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126 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
Figure 6.9 Process scheme used for the fabrication of 3D-printed hydrogel wound dressings
in this study. For images of 3D-printed hydrogel wound dressings, indocyaninegreen was only
used to distinguish between the drug compartment and the barrier layer. (Source: Reproduced
from [37] with permission from Elsevier.)
clearly showed the potential of 3D printing to develop dressings able to meet specific and
unique patient needs for achieving personalised wound therapeutics.
There are several other reported studies on 3D-printed dressings and some of these are
summarised in Table 6.2.
6.3 Summary/Conclusions
Novel methods such as 3D printing and 3D bioprinting have the capability to be a platform
for producing polymeric films for the individual patient. This will possibly resolve the
issue of the pharmaceutical industry and pharmacies to meet the future demand of custom-
ised (personalised) medicine [44].
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Table 6.2 Summary of 3D-printed wound dressings reported in the literature.
Type of dressing/bioink
material(s) Loaded actives
3D-printing
method Functional characterisation Reference
Sodium Alginate-
Polyethyleneglycol
Satureja
cuneifolia extract
Extrusion 3D
printer
FTIR, SEM, cell viability, tensile, swelling, antibacterial assay,
drug release, cell attachment and proliferation
[38]
Poly(Dimethylsiloxane) Silver
nanoparticles
Extrusion
3D-bioprinter
SEM-EDS, STEM, contact angle, in vivo wound healing, cyto-
toxicity, non-fouling assay, in vitro antibacterial assay
[39]
Carboxymethylcellulose Platelet-rich
plasma
(autologous
growth factors)
Extrusion 3D
printer
Swelling, FTIR-ATR, hardness, cohesiveness, adhesion, growth
factor release, chorioallantoic membrane (CAM) assay, cell
proliferation and migration (in vitro), in vivo wound healing
assessment
[40]
Calcium Chloride Cross-
linked Sodium Alginate
– Extrusion-based
3D bioprinter
FTIR, swelling, degradation percentage, wettability, zeta
potential, cell viability assay, live-dead assay by fluorescence
microscopy, real-time PCR
[41]
Mesoporous Bioglass
Modified With Pluronic Acid
and Sodium Alginate
Exosomes Extrusion based
cryogenic 3D
printer
XRD, FTIR, MTT assay, cell adhesion, live/dead cell staining, in
vivo animal wound healing assay, blood perfusion, Western blot
[42]
Gelatin Methacryloyl N-halamine
modified ceria
nanoparticles
Inkjet printer Swelling, filament collapse test, antimicrobial test, in vitro
cytotoxicity, hemocompatibility, whole blood clotting,
cutaneous wound healing in mice
[43]
Abbreviations: Fourier-Transform Infrared Spectroscopy (FTIR); Scanning electron microscopy (SEM), MTT, XRD, PCR, semi-crystalline elastomeric (SEM)-EDS, STEM.
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128 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
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3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside, First Edition.
Edited by Dimitrios A. Lamprou, Dennis Douroumis and Sheng Qi.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
7
3D Printing of Hydrogels
Poornima Ramburrun and Yahya E. Choonara
Wits Advanced Drug Delivery Platform Research Unit, School of Therapeutic Sciences,
Faculty of Health Sciences, Department of Pharmacy and Pharmacology, University of the
Witwatersrand, Johannesburg, South Africa
7.1 Introduction
3D printing is defined as the spatial arrangement of biomaterial, living cells, and bioactive
agents, by assembling them using a computer-aided layer-by-layer deposition technique
for fabrication of 2D or 3D constructs for tissue engineering and drug delivery applications
[1]. A gel is defined as a semi-solid jelly-like material, consisting of a liquid phase, with
textural and mechanical properties that range from soft and weak to hard and tough.
Featuring similar properties, a hydrogel is defined as a 3D crosslinked polymer network,
which can absorb and retain large amounts of water. Hydrogels maintain a solid-like state,
and can be either biodegradable or non-biodegradable, but do not dissolve in water; the
liquid phase is absorbed through swelling of the polymer chains. This behaviour of hydro-
gels imparts excellent biomimetic properties to native mammalian tissues. Printing inks
prepared from a solution of hydrogel precursors are rheologically modified to deposit
continuous and smooth layers of ink during printing. To create a 3D-printed hydrogel con-
struct, these layers are collected and stacked, or solidified in a layer-by-layer arrangement
[2]. This method of fabrication has attracted the use of 3D-printed hydrogels for various
pharmaceutical and biomedical applications due to its high precision and efficiency, thus
paving the way to materialise the notion of on-demand personalised medicines [3].
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132 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
This chapter provides an overview of the biomedical applications of 3D-printed hydro-
gels, the types of hydrogel materials used in 3D printing, and the hydrogel printing tech-
niques. The concept of printability and critical printing parameters that influence the 3D
printing of hydrogels is discussed, as well as the regulatory and manufacturing considera-
tions and limitations to drive this emerging technology to the pharmaceutical and clinical
settings.
7.2 Applications of 3D-Printed Hydrogels
Hydrogel-based 3D printing is extensively explored in tissue engineering, regenera-
tive medicine, drug delivery, cancer research, in vitro disease modelling, contact lenses,
soft robotics, and wearable flexible electronics [4]. Hydrogels are used as 3D-printed
scaffolds due to the ease of their design, synthesis, functionalisation, and versatility.
Ultimately, their hydrophilic structures, flexibility, porosity, high water content, and
swelling behaviour provides an environment that simulates native tissues and the extra-
cellular matrix (ECM), including the potential for diffusion of biological molecules,
nutrients, and gases [5]. Due to their functional groups, hydrogels can be designed to
respond to external stimuli such as moisture, light, temperature, ions, pH, electrical sig-
nals, magnetic fields, and biochemical cues for use in various biomedical applications.
Such stimuli responsive hydrogels are also known as bioresponsive or smart hydrogel
materials. The investigation of 3D-printed hydrogels in biomedical and pharmaceutical
applications is most popular in the research fields of tissue engineering, wound healing,
and drug delivery.
7.2.1 Tissue Engineering
Tissue engineering utilises the concept of biology and biomaterials science for the objec-
tive of regenerating, restoring, or replacing damaged or defective tissues. The high biocom-
patibility and biomimetic properties of hydrogels makes them excellent materials for
initiating, guiding, promoting, and supporting the growth of cells in the innate repair pro-
cess of damaged tissues. These properties also make hydrogels suited for encapsulating a
high cell density whilst maintaining cell viability – a current requisite for effective tissue
regeneration alongside the inclusion of growth factors. With the availability of printing
techniques to precisely control the fabrication 3D constructs using cell-laden hydrogels,
the biomimicry of artificial organs can be enhanced, as the 3D hydrogel constructs can
direct cell growth and morphology post printing [3].
3D-printed hydrogel scaffolds for tissue engineering applications are expected to
fulfil several essential design criteria for optimal functioning, promotion of new tissue
growth, and induction of minimal to no inflammatory or immune reaction from the
host tissue. These design criteria are derived from material selection and the inherent
physical characteristics (such as mechanical properties, biodegradability, porosity, and
swelling behaviour), and biological properties (such as biocompatibility, bioadhesion,
and bioactivity) of the hydrogel material [5]. Since 3D-printed hydrogels are investi-
gated and designed for different tissue types (e.g., skin, bone, and neural tissues), the
resulting functions and features of the hydrogel material may vary considerably as it
is defined by its intended site of application or implantation, and the in vivo environ-
mental exposure.
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3D Printing of Hydrogels 133
7.2.2 Wound Healing
Hydrogel materials are considered ideal for wound dressings as they fulfil two fundamental
requirements for an environment supportive of wound healing, particularly burn wounds;
the ability to control fluid loss from the body and the ability to maintain adequate hydration
and moisture levels at the wound site, via the swelling and absorption properties of hydro-
gels [6]. 3D-printed hydrogel scaffolds for wound healing offers the following advantages
for optimal healing: 1) customised formulations and incorporation of actives based on the
individual’s needs; 2) tailored-to-fit dimensional properties of the hydrogel dressing in
terms of size, thickness, porosity, and surface area; 3) ease of drug loading for therapeutic
or antibacterial effects; 4) availability of a wide range of natural and synthetic materials for
hydrogel preparation of tuneable properties; 5) effective oxygen penetration imparted by
the porosity and mesh-like hydrogel network structure; and 6) ability of lyophilised hydro-
gel matrices to absorb wound exudates and maintain a moist environment to promote cell
proliferation and migration [7]. 3D-printed bioadhesive hydrogel wound dressings, with a
gradually increasing rate of biodegradation, offer the added benefit of simple application
and removal of the hydrogel between dressing changes to minimise secondary tissue dam-
age, accidental removal of newly generated tissue, and scar formation [8]. These properties
suggest that 3D-printed and lyophilised hydrogel scaffolds are suitable candidates for
wound dressings and present the prospect for developing future personalised wound man-
agement therapies with high reliability and cost-effectiveness [7, 8].
7.2.3 Drug Delivery
The oral tablet is the most common pharmaceutical dosage form designed to deliver drugs
to the human body. Tablets are made by the conventional large-scale method of powder
milling and powder compression into solid dose units, a fast and economical method for
pharmaceutical industries. However, these large-scale production methods are not suitable
for the global demand of customised doses and personalised medicine; hence, the produc-
tion of fixed tablet designs, shapes, and predetermined doses of the drug [9]. 3D-printing
technology presents a strategy for developing patient-centred medicines in different types
of dosage form designs for oral and external administration via reliably tailored drug com-
binations and release profiles based on the metabolic responses and pathophysiology of the
patient [9, 10]. The versatility, biocompatibility, biodegradability, and biologically sensitive
nature of hydrogel systems offer a suitable method for encapsulation and protection of drug
compounds [6]. 3D-printed hydrogel-based tablets via extrusion-printing can yield on-
demand dosage forms of different geometries, textures (i.e., hard swallowable tablets and
soft chewable tablets), drug loading, and release profiles in a matter of minutes to accom-
modate customised oral drug delivery needs in paediatric to geriatric patient groups [11].
7.3 Types of Hydrogel Materials for 3D Printing
Hydrogels can be classified in several ways according to the origin of the polymer material,
its ionic charge, mechanism of crosslinking, and its method of preparation (Figure 7.1) [4,
12]. Hydrogels can be prepared from natural polymers, synthetic polymers, or natural-syn-
thetic hybrids. The blending of natural polymers with synthetic polymers yields hybrid
hydrogels which constitute properties of the parent polymers. Understanding these
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134 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
classifications is important for realising its effects on hydrogel preparation and the possibility
of utilising hydrogels for various biomedical applications based on their intrinsic physical
and chemical properties [5]. Hydrophobic polymer networks produce hydrogels with limited
water-absorption capacities compared to hydrophilic polymer networks that can absorb water
many times their own weight. Hydrophilic functional groups in the hydrogel network, such
as –COOH, –OH, –NH
2
, –CONH–, –CONH
2
, and –SO
3
H, allow for the absorption of water;
however, hydrogels can absorb liquids other than water, such as biological fluids [13].
7.3.1 Natural Polymers
Natural polymers are biological materials derived from either animal, plant, microbial, or
marine sources. These materials can be further classified according to their primary chemi-
cal composition, polysaccharide-based materials, and protein-based materials, which can
form gels when dispersed in water or aqueous liquid. Natural polymers are considered
suitable for biomedical and tissue engineering applications due to their biocompatibility,
biodegradability, and biologically recognisable moieties which support cellular activities
[14]. These properties result from their inherent structural resemblance to native extracel-
lular matrix (ECM); however, natural polymers may induce inflammatory or immune
responses when introduced into the human body [12]. Despite their biomimetic appeal and
improved support for cellular interactions, natural materials lack sufficient mechanical
properties for biomedical applications [15]. Hydrogels made from natural polymers often
require modification to adjust their textural and mechanical properties to match the
environment at the application site. Due to the natural source of origin, natural polymer
hydrogels may exhibit inconsistent properties between different batches of synthesised
hydrogel, thus making uniformity of properties a challenge [16].
7.3.2 Synthetic Polymers
Synthetic polymers for the synthesis of 3D-printable hydrogels comprise mainly polyester,
polyethylene, poloxamer, and acrylate polymers, which have low immunogenicity and do
not induce any inflammatory or immune responses when introduced into the body. Synthetic
Figure 7.1 Schematic of hydrogel classifications.
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3D Printing of Hydrogels 135
polymers have the advantage to be custom designed to yield specific chemical, physical,
and mechanical properties, biodegradability and functionality of high reproducibility by
manipulating the polymerisation parameters, and composition of individual monomer units
[14, 15]. Unlike natural polymer hydrogels, most synthetic polymer hydrogels are hydro-
phobic and lack inherent bioactive properties and cellular interactions [14, 17].
7.3.3 Natural-Synthetic Hybrid Polymers
To overcome the limitations of natural and synthetic hydrogel materials, natural poly-
mers can be combined with synthetic polymers to create natural-synthetic or semi-syn-
thetic hybrid hydrogels, where each material compensates a weakness in the other to offer
improved chemical, physical, or biological properties (e.g., improved mechanical strength
with bioactive properties). Hybrid hydrogels can be synthesised by photopolymerisation
of graft polymers (natural polymer grafted onto a synthetic polymer, or synthetic poly-
mer grafted onto a natural polymer) to create a crosslinked hydrogel network. The other
approach involves crosslinking a blend of natural and synthetic polymer solutions to syn-
thesise multifunctional hydrogels of adjustable properties such as crosslinking ability, bio-
adhesion, and degradation properties [13].
7.3.4 Ionically Charged Polymers
Hydrogels may be classified into four groups based on the presence or absence of an
electrical charge on the polymer chains: 1) cationic (positively charged); 2) anionic
(negatively charged); 3) ampholytic (contains both anionic and cationic groups); and
4) non-ionic (no charge, neutral). The swelling of ionic hydrogels (cationic, anionic, and
ampholytic) is directed by the pH of the aqueous medium in which they are immersed, as
pH determines the degree of dissociation of the ionic polymer chains. Cationic polymer
chains dissociate at low pH values, therefore cationic hydrogels display enhanced swell-
ing in acidic media. Anionic polymer chains dissociate at higher pH values, therefore
anionic hydrogels display enhanced swelling in neutral to alkaline media. Since ampho-
lytic hydrogels contain both acidic and basic groups in their structural repeating units,
the charges are balanced at the isoelectric point of the polymer; where a change in the pH
can change the overall ionic charge of the hydrogel [13]. The type of charge influences
the selection of multivalent metal ions for physical crosslinking of the polymer chains,
via electrostatic interactions, to form a 3D hydrogel network or a defined 3D-printed
structure. Absent of charge, ionic hydrogels swell in aqueous medium due to water–poly-
mer interactions [13].
7.3.5 Crosslinked Polymers
Hydrogels can be categorised according to the nature of crosslinking. The polymer chains
in a hydrogel system can be crosslinked with each other: 1) chemically via covalent bonds
between functional groups; or 2) physically via polymer chain entanglements or physical
interactions such as ionic interactions, hydrogen bonds, or hydrophobic interactions [12,
14]. Covalent crosslinks form permanent junctions, whereas physical crosslinks form tran-
sient junctions which may be reversed upon the input of energy into the hydrogel system
[14]. The mechanism by which polymers crosslink to form hydrogels is essential in the
3D-printing process for selecting a suitable printing technique that accommodates
crosslinking of a gel solution either pre-printing, post-printing, or during printing to pro-
duce a defined hydrogel structure.
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