ArticlePDF AvailableLiterature Review

3D printing in Ophthalmology: From medical implants to personalised medicine

Authors:

Abstract

3D printing was invented thirty years ago. However, its application in healthcare became prominent only in recent years to provide solutions for drug delivery and clinical challenges, and is constantly evolving. This cost-efficient technique utilises biocompatible materials and is used to develop model implants to provide a greater understanding of human anatomy and diseases, and can be used for organ transplants, surgical planning and for the manufacturing of advanced drug delivery systems. In addition, 3D printed medical devices and implants can be customised for each patient to provide a more tailored treatment approach. The advantages and applications of 3D printing can be used to treat patients with different eye conditions, with advances in 3D bioprinting offering novel therapy applications in ophthalmology. The purpose of this review paper is to provide an in-depth understanding of the applications and advantages of 3D printing in treating different ocular conditions in the cornea, glaucoma, retina, lids and orbits.
International Journal of Pharmaceutics 625 (2022) 122094
Available online 9 August 2022
0378-5173/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Review
3D printing in Ophthalmology: From medical implants to
personalised medicine
Greymi Tan
a
,
1
, Nicole Ioannou
a
,
1
, Essyrose Mathew
c
, Aristides D. Tagalakis
b
,
Dimitrios A. Lamprou
c
,
*
, Cynthia Yu-Wai-Man
a
,
*
a
Faculty of Life Sciences & Medicine, Kings College London, London, SE1 7EH, UK
b
Department of Biology, Edge Hill University, Ormskirk, L39 4QP, UK
c
School of Pharmacy, Queens University Belfast, Belfast, BT9 7BL, UK
ARTICLE INFO
Keywords:
3D printing
Ophthalmology
Implants
Drug delivery
Personalised medicine
ABSTRACT
3D printing was invented thirty years ago. However, its application in healthcare became prominent only in
recent years to provide solutions for drug delivery and clinical challenges, and is constantly evolving. This cost-
efcient technique utilises biocompatible materials and is used to develop model implants to provide a greater
understanding of human anatomy and diseases, and can be used for organ transplants, surgical planning and for
the manufacturing of advanced drug delivery systems. In addition, 3D printed medical devices and implants can
be customised for each patient to provide a more tailored treatment approach. The advantages and applications
of 3D printing can be used to treat patients with different eye conditions, with advances in 3D bioprinting of-
fering novel therapy applications in ophthalmology. The purpose of this review paper is to provide an in-depth
understanding of the applications and advantages of 3D printing in treating different ocular conditions in the
cornea, glaucoma, retina, lids and orbits.
1. Introduction
The rst three-dimensional (3D) printer was invented in the 1980s
by Charles W. Hull using the stereolithography (SLA) technique. 3D
printing (3DP) was then described as a process of layering materials on
top of each other to create certain objects. Hence, 3DP is also part of the
additive manufacturing (AM) technologies (Schubert et al., 2014). The
stereolithography printing technique was introduced to biomedical ap-
plications a few decades ago, which inspired new printing techniques to
emerge and had been constantly improved upon to suit different unmet
clinical needs. This new range of techniques is identied based on its
layering methods and the specic materials that could be used during
the printing process (Fan et al., 2020). The cost of AM is very expensive
when it comes to large scale production (Fan et al., 2020). However, the
3DP technology is highly cost-effective in smaller scale production.
Since the 3DP technology was introduced to the healthcare industry
for implantable modelling, it has improved our understanding of various
disease mechanisms and human anatomy (Aimar et al., 2019). The
introduction of 3D bioprinting using bioinks by combining both
biological materials and cells, was marked as an evolutionary step of
3DP for biomedical applications. Most importantly, it has opened new
doors to develop novel therapeutic approaches. 3D bioprinting is the
deposition of compatible biomaterial but also involves the incorporation
of cells or reaction with cells after the fabrication is completed
(Derakhshanfar et al., 2018). The applications of 3D bioprinting in the
medical world include but are not limited to organ transplantation (Ji
and Guvendiren, 2017; Charbe et al., 2017), surgical planning (Zein
et al., 2013; Qiu et al., 2018), medical education (Giannopoulos et al.,
2016), and drug delivery (Goyanes et al., 2016; Konta et al., 2017).
Bioinks used for 3DP are mostly composed of cells and occasionally
matrix constituents required to produce tissue-like constructs (Whitford
and Hoying, 2016). However, a single bioink cannot result in a func-
tioning tissue-like structure (Hospodiuk et al., 2017). Novel multicom-
ponent bioinks can combine the favourable characteristics of the
individual biomaterials to provide a solution (Zhang and Kha-
demhosseini, 2017). Multicomponent bioinks are characterised by one
or more types of biomaterials, cells and the addition of different mate-
rials or biomolecules. There are several categories of multicomponent
* Corresponding authors.
E-mail addresses: d.lamprou@qub.ac.uk (D.A. Lamprou), cynthia.yu-wai-man@kcl.ac.uk (C. Yu-Wai-Man).
1
Authors contributed equally to the work.
Contents lists available at ScienceDirect
International Journal of Pharmaceutics
journal homepage: www.elsevier.com/locate/ijpharm
https://doi.org/10.1016/j.ijpharm.2022.122094
Received 12 June 2022; Received in revised form 26 July 2022; Accepted 4 August 2022
International Journal of Pharmaceutics 625 (2022) 122094
2
bioinks that can be used to build different tissue structures (Table 1).
The different categories are bioinks composed of natural materials,
natural and synthetic materials, synthetic materials, and hydrogels and
particles (Ashammakhi et al., 2019).
One important feature of AM is to provide greater exibility for
specic-patient customisation (Fan et al., 2020). This advantage is re-
ected in the process of creating a 3DP medical device. It starts by the
image acquisition of the patients target organ via a computerised to-
mography (CT) or magnetic resonance imaging (MRI) scan. These im-
ages are then processed to segment the target tissue and to generate a 3D
model in a computer-aided design (CAD) software (Fig. 1). The 3D
model is then optimised for the preparation of the nal printing in a 3D
printer (Aimar et al., 2019). Printing parameters are especially impor-
tant, including printing speed, printing nozzle size, material, and the
temperature that could affect the cell viability, the materials used, the
active pharmaceutical ingredient (API), and the printability of the de-
signs (Derakhshanfar et al., 2018). The careful selection of each printing
parameter that goes into the printing process can affect the quality and
biocompatibility of the end products. Therefore, the benet of creating a
treatment plan tailored to each patient by using AM is particularly
preferred in the production of ocular, dental, and orthopaedic devices.
The potential applications of 3DP can signicantly change the cur-
rent and future prospects of treating patients with various eye disorders.
The invention of 3DP cornea can help solve the severe shortage of donor
corneas (Zhang et al., 2019). In addition, the AM technology can provide
a better anatomical match since it possesses the ability to customise a
design according to each patients needs. Many ophthalmic implants
have been manufactured using the traditional methods, such as high-
speed multi-axis computer numerical control (CNC) machining and
laser beam machining (LBM) types of subtractive manufacturing tech-
niques via casting and forging (Davis et al., 2022). They usually result in
inexible mechanical properties and untted anatomy for each patient.
The AM technology is able to craft a product with rened physical
characteristics preferred by users (Fan et al., 2020). It also allows us to
choose biocompatible materials and to easily change the printing tech-
niques to meet the various requirements of clinicians and patients.
There are some features that 3DP implants possess that traditional
fabrication lacks. For instance, 3DP tracheobronchial stent reserves self-
expandable ability to help patients with a collapsed bronchus to breathe
efciently (Zopf et al., 2014). The AM technology can also accurately
reassemble the anatomical defects in patients with fetal craniofacial
anomalies (VanKoevering et al., 2015). In ophthalmology, 3DP can be
benecial by replacing the medical treatment by an efcient 3DP drug
delivery system. The exibility and customisation of the AM technology
can also produce patient-specic glaucoma and cataract implants with
carefully selected biomaterials.
Although this approach is still facing many challenges when
choosing biocompatible materials and their printability under different
3DP techniques, the future of 3DP can benet many patients who suffer
from complications after ophthalmic surgeries and from the side effects
of medical treatments. This review paper discusses the applications of
the advanced AM technology in different elds of ophthalmology and
provides an insight of the advantages that 3DP can offer. This compre-
hensive review of 3DP in eye care is also written in order to inspire many
others who seek to utilise the AM technology in their elds of interest.
2. Cornea and external eye disease
The cornea is the transparent, outermost layer of the eye that is
responsible for transmitting and refracting light. Corneal blindness due
to bacterial infections affects millions of people worldwide. The corneal
limbus contains the epithelial stem cells that are self-renewing (Sun and
Lavker, 2004). The patients with severely damaged limbal tissues usu-
ally need corneal transplantation to regain the self-renewing epithelium.
The traditional transplantation can also help with the replacement of the
damaged corneal stroma that is usually accompanied when the limbus is
injured. However, the transplanted corneas cannot self-renew sustain-
ably and there is a shortage of corneal donors. There is thus an
increasing clinical need for a better alternative to corneal donors.
2.1. Corneal tissue bioprinting
It is feasible to use biomaterials combined with human proteins to
create 3D bioprints for corneal tissues (Table 2). The reconstruction of
corneal tissues usually requires careful selection of biocompatible ma-
terials to be used in in vitro settings. The 3D bioprinting of a stromal
structure containing human adipose tissue derived stem cells (hASCs)
was able to replicate the characteristics of native corneal stroma with
high cell survival rates (Sorkio et al., 2018). Human embryonic stem
cell-derived limbal epithelial stem cells used in a separate bioprinting
also resembled the structure and biological functions of the corneal
epithelium. The interaction of the 3DP stroma containing hASCs with a
porcine cornea also showed its preliminary biocompatibility to integrate
with the host tissue. The laser-assisted bioprinting (LaBP) technology is
a powerful printing technique that can generate high-resolution medical
devices with the exibility to virtually correspond with any type of stem
cells. Most importantly, the bioprints using these stem cells in LaBP do
not affect their biological characteristics and functional properties.
It is important that these articial corneas maintain the symmetric
curved shape and the distinct arrangement of collagen lamellae that the
native cornea possesses. In the study by Li et al., the plastic contact lens
mould was used to form the curved surface of the cornea where corneal
epithelial cells were introduced (Li et al., 2003). In 2018, Isaacson et al.
developed 3D bioprinted corneas using pneumatic 3D extrusion bio-
printing (Fig. 2) (Isaacson et al., 2018). Topographic data from adult
human cornea were used to construct the 3D models. In this study, they
tested different combinations of low viscosity bioinks, such as collagen
and alginate. The results showed that models printed with collagen-1
bioink and incorporated with alginate, had enhanced mechanical sta-
bility. After cell incorporation, high viability of corneal keratocytes was
also observed after printing and it remained high after seven days.
Hence, the conservation of high viability keratocytes indicates that
composite bioinks of collagen and alginate can be used for 3DP corneas.
As aforementioned, the cornea has a distinct organisation of collagen
brils that provides a transparent layer required for refraction and
vision. This lattice pattern of collagen in the corneal stroma affects the
transparency (Meek and Knupp, 2015). Despite novel techniques to
replicate corneal structures, including magnetism or electrospinning,
Table 1
Types of bioinks and biomaterials for the manufacturing of implants.
Types of Bioinks Biomaterials
Bioink composed of natural
biomaterials
Alginate with gelatin/brin
Silk broin with gelatin
Agarose with collagen
Chitosan with gelatin
Cellulose with alginate
Hyaluronan with cellulose
Bioink composed of natural and
synthetic biomaterials
Gelatin combined with Methacryloyl
(GelMa)
Bioink composed of synthetic
biomaterials
Poly(ethylene glycol) diacrylate (PEGDA)
Poly(ethylene glycol) methacrylate
(PEGMA)
PEGDA with alginate
Bioink composed of hydrogels and
particles
PLGA-PEG with cell-laden carboxymethyl
cellulose (CMC)
Silicates (Lithium sodium magnesium
silicate) with GelMa
Hydroxyapatite (HAp) with GelMa/
Gelatin
Tricalcium phosphate (TCP) with
alginate
Bioactive glass (BaG) with silk broin
Carbon nanomaterials with PLGA/
GelMA
G. Tan et al.
International Journal of Pharmaceutics 625 (2022) 122094
3
the results show low transparency. 3DP technology can be used to create
shear-induced bres. Since collagen bres are different from collagen
brils and can even affect corneal keratocytes, thin collagen brils
derived from decellularised corneal tissues can be used (Muthusu-
bramaniam et al., 2012; Kim et al., 2019). Kim et al. investigated the
effects of applying shear stress in a controlled manner while using ate-
locollagen brils instead of collagen bres (Kim et al., 2019). By
applying varying shear stresses, the authors observed different shear-
induced collagen brils and cellular behaviours. More specically,
shear stress can be induced by changing the viscosity of the bioink, the
ow rate, and the inner diameter of the nozzle. In addition, shear stress
can also inuence cellular processes, such as apoptosis, during the
printing process. The study induced shear stress by using three different
nozzle diameters on differentiated keratocytes. Cellular morphologies
were observed 28 days after printing. The results showed that the groups
with the highest shear pressure, namely 25G and 30G, demonstrated
higher expression levels of keratocytes. However, the 30G group also
demonstrated some corneal wounding. Samples of the 25G group were
cultured in vitro and in vivo for 28 days. Aligned cells, activated kera-
tocytes, and increased amount of secreted type-I collagen were observed
in the 25G group. Therefore, shear stress through 3DP, can be applied to
correctly orientate collagen brils to mimic the structure of the native
human cornea (Kim et al., 2019).
Contact lenses were invented for the purposes of optical correction in
the 1800 s (Key, 2007). The advent of hydrogel soft lenses was a sig-
nicant development in the development of contact lenses. The evolu-
tion of contact lenses progressed while the manufacturers were seeking
biocompatible materials that were oxygen permeable and that had
robust mechanical properties. The manufacturing process for contact
Fig. 1. 3D printing and bioprinting process.
Table 2
Studies of 3D bioprinting in ophthalmology.
Tissues Studies 3D printing techniques
Cornea Corneal tissue bioprinting Laser-assisted bioprinting/
pneumatic 3D extrusion
bioprinting
Contact lenses Digital light printing
Drug releasing patches Hydrogel-based bioink
Glaucoma Drug-eluting implants, e.g.
contact lenses
Fusion deposition modelling and
hot melt extrusion
Minimally invasive
glaucoma surgery (MIGS)
devices
Projection micro stereolithography
Retina Macular buckle CAD software 3D printing
Retinal model Inkjet bioprint
Orbit Orbital implants Computer-simulated rapid
prototyping (RP) models
Lids Adjustable eyelid crutches 3D printing
Drug-loaded punctal plugs Digital light processing (DLP) 3D
printing
Fig. 2. Forms of 3D bioprinting used in ophthalmic applications.
G. Tan et al.
International Journal of Pharmaceutics 625 (2022) 122094
4
lenses is still challenging with many steps involved and limited exi-
bility for design. 3DP can be utilised to produce many different types of
contact lenses, including the smart contact lenses that can detect and
control eye diseases. Digital light printing (DLP) is usually preferred for
light-curing-based polymerisation 3DP because it can print at a much
higher resolution, compared to the performance of the fused deposition
modelling (FDM) (Bandari et al., 2021). Asiga DentaClear Resin, a
widely used resin for the dental industry, can be used to produce
corrective contact lenses via the DLP printing (Alam et al., 2021). The
DLP 3D-printed contact lenses added with nanopatterns via the direct
laser interference patterning (DLIP) can generate smart contact lenses.
These smart contact lenses can help clinicians to monitor the changes in
patients eye health. The 3DP contact lenses with a thin polyvinyl
chloride (PVC) plastic lm can achieve light transmission to about 90%,
although it would be interesting to see the comparison of their me-
chanical, physical, and chemical characteristics between the novel 3DP
contact lenses and the traditional contact lenses. AM also grants the
freedom of generating customised contact lenses tailored to patientseye
structures and conditions.
2.2. Drug delivery
3D printed drug patches with hydrogel-based formulations can also
help release the drug efciently in the eye, such as the conjunctiva,
without causing any visual impairment or uncomfortable blinking
(Table 2). Tagami et al. proposed lyophilised ophthalmic patches
capable of producing novel dosages, that could be customised to patients
in hospitals (Tagami et al., 2022). The drug releasing patches contained
the antibiotic drug levooxacin. The 3DP drug releasing patch was
printed using a hydrogel-based bioink containing hydroxypropyl
methylcellulose (HPMC), mannitol, xylitol, and the drug. The prepara-
tion of the formulation underwent a freeze-dried process. Different
concentrations of HPMC, mannitol, and xylitol were also tested and
compared. The composition of biomaterials determined the viscosity
property of the bioink, which in turn could affect the printability of the
patches.
The physical properties, water uptake, antimicrobial activity of the
drug, and the drug release ability were also measured for these lyophi-
lised ophthalmic patches. The amounts of mannitol and xylitol used in
the composition greatly affected the viscosity of the bioink. Among the
two alcohol sugars, xylitol was also highly water soluble, therefore,
xylitol-based formulations possessed a rapid water absorption capa-
bility. In addition, these patches combined with levooxacin were able
to effectively ght against the presence of bacteria in the in vitro assays.
Most importantly, the patches can carry different active pharmaceutical
ingredients, and can be tailored to release various dosages according to
the patients needs. These eye patches can also be designed to deliver
other drug formulations, including eye drops for patients undergoing
cataract surgery (Grob et al., 2014) and mini-tablets for treating the
inferior conjunctival fornix (Moosa et al., 20142014). The chemical and
physical characteristics of the materials used in the drug release patch
can help construct an ophthalmic patch customised to each patient. The
biocompatible drug-releasing patch can help eliminate the need for re-
petitive administration of eye drops in patients after glaucoma and
cataract surgeries.
3. Glaucoma
Glaucoma is the leading cause of irreversible blindness worldwide,
currently affecting 76 million people and its prevalence is estimated to
increase to 112 million by 2040 (Tham et al., 2014). Glaucoma is an eye
condition where the optic nerve is damaged by the pressure of the uid
inside the eye, and treatment involves reducing the intraocular pressure
(IOP) using medications, laser or surgery (Sanghani et al., 2021; Fer-
nando et al., 2018). The prevention of further progression of glaucoma
aims to reduce the IOP level by decreasing production or increasing the
drainage of aqueous humour out of the eye.
3.1. Drug-eluting implants
A common treatment for glaucoma requires daily administration of
anti-glaucoma eye drops to decrease the IOP. Drug-eluting implants
represent an alternative treatment introduced for glaucoma patients
who experience non-adherence to anti-glaucoma medications (Table 2).
There are promising ocular implants embedded with efcient drug de-
livery systems for the treatment of glaucoma. The drug-eluting implants
should be biocompatible and tolerated for use in patients. Current
conventional drug implants on the market have limitations in terms of a
short period of drug release and active pharmaceutical ingredient
loading. These implantable devices can deliver drugs to the whole body
through the blood system, which will lead to systemic side effects. On
the other hand, 3DP possesses a exible capacity to customise ocular
devices with high precision (Mohamdeen et al., 2021 Dec 20). The
contact lenses designed by Mohamdeen et al. delivered the β-blocker
timolol maleate for seven days at a sustainable rate. These implantable
contact lenses were made with the combination of fusion deposition
modelling and hot-melt extrusion (HME) technologies (Fig. 2). The
combination of ethylene vinyl acetate (EVA)/poly(lactic acid) (PLA)/
timolol maleate (TML) at a ratio of 84:15:1 (wt:wt:wt) showed a great
physical blending with desirable thermal durability. The authors also
pointed out the optimal printing parameters, namely low print speed
and small nozzle diameter, in order to achieve high resolution and a
smooth surface (Mohamdeen et al., 2021 Dec 20). However, the sus-
tainability of drug release by this drug-eluting implant needs further
improvement due to the slow diffusion of the polymer mixture.
3.2. Minimally invasive glaucoma surgery (MIGS) devices
Another 3DP technique that has been used in developing therapeutic
devices for glaucoma is called projection micro stereolithography
(PuSL), which combines the benets of both DLP and SLA technologies
(Table 2). Many MIGS devices have been developed in the last decade to
increase drainage of aqueous humour from the eyes of glaucoma pa-
tients. Currently, there are commercially available devices, such as
iStent, Hydrus and XEN, and each of these devices drains aqueous hu-
mour through a different pathway (Pillunat et al., 2017). These mini-
mally invasive implants are chosen based on the specic patients
conditions. However, they all share the same limitation of short-term
efcacy due to brotic encapsulation (Siewert et al., 2017).
There are also challenges during the surgical procedure for mini-
mally invasive devices due to the requirement of high precision. AM can
be used to design a personalised instrument for surgeons to improve the
surgical procedure. 3DP technology allows great exibility to produce a
complicated surgical instrument while ensuring its functionality. A 3DP
cable-driven steerable instrument for minimally invasive surgery can be
easily assembled and handled with one hand (Culmone et al., 2021). The
design enables ergonomic handgrip, exible steering control, and high
efciency when holding tissues. The characteristics of the instrument
can help surgeons to comfortably carry out the surgery without limiting
their wrist motions. The systems manufactured by AM allow custom-
isation for different patients and surgeons by modifying the gripper
handle. In addition, 3DP surgical instruments can be easily adapted to
other elds of minimally invasive surgery.
Glaucoma management requires close monitoring of the drainage of
aqueous humour in the eye so that clinicians can manage the IOP level.
Physicians can take the advantage of 3D modelling of the anterior
chamber to assess the mechanism of aqueous humour drainage and to
understand the physiology tailored to each glaucoma patient. A 3D
printed anterior chamber can help achieve the simulation of the aqueous
humour outow (Wang et al., 2016). The validation of this device shows
the velocity, pressure, and distribution of the uid outow. It can further
help clinicians to understand the IOP changes in glaucoma patients to
G. Tan et al.
International Journal of Pharmaceutics 625 (2022) 122094
5
prevent the progression of visual eld loss and to design the most
appropriate treatment plan.
4. Retina
The retina is a complex tissue made of different cellular layers, that
detects and converts light signals into electrical signals, which are then
transmitted to the brain. Photoreceptors, known as rods and cones, are
responsible for the phototransduction. The retinal pigment epithelium
(RPE) is a monolayer found between the retina and the choroid. The RPE
provides growth factors and plays an important role in nutrient trans-
port and phagocytosis of the photoreceptors (Chiba, 2014). Any damage
to the retinal layers can lead to diseases, such as age-related macular
degeneration (AMD) and retinitis pigmentosa (RP). These diseases are
caused by photoreceptor deterioration that leads to RPE atrophy.
Therefore, retinal regeneration approaches can be used to treat the
affected eye. It is critical to maintain the retinal cell and layer organi-
sation to achieve normal function. Scaffold approaches were originally
used as a solution; however, they did not resemble the functions of the
human retina. 3DP can be used to generate the complexity of the retina
that is crucial for its function.
The 3DP technology can be used to create customised devices that
are tailored to t patients needs. With the help of CT technology, the
patients eye geometry can be captured (Chiba, 2014) and are then used
to create a 3D model using a CAD software (Fig. 1). The 3D model can be
used to determine the characteristics of the patient-tailored medical
device. Pappas et al. have demonstrated the use of CT images and 3DP
for developing a customised macular buckle in a patient with severe
myopia (Pappas et al., 2020) (Table 2). The macular buckle is designed
based on the patients eye by using biocompatible materials. The unique
design will make it easier for ophthalmic surgeons to deploy the macular
buckle and to avoid further manipulations before, during and after
implantation.
Shi et al. also reported the creation of functioning RPE and retinal
photoreceptors (Y79) using 3DP. Human retinal pigment epithelia
(ARPE-19) cells were precisely bioprinted on an ultrathin membrane
that represents the Bruchs membrane. The Bruchs membrane is a thin
tissue layer between the retina and the choroid, where RPE cells attach
themselves. Successful formation of an intact monolayer was observed
after the proliferation of ARPE-19 cells. Hence, the ARPE-19 seeded on
the ultrathin membrane represented the Bruchs membrane and RPE.
Photoreceptor (Y79) bioink was printed on the monolayer. The bio-
printed retinas were then placed in culture and no cell viability was
compromised. Using scanning electron microscopy (SEM), the bioink
was shown to be porous, which forms a suitable environment for the
proliferation of photoreceptors (Shi et al., 2017).
Furthermore, Masaeli et al. reported the development of a functional
retinal model using an inkjet bioprinting approach. They rst developed
a Bruchs membrane using gelatin methacryloyl (GelMA) thin layer, to
mimic the microenvironment of the retina. RPE cells were then bio-
printed onto the Bruchs membrane. They demonstrated that the RPE
cells proteins were similar to that of the RPE layer in vivo. Moreover,
isolated and differentiated photoreceptors from pig eyes were deposited
onto the RPE monolayer and hence mimicking the different cellular
layers of the retina. Three days after bioprinting, the presence of
correctly positioned photoreceptors was conrmed. Masaeli et al. also
reported for the rst time that both bioprinted RPE and photoreceptors
expressed essential transcription factors, validating that functional
retinal bioprinted constructs could be achieved for clinical applications
(Masaeli et al., 2020).
5. Lids and orbit
Orbital fractures occur when the bones surrounding the orbit buckle
or break due to blunt force trauma. Despite novel treatment methods
and techniques, the restoration of the orbital wall is challenging as any
implant mispositioning can lead to enophthalmos or complications in
visual acuity. The intricate concave and convex 3D structure of the orbit
remains a challenge for craniofacial surgeons. In addition, patients have
orbits of different sizes and shapes. Given that the slightest change in
orbital volume can lead to enophthalmos, which is the posterior
displacement of the eye, it is critical to precisely restore intraorbital
volume for a successful orbital wall reconstruction. Oh et al. designed
titanium-Medpor mesh implants by manipulating CT images and using
them in computer-simulated rapid prototyping (RP) models (Table 2)
(Oh et al., 2016). In this study, 104 patients with one-sided blowout
orbital fractures were included. Using the preoperative RP model that
was produced, the intact side was mirrored and superimposed onto the
fractured side to help produce the implants. After successful insertion of
the implants into the orbital wall, postoperative CT images were taken
for evaluation (Fig. 1). The volumes of both intact and injured orbits
were measured pre- and postoperatively, and the results showed no
signicant difference in the orbital volumes. Furthermore, there were no
reports of enophthalmos or any other complications in patients. Hence,
novel computerised techniques like rapid prototyping modelling can
provide solutions to overcome the limitations of reconstructing the
orbital wall. Using the RP models, the implants can be moulded into
individualised patient designs, resulting into successful and faster sur-
gical operations (Oh et al., 2016).
Blepharoptosis is a condition that can lead to severe vision impair-
ment. Surgery is the usual approach for treatment. However, blephar-
optosis can cause advanced myopathies, such as chronic progressive
external ophthalmoplegia (CPEO), that can be difcult to treat due to
the recurrence even after multiple surgeries. Crutches are placed onto
the patients glasses to lift the eyelid. Even though eyelid crutches can be
used as an alternative treatment, they lack malleability and patient-
specic designs are expensive. Sun et al. used their patients who suf-
fered from CPEO-related blepharoptosis, to develop low-cost, universal
and easily adjustable 3DP eyelid crutches (Table 2). The patients had
several eyelid surgeries but there was recurrence of the ptosis. More-
over, the patients had developed keratopathy and corneal thinning due
to the lack of blinking and weakness of the orbicularis. In order to design
3DP crutches for patients, the marginal reex distance, eyelid and
glasses frame dimensions were measured. After ve months, they re-
ported that the patients had improvements in vision and could achieve
eye closure. 3DP can thus be used to develop inexpensive and universal
eyelid crutches to improve the quality of life of patients (Sun et al.,
2019).
Xu et al. also used digital light processing (DLP) 3DP to develop
dexamethasone-loaded punctal plugs (Xu et al., 2021). The punctal
plugs were manufactured using polyethylene glycol diacrylate (PEGDA)
and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating
network (semi-IPN). The authors demonstrated that punctal plugs made
with 20% w/w PEG 400 and 80% w/w PEGDA achieved sustained
release of dexamethasone for up to 7 days, while punctal plugs made
with 100% PEGDA showed prolonged release for over 21 days (Xu et al.,
2021). DLP 3D printing thus represents a potential manufacturing
platform for personalised sustained-release drug-loaded punctal plugs in
the eye.
6. Regulatory considerations
Despite the favourable prospects of the 3DP applications in the
medical eld, the legal regulations of 3DP technology for pharmaceu-
tical products are not complete. Although the Food and Drug Adminis-
tration (FDA) approved the 3DP drug Spritam in 2015, the application
guidance for 3DP was not released until 2017 (Tsui et al., 2022). The
FDA also has no publication of ofcial regulations for 3DP technology
(Mohammed et al., 2021). It is an impediment for the implementation of
3DP medical devices and slows the clinical translation of the 3DP
products to patients. Therefore, it is impossible to dene responsibility
for litigation when it comes to the safety issues of 3DP products.
G. Tan et al.
International Journal of Pharmaceutics 625 (2022) 122094
6
However, the regulatory organisations have just initiated programs
and allocated teams to begin drafting the standard regulations for 3DP
(Mohammed et al., 2021). Following the initial efforts of the FDA in
2019, the European Medicines Agency (EMA), the Medicines and
Healthcare Products Regulatory Agency (MHRA), Health Canada,
Therapeutic Goods Administration (TGA, Australia) and other national
regulatory agencies have started to discuss the legislation of the inno-
vating 3DP applications in medicine (Tsui et al., 2022). As of 2022, the
discussion is still ongoing to provide a full regulatory guidance ensuring
the safety and effectiveness of 3DP medical devices. At present, the
manufacturing process and quality assurance of 3DP medical products
must meet the requirements of the applicable EU legislation, such as the
Medical Devices Directive 93/42/EEC (Conformity assessment proced-
ures for 3D printing and 3D printed products to be used in a medical
context for COVID-19. Docsroom - European Commission. https://ec.
europa.eu/docsroom/documents/40562. Published April 1, 2020).
7. Expert opinion & future directions
The invention of 3DP and its adaptation to the healthcare industry
has inspired new therapies for different types of ophthalmic diseases. It
has enabled us to reconstruct the stroma of the human cornea by
incorporating human stem cells. As an alternative to corneal trans-
plantation, the 3DP cornea incorporating the patients stem cells can
avoid the immune rejection that usually occurs in transplant recipients
(Tsui et al., 2022). The selection of optimal biomaterials and bioinks
determines the printability of 3DP implants. For example, a bioink
consisting of alginate and collagen was feasible and generated viable
3DP corneas (Isaacson et al., 2018). Changing the physical properties of
the bioink, such as its viscosity, induced the shear stress to mimic what
the natural human cornea experiences (Kim et al., 2019) and affected
the printability of the end product (Tagami et al., 2022).
Apart from corneal transplantation, the use of 3D bioprinting on
retinal regeneration is also under investigation. The retina is one of the
most complex human tissues in the eye and can potentially be recon-
structed by 3D bioprinting. The rat retinal cells could be successfully 3D
printed without compromising their cell viability and growth using
inkjet printing (Lorber et al., 2014). In addition, the effect of neurite
outgrowth on retinal ganglion cells contributed by the glial cells was
also preserved. This established the potential of using 3D bioprinting for
tissue regeneration of the human retina. Future investigations are
required to establish the vascular organisation to further complete the
regeneration of retinal tissues.
Each 3DP technique has its own advantages over the other tech-
niques to meet the requirements for the development of ocular devices.
For instance, DLP is preferred for printing contact lenses with nano-
patterns. This 3DP technique could add on a layer of electronic photo-
detector to monitor the physiological changes in patients eyes (Alam
et al., 2021; Park et al., 2018). These 3DP contact lenses with photo-
sensors will be helpful for patients with drug release implants to detect
the regional toxicity of the released medical agents. The drug release
implants are used for glaucoma and cataract patients and can be cus-
tomised using 3DP technology depending on individual preferences.
Hydrogel-based lyophilised eye patches equipped with the antibiotic
drug were exible in terms of releasing different dosages by adjusting
the bioink compositions (Tagami et al., 2022). The customisable 3DP is
also benecial for designing drug eluting systems to treat glaucoma. The
drug implants, however, are essential to retain a persistent drug
releasing speed while evenly diffusing to the target area (Mohamdeen
et al., 2021 Dec 20).
Ocular prostheses are necessary following enucleation and eviscer-
ation to replace the absent eye (Xu et al., 2021). The traditional
manufacturing process for articial eyes is time-consuming. In contrast,
3DP allows us to customise the design based on the anatomy of the
patients eyes and to create a mould of prosthetic eyes within a sub-
stantially shorter manufacturing time (Ruiters et al., 2016). Although
3DP currently only permits us to produce plain eyes with few cosmetic
decorations, they have the potential of having add-on photodetectors to
generate articial eyes that are functional.
3DP has been widely used for preoperative planning to help in dis-
ease treatment. Its use in manufacturing surgical instruments has also
efciently improved the outcome of surgeries and the practice of sur-
geons. For example, 3DP has helped surgeons and clinicians to shape the
orbital structure before implantation based on patient-specic cases (Oh
et al., 2016; Kozakiewicz et al., 2009). This is particularly useful for
patients suffering from orbital fracture who require orbital restoration
and implants. In addition, the customised 3DP instruments can be pro-
duced according to the specic needs of the surgeon. Their production
time has been greatly reduced compared to the conventional
manufacturing methods (Xu et al., 2021). The invention of 3DP cable-
driven steerable instruments can also assist surgeons to carry out
minimally invasive surgery smoothly and efciently (Culmone et al.,
2021).
With the right biomaterials and appropriate printing parameters
selected, 3D bioprinting can generate a biocompatible and customisable
model to meet the requirements of each patient. Therefore, the devel-
opment of a 3DP ocular device requires careful considerations when
choosing the biocompatible materials and printing techniques. Howev-
er, there are still many challenges ahead before 3DP ophthalmic prod-
ucts can reach clinical trials and eventually commercialisation. A
current concern is the sterility of the materials and biocompatibility in
patients. Most of the 3D printers can prepare sterile products, for
example bioprinters. Moreover, there are manufacturers that are
currently developing sterile 3D printers. Hospitals also have sterile areas
that could be used in the future for the manufacturing of implantable
systems.
Furthermore, the process of 3DP still requires manual segmentation
for exhaustive details. In the future, articial intelligence assisted by
human supervision will be able to increase the prociency of the seg-
mentation output. The concurrent improvement of the computational
technology, such as the CAD software, provides us with the prospect of
accurate and precise printing techniques in the future.
As 3DP techniques have been developing rapidly for the past decade,
the four-dimensional printing (4DP) incorporating the 4th dimension
(time) is slowly emerging as a newly unconventional printing technique
for medical applications. The 4DP technology allows the biomaterials to
change over time physically and functionally (Willemen et al., 2022).
This adds another layer of exibility to the development of 3DP appli-
cations, especially for the progression of tissue engineering. It helps to
construct realistic tissue organisations with added exibility. The bio-
materials used for 4DP can change their physical appearances by
responding to the changes in temperature, pH, ion concentrations etc.
Biomaterials can also result in functional changes due to the cell
maturation apart from the morphological changes.
One of the 4DP applications is to use the hydrogel, that can respond
to the environmental stimuli, for the construction of 4DP drug delivery
systems (Willemen et al., 2022). The 4DP microneedles can change their
shapes in response to dissolving, bending, and UV curing to improve cell
adhesion. The changes in physical properties while responding to
external stimuli can be useful in the development of 4DP drug-eluting
implants. These exciting designs using 4DP technologies can further
benet the ophthalmic applications, namely the drug-eluting implants
incorporating IOP-responsive biomaterials that are feasible for glau-
coma treatment.
8. Conclusions
The emergence of 3DP technology allows us to produce personalised
medical products that conventional manufacturing techniques cannot
offer. The adaptability and exibility of 3DP will enhance prospects of
therapeutic practices, including dentistry and orthopaedics. The prom-
ising discoveries of 3DP in ophthalmology encourage the medical
G. Tan et al.
International Journal of Pharmaceutics 625 (2022) 122094
7
research community to continuously provide advanced treatment and to
gain condence in patients. 3DP in the ophthalmic eld is still not fully
understood and developed, but its potential to provide revolutionary
solutions for various eye diseases is indisputable. 3D bioprinting as a
novel technology introduced in the medical eld marks a revolutionary
approach in modern medicine. The invention of bioinks in 3DP can
potentially solve the shortage of corneal transplantation and promote
the enhancement of tissue regeneration. Furthermore, the constantly
evolving 3DP techniques tailored for ophthalmic devices and drug de-
livery systems guarantee the individualisation of AM manufacturing.
The challenges and obstacles in biomedical 3DP manufacturing
require further investigation in the role of 3DP in the medical eld. Once
the ongoing establishment of legal regulation is in place for the medical
production using 3DP at the point of care, the personalised 3DP medical
products will help meet in the near future the current clinical needs as
well as satisfy patientsneeds on demand.
CRediT authorship contribution statement
Greymi Tan: Writing original draft. Nicole Ioannou: Writing
original draft. Essyrose Mathew: Writing review & editing. Aristides
D. Tagalakis: Writing review & editing. Dimitrios A. Lamprou:
Conceptualization, Writing review & editing. Cynthia Yu-Wai-Man:
Conceptualization, Writing review & editing, Supervision, Funding
acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Acknowledgements
This work is supported by the Medical Research Council (MRC, UK,
grant number MR/T027932/1).
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