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Lepowsky E and Tasoglu S

according to programmable patterns [35] . Following multiple materials can be combined into a copolymer, in
print ing, curing and soaking, the hydrogel patterns which case the relative ratios of each individual material
de velop into water-swollen networks formed by the tunes the final material properties [56,68,69] . Copolymers can
deposited hydrogel material [56–58] . These networks ex- also be utilized to control the drug release by leveraging
hibit considerable po rosity and high diffusion rates hydrophobic and hydrophilic properties of both the in-
for various substances, and of particular interest is the dividual hydrogel materials and of the added drug(s)
ability to carry and release loaded drugs. Additionally, [70,71] . For instance, the release of a hydrophilic drug can
some hydrogels even respond to pH, temperature, or be controlled and slowed by embedding it within a
enzymatic activity, enabling controlled and targeted hydro phobic hydrogel. An alternative example, a non-
release of drugs [59–61] . degrading hydrophobic hydrogel that has excellent
Hydrogels may be formed with either naturally-derived thermo-mechanical properties can be modified to be
or synthetic materials, each having nuanced properties biodegradable by the addition of hydrophilic material.
and applications. Natural hydrogel materials include Another consideration is the viscosity, surface tension,
alginate, gelatin, agarose, fibrin and chitosan [57,62] . Syn- and temperature-dependent properties of hydrogels.
thetic materials include poly (ethylene glycol) (PEG), These factors are crucial for finding or synthesizing
oligo(poly(ethylene glycol) fumarate) (OPF) and poly materials that are appropriate for 3D printing [62,72] . A
(acrylic acid) derivatives (PAA). PEG is a commonly final limitation of practically all hydrogels that should
used hydrogel material for drug delivery due to its non- be considered is the geometric precision during the 3D
toxic and non-adhesive properties, in addition to its printing process. When printing drugs, accuracy is of
compatibility with crosslinking which allows for more utmost importance, yet due to the low viscosity during
durable internal bonds to finalize the printed shape. printing and the gelatinous consistency post-printing,
A more recent hydrogel contender in the field is accurately printing corners or small designs can be very
gelatin methacryloyl (GelMA), which is an inexpensive difficult.
biomaterial naturally derived from denatured colla- As for the loading of the drug into the hydrogel,
gen and chemically modified by the addition of a two general methods have been presented: the printed
methacrylate group [63] . Similar to PEG, GelMA can be hydrogel may be placed into a liquid medium saturated
photo-crosslinked; when exposed to light in the presence with the drug, or the drug may be pre-mixed into the
of a photoinitiator, the methacrylate groups of the hydrogel material . These methods have been reported
[59]
GelMA crosslink with each other, forming a gel. GelMA as diffusion and entrapment, respectively. Diffusion
also exhibits the benefit of a temperature-dependent relies on the porosity of the hydrogel in order to take
viscosity transition which makes it ideal for 3D printing. up and store the drug. Entrapment is more suitable for
Furthermore, GelMA has been demonstrated as a drug drugs with larger molecule sizes or for more careful
delivery hydrogel by combining it with PAA, whereby and specific drug loading. Alternatively, drugs can also
the relative concentration of PAA controls the degree of be directly deposited into the middle of a print, thereby
[64]
and timing of drug release . entrapping the drug inside a hydrogel drug carrier. With
Pertaining to the formulation of all hydrogel materials, both diffusion and entrapment, once the 3D printed
various parameters must be considered to achieve ma - drug-loaded hydrogel is placed in vivo, similar to a
terial properties suitable for high-resolution drug manu- FDM-fabricated drug, the drug will diffuse out of the
facturing. The type of crosslinking directly impacts hydrogel network. The concentration gradient of the
the degradability and mechanical properties of the drug formed between the 3D print and the surrounding
printed hydrogel [65–67] . Hydrogels can be chemically environment may cause an initial burst release or a
cross linked – radical polymerization, reaction with triphasic release profile – burst release due to swelling
com plementary or end groups, and enzymatic activity and drugs eluted from the surface, followed by zero
– or physically crosslinked – crystallization, ionic inte- order release, and finished by a second phase of rapid
ractions, hydrogen bonds, and protein interactions. Each release as the hydrogel degrades – dependent on various
form of crosslinking has varying levels of rigidity and factors [59,73] . These factors include the size of the drug
degradability; stronger and greater numbers of bonds particles relative to the pore size of the hydrogel (if
are associated with stronger printed products, but at the drug is larger than the pores, diffusion is restricted,
the expense of lower degradability. For drug delivery thereby reducing the burst release effect), the distribution
application, the crosslinking bonds must be strong and of drug particles within the print (if the surface of the
plentiful enough to maintain the hydrogel for a given printed hydrogel contains a large concentration of the
time period, but must also be weak and few enough to drug, a burst release is more likely), and whether the
breakdown and degrade. In addition to the crosslinking, drug is loaded by mixing or bonding [58,73] . Herein lies
the combination of materials is also an important factor: another advantage of hydrogels over solid materials:

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