WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Prerna.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 2.786
Volume 4, Issue 04, 678-701.
Review Article
ISSN 2278 – 4357
RECENT EXPANSIONS IN AN EMERGENT NOVEL DRUG
DELIVERY TECHNOLOGY: HYDROGEL
Prerna K. Ratnaparkhi*, Vipulkumar D. Prajapati, Girish K. Jani,
Himanshu K. Solanki.
Department of Pharmaceutics and Pharmaceutical Technology, SSR College of Pharmacy,
Sayli Road, Silvassa, U.T. of D.&N.H.-396230, India.
Article Received on
12 Feb 2015,
Revised on 02 March 2015,
Accepted on 23 March 2015
ABSTRACT
With the arrival of medical science large numbers of new therapeutic
moieties are discovered and demands specialized carrier for their
delivery into specific sites of the body. Hydrogels which are three-
*Correspondence for
dimensional cross-linked polymer network that can respond to the
Author
fluctuations of the ecological stimuli. These biomaterials can
Prerna Ratnaparkhi
incorporate large quantum of biological fluids and swell. When
Department of
swelled, they are soft & rubbery and resemble the living tissue,
Pharmaceutics and
Pharmaceutical
exhibiting excellent biocompatibility. Today, drug delivery incident
Technology, SSR College
several challenges where hydrogel could be one potential answer to
of Pharmacy, Sayli Road,
those. The specific requirements of advanced drug delivery could
Silvassa, U.T. of
easily be met by hydrogels. Wide range of methods for the synthesis of
D.&N.H.-396230, India.
these novel biomaterials has extended its application from drug
delivery system to tissue engineering scaffolds, wound dressing material, gene delivery
device and biosensors. Further explore into the fundamentals of multi-polymer based
hydrogel and their properties, may give raise a novel approach for implementing the
biomaterials in the biomedical field in a better way. In this review article an attempt has been
made to describe the advancement in hydrogel for novel drug delivery as well as use of it in
various applications.
KEYWORDS: Hydrogels, Drug Delivery, Novel, Biomaterials.
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1. INTRODUCTION
Natural polymers are derived from renewable resources widely distributed in nature.[1] These
materials exhibit a large diversity of structures, different physiological functions and, may
offer a variety of potential applications in the field of tissue engineering due to their various
properties, such as pseudo plastic behavior, gelation ability, water binding capacity and
biodegradability. Many of these polymers form hydrogels that can respond to external
stimuli. Hydrogels resemble natural living tissue more than any other class of synthetic
biomaterials due to their high water content and soft consistency which is similar to natural
tissue.[2] Furthermore, the high water content of these materials contribute to their
biocompatibility and can be used as contact lenses, linings for artificial hearts, materials for
artificial skin, membranes for biosensors and drug delivery devices[2-10] Hydrogels are
polymeric materials that do not dissolve in water at physiological conditions. However, they
swell considerably in aqueous medium[3] and reveal extraordinary capacity (>20%) for
imbibe water into their network structure. Gels that exhibit a phase transition in response to
change in external conditions such as pH, ionic strength, temperature and, electric currents
are known as ―stimuli-responsive‖ or ―smart‖ gels.[4] As these are three-dimensional
hydrophilic networks they can retain a large amount of water that contributes to their good
blood compatibility and maintains a certain degree of structural integrity and elasticity.[5]
This phenomenon can be explained by the presence of hydrophilic functional groups in their
structure, such as -OH, -COOH, -CONH2, and -SO3H, capable of absorbing water without
undergoing dissolution. In spite of these many advantageous properties, hydrogels also have
several limitations. The low tensile strength of many hydrogels limits their use in load
bearing applications and can outcome in the premature dissolution or flow away of the
hydrogel from a targeted local site.[6] However, this restriction may not be important in some
typical drug delivery applications (e.g. subcutaneous injection). In the case of hydrophobic
drugs, the quantity and homogeneity of drug loading into the hydrogel may be limited. On the
other hand, the high water content and large pore sizes of the most hydrogels often result in
relatively rapid drug release, over a few hours to a few days.
The present review addresses recent developments, which have focused in hydrogel systems.
The literature is comprehensive on general aspects about hydrogels. However, the article
intends to focus on the hydrogel applications and emphasis on the drug delivery.
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2. Network Structure and Classification
Hydrogels can be deliberate to have some specifications, such as swelling and mechanical
characteristics, justifying their variety of biomedical applications, from contact lenses to
controlled release drug delivery and tissue engineering.[7,8] They can be prepared from natural
and synthetic polymer materials[9] and classified using various criteria depending on their
preparation method and physicochemical properties Table 1. Natural polymers, such as
proteins[10], polysaccharides[11], and deoxyribonucleic acids (DNAs) are cross-linked by
either physical or chemical bonds, and synthetic hydrogels can be easily prepared by crosslinking polymerization of synthetic monomers.[12] In addition, natural polymers can be
combined with synthetic polymers to obtain special properties in the same hydrogel.[13] For
example, the biodegradable property of natural polymers has been combined with several
functionalities of synthetic polymers to give new functional hydrogels.[14,
15]
Various
monomers and cross-linking agents have been used for the synthesis of hydrogels with wide
range of chemical compositions.[16]
Hydrogels, particularly, those intended for application in drug delivery and biomedical
purposes are required to have acceptable biodegradability and biocompatibility, relevant
requisites on the development of novel synthesis and cross-linking methods to design the
desired products.
Table 1. Classification of Hydrogel.[9, 18-33]
Classification
Origin
Content
 Natural
 Synthetic
Ionic charge (based on Neutral
the nature of the
 Anionic
pendent groups)
 Cationic
 Ampholytic
 Low swelling
Water content or degree
 Medium swelling
of swelling
 High swelling
 Superabsorbent
 Nonporous
Network Structure
 Microporous
(Porosity)
 Macroporous
 Superporous
 Amorphous
Network morphology
 Semicrystaline
 Hydrogen bonded structures
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References
[9]
[18-20]
[21]
[22-23]
[24-25]
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


Component
(based on the method of

preparation)



Function
(based on organization

of the monomers)



Mechanism controlling
the drug release


Super molecular structures
Hydrocolloida
Homopolymer
Copolymer
Multipolymer
Interpenetrating
Biodegradable or Nonbiodegradable
Stimuli responsive
Superabsorbent
Diffusion controlled release
systems
Swelling controlled release
systems
Chemically controlled release
systems
Environment responsive
systems
[27]
[26, 28-29]
[6, 30-33]
Thus, a great variety of cross-linking approaches have been developed to prepare hydrogels
for each particular application.[17] A great variety of chemical and physical methods to
establish cross-linking have been used to prepare hydrogels.[17] In chemically cross-linked
gels, covalent bonds are present between different polymer chains. In physically cross-linked
gels, dissolution is prevented by physical interactions, which exist between different polymer
chains. The network structure of a hydrogel will determine its properties as a drug delivery
device.
3. Hydrogel Preparation and Characterization Parameter.
Some of the important methods to prepare and measure hydrogels and some vital
characterization parameters are highlights in Table 2.[34-37]
Table 2. Hydrogels preparation and characterization parameters.
Preparation
Isostatic ultra high
pressure (IUHP)
Characterization
Parameter
Morphology/
Network pore size
Use of cross linkers
Degree of swelling
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Techniques of measurement
 Quasi-elastic laser-light
scattering;
 Electron microscopy;
 Mercury morosimetry;
 Rubber elasticity measurements;
 Dimensional changes with time;
 Aqueous medium or medium
specific pH;
 Volume or mass degree of
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Use of water and
critical conditions of
drying
Use of gelling agents
Use of nucleophilic
substitutio reaction
Use of irradiation and
freeze thawing
swelling;
 Equilibrium water content
Cross-linking
 Ultimate compressive strength,
and mechanical strength
change in polymer solubility
 Membrane permeability,
 Controlled strength experiments,
 Nuclear magnetic resonance
(NMR),
 Fourier transform infrared
(FTIR) spectroscopy,
 Scanning electron microscopy
Drug diffusion
(SEM),
 Quasi-elastic laser light
scattering.
 FTIR microscopy,
Drug distribution
 SEM
4. Responsive Hydrogels
Over the last few years, researches have devoted much attention to ―stimuli-responsive‖ or
―environment-sensitive‖ polymers. This kind of polymers are the ability to answer
concerning to small physical or chemical stimuli. Hydrogels can exhibit vivid changes in
their swelling behavior, network structure, permeability or mechanical strength in response to
different internal or external stimuli.[38] Fig 1 shows various stimuli that have been explored
for modulating drug delivery.
Fig 1. Representation of hydrogels stimuli responsive swelling.
External stimuli are produced with the help of different stimuli-generating devices, whereas
internal stimuli are produced within the body to control the structural changes in the polymer
network and to exhibit the desired drug release.[39] Versatile stimuli sensitive controlled
release systems can be fabricated, provided that the hydrogels are well designed to change
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their configuration in response to these stimuli based on almost infinitely available
mechanisms.[40]
The responsive hydrogels are highly sensitive to changes in the environment and have been
used in several applications, such as biosensors[42-44], superabsorbent polymers[44-46], site
specific drug delivery systems[41,
42,43-53]
, emerging nanoscale technologies[54-61] and tissue
engineering. Other important area for the use of polyelectrolytic hydrogels is bio and
mucoadhesive drug delivery systems.[62-64] Responsive hydrogels are unique concerning many
different mechanisms for drug release and a lot of many different types of release systems
based on these materials are formulated. For occurrence, in most cases drug release occurs
when the gel is highly swollen or swelling and is typically controlled by the rate of swelling,
the drug diffusion, or a coupling of swelling and diffusion. Other interesting characteristic of
many responsive hydrogels is that the mechanism causing the network structural changes can
be entirely reversible. This behavior is depicted in Fig 2 for a pH or temperature responsive
hydrogels.
Fig 2. Swollen temperature- and pH-sensitive hydrogels may exhibit an abrupt change
from the expanded (left) to the collapsed (syneresed) state (center) and then back to the
expanded state (right), adapted from.[65]
The ability of these systems to exhibits rapid changes in their swelling behavior and pore
structure in response to changes in environmental conditions lend to these materials favorable
characteristics as carriers for delivery of bioactive agents, including peptides and proteins.
Typical examples of environmental sensitive hydrogels are listed in (Table 3).
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Table 3. Various environmental stimuli used for triggering drug release from responsive
hydrogels.[66-101]
Environmental Mechanism
stimuli
Temperature
Competition between hydrophobic
interaction and hydrogen bonding.
Electrical
Reversible swelling or deswelling
signal
in the presence of electrical field.
Light
Magnetic fields
Physical
Ultrasonic
irradiation
Ionic strength
pH
Chemical
Chemical
agents
Glucose
Temperature change via
incorporated photosensitive
molecules; dissociation into ion
pairs by UV irradiation.
Applications
Polymers
On/off drug release,
squeezing device.
Actuator, artificial
muscle, on/ off drug
release.
Optical switches,
ophthalmic drug
delivery.
PNIPAAm;
PDEAAm
Polyelectroly
tes PHEMA
Controlled drug delivery
Applied magnetic field causes pore
while the magnetic
in gel and swelling followed by
particles, used
drug release.
formedical therapy.
Temperature increase causes
Drug delivery.
release of drug.
Change in concentration of ions
Biosensor for glucose,
inside the gel causes swelling and
used for medical
release of drug.
therapy.
Ionization of polymer chain upon
pH-dependent oral drug
pH change; pH change causes
delivery.
swelling and release of drug.
Formation of charge-transfer
complex causes swelling and
release of drug.
Controlled drug
delivery.
pH change causes by glucose
oxidase; reversible interaction
between glucose containing
polymers
Self-regulated insulin
delivery.
Copolymer
of PNIPAAm
EVAc,
Copolymer
of PNIPAAm
EVAh
Nonionic
PNIPAAm
PAA,
PDEAEM,
Chitosan PEO,
polyelectroly
tes
EVAc; pHsensitive
hydrogels;
Concanavali
n A-grafted
polymers.
Semi-IPN
with grafted
antibodies or
antigens.
Modulated drug release
in the presence of a
Antigen
specific antigen; sensor
for immunoassay and
antigen.
Note: PNIPAAm = poly(N-isopropylacrylamide); PDEAAm = poly(N,N’-diethylacrylamide);
Biochemical
Competition between polymergrafted antigen and free antigen.
PHEMA = poly(2-hydroxyethyl methacryate); EVAc = ethyl-ene-co-vinyl acetate; EVAh =
ethylene-co-vinyl alcohol; PEO = polyethylene oxide; IPN = interpenetrating network.
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4. DRUG DELIVERY AND APPLICATIONS OF HYDROGELS
4.1. Drug Delivery of Hydrogels
Controlled-release or controlled-delivery systems are intended to provide the drug at a
predetermined temporal and/or spatial way within the body to accomplish the specific
therapeutic needs. Hydrogels, among the different controlled release systems exploited so far,
have particular properties which make them to be potentially considered as one of the
ultimate future controlled release systems. There are two major categories of hydrogel based
delivery systems: 1) time-controlled systems and 2) stimuli induced release systems.[40,138]
Sensitive hydrogel systems are developed to deliver their content(s) in response to a
fluctuating condition in a way that desirably coincides with the physiological requirements at
the right time and proper place.[101] The most considerable drawback of stimuli sensitive
hydrogels is their significantly slow response time, with the easiest way to achieve fast acting
responsiveness being to develop thinner and smaller hydrogels which, in turn, bring about
fragility and loss of mechanical strength in the polymer network and the hydrogel device
itself.[102]
In all routes of drug administration, oral administration has been considered to be most
convenient, and hence the majority of dosage forms are designed for oral drug delivery.
Different types of hydrogels can be used for delivery of drugs to certain areas in the
gastrointestinal tract ranging from the oral cavity to the colon, as shown in Fig 3.
Fig 3. Tissue localization of hydrogel-based drug delivery systems.[12]
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Controlled drug delivery can be used to achieve some objectives. That is:
 Sustained constant concentration of therapeutically active compounds in the blood with
minimum fluctuations;
 Predictable and reproducible release rates over a long period of time;
 Protection of bioactive compounds having a very short half-time;
 Elimination of side-effects, waste of drug and frequent dosing;
 Optimized therapy and better patient compliance;
 Solution for drug stability problems.
Hydrogels have a unique characteristics combination that makes them useful in drug delivery
applications. Due to their hydrophilicity, it can absorb large amounts of water (>90%, w/v).
Therefore, the molecular release mechanisms from hydrogels are very different from
hydrophobic polymers. Both simple and sophisticated models have been previously
developed to predict the release of a drug from a hydrogel device as a function of time. These
models are based on the rate limiting step for controlled release and are therefore categorized
as follows [103]:
1) Diffusion-controlled systems:
a. Matrix (monolithic systems)
b. Reservoir (membrane systems)
2) Swelling-controlled systems:
a. Solvent-activated systems
b. Osmotically controlled systems
3) Chemically controlled systems:
a. Bioerodible and biodegradable systems
b. Pendent chain systems
4.2. Applications of Hydrogels: [104-107]
4.2.1. Wound Healing – Modified polysaccharide found in cartilage is used in formation of
hydrogels to treat cartilage defects. For example, the hydrogel of gelatin and polyvinyl
alcohol (PVA) together with blood coagulants are formulated.
4.2.2. Soft Contact Lenses (silicon hydrogels and polyacrylamides) – The first commercially
available silicon hydrogels adopted two different approaches. First approach by Bausch and
Lomb was a logical extension of its development of silicon monomers with enhanced
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compatibility in hydrogel forming monomers. The second by Ciba vision was the
development of siloxy monomers containing hydrophilic polyethylene oxide segments and
oxygen permeable polysiloxane units.
4.2.3. Industrial Applicability - Hydrogels are used as absorbents for industrial effluents like
methylene blue dye. Another example is adsorption of dioxins by hydrogel beads.
4.2.4. Tissue Engineering – Micronized hydrogels are used to deliver macromolecules
(phagosomes) into cytoplasm of antigen-presenting cells. This property is also utilized in
cartilage repairing. Natural hydrogel materials used for tissue engineering include agarose,
methylcellulose and other naturally derived products.
4.2.5. Drug Delivery in GI Tract – Hydrogel deliver drugs to specific sites in the GIT. Drugs
loaded with colon specific hydrogels show tissue specificity and change in the pH or
enzymatic actions cause liberation of drugs. They are designed to be highly swollen or
degraded in the presence of micro flora.
4.2.6. Ocular Delivery – Chitoni et al. reported silicon rubber hydrogel composite ophthalmic
inserts. Cohen et al. developed in-situ forming gelling system of alginate with high gluconic
acid contents for the ophthalmic delivery of pilocarpine.
4.2.7. Transdermal Delivery – Swollen hydrogels can be used as controlled release devices in
the field of wound dressing. Hydrogel based formulations are being explored for transdermal
iontophoresis to obtain enhanced permeation of products viz. hormones and nicotine.
4.2.8. Subcutaneous Delivery – Hydrogel formulations for subcutaneous delivery of
anticancer drugs are being prepared viz. crosslinked PHEMA was applied to cytarabine (Arac). Implantable hydrogels are now leading towards the development of biodegradable systems
which don‘t require surgical removal once the drug has been administered 5,6.
4.2.9. Tropical Drug Delivery – Instead of conventional creams, hydrogel formulation are
employed to deliver active components like Desonide, a synthetic corticosteroid used as an
anti – inflammatory for better patient compliance.
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4.2.10. Protein Drug Delivery – Interleukins conventionally administered as injection are
now given as hydrogels which show better compliance and form in-situ polymeric network
and release proteins slowly.
4.3. Hydrogels as Scaffold Materials
Hydrogels are an attractive scaffolding material because their mechanical properties can be
tailored to mimic those of natural tissues. As scaffolds, hydrogels are used to provide bulk &
mechanical constitution to a tissue construct whether cells are adhered to or suspended within
the 30 gel framework. The fundamental obligation of a tissue scaffold is to maintain cellular
proliferation and desired cellular distribution throughout the expected servicelife of the
construct. Therefore a critical design consideration for hydrogels in regenerative medicine is
the transition in functional dependence between the scaffoldand the emergent tissue during
scaffold biodegradation and the healing process [108]
4.4. Hydrogels with drug delivery capabilities: Hydrogels are often used as localized drug
depots because they are hydrophilic, biocompatible, and their drug release can be controlled
and triggered intelligently by interactions with biomolecular stimuli. Macromolecular drugs
such as proteins or oligonucleotides that are hydrophilic are inherently compatible with
hydrogels. By controlling the degree of swelling, crosslinking density, and degradation rate,
delivery kinetics can be engineered according to the desired drug release schedule.[109]
4.5. Hydrogels for cell encapsulation: Cell transplantations can be achieved with hydrogels
because they can provide immunoisolation while still allowing oxygen, nutrients, and
metabolic products to diffuse easily into the hydrogel. The development of a bio-artificial
endocrine pancreas, photopolymerized PEG diacrylate (PEGDA) hydrogels have been
fabricated to transplant islets of Langerhans.[110]
5. CHALLENGES OF HYDROGEL DEVICES
There are still many challenges associated with the modeling of drug delivery phenomena
and release profile related to complex hydrogel systems.
Fundamental understanding of drug transport processes helps in developing a suitable
mathematical model. Mass transport governs the translocation of drug from the interior to the
surrounding environment of hydrogel devices. Factors affecting mass transport of
encapsulated molecules are as follows.
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
Network cross linking density

Extent of swelling

Gel degradation

Size and charge of the encapsulated molecules

Physical interactions between the encapsulated molecules and the polymer matrix

Drug ligand binding present within hydrogel devices.
5.1. Dynamic Hydrogel Delivery Devices
a. Degradable hydrogels – Rate of matrix swelling and degradation mechanism govern the
diffusion of encapsulated molecules. With the help of appropriate design of polymer
chemistries and network structure, degradable hydrogel matrices are enabled with proper
degradation profiles. Mathematical modeling has enriched us with sufficient information to
facilitate the design of degradable hydrogels and identify critical parameters dictating
molecule release profiles.
b. Stimuli sensitive hydrogels- This advanced hydrogel system detects changes in complex in
vivo environments and utilize such triggers to modify drug release rates. As the swelling or
deswelling of such hydrogels is mediated by external stimuli, it is critical to model the
dynamic swelling response in order to predict solute release.[111-113]
5.2. Composite Hydrogel Delivery Devices
It has been exhausted for delivering multiple protein therapeutics for tissue engineering
applications where temporal and spatial control over drug delivery is desirable. It is of two
types which are listed below

Multilayer

Multiphase
Examples of in-vivo simultaneous delivery of multiple proteins is angiogenesis, bone
remodeling and nerve regeneration.
a. Multilayer hydrogel devices- The system comprises of a basal polymer layer, followed by
lamination of subsequent layer. Different proteins are encapsulated into each layer while
fabrication and tunable multiple protein release or unique single-protein release approach are
made possible by independently adjusting the cross-linking density of each layer. Various
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models have been developed for predicting drug release from multilayer hydrogel devices.
[114]
It employs Fick‘s second law of diffusion to predict drug release profiles[115]
b. Multi-phase hydrogel delivery devices- Prefabricated microspheres possessing one or
more proteins are uniformly embedded within a hydrogel having a second protein.[116-118] The
release of the protein encapsulated in microsphere is delayed due to the combined diffusion
resistances of the microsphere polymer and surrounding gel. Richardson and colleagues have
prepared a composite polymeric scaffold containing. It was the first heterogeneous polymeric
system for delivering two proteins with distinct release profiles which can be adjusted by
varying the protein loaded in each polymer phase.[119]
5.3. Micro/ nanoscaled hydrogel devices: Mathematical approaches proposed to predict
molecule release from hydrogel microspheres are of two types viz.

Macroscopic diffusion models

Microscopic Monte carlo simulations
For macroscopic modeling, models used are based on Fick‘s second law of diffusion. Particle
size, geometry and surface area are important parameters in this type of modeling. Further
molecule diffusivities must be considered and accurately determined.[119]
Monte carlo simulation is useful for describing the transport behavior of molecules with in
degradable microsphere system and has been widely applied to hydrophobic polymer
networks viz. PLGA61.[120]
a. In- Situ Hydrogels- Recent advancement in hydrogel engineering has led to the
development of in-situ hydrogel formation for drug delivery applications. The in-situ sol-gel
transition enables the surgery or implantation procedure to be performed in a minimally
invasive manner. Various physical and/or chemical cross linking mechanisms have been used
for insitu network formation. Physical phenomenon involved in the formation of in-situ
hydrogels are as follows

Hydrogen bonding

Hydrophobic – hydrophobic interactions.

Electrostatic interactions.
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For example, sodium alginate hydrogels are formed physically by cross-linking due to
addition of calcium ions but are unstable and disintegrate rapidly and unpredictably.[121]
b. Chemical cross linking mechanism – Covalent cross linking methods performed under
physiological conditions produce relatively stable hydrogel networks with predictable
degradation behavior. For example, photo polymerization of multivinyl macromere. It is a
fast process and can be conducted at room temperature without organic solvents.[122] Photo
polymerization of degradable hydrogels may be applied to protein and gene delivery.[123]
Finally, it is possible to conclude that many significant recent advances in biomaterials occur
at the interface of clinical medicine, materials science and engineering. This aspect creates
opportunities and training programs for individual cross disciplinary research and the
engaged in these areas can significant accelerate the advance of biomaterials and create new
applications for these materials in medicine.
6. FUTURE PERSPECTIVE AND CONCLUSION
Significant progress has been made in improving the properties of hydrogels used for drug
delivery and expanding the range of drugs and kinetics which can be achieved using a
hydrogel based delivery vehicle. However, several challenges remain to improve the clinical
applicability of hydrogels for drug delivery. One set of major challenges relates to improving
the ease of clinical usage. Designing physical gelators which gel at lower polymer
concentrations and at more precise gelation temperatures would reduce the risk of premature
gelation inside the needle upon injection. Similarly, for covalently cross-linked hydrogels, the
further development of strategies to release cross-linker in a triggered manner inside the body
would minimize the risk of syringe clogging, improve the localization of cross-linker release
to minimize in vivo toxicity, and enable mixing of the chemically reactive gel precursors in a
single syringe, eliminating the need for double-barreled syringes. The development of
hydrogel based systems where the rate of drug delivery could be easily modulated one off
over time could also be of benefit for applications requiring varying doses of a drug over time
(e.g. delivery of insulin or analgesics). Hydrogels with different degradation profiles and/or
environmentally responsive segments may help to address these kinetic issues. There is a
need for continued improvement in the delivery of not only hydrophobic molecules, but also
the delivery of more sensitive molecules such as proteins, antibodies, or nucleic acids which
can readily be deactivated or unfolded by interactions with the hydrogel delivery vehicle.
This is a particular issue with in situ cross-linking hydrogels, in which the hydrophobic
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domains formed in thermal, physically gelling polymers or the functional group chemistry
used to form covalently gelling hydrogels can significantly affect the biological activity of
the entrapped bimolecular. Progress on any or all of these challenges would greatly expand
the potential of hydrogel-based drug delivery to successfully deliver the next generation of
designed drugs at the desired rate and location in the body.
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