uses: useful debriding agent, conformable, may be left in
place for several days
Pectin, carboxymethylcellulose,
GranuGel paste(Convatec Ltd.)
propylene glycol
Pectin, carboxymethylcellulose
CitruGel (Advances medical)

6. Conclusions
In this review, some non-conventional elds of application of
a well-known polysaccharide, pectin, are provided. The chemical
and structural characteristics of this polysaccharide, as well as the
sources and methodologies of extraction, have been described to
highlight which properties may affect the gels formation and, in
particular, which ones are appealing for the different biomedical
applications.
The large variety of applications as well as the increasing number of studies on pectin hydrogels for biomedical applications
suggests that the potential of pectins as novel and versatile biomaterials will be even more signicant in the future.
Acknowledgments
This work was supported by grants from Fondazione Cassa di
Risparmio di Trento e Rovereto, 2012, to M.C. Tanzi.
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