Lithography based methods to manufacture biomaterials at small scales 2017 Journal of Science Advanced Materials and Devices

Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

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Review Article

Lithography-based methods to manufacture biomaterials at small
scales
Khanh T.M. Tran a, Thanh D. Nguyen a, b, *
a
b

Department of Mechanical Engineering, University of Connecticut, United States
Department of Biomedical Engineering, University of Connecticut, United States

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 20 November 2016
Received in revised form
30 November 2016
Accepted 11 December 2016
Available online 21 December 2016

Along with the search for new therapeutic agents, advanced formulation and fabrication of drug carriers
are required for better targeting, sensing, and responding to environmental stimuli as well as maximizing treatment efficiency. The emergence of intelligent therapeutics involves the use of functional

biomaterials to mimic biological system for prolonged circulation and to work harmoniously with the
body. One of the main concerns lies in the feasibility of creating systems with well-defined architectures
including size, shape, components, and functionality. This review provides an overview regarding current
challenges and potential of manufacturing and fabrication of biomaterials at small scales for various
biomedical applications. Accordingly, novel lithography-based fabrication approaches are introduced
together with their remarkable applications. Besides being popular in microelectronics, lithography
techniques have demonstrated a great potential use for drug delivery, tissue engineering, and diagnostic
tools.
© 2017 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi.
This is an open access article under the CC BY license ( />
Keywords:
Lithography
Biomaterials
Intelligent therapeutics
Drug delivery
Tissue engineering
Biosensors

1. Introduction
The use of biomaterials is ubiquitous in biomedical applications
which include drug delivery systems, engineered tissues, and
biomedical devices. Biomaterials are defined as synthetic or natural
materials which are in contact with biological environment in order
to treat any malfunctions of the body [1]. Accordingly, biomaterials
must function synergistically with the body and possess sufficient
biocompatibility to avoid the risk of being recognized and eliminated by the immune system. Biocompatibility which is described
as “the ability of a material to perform with an appropriate host
response in a specific application” by Williams [2] is prerequisite
for any materials operating in human body. Biomaterials are
tailored in such a way that they are able to resist the immune

response, blood clotting, or bacterial colonization. Biomaterials
have been widely investigated and implanted in human body for
applications such as skeletal repair, organ replacement, and
improvement of senses, among many others with remarkable
success. Artificial hip joint is one of the most popular implants

* Corresponding author. Department of Mechanical Engineering, University of
Connecticut, United States.
E-mail address: (T.D. Nguyen).
Peer review under responsibility of Vietnam National University, Hanoi.

employing biomaterials [3]. Hip joint prostheses are composed of
titanium, stainless steel, special high strength alloys, ceramics,
composites and ultra-high molecular weight polyethylene. The
replacement of worn-out hip joint helps restore patient ease of
movement. Likewise, heart valve prostheses also contribute to treat
cardiac abnormalities [4]. These implants are made of carbons,
metals, elastomers, plastics, fabrics together with chemically pretreated animal or human tissues to diminish immunologic activities. Other examples in this area include dental implants, cochlear
replacement, contact lenses, etc. [5]. These types of implants are
expected to possess adequate protection from degradability in order to exhibit long term stability in the biological system. On the
other hand, biodegradability is essential for micro- and nanosystems to avoid invasive removal surgeries and possible toxicity
innate to long-term implantation. Furthermore, biodegradability
can facilitate control over drug release profile.
To this extent, the notion of intelligent therapeutics has evolved
with the growth of biomaterials in response to the demand to
manufacture improved functional systems. Apart from their role as
therapeutic carriers, these systems are created to be capable of
advanced targeting or stimulating delivery, as well as detection/
diagnoses of diseases. In the interest of fabricating intelligent
therapeutics, these systems need to be responsive to a biological

environment. To do so, it is necessary for them to imitate the nature

/>2468-2179/© 2017 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi. This is an open access article under the CC BY license
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K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

of their surrounding in terms of characteristics, sizes, and structures, which together present compelling challenges for scientists
to overcome. So far, significant chemical progresses have contributed to the success of producing micro- or nano-sized bio-systems
that are suitable for certain kinds of diseases. Current attempts have
mainly involved the employment of polymers and lipids to form
drug particles through chemical cross-linking, emulsion, selfassembly, and dispersion alongside with chemical moiety modification for enhancing penetration, prolonging circulation, and
controlled delivery [6,7]. However, particular difficulties remain in
synthesizing precise architectures with regard to size, shape, and
components as well as manipulating functionalized properties
[8,9]. Recent works have explored physical micro- and nanofabrication methods in addition to conventional chemical ones,
offering superior techniques for drug delivery, tissue engineering,
biosensing, and disease-diagnostics.
Lithography is a micro- and nano-fabrication technique that
enables formation of precise and complicated two-dimensional or
three-dimensional structures at extremely small scales. The technique originated from a method of planographic printing on smooth
surfaces of a plate or stone. This method was invented by the work of
a Bavarian author, Alois Senefelder, in 1976 [10]. The application of
lithography has advanced the field of electronics by enabling the
mass production of semiconductors, electronic components and
integrated circuits [11]. In the early twentieth century, there was a
limited use of photolithography for biomedicine despite the development of advanced techniques in micro-patterning. This was
mainly due to the high cost, complex operation and inaccessibility of

photolithography techniques to scientists [12]. Later on however,
momentous growth of lithography has occurred due to increased
access to fabrication tools (clean-room facilities) in many research
institutes as well as lowering costs of production. This further
became a driving force to expand lithography for studies in science
and technology, especially in biomedical areas [13]. Early works
include the development of Bio-microelectromechanical systems
(Bio-MEMS), nanoelectromechanical systems (NEMS), microfluidics, photonics, optics, and multifunctional devices. Moreover,
the advantages of creating well-controlled morphology present
alternative opportunities to create intelligent therapeutics; subsequently, there is a significant interest in further exploration of these
approaches.
This review aims to provide the current status of chemicallyfunctionalized biomaterials at micro- and nano-scales and further
describe advances in employing lithography-based micro- and
nano-fabrication methods, producing biomaterials for medical
applications.
2. Functionalized biomaterials for biomedical applications
2.1. Functionalized biomaterials with certain physical and chemical
properties to cross biological barriers
In the attempt to administer therapeutic agents, the foremost
concern is their ability to bypass natural barriers. The presence of
these barriers primarily serves as ultimate regulating entrances of
solutes and compounds; thereby, protecting the body against invasion of foreign factors. One of the most restrictive barriers in
human body to be mentioned is blood brain barrier which only
permits diffusional transport of small lipid soluble molecules with
molecular weight under 400 Da [14,15]. The gastrointestinal barrier,
although viewed as a highly vascularized surface, presents selective
uptake activity by composing of enterocyte membranes, tight
junctions and specialized immunologic factors [16,17]. Another type
of barrier is the stratum corneum (SC) situated on the upper layer of
skin. SC is comprised mainly of multiple lamellar bilayer

corneocytes surrounded by an extracellular milieu of lipids; hence, it
only prefers entrance of low molecular weight lipophilic compounds [18]. These barriers together pose considerable challenges to
the field of drug delivery. To deliver drug into desired organs, it is
therefore desirable to deceive the barriers by creating drug carriers
with special functions. This requires the modulation of physical and
chemical features of drug particles. One of the initial efforts is to
reduce particle size of drugs to the range of nano to a few microns.
There are two common approaches to fabricate nanoparticles in
which the particles are built up from molecules (bottom up) or
partitioned from larger ones (top down). Although small particles
are proven to cross the barriers more effectively, nanoparticles with
diameters smaller than 6 nm can be excreted by kidneys [19],
whereas those larger than 200 nm might accumulate in the spleen
and liver. Nevertheless, the particle size is not the only concern in
designing a drug delivery system. In a review by Albanese and coworkers [20], they studied the correlation between the properties of
nanomaterials (size, shape, chemical functionality, compositions,
and surface charge) and theirs biomolecular signal, kinetics, distribution, and toxicity. For instance, Yan Geng et al. [21] showed that
rod-shape micelles could prolong circulation when compared to
spherical ones. Also, the surface charge of particles have effects on
blood half-life. Neutral nanoparticles possess the highest circulation
time whereas other charges result in fast clearance, or interact with
proteins (e.g. immunoglobulin, lipoproteins) occurring in body
fluids causing hemolysis, platelet aggregation, and coagulations
[22]. Besides efforts to modify physical properties of therapeutic
particles, functionalized particles can promote transport across
different biological barriers [23]. These include the employment of
uptake-facilitating ligands such as apolipoprotein E (ApoE) [24] and
transferrin [25] for drug delivery to brain or co-administration with
P-glycoprotein inhibitors [26] for oral delivery or penetration enhancers [27,28] for transdermal delivery.

2.2. The use of biomaterials for controlled drug delivery
Since each of therapeutic agents possesses unique properties in
terms of water-solubility, crystallinity and chemical characteristics, they need to be encapsulated into appropriate carriers or
biomaterials prior to manufacturing in order to meet individual
compatibility and maximal drug-efficiencies. Several techniques to
formulate drug delivery systems are comprehensively developed,
namely liposomes [29], micelles [30], emulsions [31,32], solid lipid
nanoparticles [33], solid dispersion [34,35], drug-cyclodextrin
complexation [36,37], and prodrugs [38,39]. Due to the poor
water-solubility of some therapeutic agents and the nature of
biological barriers, the formulated systems usually possess certain
degree of hydrophobicity. Additionally, these formulations require
extensive use of additives for stabilization and prevention of
coalescence. These additives are, however, associated with potential toxicity. This concern demands the implementation of
biomaterials with Food Drug Administration (FDA)’s approval and
biodegradability. The search for sources of natural and synthetic
polymers suitable for biomedical applications has been widely
carried out [40].
Designs of drug delivery systems have to be in accordance with
different routes of administration and purposes of treatment. A
challenge for most biomaterials entering the body is the risk of
being eliminated. In a common approach, rapid clearance by
phagocytic cells of mononuclear phagocyte system can be avoided
by attaching polyethylene glycol (PEG) to surface of the particles.
This process, alternatively so-called PEGylation, prevents opsonization, thereby enhancing blood half-life of biomaterials [41]. PEG
is approved by the FDA for usage in foods, cosmetics, and pharmaceuticals with little toxicity and is able to be further eliminated


K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

in urine or feces [42,43]. Pegylated liposomes that form hydrated
cover have shown positive impacts not only on extending circulation time, increasing half-life, and decreasing plasma clearance by
protection from proteins and reticuloendothelial uptake but also
better drug encapsulation and leakage prevention, thereby maximizing treatment efficacies [44,45].
2.3. The use of biomaterials for tissue engineering
Biomaterials contribute to engineered tissues to replace parts of
the human body and harmoniously function with biological systems
[1]. There exist several interests to engineer tissue properties and
performance by using biomaterials. The interference of tissueengineered products with the extracellular fluids is significant
since it would trigger an inflammatory response. Considering potential long-term toxicity, biomaterials which have a degradability
rate matching with tissue regeneration rate are desirable. In accordance with dysfunctions of native organs, the implanted tissues
would preferably start to operate at time of treatment to replace
impaired ones. Alternatively, they may convert into expected form
upon implantation [46]. Thus, the composition, architecture, 3D
environment of the scaffold, and biocompatibility of materials are
challenging factors that strongly impact formulation of implanted
tissues [47]. Biomaterials should be processable to complex shapes
with porosity and sufficient mechanical strength [48]. Moreover,
consistency and uniformity are requirements to manufacture tissueengineered products. Also, tissue and cell preservation from function loss during long-term storage needs to be improved [49]. Efforts
have also been made to mimic the extracellular matrix for tricking
the body immune response. A number of natural materials have
been employed to this end including alginate [50], chitosan [51],
hyaluronic acid [52], etc. Another attempt is to incorporate signal
peptides (RGD) into materials [53].
3. Chemical modulation of biomaterials
Numerous efforts have been made to study and obtain desired
properties of biomaterials for different medical applications.
Chemical methods have been tremendously used to successfully
modulate biomaterials by adding or combining functional chemical
groups, which can response to specific stimuli and environments.

As such, we briefly cover some important chemical modulations
before describing in more details lithography-based technology as a
powerful supplemental approach to manufacture biomaterials.
3.1. Responsive-biomaterials
Considerable amounts of agents used for pharmacotherapy may
exhibit side-effects besides advantageous activity when delivered to
wrong targets or healthy tissues. This phenomenon is usually present in cancer therapy in which cytotoxic compounds can kill
normal cells in addition to cancer cells. Efforts have been made toward chemical modifications of biomaterial carriers' structures and
surfaces for specific delivery or drug targeting [54]. The implications
of stimuli-responsive biomaterials propose an opportunity to
fabricate active drug carriers that can release therapeutic agents
through particular triggers including biological stimuli such as pH,
temperature, redox microenvironment or artificial stimuli such as
light, magnetic, etc. In a review by Ganta et al. [54], various stimuliresponsive nano-systems are comprehensively discussed. According to Caldorera-Moore et al. [55], responsive biomaterials can be
categorized into two groups. The first group refers to passive carriers
which respond to external conditions (pH, thermodynamic, ionic
strength, magnetic, and electrical) by physicochemical interactions.
On the other hand, functionalization of materials can be performed

3

to form ligand receptors which interact and act in response to biomarkers or bioanalytes present in a medium or diseased tissue.
3.2. Polymer-based biomaterials
Many polymer-based biomaterials have been widely studied.
Among them, crosslinking hydrophilic polymers or hydrogels appear
as one of the most potentially effective systems for medical applications since they permit the incorporation of functional groups
directly into theirs networks. Additionally, the high water affinity
and swelling property of hydrogels are believed to importantly
contribute to their interesting behaviors towards environmental
stimuli. The working mechanism of such responsiveness relies on

the side chain groups, branches, and crosslinking structures of
polymeric materials. The pH-sensitive hydrogels consisting of
pendant acidic and basic groups (e.g. carboxylic, sulfonic acids,
ammonium salts) can simultaneously accept or release protons
corresponding to medium pH through movement of solutions into
the networks [56] as presented in Fig. 1. Some of the most studied
polymers for this area to be named are poly(acrylic acid) (PAA) [57],
poly(N,N9-diethylaminoethyl meth acrylate) (PDEAEM) [58], poly(methacrylic acid) (PMA) [59], carrageenan, alginate [60] etc. The
pH-sensitive hydrogels have been applied to control drug release
rate in a gentle manner for specific sites such as gastro-intestinal
[61e63], transdermal [64e66]. A recent review by Karimi and coworkers [67] has thoroughly addressed several stimulus-responsive
nano-carriers for controlled drug release. Besides pH sensitivity,
other environmentally sensitive systems have been investigated
[68]. Several polymers possess reversible phase transitions upon
temperature variations owning to the presence of hydrophobic
groups namely methyl, ethyl, and propyl [69]. Different polymers
have been widely studied for these works are poly (N-isopropylacrylamide) [70], poly (N-vinylcaprolactam) [71]. Efforts have
been made to create multi-functional systems for better drug
transporting and targeting [72e74]. Furthermore, hydrogels have
presented great applications for tissue engineering scaffolds which
are discussed in several papers [7,75,76] due to their high density and
structural support while preserving in vivo environment. Another
polymer-based system is emulsified microparticles, so-called
microemulsions. Microemulsions are isotropic, thermodynamically
stable systems of oil, water, and surfactant, frequently in combination with a co-surfactant [77]. The performance of microemulsion as
drug delivery systems is remarkable. Their low surface tension and
small droplet size enhance the absorption and permeation rate
through membranes. Solid dispersion has also been studied as an
effective strategy for drug delivery systems. The process creates
active ingredients dispersed in an inert carrier matrix [78]. The

enhanced dissolution rate of drug by solid dispersion may contribute
to the increased drug solubility due to the reduction of the dispersed
particle size, conversion from crystalline to amorphous state, and
drug wetting improvement. The two most common methods used to
produce solid dispersion are melting and solvent evaporation.
Several polymers that have been tested as carriers for solid dispersion systems, including PEG, polyvinyl pyrrolidone (PVP), cellulose
derivatives, polyacrylates, and polymethacrylates, among many
others [79]. Table 1 lists different lithography-based methods which
could be used to manufacture such polymer-based biomaterials.
3.3. Limitations of current chemical methods and the need of
lithography-based technology
Despite tremendous advantages and achievements of chemical
methods, the clinical utilizations of chemically-engineered nanoand micro-carriers have been limited by the difficulties associating
with uniformity and consistency in terms of controlling specific


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K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

Fig. 1. Diffusion of drug in response to pH variations [166].

Table 1
Lithography-based technology in forming polymer-based biomaterials.
Lithography-based
technology

Polymer-based
biomaterials

Method

Advantages

References

Photolithography

Proteins, cells,
extracellular matrices

Photon upconversion lithography
(PUCL)

[152]

Soft lithography

Emulsified polymeric
systems

Microfluidic devices

Photolithography

Solid dispersion
polymeric systems

PVP solution was dispensed into
lithographically patterned

microcontainers.
Ketoprofen was impregnated in
polymer matrix by using supercritical
carbon dioxide e loading medium.

Providing high resolution in noncontact manner which
prevents contamination.
Less photo-damage by the use of near infrared light and
deeper penetration into tissues.
Large scale pattering.
Systems with better control over size, structure, and
composition.
Scalability, low cost, reproducibility, and high throughput
Higher efficiency when compared to conventional
dispersing methods.

size, shape, chemical components, and functionality [80,81]. For
instance, self-assembling structures such as liposomes, micelles,
emulsions exhibit a dynamic instability, thereby presenting challenges in manipulation of exact size, shape, and drug encapsulation
or dosing [82,83].
The emergence of lithography-based techniques to engineer
micro- and nanocarriers and to produce better controlled system
properties has offered a promising alternative in the field of
biomedicine. One of recent papers in our group has thoroughly
addressed up-to-date applications of advanced 3D technologies to
create well-structured micro- and nano-carriers for controlled drug
delivery system [84].
4. Lithography technology
4.1. Photolithography
Photolithography or optical lithography is defined as a process

using light to transfer patterns from a photomask to a photoresist
(light-sensitive chemical) on a substrate and then selectively
remove unused parts out of the substrate. Photolithography technique is based on a top down approach. Different processing protocols and materials are required for different implementations of
photolithography; however, they largely follow a basic common
procedure as presented in Fig. 2. To prepare for photoresist coating,
a substrate like silicon wafer must be removed of any contaminants

[146]

[171]

Higher precision of drug dosing is obtained together with
better dissolution results.

including solvents stains (methyl, alcohol, acetone, etc.), dust from
atmosphere, operators, and equipment, microorganism, aerosol
particles, etc. on the surface [85,86]. The process requires operation
under cleanroom facilities enclosed in a strictly environmentally
controlled space in terms of airborne particulates, temperature, air
pressure, humidity, vibration, and lighting [87]. For certain cases
especially in biomedical applications, the silicon wafer basically
serves as a solid support on which additional layers of materials are
deposited due to its ideal characteristics namely rigid, flat, low cost,
and smooth [13]. The wafer is coated with a thin layer of photoreactive materials that generally are monomers, oligomers, or
polymers. For patterning biomaterials like proteins and cells, nearinfrared (NIR) light is more preferable than UV since it is less photodamaging and deeper penetration [88]. To this extent, depending
on the nature of photoresists, there are different ranges of radiation
which can be used such as electron beams, ion-beam, and X-ray.
The fundamental principle of photolithography lies in the chemical
alterations of the resist upon light exposure [89]. By shining UV
light through a photomask which consists of non-transparent

patterns printed on a transparent plate, the patterns are transferred onto the photoresist. In the next developing step, the
remaining parts of the photoresist after exposure relied upon
whether positive or negative photoresist is employed which subsequently dissolve exposed and unexposed regions respectively.
Photolithography has established a fundamental foundation for
further development of other advanced methods (see Fig. 3).


K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

5

Fig. 2. Schematic of photolithography [167]. (a) The wafer is cleaned to remove any unwanted contaminants. (b) The photoresist is spin coated onto the wafer. (c) The photomask is
placed above the photoresist. UV light is exposed through the mask. (d) The unexposed part is removed by solvents leaving the desired patterns.

Fig. 3. Schematic process of (a) polymer mold fabrication from a master and (b) UV nanoimprint with the polymer mold. Reprinted from reference [168] with permission from
Elsevier.

4.2. Advanced lithography-based methods
4.2.1. Soft lithography
Despite the fact that photolithography is prevalent in both microelectronics and biomedical fields, there exists certain limitations
restricting it from being suitable for all applications. For example,
the process of photolithography requires expensive facilities
(cleanroom, photomasks fabrication, projecting systems). The
conventional lithography techniques, although being wellestablished in semiconductors industry, encounter noticeable impediments owning to the rigorous processes. Several
manufacturing steps such as cleaning, baking, exposing, which
require the presence of high-temperature, ion-etching, solvents,
often result in degradation of biomaterials [90]. Additionally,
photolithography has neither control over surface chemistry nor
implementations on curved/non-planar surface [91]. Based on the
conventional method of lithography, scientists have developed an

alternative set of micro-fabrication working on “soft-matter”

(organic materials, polymers, complex biochemical) and the
pattern-transfer by molding using elastomeric biomaterials named
as soft lithography [92,93]. The method of soft lithography is
fundamentally based on printing, molding, and embossing and has
been extensively described in many literatures [12,91,94]. Soft
lithography involves techniques of using elastomeric stamps,
molds, and photomasks to fabricate or replicate structures [94].
Some of the most well-studied patterning techniques are microcontact printing (mCP) [95], replica molding (REM) [96], micro- and
nano-transfer molding [97,98], solvent-assisted micromolding
(SAMIM) [99], phase-shifting edge lithography [100], decal transfer
lithography [101], and nanoskiving [102].
4.2.2. Nanoimprint lithography
Nanoimprint lithography is defined as the process of pressureinduced transferring of patterns from a rigid mold to a thermoplastic polymer film heated above its glass transition temperature.
This method alternatively refers as hot embossing. Recent review


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K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

by Traub et al. [103] has extensively discussed the principle of
nanoimprint lithography and its wide applications in different
fields. Essentially, the nanostructured mold is duplicated in a thin
resist film casted on a substrate by applying adequate pressure
[104]. This stage involves heating the resist above its glass transition temperature where it becomes viscous and deformable into
shape. The mold is then removed together with residual resist in
the compressed parts. Since the process is associated with heat and
pressure, it is important to select appropriate resist materials which

have relatively small thermal expansion and pressure shrinkage
coefficients. Bender et al. [105] first introduced a modified nanoimprint lithography operating at room temperature and low pressure, which is based on UV-irradiation and photopolymerization
(Fig. 1). Similarly, the polymer UV-transparent mold (quartz or
silica) is pressed onto the substrate coated with UV-curable resist.
Following exposure, the precursor liquid crosslinks and constructs
stable patterns. Ever since introduction, nanoimprint has made a
significant progress due to its simplicity, efficiency, high
throughput, and low production cost. Moreover, research pertaining to the field includes enhancing resolutions of the patterned
nanostructures [106]. To this extent, Koo et al. [107] investigated
the effects of mold materials on the fabrication process. Their works
showed that toluene diluted poly(dimethylsiloxane) (PDMS) was
capable of homogeneously defining 50 nm resolution patterns on 4
in wafer with single imprint. Other concerns and applications
regarding nanoimprint techniques to fabricate biomaterials have
been addressed in several literatures [108,109].

4.2.3. Nano-molding PRINT particles
The method of Particle Replication In Nonwetting Templates
(PRINT) was first developed by DeSimone et al. in 2004. Ever since,
it has drawn significant attention from scientists due to its ability to
generate monodisperse micro- and nano-carriers with simultaneous control over particle size, shape, composition, and functionalities by employing the advances of soft lithographic molding
technology. The initial effort in the PRINT process is to formulate
particle composition liquid which consists of essential chemotherapeutics or functionalized features. Different particles ranging
from 80 nm to 20 mm, composed of poly(D-lactic acid) (PDLA) and
derivatives [81], PEG hydrogels [110,111], and proteins [112] have
been successfully manufactured. Secondly, the solution is then
placed onto a prepared mold and allowed for solvent evaporation
or polymerization. The stage involves the process to pattern replica
molds with desired size and shape to emboss liquid precursor
compounds. In this regard, the silicon master templates were firstly

constructed by patterning silicon wafer coated with poly(methyl
methacrylate) (PMMA) resist using e-beam lithography. Subsequently, photocurable perfluoropolyether (PFPE) was pooled onto
the templates and chemically cured to form elastomeric PFPE
molds [113]. PFPE appears to be one of the most suitable materials
because of its nonwetting and nonswelling fluorinated surfaces to
both organic and nonorganic solvents [114]. This enables the creation of isolated, harvestable “scum-free” particles without harsh
processes. With this in mind, the final step following mold filling is
to harvest the particles. One physical method uses the sharp end of
a glass side to remove the particles; however, numbers of disadvantages arise that are damaging the mold surface, aerosolizing dry
particles, and inability to scale the process. Hence, a gentler process
was investigated by laminating an adhesive release layer such as
PVP or cyanoacrylate on a flexible or rigid backing PET or glass
slides on the open side of the mold. After that, the mold is peeled
away, leaving the array of free-standing particles. Dissolution of the
adhesive film results in free-flowing particles in solutions [115].
Additional purification steps are performed accordingly such as

dialysis, centrifugation, filtration, and magnetic purification in order to eliminate residual or debris chemicals [113,116].
5. Applications of advanced lithography-based methods for
biomedicine
5.1. Drug delivery systems
5.1.1. PRINT particles
PRINT has offered an advanced lithography-based method to
operate with a wide range of organic materials containing biological elements such as oligonucleotides, proteins, pharmaceuticals,
and synthetic viruses. In a studied by Gratton et al. [113], cellular
internalization, cytotoxicity of monodisperse 1 mm cylindrical
PRINT particles and the effect of surface charge on endocytosis
were investigated using confocal microscopy, flow cytometry, and
transmission election microscopy. Fig. 4 describes the result of
PRINT fabrication process. The particles were readily distributed

into tested cells: HeLa, NIH 3T3, OVCAR-3, MCF-7, and RAW 264.7
with little cytotoxicity obtained. Also, higher endocytosis rate was
observed in particles with positive zeta potential as compared to
negative ones. On-going research in the field focuses on formulating stimuli response targeted nanoparticles [117,118]. All in all,
PRINT e a highly versatile method - has become uniquely suitable
for large scale manufacturing monodisperse organic and nonorganic nanoparticles with precise size, shape, composition, surface properties dedicating to applications in nanomedicine.
5.1.2. Nanoimprint applications
Nanoimprint is suitable for various polymeric materials such as
biomolecules [119,120], block copolymers [121,122] with feature
sizes down to 5 nm and high aspect ratios. In a remarkable study of
Glangchai et al. [8], by employing nanoimprint techniques, they
were able to synthesize enzyme-triggered release nanoparticles of
antibodies (Streptavidin-CY5) and nucleic acids (plasmid DNA)
with well-defined sizes and geometries (square, triangular,
pentagonal). The responsive and biocompatible properties were
obtained through combination of PEG diacrylates (PEGDA) or
dimethacrylates (PEGDMA) polymers and an acrylated, enzymatically degradable peptide Gly-Phe-Gly-Lys-diacrylated (GFLGK-DA).
Additional biocompatible photoinitiator (2-hydroxyl-1-[4-(hydroxyl)phenyl]-2-methyl-1-propanone) was added to trigger photopolymerization when performing UV exposure. Nanoimprinting
was conducted using the Step and Flash Imprint lithography (S-FIL)
method (Fig. 5). After imprinting, the nanoparticles were isolated
by reactive ion etching (RIE), removing residual areas between
particles. And the nanoparticles were collected into poly(vinyl
alcohol) (PVA) solutions. Elucidations and drug release studies
demonstrated the efficiency of nanoimprint to fabricate longcirculating nanocarriers as small as 10 nm with controlled size
and shape which responded to environmental stimuli. Also, the
method proved its mildness for biological agents without the use of
high temperature, high shear, extended UV exposure, and organic
solvents. The presence of available groups to attach specific ligands
on the chemical structures of formulated materials offers great
opportunities for targeted drug delivery and imaging [123].

5.1.3. Microneedles
Transdermal delivery emerges as a potential route of administration since it offers a direct drug application to an affected site,
steadier drug concentration in plasma, and limits systemic exposure by the absence of hepatic first pass metabolism [124]. Yet, the
presence of stratum corneum (SC) as skin barrier functions as the
most significant regulator for entry into the body. SC prevents
entrance of therapeutic agents except for that of lipophilic and low


K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

7

Fig. 4. Results of the PRINT process. Top row, left to right: a) SEM of an etched silicon wafer master template of 3 mm posts having a height of 1.7 mm; b) cured PFPE mold of the
master template shown in A; c) PFPE mold containing PEG particles prior to harvesting; d) harvested and dispersed PEG PRINT particles. Bottom row, left to right: e) SEM of an
etched silicon wafer patterned with approximately 400 billion posts that are 100 nm in diameter and 400 nm tall; f) a cured PFPE mold of the silicon master template shown in E; g)
100 nm PEG particles made using PRINT and transferred to a medical adhesive layer for surface functionalization and subsequent harvesting. Reprinted from reference [169] with
permission from Elsevier.

Fig. 5. Step and Flash Imprint lithography (S-FIL) method: 1. PVA release layer and PEGDA is applied to BARC coated silicon surface. 2. The quartz template is pressed onto PEGDA
and exposed to UV light. 3. The template is removed to reveal particles with thin residual layer. 4. Brief oxygen plasma etch is performed to remove residual layer. 5. Particles are
harvested directly in water or buffer by one-step dissolution of the PVA layer. Reprinted from reference [8] with permission from Elsevier.

weight molecules. Efforts have been made to formulate in situ
topical applications, particularly patches [125], gels, and creams
[126]. Some of the well-studied systems in this field are available in
the market [127]. However, these conventional systems possess
certain disadvantages namely high viscosity, lack of flexibility,
visibility, and inadequate retention on skin which then requires
repetitive dosing and poor patient compliance. For the past decade,
microneedles have provided a straightforward method to directly

administrate therapeutic agents bypassing the SC in a minimallyinvasive manner [128]. The system only needs to pierce pass
10e15 mm nerve-free layer for drug to diffuse through the highly
permeable viable epidermis to capillaries. Unlike regular hypodermic needles, microneedles create micro-dimensional painless
pathways to transport small drug particles, macromolecules,

proteins, and fluid with a high localization, correct-targeting, and
controlled release. The development of microneedles has been
accompanied by the revolution of lithography methods in
biomedical research.
The first attempt to produce microneedles based on photolithography techniques was reported by Henry et al. in 1998 [129]. In
this process, 〈100〉-oriented, prime grade, 450e550 mm thick,
10e15 U-cm silicon wafers supplied by Nova Electronic Materials
Inc. (Richardson, TX) were initially cleaned in a mixture of deionized water, hydrogen peroxide, and ammonium hydroxide at
approximately 80  C for 15 min, and followed by dehydration
baking at 150  C for 10 min. Chromium was deposited onto the
wafers and patterned into 20 Â 20 arrays of 80 mm diameter dots
with 150 mm center-to-center spacing by UV exposure of the


8

K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

photoresists coated on a chromium layer. Through immersing the
wafers to a liquid developer, the exposed photoresists were
removed. Then the chromium exposed during previous photolithography was etched, revealing dot arrays of chromium on the
silicon wafers which were further used as masks for microneedle
fabrication. Solid microneedles were manufactured by deep reactive ion etching (RIE) silicon substrates with 20 standard cm3/min
(sccm) SF6 and 15 sccm O2 at a pressure of 20 Pa and power of
150 W for roughly 250 min [130]. The parts covered with chromium

formed the microneedles. The etching was continued until the
masks completely under-etched and fell off, forming arrays of sharp
silicon spikes. From this early study, microneedles demonstrated
their potential in painlessly piercing into skin without breaking or
disrupting skin nature. Additionally, in vitro results indicated
enhanced calcein permeability by 25000-fold and prolonged
release for 5 h. Microneedles have opened a new perspective for
transdermal delivery.

Despite the fact that silicon possesses comprehensive processing experience, it is considered to be fragile, arguably
biocompatible, and comparably expensive [131]. Later works have
employed metals [132], glass [133], ceramics [134], and biodegradable polymers [135] to fabricate microneedles in different
shapes and sizes for specific applications. Solid microneedles were
later manufactured to possess beveled-tip, chisel-tip, and taperedcone needles as presented in the work of Park et al. [131]. The
fabrications are fundamentally based on conventional photolithographic process, etching, laser cutting, metal electroplating,
electropolishing, and micromolding [136e139]. A review by
McAllister and co-workers [140] has extensively described
different approaches using metals and polymers for transporting
macromolecules and nanoparticles. Generally, microneedles are
classified into solid microneedles including drug-coated microneedles, dissolving microneedles and hollow microneedles (Fig. 6).
Properties of each kind are discussed in Table 2. For instance,

Fig. 6. (a) Solid microneedles, (b) Coated microneedles, (c) Dissolving microneedles, (d) Hollow microneedles. Reprinted from reference [170] with permission from Elsevier.
Table 2
Comparison of different microneedles fabricating approaches [170].
Types of microneedles

Drug loaded

Dipping or spraying drugSolid

Coated
microneedles microneedles formulated solution onto solid
microneedles. Additional use of
[172]
surfactants to facilitate wetting
process and stabilizing agents,
which protect drug from drying and
storage.

Dissolving
Therapeutics are encapsulated in
microneedles formulated polymers which are
able to solidify or polymerize
during micromolding.

Hollow
microneedles

Therapeutics especially in liquid
formulations are entrapped in the
reservoir and injected through the
hollow space of microneedles.

Release mechanism

Limitations

Applications

Drug coated on microneedles

dissolves into tissues upon
insertion and contact with
biofluids.

Limit to drugs with small doses.
Coating solutions should possess
water-solubility, good mechanical
resistance, and pharmaceutical
acceptance.

The polymer microneedles
completely dissolve or degrade
in the skin as responding to
stimuli (temperature, pH,
solvents), and leaving no biowastes after administrations.
The flow of liquid through
microneedles is generated
using a syringe of actuators that
are controlled by CO2 gas
pressure, a spring, a piezoelectric
micropump, a piezoelectric
linear servo motor, a syringe
pump and a micro-gear pump
[193,194].

Some formulations require long
remained time on skin to
sufficiently dissolve. Materials and
fabrication methods should be
carefully tailored for specific

therapeutic agents.
Fluid flow rate in certain cases
might depends on insertion depth,
pressure, needle tip shape, and
spreading factor [195]. Hollow
microneedles require more
advanced fabrication techniques
than previously mentioned ones.

Small molecules: vitamin B,
fluorescein [173]
Macromolecules: insulin
[174], verapamil
hydrochloride and
amlodipine besylate [175],
epigallocatechin-3-gallate
[176], hormone [177],
bovine serum albumin
[178], desmopressin [179]
Vaccines [180]: hepatitis B
surface antigen [181],
influenza virus [182],
human papillomavirus
[183], measles vaccination
[184], inactivated
chikungunya virus [185],
hepatitis C DNA vaccine
[186], herpes simplex virus
[187]
Sulforhodamine [188],

insulin [189],
erythropoietin [190],
human growth hormone
[191],
Hepatis B vaccination [192]
Insulin [196], doxorubicin
[197], phenylephrine [198],
vaccine [199], inactivated
polio vaccine [200]


K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

9

hollow microneedles have been developed as means of delivering
insulin and vaccines by infusion [132]. In fact, hollow microneedles have adapted techniques in MEMS fabrication. Similarly,
photoresist was deposited and patterned onto silicon wafers.
Straight-walled holes were yielded by utilizing Bosch modified
inductive coupled plasma reactive ion etching (ICP-RIE) [141].
Another interesting work by Kim et al. [142] designed a responsive
system to separate microneedles into skin upon contacting the
biofluid, which was triggered by swelling of hydrogels. The polyNisopropylacrylamide (PNIPAAm) hydrogels microparticles prepared by emulsification method were filling into the cavities of the
mold prior to microneedle construction by micromolding polylactic-coglycolic acid (PLGA). The systems were studied in vivo
by inserting microneedles to porcine cadaver skin. Sustained drug
release evaluation was performed in vitro through Franz cell
model. The drug release mechanism was due to the dissimilar
degrees of swelling among hydrogels and needle matrix polymer
causing cracking of microneedles. In vivo study on mouse skin has
also drawn analogous findings that the formulated microneedles

successfully released drug into the skin. Collectively, fabrication of
microneedles for transdermal drug delivery using lithographybased method has been on the edge of development due to the
ability of microneedles to effectively drive drugs into skin in a
controlled and targeted manner together with high patient
compliance and ease of large scale production.

5.1.4. Microfluidic devices to fabricate drug particles
Microfluidic devices offer powerful tools to fabricate monodisperse microparticles in a high throughput manner [143]. The
most common materials used to manufacture microfluidic devices
are (PDMS). Employed in the photolithography fabricating process,
PDMS enables formation of small scale and complex channels in the
devices (Fig. 7). Briefly, the SU-8 photoresist is coated in silicon
wafer and patterned. The resist structures are further used as
negative mold masters to pattern PDMS. The PDMS is poured over
the mold master and cured for 1 h at 70  C. After being peeled off,
the PDMS mold is attached to a glass slide for further serving as
microfluidic devices [144]. In a study by Xu et al. [145], monodisperse biodegradable drug-loaded microparticles were successfully fabricated by microfluidic flow-focusing generators and rapid
solvent evaporation from resulting droplets. The particle size could
be modulated through controlling the flow conditions within the
devices. Drug release studies had shown that particles prepared by
this method exhibited critical reduction in burst release effect and
slower release rate in comparison with conventional emulsion
methods; hence, presenting potential for prolonging drug release.

Fig. 7. Basic microfluidic device fabricating process. Reprinted with permission from
reference [144]. Copyright 2002 American Chemical Society.

Fig. 8. Schematics of bilayer embossing process. The inset shows the top-view of the
skeleton. Reprinted from reference [156] with permission from Elsevier.

10

K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

Other drug delivery system formulated using microfluidic devices
are emulsion [146], microgels [147], chitosan-based nanoparticles
[148], polymeric microcapsules [149], and pH responsive polymer/
porous silicon composites system [150]. Riahi et al. [151] discussed
current expert opinion in microfluidics for advanced drug delivery.
All in all, this effective, simple, and inexpensive fabricated microdevice is predicted to continue to flourish in biomedical research.
5.2. Tissue engineering
Microfabrication techniques have been used to replicate structures with well-controlled microenvironments of individuals, interactions of multiple cell clusters, and with sizes ranging from 0.1
to 10 mm. Thus, microfabrication techniques are viewed as a
potentially effective approach to promote highly-organized scaffolds in tissue engineering. Photolithography has been used to
pattern biomaterials such as proteins, cells, and extracellular
matrices [152]. Soft lithography implements master molds such as
PDMS elastomers to product PLGA scaffolds [153e155]. One study
by Yang et al. [156] developed a biologically benign CO2 assisted 3D
scaffolds using micromolding. Photolithography was first used to
construct desirable patterns of SU-8100 on a substrate following by
dispersion of PDMS resin. The inverse PDMS mold was peeled off
after 2 h curing at 65  C. In the next step, bilayer PLGA skeletons
were precisely patterned by being melt at 220  C and then
embossed with PDMS mold at 0.1e3 MPa as illustrated in Fig. 8. The
bonded scaffolds were created by pressured saturation with CO2 at
0.69 MPa and low temperature for 1 h. Cell culture study indicated
the cytocompatibility of scaffolds. This work contributed a powerful, solvent-free, and low cost method to engineer well-defined

Fig. 9. Cross-sectional schematic of the cantilever/polymer structure with the various

dimensions. Reprinted from reference [163] with the permission of AIP Publishing.

structure scaffolds. However, possessing a common problem in
tissue engineering, micro-fabricated tissue scaffolds have a limited
control and ability to create effective microvascular systems within
the scaffold structure [157].
The merger of microfabrication and hydrogels have indeed
proposed great feasibility to overcome current limitations and open
new functional applications in tissue engineering [55]. A review by
Khademhosseinia and Langer [158] has broadly discussed perspectives of various hydrogels synthetic approaches especially
microfabrication as well as its applications in tissue engineering.
For instance, shape-controlled cell-laden microgels fabricated by
micromolding photocrosslinkable hydrogels are able to be seeded
with diverse cell types and assembled to form 3D structures in
highly-governed structures and cell interactions [159]. Additionally, the microengineered hydrogels are of great benefits for their
surface modifications. Through covalently immobilized cell integrin ligand (ephrin-A1 and Arg-Gly-Asp-Ser), a vascular development factor, on PEG hydrogels surface using photopolymerization,
the adhesion of endothelial cells is improved together with better
control over angiogenic functions [160]. A remarkable research of
Yeh et al. [161] also used a micromolding technique to entrap
mammalian cells in 3D microscale photocrosslinked harvestable
hydrogels of controlled size and shapes.
5.3. Biosensors
Photolithography has been employed to micropattern hydrogels
for biological sensors due to the ability of hydrogels to capture a
wide range of biological sensitive factors. The 3D structures of
microgels provide greater density of receptor molecules, hence
improving sensing capacity when compared to 2D systems [162].
For example, Bashir et al. [163] patterned an environmentallyresponsive antibody-laden hydrogel onto a MEMS microcantilever (Fig. 9). When absorbing targeted proteins, this sensitive
system swelled and deflected the MEMS cantilever. The degree of
deflection was then calculated by refractive optics. Investigations

on pH and thermal sensitive hydrogels were carried out and
resulted in similar findings [164]. In another study, PEG hydrogels
were developed as biotin-streptavidin biosensors by combining
methods of surface graft polymerization and photolithography
[165]. Modifications of protein-repellent PEG hydrogels surface
were made by grafting poly(acrylic acid) (PAA) as monomers and

Fig. 10. Micropatterning of PAA on the PEG hydrogel surface. Optical image of 100 mm diameter circles of PAA on PEG hydrogel surface. Reprinted from reference [165] with
permission from Elsevier.


K.T.M. Tran, T.D. Nguyen / Journal of Science: Advanced Materials and Devices 2 (2017) 1e14

benzophenone as surface initiator via photoinduced surface polymerization. A photolithographic process transformed the graft
polymerization surface into well-defined, pH-responsive PAA
micropatterns deposited on PEG hydrogels (Fig. 10). The PAA
micropatterns further presented their potential as biosensors
through successful molecular recognition and binding with biotin
and streptavidin.
6. Conclusion
With the emergence of lithography in biomedical research,
several novel sets of techniques have been utilized to manufacture
biomaterials with desired chemical, physical, and biological features. Based on photolithography techniques, scientists have been
able to develop more advanced fabrication methods which are
more precise, suitable to different biomaterials and at large scale
production. These include but are not limited to soft lithography,
micromolding, nano imprint lithography, and nano-molding PRINT
particles. The fact that micro- and nano-fabrications are applicable
to manufacture a variety of biomaterials with a high throughput
and low-production cost presents promising opportunity to rapidly

bring biomaterials into clinical studies and applications. These
methods overcome some limitations of the chemically prepared
formulation approaches. Nevertheless, future research is expected
to focus on combining the advantages of the two approaches for
maximal treatment efficacy.
Conflict of interest
The authors confirm that this article content has no conflicts of
interest.
Acknowledgments
We thank Albert Miller and Atta Henoun for proof-reading the
manuscript. We thank Academic Plan program at UConn for support on our work.
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