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Prodrugs as self-assembled hydrogels: a new paradigm for


biomaterials
Praveen Kumar Vemula1,2, Nikken Wiradharma3, James A Ankrum3,
Oscar R Miranda3, George John4 and Jeffrey M Karp3

Prodrug-based self-assembled hydrogels represent a new clearance. Furthermore, only 16% of newly developed
class of active biomaterials that can be harnessed for medical drugs in the US from 1993 to 2004 entered the market [1],
applications, in particular the design of stimuli responsive drug while others failed to enter the clinic or were withdrawn
delivery devices. In this approach, a promoiety is chemically from the market because of off-target toxicity [2,3]. To
conjugated to a known-drug to generate an amphiphilic reduce the systemic toxicity and increase the half-life of
prodrug that is capable of forming self-assembled hydrogels. drugs, several approaches have been developed, in-
Prodrug-based self-assembled hydrogels are advantageous cluding physical encapsulation of the active drug in an
as they alter the solubility of the drug, enhance drug loading, inert delivery system and control of drug activity through
and eliminate the use of harmful excipients. In addition, self- conversion into a stimuli responsive prodrug (Figure 1).
assembled prodrug hydrogels can be designed to undergo Prodrug molecules are usually pharmacologically inert
controlled drug release or tailored degradation in response to derivatives of the parent drug that require a stimulus
biological cues. Herein we review the development of prodrug- such as enzyme, pH, temperature, and/or a tissue micro-
based self-assembled hydrogels as an emerging class of environment, to be transformed into its active form.
biomaterials that overcome several common limitations Functional groups such as esters, carbamates and amides
encountered in conventional drug delivery. within prodrugs can be hydrolyzed by carboxyesterases
that are ubiquitous in the human body with broad sub-
Addresses
1
Institute for Stem Cell Biology and Regenerative Medicine (inStem), strate specificity [4]. Similarly, disulfide-based analogs
National Centre for Biological Sciences Campus, UAS-GKVK Post, can be cleaved in response to pH changes. Prodrug-based
Bellary Road, Bangalore 560065, India strategies have been reported in the literature to over-
2
Ramalingaswami Fellow, Department of Biotechnology, Government of come routinely encountered limitations in drug delivery
India, India
3
Division of Biomedical Engineering, Department of Medicine, Center for
(Figure 2) [5,6,7,8]. As such, molecular prodrug
Regenerative Therapeutics, Brigham and Women’s Hospital, Harvard formulations can be used to enhance oral bioavailability
Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of through improved gastrointestinal absorption and to
Health Sciences and Technology, 65 Landsdowne Street, Cambridge, increase plasma concentration through improved diffu-
MA 02139, USA
4 sion across the endothelium. Herein we highlight a new
Department of Chemistry, The City University of New York and the
Institute of Macromolecular Assemblies, New York, NY 10031, USA class of prodrugs developed to enhance drug loading: self-
assembling prodrugs (Figure 1c).
Corresponding authors: Vemula, Praveen Kumar (praveenv@ncbs.
res.in) and Karp, Jeffrey M (jkarp@rics.bwh.harvard.edu, While molecular prodrugs address many critical chal-
jeffkarp@mit.edu) lenges experienced with small molecule drugs, numerous
limitations remain. Once administered at the injection
site, prodrugs are often rapidly converted into their active
Current Opinion in Biotechnology 2013, 24:1174–1182
drug form, limiting extended release. Delivery of mol-
This review comes from a themed issue on Pharmaceutical ecular prodrugs often requires excipients, some of which
biotechnology
have been implicated in triggering adverse effects, in-
Edited by Ajikumar Parayil and Federico Gago cluding acute hypersensitivity reactions and peripheral
For a complete overview see the Issue and the Editorial neuropathy [9,10]. Thus, to alter solubility of drugs,
Available online 1st March 2013 enhance drug loading and eliminate the use of harmful
excipients, ‘self-assembled prodrugs’ that self-assemble
0958-1669/$ – see front matter, Published by Elsevier Ltd.
to form nano/micro architectures have been developed
http://dx.doi.org/10.1016/j.copbio.2013.02.006
(Figure 1c). Elimination of excipients and inert carriers by
designing prodrugs into their own self-assembling carriers
dramatically increases drug loading and alleviates con-
Introduction cerns over excipient-associated adverse effects. In
Despite recent advancements in drug discovery, signifi- addition, self-assembled prodrug amphiphiles can be
cant challenges remain in their delivery. Drug efficacy is designed to undergo slower degradation (either
hindered by poor bioavailability as small molecules and enzyme-mediated or hydrolysis-mediated) as compared
biologics often suffer from low plasma half-life due to to the free (unassembled) molecular prodrugs, enhancing
metabolism, poor cell permeability, and rapid systemic controlled/sustained delivery.

Current Opinion in Biotechnology 2013, 24:1174–1182 www.sciencedirect.com


Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials Vemula et al. 1175

Figure 1

(a) LIMITATIONS (b) LIMITATIONS


- Inadequate encapsulation efficiency - Uncontrolled release of the drug
- Low drug loading - Rapid degradation of prodrug
- Metabolic burden of inert vehicle - Absence of sustained release of the drug
Molecular prodrugs Crossing
Uncontrolled release biological barrier

Molecular
Encapsulation in inert delivery systems prodrug
Drug release
(hydrogels, liposomes, micelles and nanoparticles)

Drug
(c)

Self-
assembly

Enzyme

Self-assembled Hydrogel
prodrug Controlled drug release
(3D-network)

LIMITATIONS ADVANTAGES
- Case specific design - High drug loading
- Need to tailor the system to achieve therapeutic - No burst release of drug
relevant concentration of drug - No drug leakage
- Difference in endogenous enzyme concentration - Enzyme responsive drug release
may lead to variable release of drug - No burden of inert vehicle
- Release may differ from patient-to patient

Current Opinion in Biotechnology

Widely used approaches in delivery of the drugs. (a) Encapsulation of the drug in an inert delivery vehicle. (b) Conversion of drug into molecular
prodrug to increase pharmacokinetics. (c) Self-assembled prodrugs; synthesis of amphiphilic prodrugs that could self-assemble to form hydrogels,
delivery vehicle, and bio-stimuli (an enzyme) mediated drug release.

Prodrug-based self-assembled hydrogels application of polymeric hydrogels in regenerative medi-


Hydrogels are materials whose mechanical properties lie cine. Like polymers, small molecular amphiphiles are also
between elastic solids and viscous liquids. Hydrogels are capable of forming 3D fibrillar or tape-like structures
formed through gelation of solutes in aqueous solutions in under specific conditions. These structures then form
the presence of a gelator. Gelators are molecules that form hydrogels, also called low-molecular-weight gels or mol-
three-dimensional (3D) networks through either covalent ecular gels. Significant contributions from Stupp, Zhang,
crosslinking or noncovalent intermolecular interactions. Hubbell, Pochan, Schneider and collaborators have led to
This results in the formation of a gel phase balanced the development of a subgroup of self-assembled peptide
between precipitation and solubilization of the molecules hydrogels [15–21]. Peptide hydrogel scaffolds can mimic
in the solvent [11]. many characteristics of native extracellular matrices pro-
viding support for cell culture, thus serving as valuable
Biodegradable polymer hydrogels have emerged as one of tools in biological research [22,23]. A number of studies
the most established material ‘toolkits’ to address clinical have demonstrated that self-assembled peptides can be
challenges. Decades of research have developed polymer- formulated into injectable hydrogels for tissue engineer-
based hydrogels for a broad range of applications ing applications [17]. For example, Pochan and Schneider
including drug delivery, tissue engineering, and regen- showed that a molecularly designed peptide could be
erative medicine [12,13]. Peppas et al. [14] pioneered the triggered to self-assemble and undergo gelation due to

www.sciencedirect.com Current Opinion in Biotechnology 2013, 24:1174–1182


1176 Pharmaceutical biotechnology

Figure 2

To improve solubility
CF3
N O OH
HO
N P
N O O
O
N
O NH
O
O S
O O S Na+
Na+ N-
N-

O O

Celecoxib prodrug Parecoxib prodrug Fosphenytoin

Ester-based prodrugs
O O O
S O O
O O H NH O
H N O
N O
O O HN
N
O H NH2
NH2 HO
Pivampicillin Benazepril Oseltamivir

Nucleoside transporter-based prodrugs


O O O
HN N HN N N
HN
H2N N N H2N N N H2N N N
O O

O O OH O O
O O O
O
H2N H2N
Valaciclovir Valganciclovir Famciclovir

Current Opinion in Biotechnology

Literature examples of molecular prodrugs that have been developed to improve pharmacokinetics and pharcodynamics of small molecular drugs ([6],
references therein).

the ionic strength of the solvent. Such noncovalent gela- through self-assembled amphiphilic prodrugs, known as
tion allows the gel to undergo shear-thinning, enabling self-assembled prodrug hydrogels [11,24–29].
encapsulation of C3H10t1/2 mesenchymal stem cells and
delivery through a small hypodermic needle [20]. In Inherently, self-assembled hydrogels suffer from limita-
addition, peptide hydrogels can also be used to encapsu- tions as drug delivery vehicles. These include low-drug
late and release growth factors and small molecule drugs. loading capacity, drug leakage during encapsulation, and
Compounds can be loaded into pre-formed gels or mixed inefficient preservation [30,31]. As self-assembly is a
during the self-assembly process without causing detri- delicate process that relies on intermolecular interactions
mental effects to their structure [21]. However, self- of amphiphiles, the presence of excess foreign molecules
assembled hydrogels are often mechanically weak, and weakens self-assembly and disrupts gel formation. There-
are therefore inappropriate for many tissue engineering fore drug encapsulation is limited to a fraction of the gel.
applications where mechanical strength and stability are In addition, encapsulated drugs often rapidly leak out of
required. Nevertheless, they remain an easy-to-use and the gel, leading to burst release of the drug. Recently, we
attractive local drug delivery strategy. In this review, we have demonstrated that limitations such as low-drug
limit our discussion to a specific class of hydrogels formed loading and burst release of encapsulated drug can be

Current Opinion in Biotechnology 2013, 24:1174–1182 www.sciencedirect.com


Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials Vemula et al. 1177

overcome through specific selection and design of amphi- phenolic alcohol into an ester by attaching a biocompa-
philic prodrugs to enhance intermolecular interactions tible fatty acid, a series of amphiphiles and bolaamphi-
and enzyme responsive degradation [32]. In this philes has been synthesized (Figure 3). Acetaminophen-
approach, a promoiety, an inert functional group, is cova- based self-assembled prodrugs (Ace-SAPDs) were shown
lently conjugated to a parent drug, generating an amphi- to self-assemble in an aqueous solution to form hydrogels
philic prodrug capable of forming a self-assembled [33]. Ace-SAPD-derived hydrogels formed branched or
hydrogel in aqueous solution (Figure 1c). A significant fibrous sheet-like networks consisting of lamellar struc-
advantage of this approach is that every molecule in the tures at the microscopic level (Figure 3). It is noteworthy
gel contains a drug molecule, dramatically increasing the that transformation of acetaminophen into a self-deliver-
effective drug loading. In addition, as the drug is in a able vehicle enabled the loading of a second drug (cur-
prodrug form, burst release of the drug is greatly reduced. cumin, a known chemo-preventive drug) in these
hydrogels through traditional physical encapsulation.
To design a self-assembled prodrug, selection of the Upon exposure to an esterase (lipase) at physiological
promoiety that enables intermolecular interactions is temperature, Ace-SAPD hydrogels degraded to release
critical. By using surfactant-like molecules to convert active forms of both acetaminophen and curcumin. Intri-
drugs of interest into amphiphilic prodrug structures, guingly, without enzyme present, the dual-release hydro-
numerous self-assembled prodrugs have been developed gels exhibited hydrolytic stability over several months
[33,34,35,36,37–39]. Such self-gelling drugs exhibit [33]. This stability could be due to the presence of
diverse formulations and controlled release under either tightly self-associated prodrugs, protecting ester bonds in
chemical hydrolysis or phase disassembly. hydrophobic segments and reduced accessibility of water
molecules compared to the dissolved molecular form. A
Self-assembled prodrug hydrogels are currently in the distinct advantage of the self-assembled prodrug
early development stage and their potential is yet to be approach is the attenuation of burst release, a major
realized in clinical applications; however, several limitation in current hydrogel-based drug delivery sys-
important in vitro proof of concepts have been demon- tems [40]. This is the first example of self-assembled
strated. For example, multiple groups have demon- prodrugs that form gels in both polar and nonpolar sol-
strated the design, synthesis and assembly of self- vents and are enzyme responsive, thus enabling the
assembled prodrugs from known parent drugs. Exten- release of drugs in response to inflammation.
sive in vitro characterization of hydrogels derived from
self-assembled prodrugs has been reported to show Using ibuprofen, Kim et al. developed a series of self-
increased drug loading and reduced burst release of assembling prodrug amphiphiles by introducing a pro-
drug. While these systems may some day be locally moiety consisting of a dipeptide motif [38]. A dipeptide
delivered for the treatment of arthritis, wound healing, glycine–glycine backbone was incorporated into (S)-(+)-
cancer, chronic pain, and other ailments, their in vivo ibuprofen and successfully transformed into an ibupro-
efficacy is yet to be ascertained. Herein, we focus fen-based self-assembled prodrug (Ibu-SAPD) that
on the recent development of these self-assembled formed hydrogels (Figure 3). Interestingly, the glycine–
prodrug hydrogels. glycine analog of ibuprofen formed hydrogels, but ibu-
profen derivatives of glycine–alanine, glycine–serine,
Reversible prodrug-based self-assembled glycine–phenylalanine and glycine–histidine failed to
hydrogels self-assemble into hydrogels [38]. In addition, incubation
Through covalent transformations, the majority of com- of Ibu-SAPDs-based hydrogels with carboxypeptidase
mercial drugs can be converted into prodrug forms. A enzyme for 24 hours degraded Ibu-SAPDs triggering
prodrug is considered reversible when the addition of the the release of active ibuprofen.
promoiety inhibits the bioactivity of the parent drug.
Prodrug chemistry can be tailored to produce custom Beta-glucosidase-responsive self-assembled prodrug
prodrug amphiphiles that convert to their bioactive form hydrogels have been created by converting an anticancer
in response to specific stimuli. Here we discuss examples agent, amygdaline [41,42], into prodrug analogs through
of reversible self-assembled prodrugs that can undergo addition of fatty acids [34]. Amygdalin, a cyanogenic
either hydrolytic or enzymatic degradation to regenerate glycoside, has a sugar backbone with multiple secondary
the active drug (Figure 3). hydroxyl groups and a primary alcohol group (Figure 3).
Amygdalin was converted into amygdalin-based self-
One of the early examples of reversible self-assembled assembled prodrugs (Amy-SAPDs) by tethering natural
prodrug hydrogels was the generation of prodrugs based fatty acids with an enzyme-cleavable ester linker [34].
on acetaminophen [33]. In general, the majority of Furthermore, to evaluate the ability of Amy-SAPD gels to
prodrugs are synthesized through ester bonds, and it is deliver multiple drugs simultaneously, akin to acetami-
estimated that 49% of all marketed prodrugs are activated nophen prodrugs, curcumin has also been encapsulated
by enzymatic hydrolysis [7]. Through conversion of a within the Amy-SAPD hydrogels. Lipase-susceptibility

www.sciencedirect.com Current Opinion in Biotechnology 2013, 24:1174–1182


1178 Pharmaceutical biotechnology

Figure 3

50 µm 50 nm

O O O O

H 3C N O O N CH3
H 6 H
O
+ O O

H3C N O OH
H 6

O Esterase
H3C N OH

C 13
H

H 27
Acetaminophen 55

O
OH

OH

HO O
e4

H
ym

O
O

Carboxy voz
No 0.5 µm
OH

peptidase
N
H

N
H

OH

O
HO
O

OH
Amygdalin

HO O
O

Ibuprofen

HO

H
+ O

O
H
N

H
N

O
O

OH O
Drug HO

O
HO

OH
O Esterase

O
0.5 µm OH O

NC
Paclitaxel NC

OH O
OAc

O NHBz
O 1 µm
H Ph
AcO HO OH
BzO

OH O
OAc

O NHBz
O
H Ph
AcO HO O
BzO

O +N
H3C
O

Hydrogel

Current Opinion in Biotechnology

Examples of reversible prodrug-based self-assembled hydrogels. In this approach, small molecular drugs have been converted into prodrugs that can
self-assemble to form hydrogels. Upon chemical/enzymatic mediated degradation hydrogels degrade, and active drug is released. References:
acetaminophen prodrugs [33], amygdalin prodrugs [34], paclitaxel prodrugs [39], and ibuprofen prodrugs [38].

of the ester-based Amy-SAPD amphiphiles facilitates One of the most potent chemotherapeutic agents used
esterase-mediated enzymatic degradation. Furthermore, for cancer therapy, paclitaxel, has also been converted
control over gel degradation allows programmable drug into a self-assembly form [43,44]. Despite its superior
release through modulation of either enzyme concen- efficacy, its extremely low water solubility limits effec-
tration and/or incubation temperature. Interestingly, tive in vivo delivery, restricting its wider use. Formu-
Amy-SAPDs-based hydrogels did not exhibit any detect- lation of paclitaxel using conventional delivery vehicles
able burst release profile, akin to hydrogels made from such as nanoparticles, colloids, and liposomes has been
Ace-SAPDs. developed to enhance its in vivo delivery [45–48]. In

Current Opinion in Biotechnology 2013, 24:1174–1182 www.sciencedirect.com


Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials Vemula et al. 1179

addition, numerous taxol-based molecular prodrugs degradation of the methylpyridinium acetate promoiety
have also been reported [49]. For example, Nicolaou group.
group developed an injectable hydrogel by attaching a
methylpyridinium acetate promoiety at the 20 hydroxyl Irreversible prodrug-based self-assembled
group of taxol to form a taxol-based self-assembled hydrogels
prodrug (Tax-SAPD, Figure 3) [39]. Depending on Recently, Xu and coworkers developed a new class of
the nature of the solvent, Tax-SAPD formed several irreversible prodrugs that maintain their bioactivity in
self-assembled structures, including regular helices prodrug form. In this approach, parent drugs are con-
and micelles, Tax-SAPD also exhibited enhanced bioa- verted into prodrugs by attaching a promoiety that pre-
vailability over free paclitaxel due to increased solubi- serves the active groups of the drug and directs their
lity of Tax-SAPD in aqueous solution and delayed self-assembly to form hydrogels.

Figure 4

OH

OH
O OH
O
OH
O
O Cl
O O
H Cl OH
HO H O
O N N O
H H O
H N N H
NHN H N N
O
O H
O
O
HO OH
OH
OH
HO

HO
O

O
H
HN
O

OH
HO

O
H
N

O
O

OH
Cl

O
O
H
N

OH
OH

O
OH

Cl
N

O
H

H
O

OH
O

O
H

H
N

Vancomycin
uco Gl

Drug
Pa
OH

HO
O

cl

sa
O
Ac B

H OH
ita
OH

2N
min
O zO
H HO

OA
O

xe
O
Ac B

HO
l

O
O zO
H H

OH
OA

O
c

O
O

NH
O

Bz

N
OH

H
Ph
NH

H
OH
O

O
Bz

N
O

Ph

OH
NH

O
O

Ph
HN

HO
N

HO
H

O
25

Ph
NH
0
nm

500
HN

nm
O
OH

OH

Current Opinion in Biotechnology

Examples of irreversible prodrugs-based self-assembled hydrogels. In this approach, small molecular drugs have been converted into prodrugs that
can self-assemble to form hydrogel. In these instances, prodrugs cannot be cleaved to release the parent drug, however, prodrugs themselves
showed significant therapeutic efficacy as compared to the parent drug. References: vancomycin prodrugs [35], glucosamine prodrugs [36], and
glucosamine prodrugs [37].

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1180 Pharmaceutical biotechnology

In contrast to the reversible Tax-SAPD developed by drugs. Recently, prodrug-based self-assembled hydrogels
Nicolau et al., Xu and coworkers studied the therapeutic have emerged as promising drug delivery systems by over-
bioactivity of irreversible self-assembled prodrugs derived coming limitations that have plagued physically encapsu-
from paclitaxel (Pacli-SAPD) [36]. Before prodrug syn- lated hydrogel-based systems. Their high drug loading and
thesis, paclitaxel was modified into a drug-based precursor mitigation of the burst release presents a significant ad-
that imparted aqueous solubility. Enzyme-mediated in situ vancement in drug delivery and opens the door for
dephosphorylation triggered self-assembly of Pacli-SAPD improved formulations and therapeutic efficacy of drugs
to form hydrogels (Figure 4). Detailed cytotoxicity studies of all classes.
revealed that the bioactivity of Pacli-SAPD was preserved.
Interestingly, even in its hydrogel form, Pacli-SAPD Although prodrug-based self-assembled hydrogels show
exhibited anticancer activity against HeLa cells compar- many advantages such as enhanced drug loading, con-
able to that of unmodified paclitaxel. This highlights the trolled drug delivery, reduction of burst release, and sim-
importance of performing thorough bioactivity and toxicity ultaneous delivery of multiple drugs, some limitations
analysis of newly synthesized molecular prodrugs. remain. Prodrug-based self-assembled hydrogels have
weak mechanical properties, which limit the use of these
Using the same concept, Xu et al. converted vancomycin, materials in structural tissue engineering. Despite this
one of the most potent antibiotics from the glycopeptidic limitation, these self-assembled hydrogels are promising
family, into an irreversible self-assembling prodrug [50]. as new injectable biomaterials that can be used for local
Despite its high water solubility, vancomycin can form drug delivery applications. Furthermore, this presents an
multiple intramolecular hydrogen bonds in aqueous opportunity to develop next generation bioengineered
solution. Thus, Xu and coworkers modified vancomycin self-assembled prodrugs with improved mechanical prop-
by introducing a pyrene group to the C-terminal of its erties. The second limitation is the dependence of hydro-
backbone (Van-SAPD, Figure 4) [35]. In contrast to gel degradation rate on the level of endogenous enzymes in
most of the structural modifications of commercial drugs vivo. Degradation of prodrug to release the parent drug is
that usually results in a loss of activity, Van-SAPD exhib- largely designed based on scission in response to endogen-
ited unusually high potency, approximately three orders ous enzymes. However, concentration of endogenous
of magnitude more potent than vancomycin against van- enzymes might significantly vary from patient to patient.
comycin-resistant enteroccoci (VRE). The enhanced ef- Thus, a deep understanding of enzyme concentrations in a
ficacy might have resulted from increased adsorption of large population and their effect on hydrogel degradation
Van-SAPD hydrogel onto the surface of bacteria cells will be useful to advance toward clinical application.
[51]. While the modified vancomycin showed promising Finally, both reversible and irreversible self-assembled
potency, the toxicity of this modified drug toward mam- prodrugs will likely be considered as new investigative
malian cells remains to be evaluated. drugs by regulatory agencies, thus extensive investigation
on the safety and efficacy of these molecules in animal
Therapeutic efficacy of self-assembled prodrugs has also models is needed. Continued success of self-assembled
been demonstrated by a series of glucosamine-based pro- prodrug hydrogels in proof-of-concept studies should gen-
drugs [37]. Glucosamine plays a significant role in the erate considerable excitement about their therapeutic
process of wound healing. In particular, Shaunak et al. have potential. Overcoming the current challenges outlined in
demonstrated that conjugation of glucosamine with poly- this article should enable development of locally injectable
valent dendrimers generates an irreversible prodrug that self-assembled prodrug hydrogels for the safe, effective,
prevents scar tissue formation [52]. In addition, glucosa- and lasting treatment of patients in the years to come.
mine has been used as an oral supplement for the man-
agement of osteoarthritis. Judicious conjugation of Acknowledgements
napthyl-L/D-phenylalanine to glucosamine has produced PKV acknowledges support from the Department of Biotechnology, India
for Ramalingaswami Re-entry Fellowship. NW acknowledges funding
glucosamine-based self-assembled prodrugs (Glu-SAPD, support from the Beta Cell Biology Consortium. JAA thanks the Hugh
Figure 4) [37]. In addition to enhancing the net drug Hampton Young Memorial Fund for their generous support. JMK
loading, Glu-SAPD accelerated healing and reduced scar acknowledges funding support from the Brain Science Foundation. ORM
thanks arthritis foundation for postdoctoral fellowship. GJ acknowledges the
tissue formation at wound sites in a mouse dermal model. grant support from NSF.

Conclusions and future perspectives References and recommended reading


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have been highlighted as:
potential in tissue engineering and regenerative medi-
cine, self-assembled small molecular hydrogels are find-  of special interest
ing their way into biomedical and drug delivery  of outstanding interest
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