self assembling
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DOI: 10.1002/asia.201000592
Self-Assembled Gels for Biomedical Applications
Warren Ty Truong,*[a] Yingying Su,[b] Joris T. Meijer,[a] Pall Thordarson,[a] andFilip Braet[b]
30 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2011, 6, 3042
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Abstract: Natural and synthetic gel-like materials have
featured heavily in the development of biomaterials for
wound healing and other tissue-engineering purposes.
More recently, molecular gels have been designed and
tailored for the same purpose. When mixed with, or con-
jugated to therapeutic drugs or bioactive molecules, thesematerials hold great promise for treating/curing life-
threatening and degenerative diseases, such as cancer, os-
teoarthritis, and neural injuries. This focus review explores
the latest advances in this field and concentrates on self-
assembled gels formed under aqueous conditions (i.e.,
self-assembled hydrogels), and critically compares their
performance within different biomedical applications, in-
cluding three-dimensional cell-culture studies, drug deliv-
ery, and tissue engineering. Although stability and toxicity
issues still need to be addressed in more detail, it is clear
from the work reviewed here that self-assembled gelshave a bright future as novel biomaterials.
Keywords: biomaterials gels medicinal chemistry self-
assembly solgel processes
Introduction
Since antiquity, humanity has used materials to replace parts
of the body. Initially, naturally available materials like wood
were used. With advances in modern technology, these ma-terials were superseded by synthetic polymers, ceramics, and
metal alloys, which provided better performance, increased
functionality, and enhanced reproducibility (in terms of
their properties) than their naturally derived components.[1]
The field of biomaterials has progressed from crude sutures
constructed from plant or animal gut, to the more-advanced
sutures used these days for wound closure, to the advent of
contact lenses and drug-infused wafers[2] that are implanted
within the body.
Currently, there is a pressing need for better biomimetic
materials, especially those that can mimic the extracellular
matrix (ECM), which itself is a biological gel-like material.[3]
The interest in ECM biomimetic materials arises from the
fact that, if designed correctly, ECM biomimetic materials
could, for instance, stimulate a particular type of cell growth
or differentiation of stem cells. To fully realize the potential
that any ECM biomimetic material may have requires a
proper understanding of their structurefunction relation-
ship. For self-assembled gels, this will always be difficult
without a proper initial understanding of how these struc-
tures are formed in the first place.
Over the years, natural materials, such as reconstituted
collagen, chitosan,[4] and other naturally derived polymeric
gels, have featured heavily in the development of new bio-
materials for wound healing and other tissue engineering.
[5]
On the basis of successful outcomes of these classes of natu-
rally based polymeric gels, numerous chemically engineered
polymeric gels have been designed and tailored for the same
purpose in recent times.[6]
More recently, self-assembling gels (Figure 1) made from
low-molecular-mass organic gelators (LMOGs) have
sparked interest in the field of biomaterials because of theirlow immunogenicity and cytotoxicity to tissues and cells.[7]
Self-assembled gels (also known as supramolecular or physi-
cal gels) comprised of LMOGs would theoretically be better
suited to the field of biomaterials relative to polymer bioma-
terials because their scaffold of nanofiber networks are on
the same order of magnitude as found in the ECM, thereby
providing a pseudo in-vivo environment for cell migration,
growth, and differentiation. Furthermore, many small-mole-
cule gelators (LMOGs), being derived from biocompatible
components and held together by noncovalent forces, de-
grade more-easily than the more prevalent polymer gels.[8]
[a] W. T. Truong, Dr. J. T. Meijer, Dr. P. Thordarson
School of Chemistry
The University of New South Wales
NSW 2052 (Australia)
[b] Y. Su, Prof. F. Braet
Australian Key Centre for Microscopy and Microanalysis
The University to Sydney
NSW 2006 (Australia)
Fax: (+61)2-9351-7682
Figure 1. Gels can be either made up of polymeric (below the horizontal
line) or self-assembled gel fibers (above the horizontal line). The solvent
that makes up the majority of the gels (by weight) can either be water
(left: hydrogels) or organic solvent (right: organogels). Self-assembled
gels are also known as molecular or physical gels.
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It is worth mentioning here that self-assembled fibrillar
structures are also found in nature, and although they do
not form true self-assembled gels, their functional properties
do arise from their fibrillar nature rather than their building
blocks per se. The most recognizable examples of this kind
are the b-amyloids that are associated with diseases such as
Alzheimers disease.
[9]
A few natural peptide and proteinhormones self-assemble into non-disease-related aggregates
near or within their storage sites.[10]
Finally, it is important to note that self-assembled gels are
dynamic in nature, akin to naturally occurring self-assem-
bled systems, such actin filaments and the above-mentioned
b-amyloids. The dynamic nature of self-assembled gels
allows them to adapt better to their environments and the
changes in their surroundings, including inside living tissue.
It is quite probable that the dynamic nature of self-assem-
bled gels is the underlying explanation for the apparent ad-
vantage that they seem to have over conventional polymer-
based gels in applications such as a tissue engineering and
drug delivery.
What Are Gels?
Although somewhat difficult to define in an exact manner,
gels are typically considered as a two-component system
comprised of a three-dimensional matrix of entangled fibers
that encapsulate a solvent by means of capillary forces and
surface tension (Figure 1).[11]
Abstract in Chinese:
Warren Ty Truong was born in Sydney,
Australia in 1987. He received his BSc in
Nanotechnology from the University of
New South Wales in 2009. Currently, he is
pursuing his PhD under the supervision
of Pall Thordarson. His interests include
self-assembling systems for biomedical
applications and reading graphic novels,
in particular anything with Batman.
Yingying Su obtained her BSc in Bio-
chemistry & Biotechnology in 2004 at theSun Yat-Sen University (Guangzhou,
China). Soon after, Su started her training
as a master in Applied Sciences and at-
tained a major in Molecular Biotech-
nology in 2006 at the University of
Sydney (Australia). Currently, she works
as a PhD student together with Filip
Braet and Pall Thordarson on the appli-
cation of biomodified hydrogels as a ther-
apeutic means to treat colon cancer.
Joris T. Meijer received his masters
degree from Utrecht University. He ob-
tained a PhD from Radboud University
Nijmegen working with professor Jan
C. M. van Hest. After postdoctoral work
at the Radboud University he joined the
group of Pall Thordarson at the Universi-
ty of New South Wales. His current inter-
ests include peptide synthesis, self-assem-
bled systems, and biomaterials.
Pall Thordarson obtained his BSc from
the University of Iceland in 1996 and aPhD from The University of Sydney in
2001, followed by a Marie Curie Fellow-
ship at the University of Nijmegen, The
Netherlands. He returned to Australia in
2003 and obtained an ARC Australian
Research Fellow at The University of
Sydney in 2006. He was appointed a
Senior Lecturer at the University of NSW
in 2007 where he leads a research group
of ten people working on light-activated
bioconjugates for controlling enzyme ac-
tivity and self-assembled gels for drug de-
livery.
Filip Braet received his postgraduatetraining in clinical chemistry and biomed-
icine and obtained his PhD in 1999 at the
Free University of Brussels (Belgium).
Currently, he holds the positions of Asso-
ciate Professor, Biomedical Scientist, and
Deputy Director in the Australian Centre
for Microscopy & Microanalysis at the
University of Sydney. His research inter-
ests include the application of correlative
biomolecular microscopy techniques for
exploring structurefunction relationships
in biological systems, particularly in the
areas of nanobiology, chemical biology,
structural biology, and cancer biology.
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Chemical and Physical Definitions
In most gels, it is the solvent that makes up the majority (by
weight) of the gel. Self-assembled gels typically consist of
0.110% w/w of the gelator, whereas in polymeric gels the
weight percentage of the covalent polymer tends to be
higher. If the solvent is organic, then the gel is known as anorganogel (Figure 1, right), whereas if the solvent is water,
then the gel is a hydrogel (Figure 1, left). Because of their
high water content, hydrogels offer excellent biocompatibil-
ity. Furthermore, owing to their ability to adjust to any
shape required of them and their inherent mechanical stiff-
ness, gels are different to injectable solutions. Consequently,
the focus here will naturally be on hydrogels, although some
interesting medical applications of organogels have been re-
ported. For example, Leroux and co-workers have shown
that organogels formed from N-stearoyl-l-alanine methyl
ester 1 in refined safflower oil can be used for the controlled
delivery of rivastigmine, which is used to treat Alzheimers
disease.[12]
Our recent cytotoxicty studies on the related fattyacid amino acids LMOGs 25 showed that they are only
moderately cytotoxic at concentrations of 0.5 mm.[13]
Based on the bonding interactions that are involved intheir assembly, all gels can also be classified into polymeric
(covalently bonded, high molecular weight (MW)) and self-
assembled (or supramolecular) gels from low MW building
blocks. The nomenclature within the field is still evolving, so
sometimes it is difficult to discern in the literature whether
we are dealing with polymeric or self-assembled hydrogels
(Figure 1, top vs. bottom).
Traditionally, gels have been polymer based, with the mo-
nomer units of the polymers linked through covalent forces;
this leads to mechanically strong gels. However, the gel-for-
mation is not reversible, and as a result, degradation and re-
moval of the gel is limited by the polymer properties. [14] Fur-
ther, properties of polymer gels can vary considerably from
batch to batch owing to the lack of control over the length
and shape (branching) of the polymers useda problem
that persists in the field of polymer chemistry despite some
recent advances in controlled polymerization techniques.
Self-assembled gels formed from LMOGs rely on nonco-
valent forces between these gelator molecules to self-assem-ble into larger structures. It is the combination of these
forces (which by themselves are relatively weak) that ena-
bles large assemblies of the gelator molecules to interact
and form the matrix of the gel.[8] These noncovalent forces
are notably hydrogen bonds, electrostatic interactions, hy-
drophobic interactions, van der Waals interactions, pp
stacking, and water-mediated hydrogen bonds.[15] Self-assem-
bled hydrogels are attractive because of their potential ap-
plications in areas such as drug delivery, [16] tissue engineer-
ing,[17] three-dimensional cell cultures,[18] and as a scaffold
for making wires.[19]
The Use of Traditional Polymeric Gels in Biologyand Biomedicine
For historical reasons,[20] most work has been performed so
far on polymeric hydrogels that have been widely studied
for drug delivery[21] and tissue engineering. Before reviewing
how self-assembled gels have been used in biomedical appli-
cations, it is worth looking briefly at some representative ex-
amples of how their polymeric counterparts have been used
for these purposes.
In the area of tissue engineering, Quinchia Johnson
et al.[22] were able to restore the vocal folds in rabbits six
months after injection with a slightly modified polymeric gel
compound, Extracel. In brief, the extracellular matrix of the
vocal folds was treated onsite by using an injectable gel that
was basically composed of a mixture of a thiolated deriva-
tive of gelatin (i.e., gelatin-3,3dithiobis(propionichydrazide)
(DTPH)) that was covalently co-cross-linked with Carby-
lan S by using polyethylene glycol diacrylate as the thiol-re-
active cross-linker. This was next functionalized with hyalur-
onic acid (HA), thus forming the basis of the HA-based hy-
drogel for tissue-regeneration purposes. The authors found
that the treated animals had significantly less fibrosis and
concurrently a significant improvement of the biomechanical
properties of the vocal areas was registered. The authorsconcluded that vocal fold scars, the cause of significant dys-
phonias, can be minimized by the prophylactic use of chemi-
cally engineered HA gels at the time of surgery.
In the field of controlled drug release, Lee et al.[23] dem-
onstrated the use of an in situ hydrogeldrug complex as an
intradiscal drug-delivery system for the treatment of lower
back pain (Figure 2). In this study, the polymeric compound
Pluronic F127 together with sodium hyaluronate was used
as a local drug-delivery system to release the anesthetic bu-
pivacaine, which itself was encapsulated within microspheres
(MS) of polymer (polycaprolactone and poly(vinyl alcohol)
(PVA)). This encapsulation was to compensate for the fast
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release of the drug from the gel itself. In this preclinical
study, the geldrug compound was tested for its injectability
and onsite delivery in cadaveric intervertebral discs. This all
was monitored by means of X-ray radiographs and corre-
sponding drug-release profile studies. In-vitro tests showed
that 3% (w/w) of the anaesthetic loaded in the MSs were re-leased over 42 days, thereby demonstrating a good potential
for sustained release of bupivacaine.
For the purpose of chemotherapy, Yi et al.[24] demonstrat-
ed that polyethylene glycol (PEG)-based hydrogels loaded
with the anticancer drug 5-fluorouracil (5-FU) formed an ef-
fective formulation to combat malignant cells in tumuor-
bearing rats and nude mice. Pharmokinetic and drug release
studies showed that this geldrug formulation resulted in a
drug residence time that was 6- to 14-fold higher than those
for the free administration of 5-FU. Concurrently, the
tumuor volume was significantly reduced in the 5-FU-
loaded hydrogel group when compared to the free 5-FU
drug treatment group. This is to the best of our knowledge
the first paper that unambiguously demonstrated that hydro-
gel-based anticancer drug complexes should be considered
by cancer biologists and drug designers as a new alternative
delivery approach to combat cancer onsite. The advantages
to the patient are obvious and include sustained exposure to
the drug at much higher local concentrations onsite upon
application of the hydrogel, thereby decreasing unwanted
systemic side effects that are typically inherent to traditional
chemotherapy methods. Furthermore, the chance of disease
recurrence is also most likely to decrease because of the sus-
tained exposure to the anticancer drug.
Finally, by using a melanoma in vitro cancer model, ibu-profen-releasing polymeric hydrogels (Pluronic F127) have
been shown to be an effective formulation for the onsite de-
livery of nonsteroidal anti-inflammatory drugs that reduce
cancer-cell migration.[25]
Polymeric Gels Versus Self-Assembled Gels
There are, as already outlined earlier, fundamental differen-
ces between polymeric and self-assembled hydrogels. Data
continue to accumulate and show that the latter is a superior
class of hydrogels because of the chemical and physiological
advantages they possess. From the chemical perspective,
these include their easily controlled gel-to-sol state reversi-
bility (e.g., pH changes) and the fact that their chemistry
(e.g., incorporation of functional molecules) is much easier
to manipulate than that of polymer hydrogels.
To some degree, polymeric and self-assembled hydrogels
are also complementary: self-assembled hydrogels will un-doubtedly excel at relatively rapid and specific release when
complexed to proteins or drugs, whereas polymer gels might
be more stable in biological environments (>72 h) and
prove better for long-term delivery.[26] On the other hand, as
useful polymeric hydrogels are, it is difficult to control their
exact composition and their lack of biodegradabilityin
contrast to self-assembled hydrogelshinders in part their
use in biomedicine.
Self-assembled hydrogels can change their pore sizes as a
result of their dynamic nature and thus readily reassemble
during shrinkage/swelling processes.[27] In contrast, polymer-
ic hydrogels have less-flexible pore sizes because their ma-
trices are linked by covalent bonds. The ability of self-as-sembled gels to self-adjust their pore sizes makes them at-
tractive candidates for the creation of smart matrices for
controlled drug release.
Self-assembling hydrogels are also readily biodegradable
due to the weak nature of the forces that hold their supra-
molecular structure together. This is in addition to their
high water content and the fact that most self-assembled
gels are formed from naturally occurring components such
as peptides and lipids, both of which are factors that assist
with their biodegradability. For example, Banwell et al. ra-
tionally designed and fully characterized two-component
self-assembling hydrogels based on complementary standard
linear peptides such as 6 and 7 with purely helical struc-
tures.[28] These peptides formed self-supporting hydrogels of
>99% water content that interestingly gelled only on
mixing the two complementary peptides. They were capable
of sustaining both the growth and differentiation of rat adre-
nal pheochromocytoma cells for sustained periods in culture.
Also the versatility of their synthesis opens up the possibili-
ty of incorporating therapeutic drugs into the gelling compo-
nent without the need to trap the compound inside the gel
scaffold.
The formation of self-assembled hydrogels can also be
triggered using external biologically occurring stimuli such
as a phosphatase enzyme.
[29]
The phosphatase catalyzes thedephosphorylation of a LMOG precursor 8 to trigger the
self-assembly of the resulting b-amino acid derivate 9, there-
by resulting in the formation of self-assembled hydrogels,
which exhibit excellent in vivo biostability. It is noteworthy
that this paper also demonstrated that b-amino acid deriva-
tives afford self-assembled hydrogels with longer biostability
than that of the related self-assembled gels generated by de-
phosphorylation of the a-amino acid derivative 10 to the
LMOG 11.
Although there already exist numerous recent reviews on
polymeric gels,[30] this review will highlight recent important
developments in the field of self-assembled hydrogels for
Figure 2. Schematic for the in-situ delivery of geldrug complexes for
pain treatment of the lower back. Reproduced by permission from John
Wiley & Sons.[23]
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biomedical applications. We will also be discussing their po-
tential possibilities in terms of approaches to specific sophis-
ticated and practical applications.
Applications
Numerous potential applications for self-assembled gels
have been outlined in the literature; however, here the main
focus will be on successful examples of biomedical applica-
tions, including 3D cell-culture scaffolds, drug delivery,
tissue engineering, and regenerative medicine.
Three-Dimensional Cell-Culture Scaffolds
It is well known that cells behave structurally and function-
ally different when seeded on thin surface-coated substrates
(i.e., 2D) versus a thick layer of polymeric molecules (i.e.,
3D), which more closely mimics their natural environ-
ment.[31] Biomedical researchers have become increasingly
aware of the limitations of the long-established 2D cell cul-
ture and over the years much attention has been paid to ar-
tificial cell-culture substrates or scaffolds that closely mimic
the natural ECM.[32] There is an increasing awareness that
evaluating drug efficacy in preclinical high-throughput stud-
ies should be preferably performed in 3D in vitro cell-cul-
ture models instead of 2D cell cultures.[33] The 3D cell cul-
tures can offer a much better approximation of the natural
micro- and local environment compared to the 2D cultur-
es.[26b] Moreover, the functional properties of cells can be
observed and manipulated in ways that are not possible inanimal models. Surprisingly, the mentioned differences in
cell behavior between 2D and 3D cell cultures are inde-
pendent of whether the culture substrates are derived from
naturally purified extracellular matrix components or com-
ponents obtained synthetically. Therefore, hydrogels (poly-
meric or self-assembled) hold great promise as an alterna-
tive 3D cellular microenvironment for tissue studies.[34] Not
only because their elastic moduli closely resembles that of
natural tissues, but also because their composition can be
tailored to bear the appropriate chemical, physical and bio-
logical structures that facilitate the development of tissue-
like, and hence organoid-type cultures in vitro.[35] The impli-
cations of 3D cell cultures would be profound.Ideally, hydrogels need to be stable and amenable to han-
dling under physiologically relevant conditions such as a
temperature of 37 8C, pH value of 7.27.8, and in the pres-
ence of the required concentrations of dissolved molecules
and enzymes required for cell cultures. Furthermore, the
rate of gel degradation should be controlled in such a way
that they warrant stability for the duration of the experi-
ment and/or application, that is, commonly between 24 and
96 h. Finally, synthetic hydrogels and their degradation
products should not inflict any unwanted adverse cell reac-
tion(s) such as immunogenic responses or decreased cell via-
bility.
It is obvious from these considerations that self-assembled
hydrogels offer significant advantages over polymeric hydro-
gels. The well-defined chemical nature of self-assembled
gels (all LMOG molecules in a self-assembled gels are the
same) is of special note here, but batch-to-batch reproduci-
bility problems in the making of polymer-based hydrogels
makes their application in 3D cell culture for research pur-
poses challenging.
Of particular interest are the findings by Liebmann and
colleagues,[36] who demonstrated that self-assembling 9-fluo-
renylmethoxycarbonyl (Fmoc) dipeptides such as Fmoc-
Phe-Phe 12 (Phe=phenylalanine) form hydrogels that can
serve as a 3D cell-culture scaffold at the microscale (Fig-ure 3ac and Table 1). This is important not only because
3D gels better mimic the in vivo cell and tissue growth situa-
tion than the conventional 2D cell-culture surfaces, but also
because the composition and matrix density of the gel can
be fully controlled by chemical tailoring approaches. This is
a huge advantage when compared to the commercially avail-
able cell-culture matrices, whether naturally derived or syn-
thesised by means of large-scale biotechnological methods.
The authors also succeeded in generating effective patterned
3D cultures by using scaffolds when forming the gels within
cell-culture chambers. Applications were diverse and al-
lowed careful modelling of specific in vivo growth patterns,
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thereby closely mimicking the microanatomy of the tissue of
interest. The key to success was that cells were seeded to-
gether in the presence of the gelling agent in the cell cham-
ber. By subsequently initiating the hydrogel self-assembly,
the cells were immobilized within the gel and immediate
local perfusion of the growth medium, after the gel was
formed through the gel scaffold allowed the viability and
growth of cells to be maintained over time.
The flexibility of the approach of using these small self-as-
sembling molecules is demonstrated in a paper by Zhou and
co-workers.[37] One key to success to the practical applica-
tion of hydrogels is the functionalization of the highly hy-
drated gel complex with amino acids that code for the adhe-
sion peptide sequence RGD (Arg-Gly-Asp) or RGDS (Arg-
Gly-Asp-Ser). This has proven be a highly valuable molecu-
lar alteration to increase cellgel interactions.[38] These short
amino acid sequences are well known to play a key role inmany recognition systems involved in cell-to-cell and cell-to-
matrix adhesion.[39] A gel was created that contained not
only Fmoc-Phe-Phe 12 but also that incorporated the cell-
adhesion peptide RGD (Arg-Gly-Asp) as Fmoc-RGD 13.
This mixture resulted in a three-dimensional biomimetic
nanoscaffold, which successfully allowed the adhesion,
spreading, and proliferation of human adult dermal fibro-
blasts. This specific mixture was shown to form a gel at
physiologically relevant 37 8C and a pH of 7.0.
Interestingly, when reviewing the literature, the success to
exposing and maintaining cells under viable conditions on
hydrogels in culture is largely dependent on both the cell
type used and the introduction of chemical functionalitygroups. Fibroblasts and chon-
drocytes or other cell types of
mesenchymal origin seem to
be a key to success when it
comes to in vitro biocompati-
bility studies. This is not sur-
prising as those cells have the
cell-membrane receptors to in-
teract with the surrounding
connective tissue (e.g., ECM).
Some of these cell types se-
crete natural ECM compo-
nents by themselves.
Evidently, the addition of
smart functional groups to the
gel, such as a multitude of
NH2 or OH groups, creates the
ideal microenvironment for
tight interactions of cell-sur-
face receptors (e.g., integrins)
with the gel components. For
example, Jayawarna et al.[18,40]
elegantly demonstrated that
mixing different LMOGs in
self-assembled hydrogels en-hances the compatibility of the
gel with different cell lines
(Table 1). They showed that Fmoc-Phe-Phe 12-based gels
proved to be good cell substrate for various mesenchymal-
derived cell types. When self-assembled gels were formed by
a 1:1 mixture of Fmoc-Phe-Phe 12 and Fmoc-Ser 14, a supe-
rior hydrogel scaffold was achieved for cell culture (Fig-
ure 3d and e).[40]
A similar approach in adding functional groups to a self-
assembled gel was shown recently by Hartgerinks research
group. They successfully fabricated a series of self-assem-
bled gels based on the multidomain peptide 15 for cell-cul-
Figure 3. Cell culturing of different cell types on self-assembled hydrogels. a)c) The in-situ growth of cells in
three dimensions (3D) within a self-assembled hydrogel from Fmoc-Phe-Phe 12.[37] a) Microchamber designed
for the in-situ polymerization of the hydrogel (fibers) together with cells in suspension (spheres). b) COS-7 cells
immobilized in a 3D self-assembled hydrogel within a microchamber, as depicted in (a). c) Illustration of the
3D growth of MDCK cells within the microchamber. Scale bar, 50 mm. Reprinted with permission from
BioMed Central.[37] d)f) Illustration of the long-term (6 days) cell culture of chondrocytes (d), 3T3 fibroblasts
(e), and human dermal fibroplasts (HDF) (f) cells on self-assembled gels from a 1:1 mixture of Fmoc-Phe-Phe
12 and Fmoc-Ser 14.[40] In these histological light microscopy sections, the dark layer represents the cells grown
on top of the self-assembled hydrogels (fiberlike structures). Reprinted with permission from Elsevier.[40]
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ture studies (Table 1). Three analogues of 15 were synthe-
sized; 16 includes the cell adhesion motif RGD, 17 incorpo-
rated an MMP-2 cleavage site, and 18 combines both
(Figure 4).[41] The combination of both the RGD and
MMP-2 motifs in 18 resulted in the largest improvements in
cell viability as well as marked differences in cell spreading
and morphology. In summary, the peptide functionalization
data discussed above highlights once more the importance
of functional tailoring of hydrogels to warrant optimal cell
and tissue functioning.
Drug Delivery
Traditional methods of drug delivery rely on the bodys own
systemic and cellular transport mechanisms to deliver drugmolecules to their target destination. Drugs are generally
delivered into the body through oral or intravenous routes.
The disadvantage of these methods is that drug molecules
can come into contact with healthy tissues, thereby causing
major side effects that prohibit treatment. This situation is
often the cause of chemotherapy failure when bone marrow
cell death prevents the patient from undergoing a complete
treatment.[21]
Localised drug delivery, on the other hand, offers numer-
ous advantages compared to conventional dosage forms in-
cluding improved efficacy, reduced toxicity, and improved
patient compliance and convenience.[21] Currently, localised
drug-delivery systems rely
heavily on synthetic polymers
to carry the drugs.[21] A good
example of this is the FDA-ap-
proved Gliadel polymer inserts
for the treatment of glioblasto-
ma multiforme, an aggressiveform of brain cancer. The Glia-
del polymer comes in the form
of wafers that are implanted in
resected tumor sites. A chemo-
therapeutic carmustine
(BCNU) is then released from
within the wafers. The aim of
this localized form of delivery is to prevent any cancerous
cells that were not removed during resection from metasta-
sizing.
There are basically two approaches for localized delivery
with hydrogels, be they polymeric or self-assembled. The
first is to encapsulate a therapeutic within the voids of a hy-drogel.[42] The gel can then be topically applied, and it is
then degradation of the gel and/or diffusion of the therapeu-
tic that allows the drug to act at the target site.[21] The
second method is by developing drug-based gelators, that is,
either covalent polymers that present drug molecules as side
chains or LMOG molecules that self-assemble into a hydro-
gel while presenting a therapeutic effect.
Self-assembled gels are now showing significant promise
in the field of localized drug delivery. Inherently, gels can
easily fit into any shape that is required; this is necessary for
easy application and efficacy, especially in the field of local-
ized drug delivery. Also, because self-assembled gels can be
triggered to gelate (i.e., transition from sol to gel) by means
of various stimuli, they offer specific advantages for local-
ized drug delivery relative to other forms of drug-delivery
methods. For example, drugs mixed within a solution of
LMOG, which forms a self-assembled gel on contact with
bodily fluids such as blood (e.g., due to the resulting pH
changes), could be delivered topically or by injection after
tumor resection. On gelation, the gel theoretically would
then be held in the cavity, thereby allowing the drugs to act
locally.[43]
For instance, when a self-assembled gel formed from a
peptide amphiphile 19 that binds to heparin[44] was mixed
with diazeniumdiolate nitric oxide donors, the resulting gelsystem can release nitric oxide. It was noted that the mixing
of the nitric oxide within the gel extended the release of the
nitric oxide significantly to four days in vitro. This mixture
was then applied directly to the exterior of an injured blood
vessel (rat model) after angioplasty. As an example of this
first approach to localized drug delivery, the system showed
clinically promising results in the limiting of neointimal hy-
perplasia by up to 77% compared with the controls and also
limited inflammation in the injury site.[45]
One prominent example of the drug-gelator approach is
in the modification of vancomycin with a pyrene group by
Xing and co-workers, which enabled the formation of a self-
Table 1. Cell lines used in cell-culture experiments with self-assembled g els.
Gelators Cell type/line Reference
Fmoc-Phe-Phe 12 kidney fibroblast cell line (COS-
7)
[37]
MadinDarby canine kidney cells
(MDCK)
[37]
rat cortical astrocyte cell line
(CTX TNA2)
[37]
Fmoc-Phe-Phe 12/Fmoc-Ser 14 (1:1) rat-brain astrocytes cell line (DI
TNC1)
[40]
mouse fibroblasts (3T3) [40]
human dermal fibroblasts [40]
ABA multidomain peptide (MDP) with RGD and MMP rec-
ognition sites 1518
human mesenchymal stem cells
(SHED)
[41]
Figure 4. The structure of the multidomain peptides 1518 made by Hart-
gerink and co-workers to form self-assembled gels for cell-culture stud-
ies.[41] The parent ABA-block peptide 15 forms self-assembled gels in
water. Peptides 16 and 18 incorporate the RGD cell adhesion motif
(light gray). Peptides 17 and 18 include a MMP-2 cleavage motif (dark
gray) with the cleavage site shown by an arrow. See also Table 1 for de-
tails.
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assembled gel from the pyrene modified vancomycin 20.
Vancomycin is an antibiotic used in the prevention and
treatment of infections caused by Gram-positive bacteria. In
levels of antibiotic activity, the pyrene-modified vancomycin
20 showed an 11-fold increase, relative to plain vancomy-
cin.[46]
Undoubtedly, hydrogeldrug complexes can largely con-
tribute to the treatment of various cancers as an alternative
means, through localized and sustained chemotherapy. In
combination with surgery, local chemotherapeutic delivery
using hydrogels is especially well suited to deliver the treat-
ment to the site of a recently resected tumor. This has been
demonstrated before in polymer-based gels.
In work by Kim and co-workers,[47] a self-assembled gel
for possible chemotherapy was investigated. A peptide am-
phiphile with a matrix metalloproteinase-2 (MMP-2) 21; the
sensitive peptide sequence formed a gel when complexation
of the carboxylic acids in the peptide sequence with cisplatin
(CDDP) occurred, as has been shown in similar studies.[48]
The rationale behind using an MMP-2-sensitive peptide se-
quence was because it is known that MMP-2 is overex-
pressed in different kinds of invasive tumors, and it plays a
critical role in tumor progression, angiogenesis, and metasta-sis.[49] The CDDP complex is one of the extensively used
chemotherapeutics for the treatment of various cancers such
as testicular cancer and glioma.[50] However, severe side ef-
fects such as acute nephrotoxicity and neural toxicity have
limited the clinical use of CDDP. [51] To reduce these adverse
effects and enhance its anticancer activity, the tumor-specific
accumulation and controlled release of CDDP at the site
was investigated (Figure 5). As expected, CDDP release
from the peptide amphiphile gel was triggered by the cleav-
age of the MMP-2-sensitive sequence in the peptide amphi-
phile and was found to be dependent on the concentration
of the enzyme. Also, the amounts of CDDP loaded in the
gel were found to be approximately 2.53-fold greater than
its aqueous solubility. Although this study was preclinical, it
demonstrates the potential of self-assembled gels for drug
delivery.
Another chemotherapeutic delivery system was investigat-
ed by Gao and co-workers, who modified paclitaxel (Taxol)
through the 2-position with a linker, self-assembling motif,
and enzyme-cleavable group to yield 22.[52] Upon the addi-
tion of alkanine phosphatase, dephosphorylation of 22 gives
23, which readily forms self-assembled gels in water. Pacli-
taxel is a notoriously highly insoluble hydrophobic anticanc-
er drug, and the group established a new, facile method to
convert this drug into a gel without compromising its biolog-
ical activity. This work demonstrates the versatility of self-
assembled gels in being the first enzyme-instructed, self-as-
sembly, and hydrogelation of a complex, bioactive smallmolecule. It further proves that a therapeutic can act as
both the drug-delivery vehicle and the drug itself.
In contrast to enzyme-triggered hydrogels, there are also
pH-triggered gels such as 24 and 25, which can form self-as-
sembled gels that encapsulate the chemotherapeutic doxoru-
bicin.[53] Self-assembled gels from Fmoc-Phe-Phe 12 and re-
lated dipeptides conjugated to other bulky aromatic groups
(such as naphthalene in the case of 26 and 27) that are trig-
gered by pH changes have been investigated in detail by the
groups of Xu,[54] Ulijn,[37,40] and Gazit.[55] They have been
shown to self-assemble in the right conditions, based mainly
on a change in pH.[56]
Figure 5. Release profiles of CDDP from CDDP mixed with self-assem-
bled gels from 21 at different concentrations of type IV collagenase
(MMP-2) solution. The release study was performed with Franz diffusion
cells at 37 8C, and the enzyme solution was prepared in phosphate buffer
solution (PBS) containing 0.5 mm CaCl2. *All points are significantly dif-
ferent from those of 2 mgmL1 collagenase (p
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Topical application of hydrogeldrug formulations at the
site of injury/disease undoubtedly offers additional advan-
tages of delivering the active drug compound to the specfic
site. For instance, in a study from the Xu group, it was
shown that the topical application of a self-assembled hydro-
gel based on the mixture of Fmoc-Leu 28, the uranyl nitrate
binding ligand pamidromate 29, and e-Fmoc-Lys 30 could be
used to treat wounds on the skin of mice that had been con-
taminated with uranyl nitrate. The treated mice recovered,
whereas untreated mice weighed 35% less or died, presuma-
bly from radiation damage caused by the uranyl-nitrate-con-
taminated skin wounds.[57]
In localised drug delivery, the rate of drug release is an
important aspect. Self-assembled hydrogels have shown to
be capable of having controlled release kinetics. Liang and
co-workers did the first in vivo imaging of a self-assembledhydrogel formed from a naphthalane d-Phe dipeptide 31
and showed that it had controlled release kinetics by using125I isotopes.[58]
For example, Ellis-Behnke et al. demonstrated that the
known self-assembling peptide Ac-(RADA)4-NH2 32[59]
(RADA=Arg-Ala-Asp-Ala) forms a self-assembled gel on
contact with bodily fluids such as blood. They reported that
the self-assembling peptide 32 establishes a nanofiber barri-
er (
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The peptide amphiphile 33 was designed to form cylindrical
nanofibers that display to cells in the spinal cord the laminin
epitope IKVAV (Ile-Lys-Val-Ala-Val). As a control in these
experiments, a peptide amphiphile 34 with the nonphysio-
logical epitope EQS (Glu-Gln-Ser) was also synthesized.
The three-dimensional network of nanofibers constructed
from the peptide amphiphiles incorporated the pentapeptideepitope IKVAV, which is also found in laminin, a protein
found in the extracellular matrix. The IKVAV epitope was
incorporated within the gel because it is known to promote
neurite sprouting and to direct neurite growth. The ability
to have a dense population of biologically active factors
(IKVAV) incorporated in the self-assembled nanofibers of
the gel from 33 presenting themselves to the NPCs was de-
termined to be the critical factor in the observed rapid and
selective differentiation of cells into neurons compared to
the peptide amphiphile control 34 (Figure 6).[61]
Following on from the work in 2004, Stupp, Tysseling-
Mattiace, and co-workers in 2008[63] used the same peptide
amphiphile 33 without exogenous proteins or cells as a ther-
apy in a mouse model of spinal cord injury (SCI). When a
liquid solution of the peptide amphiphile was injected,
changes in ionic strength of the in vivo environment trig-
gered self-assembly within the extracellular spaces of the
spinal cord, thereby resulting in nanoscale gel-like struc-
tures. In this work, in vivo treatment with the gel after SCI
reduced astrogliosis, reduced cell death, and increased the
number of oligodendroglia at the site of injury. Furthermore,the nanofibers promoted regeneration of both descending
motor fibers and ascending sensory fibers through the lesion
site. Treatment with the peptide amphiphile 33 also resulted
in significant behavioral improvement, that is, at nine weeks,
the control groups demonstrated no hindlimb movement,
whereas the peptide amphiphile IKVAV epitope group had
hindlimb movement.[63] Another example from the field of
tissue engineering comes from the group of Kisiday et al.,[64]
which designed a peptide 35 (KLD12) related to the above-
mentioned RADA peptide 32. The KLD12 peptide 35
formed a self-assembled hydrogel that was used as a scaffold
to support chondrocyte growth and development for carti-
lage repair. During one month of culture in vitro, chondro-cytes seeded within the hydrogel retained their morphology
and developed a cartilage-like extracellular matrix rich in
proteoglycans and type II collagen, which is indicative of a
stable chondrocyte phenotype. As time progressed, the stiff-
ness of the material increased, thereby indicating that new,
mechanically functional cartilage was formed. The outcome
of this experiment established the potential of a self-assem-
bling peptide hydrogel as a tool for the synthesis and accu-
mulation of a cartilage-like extracellular matrix for tissue re-
generation.
The versatility of self-assembled gels in medical applica-
tion is neatly demonstrated in their combination with a tra-
ditional prosthetic material for regenerative medicine. The
regeneration or replacement of hard tissue in the body has
proven to be a challenge due to its mechanical properties.
One approach is the use of a metal implant to replace the
tissue. However, these materials do not incorporate a bioac-
tive component. A peptide amphiphile 36 formed a self-as-
sembled gel within a porous Ti-6Al-4V bone implant. This
hybrid material was shown to be able to mineralize with cal-
cium phosphate and cells could be encapsulated in these hy-
brids in a controlled manner. In vivo experiments showed
that de novo bone is formed adjacent to and inside the PA
Ti hybrid by 4 weeks, thus offering strong evidence of osteo-
conduction.
[65]
Figure 6. Percentage of total cells that differentiated into neurons after
1 d in nanofiber networks containing different amounts of IKVAV-PA 33
and EQS-PA 34 (solid line) and in EQS-PA nanofiber networks to which
different amounts of soluble IKVAV peptide were added (dashed line).
Reprinted with permission from AAAS.[61]
40 www.chemasianj.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2011, 6, 3042
FOCUS REVIEWSW. T. Truong et al.
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In the area of tissue engineering, the previously men-
tioned Ac-(RADA)4-NH2 32 peptide was originally reported
by Zhang and co-workers[59] to form a self-assembled hydro-
gel (0.51.0% w/v), which was later patented under the
tradename PuraMatrix. It self-assembles to form macroscop-
ic gels in aqueous solution by hydrophobic and ionic bond-
ing due to the beta sheet structure that is encoded in itsamino acid sequence. Its mechanical properties are depen-
dent on its initial concentration. The peptide 32 is soluble at
low pH and osmolarity; when the conditions are changed to
physiological pH and osmolarity, it quickly forms fibers on
the order of 510 nm and assembles into interwoven 3D
scaffolds. The high volume fraction (%99%) of water within
these hydrogels and the structural resemblance of these pep-
tides to natural collagen along with the ability to customize
the peptide backbone have yielded favorable cell-culture re-
sults such as the culture of osteocytes,[66] neural cells,[67] and
chondrocytes.[64] For the application of liver-tissue engineer-
ing, in comparison with primary hepatocytes cultured on
collagen, primary hepatocytes cultured on the self-assem-bled hydrogel, PuraMatrix (made from 32) yielded better
liver-specific function. This is promising in the field of liver-
tissue-engineering applications.[68]
Conclusion and Perspectives
Since the start of the new millennium, a variety of self-as-
sembled hydrogel complexes have been shown to be suc-
cessful candidates for biomimetic materials. They have been
shown to be a viable material for in-vitro 3D cell studies be-
cause they closely mimic the in vivo environment for the
cells. Furthermore, self-assembled hydrogel-based drug-de-
livery complexes have been proven to be useful as an attrac-
tive therapeutic alternative to the existing arsenal of drug-
carrier systems, such as liposomes and metal-based nanopar-
ticles, and as such can be used to cure life-threatening dis-
eases. Finally, the materials themselves have been shown to
be viable candidates to treat various pathological conditions.
However, despite these promising findings, key challenges in
the synthesis and functionalization remain before self-as-
sembled gels can be completely implemented for therapeu-
tic purposes in humans. This challenge goes to the heart of
one the key problems in the areawe simply do not under-
stand self-assembled gels.
[69]
A better understanding of themechanism and structure of self-assembled gels will also
allow us to tackle some of key questions with regards to
their applications in medicine, including how we can control
their stability.
There is no doubt that self-assembled gels have a bright
future ahead as novel biomaterials; however, careful assess-
ment on their biocompability and the possible immunogenic
response they may inflict remains a topic of great interest.
Furthermore, the development of innovative ways in admin-
istrating or applying these gels in situ is a major challenge.
Much can be expected in fabricating gel complexes that
gelate onsite under carefully controlled conditions such as
changes to local pH environment or temperature; further-
more, enzyme-controlled gelation reactions or multicompo-
nent systems are possible ways forward. Besides the produc-
tion of these responsive hydrogels, the material should be in
such a form that it can be easily handled within cavities and/
or tissues. The use of an injection device that subsequently
allows local gelation and incorporation of compounds of in-terest would be the preferred modus operandi.
The major advancement in the near future should be
sought for in the fabrication of smart self-assembled gel
complexes that specifically recognize the target of interest
(i.e., stealth-based delivery). Even more, the ideal gel com-
plex should only release its cargo and/or stimulate the cellu-
lar target when in the vicinity of the targeted cell population
or tissue. Finally, in this context, the addition of a fluores-
cent reporter molecule would be a welcomed addition. This
would not only allow researchers to monitor the effective-
ness of the gels in vivo but also assist the operator in apply-
ing the gel more effectively at the site of interest by using
fluorescence-assisted imaging technology. The inherent mod-ularity of self-assembled gels will be an important asset in
the challenge to incorporate all these functionalities in the
functional material.
Acknowledgements
The authors acknowledge the facilities, and technical and administrative
assistance from staff of the AMMRF at the Australian Centre for Micros-
copy and Microanalysis (ACMM), The University of Sydney. We would
also like to thank the Australian Research Council (ARC) for a Discov-
ery Project Grant (DP0985059) to P.T. and F.B. as well as the NSW
Cancer Institute (08/RFG/1-29) for supporting our work and the Univer-sity of New South Wales for a Scholarship to W.T.T.
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