Int Ophthalmol (2022) 42:3253–3272

https://doi.org/10.1007/s10792-022-02320-7

REVIEW

Dry eye syndrome: comprehensive etiologies and recent

clinical trials
Ruojing Huang · Caiying Su · Lvjie Fang ·
Jiaqi Lu · Jiansu Chen · Yong Ding

Received: 9 August 2021 / Accepted: 18 April 2022 / Published online: 9 June 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022

Abstract Dry eye syndrome (DES) is multifacto- Introduction

rial and likely to be a cause of concern more so than
ever given the rapid pace of modernization, which is DES is a relatively common clinical ophthalmic
directly associated with many of the extrinsic causa- condition, characterized by a disorder of the preocu-
tive factors. Additionally, recent studies have also lar tear film and affecting approximately 1 out of 7
postulated novel etiologies that may provide the basis individuals aged 48 and above [1]. Besides DES, this
for alternative treatment methods clinically. Such condition can also be known as keratoconjunctivitis
insights are especially important given that current sicca (KCS), dry eye disease (DED), ocular surface
approaches to tackle DES remains suboptimal. This disease (OSD) or dysfunctional tear syndrome (DTS)
review will primarily cover a comprehensive list of [2]. It is a dysfunction of the nasolacrimal unit (nasol-
causes that lead to DES, summarize all the upcom- acrimal glands, corneal surface and eyelids) which
ing and ongoing clinical trials that focuses on treating leads to defective or insufficient tear film formation
this disease as well as discuss future potential treat- [3].
ments that can improve inclusivity. The maintenance of a physiologically complete
tear film is imperative for normal vision as it is, along
Keywords Dry eye syndrome · Lacrimal functional with the cornea, responsible for focusing light onto
unit · Ophthalmology the retina [4]. Additionally, it also functions to lubri-
cate the eye, remove debris from the ocular surface
as well as maintain nutrition and oxygenation of the
ocular structures [5]. Patients who developed DES
Ruojing Huang, Caiying Su, Jiansu Chen and Yong Ding may experience ocular burning, blurred vision or
have equally contributed to this work.
even pain and often have a reduced quality of life as
R. Huang · C. Su · L. Fang · J. Lu · Y. Ding (*) common daily tasks that require visual attention (e.g.
Department of Ophthalmology, The First Affiliated reading, computer work, etc.) become significantly
Hospital of Jinan University, Huangpu Avenue West 613, challenging. However, while treatments are avail-
Tianhe District, Guangzhou 510630, China
able to minimize the negative impacts, they are often
e-mail: dingyong@jnu.edu.cn
suboptimal and unable to specifically target the root
J. Chen (*) cause(s) of this disease.
Institute of Ophthalmology, Medical College, Jinan It is now known that DES can be caused by a non-
University, Huangpu Avenue West 601, Tianhe District,
exhaustive list of factors which include autoimmun-
Guangzhou 510632, China
e-mail: chenjiansu2000@163.com ity, hormonal imbalance, deleterious environmental

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settings and many more. Unbeknown to many, symp- Secreted mucins are present in the aqueous compo-
toms associated with dry eyes may even at times be nent as well and are produced by the goblet cells pre-
indicative of undiagnosed systemic diseases which, if sent in the conjunctiva while transmembrane mucins
treated timely, may avoid life-threatening outcomes (glycocalyx) that can extend up to 500 nm from the
[5]. Over the years, given a more profound under- plasma membrane are formed on the apical surfaces
standing of the various mechanisms involved in the of the corneal and conjunctival epithelia [19]. Mucins
development of this condition, a wide range of novel are large high molecular weight glycoproteins that
treatments are underway to provide more effective contain one of more protein domains which are rich
results and overcome limitations posed by conven- in serines and threonines extensively glycosylated via
tional therapeutics utilized in the clinic currently. O-glycan attachments [20, 21]. They are essential for
This review aims to summarize the causes of DES providing lubrication, hydration as well as protection
and its respective mechanism, explore ongoing clini- against infection and injury [22, 23]. On the ocular
cal trials for DES treatment and lastly, discuss prom- surface, it was shown recently that they further main-
ising technologies that can potentially shape future tain a disadhesive property to the apical epithelial
treatment strategies. cells such that, during blinking or sleeping, cell sur-
faces facing each other like the cornea and conjunc-
tiva do not adhere to each other [24]. Together, these
Secretory components and tear film composition constituents maintain the tear film and any slight
dysregulation such as decreased aqueous volume or
The tear film is regulated by an integrated lachrimal abnormal production of mucins or lipids will lead to
functional unit (LFU) which consists of the lachri- DES [25, 26].
mal glands, cornea, conjunctiva, eyelids, meibomian
glands, goblet cells as well as the sensory and motor
nerves that connect them [6]. As measured by ultra- Etiology of DES
high resolution optical coherence tomography (OCT)
and validated with interferometry techniques [7, 8], it There are a multitude of factors that have been discov-
was found that the tear film, when spread across the ered to result in such dysregulations which, in gen-
exposed conjunctiva and cornea, is approximately 2 eral, can be classified as intrinsic and extrinsic. Intrin-
to 5.5 μm thick [9]. Correspondingly, this extremely sic factors are defined as conditions present within the
thin layer of film is constituted by an even thinner top body and include autoimmunity [3, 27, 28], hormonal
layer of lipid (about 42 nm) [10] and a mucin-aque- imbalance [29, 30], systemic diseases [31–34], hered-
ous (mucoaqueous) layer with decreasing concentra- itary diseases [35, 36], nerve damage [37, 38] and gut
tion of mucins from the cornea epithelium towards dysbiosis [39, 40]. On the other hand, extrinsic ele-
the lipid layer [11, 12]. ments are derived from stimulus that occur outside
The lipid layer is derived from meibum produced the body and consist of environmental influences [41,
by the meibomian gland and secreted through the 42], behaviour and/or habits [43–46], eye accessories
lid margins. Meanwhile, blinking helps to spread the [47] and eye surgeries [48, 49] (Fig. 1).
lipid layer across the tear film through surface ten-
sion forces. This configuration functions to stabilize
the film by preventing the aqueous component from Intrinsic factors
evaporating too rapidly [13–15]. The aqueous fluid in
the tear film, which contains water, electrolytes, small Autoimmunity
molecule metabolites, plethora of proteins (more than
1500 detected [16]) and peptides (more than 200 Dry eyes caused by autoimmunity could be attrib-
[17]) is mostly produced by the lacrimal glands. The uted to Sjörgen’s syndrome (SS), a chronic autoim-
aqueous portion in the mucoaqueous layer provides mune disorder that primarily affects the salivary
oxygen and nutrients to the underlying avascular and lacrimal glands. Specifically, these exocrine
corneal tissue and assist in flushing away epithelial glands are heavily infiltrated with lymphocytes (T
debris, toxins and foreign bodies [18]. cells and B cells) and macrophages which produces

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Fig. 1  Schematic of dys-

regulated tear film during
DES and the various intrin-
sic (blue background) and
extrinsic (red background)
etiologies

pro-inflammatory signalling molecules such as IL-1, Other biomarkers include MMP-9 [58, 59], HLA-DR
TNF-α and IFN-γ [28, 50–52]. ­CD4+ T cells are the [60, 61] and potentially MUC5AC [62].
primary immune effectors [53] and interact closely Graves’ opthalmopathy, also known as thyroid eye
with antigen presenting-macrophages to provoke disease, is another autoimmune condition that can
ocular disease development through inflammation- lead to DES [63]. Patients afflicted with this disease
induced (IL-1 and IFN-γ) local tissue damage [51]. produce excessive thyroid hormones which induce
Additionally, they are also associated with peripheral an inflammatory response in the orbital tissues [64].
neuropathy in the lacrimal glands, suggesting possible Mechanistically, DES is caused by a combination of
denervation and loss of function [54]. Besides C ­ D4+ mechanical impairment of the lids [65] and autoan-
T cells, it was recently observed that highly cytotoxic tibodies targeting the thyroid-stimulating hormone
activated ­CD8+ T cells are correlated with lacrimal receptors on the lacrimal gland [66]. Incomplete
gland epithelial cell death [50] and may account for blinking due to lid impairment results in inadequate
the reduction in tear production. Given the varied tear distribution over the ocular surface and exces-
possible causes of DES, the diagnosis of SS-induced sive tear evaporation [65] while autoantibodies bind-
dry eyes is relatively tedious and requires defined bio- ing causes aberrant signal transduction in the lacrimal
markers for validation. Accordingly, it is known that gland and subsequent tear hyposecretion [66].
the tear film of patients who developed SS contained While not commonly known, multiple sclerosis,
elevated amounts of pro-inflammatory cytokines such where the central nervous system (CNS) becomes
as IL-1, IL-6, IL-8 and TNF-α. Their presence also demyelinated, is also an autoimmune disease that is
corresponded to lower tear secretion levels [55–57]. correlated to DES. Specifically, poor corneal sensory

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impulse conduction due to demyelination can lead to conjunctival epithelium damage due to increased lev-
insufficient tear production [67]. els of HbA1c in blood serum [87]. HbA1c are gly-
cated haemoglobins and provide an estimate of the
Hormonal imbalance blood sugar levels of an individual over the last three
months [88]. As the conjunctiva epithelium contains
Hormones are known to influence both the lacrimal goblet cells, the damage sustained will also be asso-
and meibomian glands [68]. Sex hormones, particu- ciated with diminished mucin production. Addition-
larly androgens, appeared to account for many of ally, hyperglycemia has been shown to activate aldose
the sex-related disease susceptibility of the lacrimal reductase, an enzyme that catalyzes the conversion of
gland in a variety of species [69]. For instance, tes- glucose to the cytotoxic sorbitol [89]. Correspond-
tosterone was able to upregulate and downregulate a ingly, elevated amounts of sorbitol within cells will
substantial amount of lacrimal gland genes found to lead to cellular apoptosis and ultimately lacrimal
be highly and lowly expressed respectively in male gland structure dysfunction followed by the reduction
vs. female mice [70, 71]. On the other hand, estrogen in tear secretion [31].
and progesterone only impacted a small percentage Xerophthalmia is a systemic disease that consists
[71] of these differentially expressed genes between of a variety of eye disorders, including DES [90]. It
male and female mice [70]. Mechanistically, andro- is attributed to vitamin A deficiency and is the only
gens have been demonstrated to regulate the lacrimal vitamin deficiency disease in the world that causes
glands’ fluid and protein secretion [72–74] through major concern to the public health personnel [91,
saturable, high-affinity and steroid-specific receptors 92]. Vitamin A is crucial for maintaining the dif-
binding in acinar and ductar epithelial cells [69, 75]. ferentiation and proliferation of the conjunctiva and
Accordingly, the lack of androgens was linked to lac- corneal epithelium [93] by inhibiting the upregula-
rimal gland dysfunction and corresponding aqueous tion of apoptotic signals [94]. The lack of vitamin A
tear deficiency [30, 76], which helps to explain the will therefore lead to loss of goblet cells and mucin
higher DES prevalence among females [77, 78] since production.
they are prone to reduced serum androgen levels dur-
ing various stages of their life (lactation and meno- Hereditary diseases
pause) [79, 80]. The meibomian glands, which are
sebaceous in nature and contain acinar epithelial cells Familial dysautonomia (FD), also known as Riley-
with androgen receptors, are also regulated by andro- Day syndrome, is a rare, hereditary autosomal reces-
gens [81, 82]. This form of regulation is dependent sive disorder that impairs the development of specific
on 5α-reductase, an enzyme crucial for the produc- sensory and autonomic neurons during embryogen-
tion of the potent androgen, 5α-dihydrotestosterone esis [35]. As a result of this maldevelopment, patients
(DHT). In the presence of DHT, these acinar cells with FD are highly vulnerable to optic neuropathy
display enhanced synthesis and secretion of lipids. during their childhood, which becomes worse as they
Conversely, a reduction in DHT resulted in attenuated age [36]. Without proper control of their LFU, they
gland activity, size and lipid release [82, 83], which, lack the ability to produce tears at a basal, reflex and
in the context of DES, leads to the formation of an emotional level [95].
unstable tear film attributable to the increased rate of
evaporation. Nerve damage

Systemic diseases All the secretory functions in the LFU are regu-
lated by autonomic nerves. The lacrimal gland
Diabetes mellitus (DM) is regarded as one of the is largely innervated by the Vasoactive Intestinal
leading systemic risk factors for DES due to the high Peptide immunoreactive (VIP-IR) parasympathetic
prevalence (~ 18% to 54%) observed in Type 2 dia- nerve fibers (secretory control) [96, 97] and, to a
betic patients [84–86]. However, regardless of Type lesser extent, sympathetic nerve fibers (vasculature
1 or 2 diabetes, both conditions heighten the risk of control) immunoreactive to Neuropeptide Y (NPY-
developing LFU dysfunction such as corneal and IR), Tyrosine Hydroxylase (TH-IR) and Dopamine

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β-Hydroxylase (DBH-IR) [98]. Upon stimulation, Gut dysbiosis

water and electrolytes, supplied by the blood, are
transported into the duct system by the coordinated The human body is host to trillions of microbiota.
activation of ion channels and pumps [99–101]. Among the various regions, such as the oral cav-
Meanwhile, proteins produced and stored in the ity, respiratory tract, skin and gastrointestinal tract,
secretory granules of the lacrimal gland acinar cells that harbor these microorganisms [110], the colon is
will be released through stimulus-induced exocyto- the organ which consists of the densest number of
sis [102] and carried along with the ionic fluid. microbes [111]. This additional diversity of microbi-
The meibomian gland and goblet cells in the con- ome serves as a functional expansion of host genomes
junctiva is regulated by both parasympathetic VIP- [112] and produces signaling molecules that facilitate
IR and sympathetic DBH-IR and NPY-IR nerve fib- host metabolism and regulation of host physiology
ers as well [97, 103, 104]. VIP-IR nerve fibers are [113]. Studies have revealed correlations between gut
located in close proximity to the acini and central dysbiosis, defined as an imbalance of the gut microbi-
duct of the meibomian gland where they influence ota diversity (disturbed or inversed Firmicutes/Bacte-
the secretion of lipids, contributed by the meibo- roidetes ratio), and DES. Specifically, this connection
cyte acinar cells, into the lumen of the duct system was hypothesized to occur through the gut dysbiosis-
[97, 105]. On the other hand, VIP-IR nerve fibers ocular surface-lacrimal gland axis which consists of
are located at the epithelial-stroma junction in the five proposed immune-related mechanisms describing
conjunctiva, near the basal membrane of the goblet how ratio changes of gut commensal can lead to DES
cells [104]. Upon receiving an appropriate stimu- [114, 115]. For example, one of the mechanisms pro-
lus, the secretory granules within the goblet cells posed involve the migration of gut dysbiosis-activated
fuse with each other and with the apical membrane ­CD103+ or C ­ XCR1+ dendritic cells or monocytes/
to release the mucins, along with some amount of macrophage to the ocular surface where they prime
water and electrolytes, onto the ocular surface. T cells to secrete pro-inflammatory cytokines in the
Correspondingly, the activity of these autonomic ocular surface and lacrimal glands [114]. Conse-
nerves are dependent on reflexes initiated by the quently, the immune response mounted will lead to a
activation of sensory neurons, which are present decrease in goblet cells and acinar cells in the con-
in high density, on the ocular surface [38]. At that junctiva and lacrimal glands, respectively, resulting in
location, they are very susceptible to direct injury reduced mucin and tear secretion.
caused by environmental factors and mechanical
trauma [38]. Indirect forms of injury can also occur.
For example, patients with aqueous tear deficiency Extrinsic factors
from other causes may blink too frequently, which
can generate enough stress to damage terminal Environmental influences
nerve branches. Besides that, inflammation also
plays a key role in altering the physiological state The LFU is well-equipped to withstand tolerable
of the peripheral sensory neurons. Specifically, pro- amounts of impurities in the environment and pre-
inflammatory signalling molecules are able to either vent ocular surface damage through tear secretion.
reduce the sensory neurons’ threshold for activa- However, the protection provided by the tear film can
tion (sensitization) or increase their ongoing nerve be eroded if the pollution becomes too overwhelm-
activity (excitation) [106]. Such changes are linked ing, especially if it affects the function of the various
to the kinetics of the transduction ion channels and secretory components in the LFU. Particulate matter
voltage-gated ion channels in the axonal membrane smaller than 2.5 and 10 μm ­(PM2.5 and ­PM10), which
[107], affecting the generation and propagation of consists of inorganic dust, dirt, soot particles and
action potentials [108, 109]. Without consistent organic allergens like pollen grains, mold and micro-
control over the activation of the autonomic nerve bial colonies, are common pollutants associated with
fibers, tear production will therefore be defective. DES [116–121]. Excessive and prolonged exposure
of these pollutants to the ocular surface were shown
to trigger chronic inflammatory responses and induce

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oxidative stress, both of which have cytotoxic effects of contact lens to the ocular surface poses a host of
on the secretory cells [41]. Similarly, gaseous pollut- issues to the LFU and the tear film.
ants such as N­ O2, ­SO2, ­O3 and volatile organic com- When fitted correctly, the contact lens cover
pounds (VOCs) such as formaldehyde, toluene and the cornea completely and extends by ~ 2 mm onto
acetone were all found to be positively correlated the conjunctiva. In this configuration, every blink
with DES through inflammatory and cytotoxic causes will cause it to move along the conjunctiva, which
[122–125]. induces mechanical friction and goblet cells damage
Even in the absence of impurities and reactive within the epithelium [135] over time [136, 137]. A
gases, constant exposure to extreme environmental reduction in goblet cell density will therefore lead
conditions such as strong winds, low humidity, high to decreased mucin production and secretion, which
temperature and high altitude can directly affect ocu- affects tear film spreading. Besides that, contact
lar health as well [125–127]. These scenarios reduce lenses have also been associated with the loss of the
the tear film stability and cause faster tear evaporation meibomian gland and its orifice obstruction, result-
[41], resulting in DES. ing in impeded lipid synthesis and their transport to
the tear film. Together, these dysregulations reduce
the stability of the pre-lens tear film (PrLTF), the thin
Behaviour and/or habits
layer of fluid constrained between the cornea and the
contact lens which is half the thickness of the normal
Tobacco consumption is one of the main causes
pre-corneal tear film [138], and cause it to be suscep-
of morbidity and mortality globally and has been
tible to rapid evaporation, rupture and dry spot forma-
associated with a number of systemic disorders and
tion [139]. The lack of a consistent PrLTF is therefore
conditions, including DES [43–45]. Besides con-
a manifestation of DES.
ventional cigarettes, battery-powered electronic ciga-
rettes (ECs), which deliver nicotine through a heated
Eye surgeries
vapor [128], are also recently shown to increase the
risk of developing dry eyes [129]. Accordingly, both
Surgical procedures for ocular refractive errors such
types of cigarettes affect ocular functionality through
as laser-assisted in situ keratomileusis (LASIK),
the smoke and/or combustion by-products produced,
photorefractive keratectomy (PRK) and small inci-
leading to inflammation and subsequent decreased
sion lenticule extraction (SMILE) are recognized risk
quantity and quality of tear secretion as well as ocular
factors for developing dry eye [48, 49, 140]. This is
surface damage [129, 130].
attributable to a limitation posed by these surgical
Additionally, long-term usage of computer, tablet
procedures where the sensory nerves present on the
and cell phone can also result in DES [131]. It was
ocular surface will inevitably get damaged [48, 49,
observed that users blink less when using such dis-
140]. Without reliable sensory detection, the cor-
play devices with a screen, which prevented the for-
neal sensation become impaired, which decreases
mation of a stable tear film and therefore leading to a
basal and reflex tearing as well as rate of blinking
faster rate of tear evaporation [46].
[141–143]. Moreover, sensory denervation will also
disrupt tear production by the lacrimal gland, lead-
Eye accessories ing to reduced tear secretion [144]. In addition to
nerve damage, these refractive surgeries are also
Contact lenses provide an aesthetic means for ocular known to inflict damage to the conjunctival goblet
refractive error correction over glasses and an esti- cells [145–147]. Consequently, a reduction in goblet
mated 140 million people in the world use them [132]. cell density signifies reduced mucin production and
This estimation has remained relatively consistent therefore, reduced tear film stability. Inflammatory
over the past decade despite numerous improvements responses induced as a result of postoperative wound-
in contact lens technology [133]. Correspondingly, a healing process is the last contributing factor to DES.
major reason for this observation arises from eye dis- Altogether, these factors constitute the major
comfort, mostly the sensation of dry eyes, after pro- known causes of DES. For clarity, they are compiled
longed usage [134]. Specifically, the close proximity and summarized in Table 1.

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Table 1  Summary of all the intrinsic and extrinsic etiologies and how they lead to dry eyes
Etiology How it leads to DES References

Autoimmunity Sjörgen’s syndrome - Lymphocytes and macrophages infiltrate lacrimal [28, 50–52]
glands
- ↑ inflammatory cytokines, ↑ cell death, ↓ tear
secretion
Graves’ opthalmopathy - Excessive thyroid hormones [64–66]
- ↑ inflammation in orbital tissue
- Lid impaired mechanically, ↓ rate of blinking, ↑
tear evaporation
- Autoantibodies target lacrimal gland, ↓ tear secre-
tion
Multiple sclerosis - Poor corneal sensory impulse conduction [67]
- ↓ tear secretion
Hormonal imbalance Androgens - Androgens bind to steroid-specific receptors in [30, 69, 72–76, 82, 83]
epithelial cells
- ↓ androgens, lacrimal and meibomian gland
dysfunction, ↓ tear secretion, ↓ lipid secretion, ↑
tear evaporation
Systemic diseases Diabetes mellitus - ↑ HbA1c in blood serum [31, 87, 89]
- Corneal and conjunctival epithelium damage,
lacrimal gland dysfunction
- ↑ goblet cell death, ↓ mucin secretion, ↓ tear
secretion
Xerophthalmia - Vitamin A deficiency [91–94]
- ↓ goblet cells, ↓ mucin secretion
Hereditary diseases Familial dysautonomia - Impaired sensory and autonomic neurons [35, 95]
- Lack LFU control, no tears produced
Nerve damage VIP-IR nerve fibers - VIP-IR nerve fibers regulate lacrimal and meibo- [38, 96, 97, 103, 104]
mian gland and goblet cells
- Damage to the nerve itself or to its corresponding
sensory neurons leads to ↓ tear secretion, ↓ lipid
secretion, ↓ mucin secretion
Gut dysbiosis Firmicutes/Bacteroidetes ratio - Altered ratio lead to dendritic cells’ and mac- [114, 115]
rophages’ migration to ocular surface
- T cells primed by their presence, secrete pro-
inflammatory cytokines
- ↓ acinar and goblet cells, ↓ tear and mucin secre-
tion
Environment PM2.5 and ­PM10 - Prolonged exposure to ocular surface causes [41]
inflammation and damage
- ↓ secretory cells
Gaseous pollutants - Prolonged exposure to ocular surface causes [122–125]
inflammation and damage
- ↓ secretory cells
Extreme weather conditions - Strong winds, low humidity, high temperature and [41, 125–127]
high altitude
- ↓ tear film stability, ↑ tear evaporation
Behavior and/or habits Conventional and battery- - Smoke and/or combustion by-products produced [129, 130]
powered electronic ciga- - Ocular surface inflammation and damage
rettes - ↓ quality and quantity of tear
Display devices - ↓ rate of blinking, ↓ tear film stability, ↑ tear [46]
evaporation

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Table 1  (continued)
Etiology How it leads to DES References

Eye accessories Contact lenses - Mechanical friction, ↓ goblet cells, ↓ mucin secre- [135–139]
tion
- Meibomian gland damaged, ↓ lipid secretion
- ↓ tear film stability, ↑ tear evaporation
Eye surgeries LASIK, PRK, SMILE - Damaged sensory nerves and goblet cells [48, 49, 140–147]
- ↓ rate of blinking, ↓ mucin production, ↓ tear
secretion, ↓ tear film stability, ↑ tear evaporation

Upcoming clinical trials for DES treatment molecules that are synthesized chemically and have
well-characterized molecular structures. Based on
Method of search the classification, around 50% of the recent clinical
trials will be utilizing biologics and drugs for DES
A primary search was conducted using ClinicalTri- treatment. These therapeutics vary greatly and will
als (http://​clini​caltr​ials.​gov) and the key words used mostly be concocted into a solution for delivery as
were dry eye, keratoconjunctivitis sicca, dryness, eye drops. Among them, cyclosporine will be one of
ocular, ophthalmic and optic. The search filters ‘Not the most commonly tested anti-inflammatory drug.
yet recruiting’, ‘Recruiting’, ‘Enrolling by invitation’ Even though cyclosporine was already approved for
and ‘Active, not recruiting’ were then applied to sieve use in clinics to treat DES [207, 208], many of these
out all the upcoming clinical trials related to these studies are attempting to further improve its potency
keywords. From there, the studies were reviewed by testing different concentrations (NCT04835623),
and included only if they are associated with DES duration (NCT04144413) and delivery method such
treatment. as sustained release (NCT04541888) and nanoencap-
sulation (NCT04172961). On the other hand, hyalu-
Search results ronic acid and its salt derivative, sodium hyaluronate,
will be the most popular biologics utilized in these
All the pending and current clinical trials that focused studies to constitute artificial tears with lubricating
on DES treatment were compiled and tabulated [156, 209] and antibacterial properties [210, 211].
in Table 2. Applying the ‘Not yet recruiting’ filter As they were also FDA approved, improvements
yielded a total of 47 studies, of which 14 were rel- included the addition of other dietary supplements
evant for this review. For the ‘Recruiting’ filter, there (NCT04485533) and lubricants (NCT03697876).
were a total of 146 studies and 34 of them were rel- Besides biologics and drugs, medical devices
evant. Meanwhile, the ‘Enrolling by invitation’ fil- are also quite commonly employed, especially for
ter provided a total of 10 studies and 5 of them were DES caused by Meibomian Gland Dysfunction
found to be relevant. Lastly, the ‘Active, not recruit- (MGD). These commercial devices such as Tear-
ing’ filter returned a total of 23 studies and 7 of them Care System (NCT04309799, NCT04795752) and
were screened to be relevant. MiBo Thermoflo (NCT03767530) usually have
For each of these filter categories, the studies-of- components that are attached to the users’ eyelids
interest were further grouped according to various for providing heat and/or pressure which enhances
treatment types such as biologic, drug, device, drug meibum lipid flow [162, 212]. For other causes of
delivery system, dietary supplement, physical activ- DES, one study will be investigating the efficacy of
ity, combinatorial as well as unknown. Here, bio- quantum molecular resonance (QMR) on patients
logics are distinct from drugs and defined as large with DES (NCT04320563). QMR is a recent inno-
complex biological molecules or a combination of vative technology that involves the application of
molecules that can be derived from carbohydrates, low-power high-frequency oscillating electrical
lipids, proteins, nucleic acids, whole cells and even currents (4 to 64 MHz), a range which resonates
tissues. On the other hand, drugs are designated as with biological tissues, in order to elicit cellular

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Table 2  A summary of upcoming and ongoing clinical trials for DES treatment as of Feb 2022. Most of the treatments will be deliv-
ered in the form of eye drops
Identifier Status Treatment/Interven- Treatment type Route of adminis- Phase Related literatures
tion tration

NCT05169931 Not yet recruiting Amniotic membrane Biologic Ophthalmic (Eye 1 [148, 149]
extract drops)
NCT04938908 Not yet recruiting Probiotic from Biologic Ophthalmic (Eye 2 [150]
bacterial lysate drops)
NCT04608084 Not yet recruiting Autologous platelet Biologic Ophthalmic (Eye 4 [151, 152]
rich plasma drops)
NCT04510428 Not yet recruiting Ocular Surface Biologic Ophthalmic (Eye 2 N.A
Immune Globulin drops)
(OSIG)
NCT04819269 Not yet recruiting Tivanisiran (siRNA Biologic Ophthalmic (Eye 3 [153, 154]
against TRPV1) drops)
NCT04704531 Not yet recruiting Lagricel Ofteno Biologic Ophthalmic (Eye 2 [155, 156]
(Sodium hyaluro- drops)
nate 0.4%)
NCT03953703 Not yet recruiting Levocarnitine Drug Oral 2 [157]
NCT04668118 Not yet recruiting Diquafosol Drug Ophthalmic (Eye 4 [158, 159]
drops)
NCT04835623 Not yet recruiting Cyclosporine 0.09% Drug Ophthalmic (Eye 4 [160]
ophthalmic solu- drops)
tion
NCT04965974 Not yet recruiting Digital blue light Device N.A N.A N.A
blocking filter
NCT04877483 Not yet recruiting Acupuncture Device N.A N.A [161]
NCT04309799 Not yet recruiting Tear Restore Mask Device N.A N.A [162]
(warms the
eyelids)
NCT04541888 Not yet recruiting CsA eye gel Drug delivery Ophthalmic (Eye 3 [163]
(cyclosporine- system drops)
based gel)
NCT04679883 Not yet recruiting 5% GLH8NDE N.A Ophthalmic (Eye 2 N.A
drops)
NCT05136170 Recruiting Oxervate (ceneg- Biologic Ophthalmic (Eye 3 [164]
ermin a.k.a. drops)
rhNGF 20mcg/
mL)
NCT05109702 Recruiting Tanfanercept Biologic Ophthalmic (Eye 3 [165]
(0.25% HL036 drops)
ophthalmic solu-
tion)
NCT04899518 Recruiting ALY688 ophthalmic Biologic Ophthalmic (Eye 2 and 3 [166]
solution drops)
NCT04633213 Recruiting HBM9036 (TNF-α Biologic Ophthalmic (Eye 3 [167, 168]
inhibitor) drops)
NCT04615455 Recruiting Allogeneic adipose- Biologic Transplant 2 [169]
derived mesen-
chymal stem cells
(injection into
lacrimal gland)
NCT04877210 Recruiting Insulin (in diabet- Biologic Ophthalmic (Eye 1 [170]
ics) drops)

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Table 2  (continued)
Identifier Status Treatment/Interven- Treatment type Route of adminis- Phase Related literatures
tion tration

NCT04683796 Recruiting Autologous platelet Biologic Ophthalmic (Eye 3 [171–173]

rich plasma vs. drops)
autologous serum
NCT04217785 Recruiting Umbilical cord Biologic Ophthalmic (Eye 1 and 2 [174, 175]
serum drops)
NCT03953118 Recruiting Azithromycin (anti- Drug Oral 4 [176]
biotic)
NCT04357795 Recruiting CequaTM (Cyclo- Drug Ophthalmic (Eye 4 [177]
sporine 0.09%) drops)
ophthalmic solu-
tion
NCT05213156 Recruiting Oxatrex (0.3% Drug Ophthalmic (Eye 4 [178]
ofloxacin) drops)
NCT04030962 Recruiting AGN-242428 Drug Ophthalmic (Eye 1 and 2 [179]
(RORγ inhibi- drops)
tor) + AGN-
231868
(chemokine
antagonist)
NCT05056155 Recruiting Systane Complete Drug Ophthalmic (Eye N.A N.A
(0.6% propylene drops)
glycol)
NCT04735393 Recruiting Reproxalap (cova- Drug Ophthalmic (Eye 3 [180, 181]
lent inhibitor of drops)
RASP)
NCT04734210 Recruiting SURF-200 (beta- Drug Ophthalmic (Eye 2 N.A
methasone sodium drops)
phosphate)
NCT04172961 Recruiting Nanomicellular Drug Ophthalmic (Eye 4 [160]
cyclosporine drops)
formulation
NCT04144413 Recruiting Ikervis (1 mg/ Drug Ophthalmic (Eye 3 [160]
ml cyclosporine drops)
formulation)
NCT04553432 Recruiting Omnigen (processed Device N.A 4 [182]
amniotic mem-
brane)
NCT05203796 Recruiting Transcutaneous Device N.A N.A [183]
pulsed electri-
cal stimulation
(NuEyne 02)
NCT04795752 Recruiting TearCare system Device N.A N.A [184]
(thermal treat-
ment)
NCT04120584 Recruiting Forma eye applica- Device N.A N.A N.A
tor (radio fre-
quency treatment)
NCT04320563 Recruiting Rexon-eye (4 to Device N.A N.A [185]
64 MHz, quantum
molecular reso-
nance)

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Table 2  (continued)
Identifier Status Treatment/Interven- Treatment type Route of adminis- Phase Related literatures
tion tration

NCT03767530 Recruiting MiBo Thermoflo Device N.A N.A [186]

(thermal therapy)
NCT04730336 Recruiting Tixel (peri-orbital Device N.A N.A N.A
fractional thermo-
mechanical treat-
ment)
NCT04763018 Recruiting iTEAR100 (neuro- Device N.A N.A [187]
stimulate external
nasal nerve)
NCT04096898 Recruiting Senofilcon A con- Device N.A N.A [188, 189]
tact lens
NCT04498468 Recruiting DEXTENZA Drug delivery Implant 4 N.A
(Dexamethasone- system
loaded intracanali-
cular insert)
NCT05119920 Recruiting Pilocarpine ophthal- Drug delivery Eyelid 2 N.A
mic topical cream system
NCT04527887 Recruiting Dexamethasone- Drug delivery Implant 4 [190]
loaded intracanali- system
cular insert
NCT04645446 Recruiting Pro-ocular gel Drug delivery Transdermal 2 [191]
(loaded with 1% system
progesterone)
NCT05027087 Recruiting Blueberry gummy Dietary supplement Oral 3 [192]
NCT04785261 Recruiting Artelac eye Drug + Biologic Ophthalmic (Eye 2 [193]
drops + Vidisic drops) + Oral
gel + traditional
chinese medicine
formula
NCT04413279 Recruiting Dexamethasone- Drug delivery sys- Implant 4 [190, 194]
loaded intracanali- tem + Device
cular insert + Lipi-
Flow thermal
pulsation
NCT03652051 Recruiting AZR-MD-001 (topi- N.A Ophthalmic (Eye 2 N.A
cal ointment) drops)
NCT03302273 Enrolling by invita- Corneal epithelial Biologic Transplant N.A [195, 196]
tion stem cells
NCT04056221 Enrolling by invita- Acupuncture Device N.A N.A [161]
tion
NCT04884217 Enrolling by invita- Pro-ocular gel Drug delivery Transdermal 2 [191]
tion (loaded with 1% system
progesterone)
NCT04421300 Enrolling by invita- Smiling exercise Physical activity N.A N.A [197]
tion
NCT04658927 Enrolling by invita- iLUX (applies heat Device + Drug Implant 4 [190, 198]
tion and compression delivery system
to eyelids) + Dexa-
methasone-loaded
intracanalicular
insert

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Table 2  (continued)
Identifier Status Treatment/Interven- Treatment type Route of adminis- Phase Related literatures
tion tration

NCT03697876 Active, not recruit- PRO-165 (con- Biologic Ophthalmic (Eye 1 [156, 199]
ing tains chondroitin drops)
sulphate, sodium
hyaluronate)
NCT03937882 Active, not recruit- RGN-259 (contains Biologic Ophthalmic (Eye 3 [200, 201]
ing Tβ4) drops)
NCT03878628 Active, not recruit- Allogeneic adipose Biologic Transplant 1 [169]
ing tissue-derived
mesenchymal
stem cells (injec-
tion into lacrimal
gland)
NCT04485533 Active, not recruit- VisuXL gel (con- Biologic Ophthalmic (Eye N.A [156, 202, 203]
ing tains Coenzyme drops)
Q10, Vitamin E,
sodium car-
boxymethylcel-
lulose) + HYLO
(contains sodium
hyaluronate)
NCT04425551 Active, not recruit- Micropulse laser Device N.A N.A [204]
ing
NCT04608942 Active, not recruit- Jett Plasma Medi- Device N.A N.A [205]
ing cal Lift (remove
hyperkeratinized
layer to unblock
gland ducts)
NCT04181593 Active, not recruit- OmegaD softgels Dietary supplement Oral 3 [206]
ing (Omega-3)

responses [213]. This procedure will be performed Future prospects for DES treatment
using Rexon-Eye, a noninvasive, QMR-based pat-
ented instrument. Patients will wear the device like As discussed, DES could be caused by a large vari-
an eye mask and electrodes will stimulate their ety of factors. However, current treatments mainly
periorbital region during the therapy for enhanced addressed the symptoms by hydrating or lubricating
tear secretion. the ocular surface without tackling the root prob-
The rest of the treatment types form the minor- lems [148]. Besides creating unhealthy depend-
ity within the list of clinical trials. These included ence in patients, such approaches will also lead to
drug delivery systems that will provide sustained significant financial burden due to recurring treat-
release through dexamethasone-loaded implants ment costs. Therefore, it is encouraging to witness
(NCT04527887, NCT04413279, NCT04658927) the trajectory of upcoming DES treatment strate-
and hydrogels (NCT04541888, NCT04645446, gies where cellular and tissue regeneration in the
NCT04884217), dietary supplements consist- LFU are the key focus. Specifically, studies that
ing of vitamins and lipids (NCT04181593) as employ blood components such as platelet rich
well as physical activities for boosting well-being plasma or serum hold great promise in the clinics
(NCT04421300). not only for treating DES but for other diseases as
well [214]. However, like many other treatment

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options, allogeneic stem cell and body fluid therapy Another prospective DES treatment option is fecal
come with their own limitations that cannot be eas- microbiota transplantation (FMT), which is the trans-
ily circumvented. Most notably, they involve inva- fer of fecal materials from a healthy donor into the
sive procedures and may deter patients from opting intestinal tract of an ill or diseased recipient. By doing
for this method. Additionally, the effectiveness of so, the recipient’s gut microbial composition can be
these components in inducing favorable outcomes is adjusted to resemble the healthy donor’s, thereby con-
highly dependent on the patients’ suitability as well. ferring health benefits [223]. Since DES was found to
Therefore, for treatments to be inclusive, they be associated with gut dysbiosis, FMT is a potentially
should be varied and multipronged. In our opinion, relevant and practical technique for treatment. How-
one promising alternative is gene therapy, which ever, there were not many clinical trials investigating
enables the alteration of genetic sequences within the efficacy of FMT on DES patients as it was only
tissues and cells with recombinant nucleic acids quite recently that a correlation between DES and gut
[215]. Commonly used nucleic acids such as DNA, dysbiosis was uncovered. The first and only study was
mRNA, siRNA, miRNA and anti-sense oligonu- completed on June 2020, which explored the effects
cleotides can be strategically delivered into a defec- of FMT on patients with SS (NCT03926286). Alter-
tive target cell or tissue in order to either restore natively, we may also expect ocular microbiota trans-
the gene(s) responsible for disease suppression or plantation in future as studies have identified microbi-
inhibit the gene(s) related to disease development ome differences between closed dry eye patients and
[216]. Besides its versatility, these nucleic acids can healthy closed eye patients [224–226].
also be administered noninvasively for DES treat-
ment. Accordingly, the efficacy of this technology
will be investigated in one of the upcoming clini-
cal trials listed in Table 2 which utilizes Tivanisiran Conclusion
(NCT04819269), a novel 19 nucleotide siRNA for
suppressing the expression of the transient recep- DES is a relatively common ophthalmic disease that
tor potential cation channel subfamily V mem- can manifest in various degrees of severity and can
ber 1 (TRPV1) [153]. TRPV1 is a pain receptor be caused by many factors. While not life threaten-
found in some components of the LFU [217] and ing, patients may often have to continuously endure
the responses it mediates in the sensory neurons discomfort or even pain, which puts a damper in their
was found to be associated with the development quality of life. Given the multitude of conditions
of inflammation and neuropathic pain [218]. The which DES can originate from, a variety of treatment
delivery of this siRNA-based of eye drop will poten- options is critical to ensure inclusivity and effective-
tially result in the reduction in TRPV1’s expression ness. Encouragingly, current clinical trials are trend-
in the ocular tissues and therefore, alleviate inflam- ing towards this notion and investigating promising
mation and improve tear secretion [219]. Of note, research-backed treatments like stem cell therapy,
naked nucleic acids are very inefficiently uptaken blood component therapy and gene therapy. If suc-
by cells as they possess similar negative charges cessful, these strategies may define treatments for
as the cell membrane, which leads to electrostatic other diseases in future as well.
repulsion [220, 221]. Delivery vehicles are required
to transport nucleic acids across the cell membrane Author contributions RJH, CYS, LJF and JQL wrote and
edited the manuscript. JSC and YD proofread and edited the
and herein determines the success of gene therapy. manuscript. JSC and YD provided guidance and the funding
Recently, a breakthrough in vaccination strategy has for this work.
shed valuable insights about the optimal form of
nucleic acid carriers. Specifically, the Pfizer vaccine Availability of data and material Not applicable.
for Covid-19 utilizes a specially formulated lipo-
Code availability Not applicable.
some for delivering mRNAs into cells with great
efficiency [222]. With the approval of this revolu- Declarations
tionary delivery platform, gene therapy is thus in a
favorable position to take off.

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Conflict of interest All authors certify that they have no af- 14. Bron AJ, Tiffany JM, Gouveia SM et al (2004) Func-
filiations with or involvement in any organization or entity with tional aspects of the tear film lipid layer. Exp Eye Res
any financial interest (such as honoraria; educational grants; 3:347–360
participation in speakers’ bureaus; membership, employment, 15. Knop E, Knop N, Millar T et al (2011) The international
consultancies, stock ownership, or other equity interest; and workshop on meibomian gland dysfunction: report of the
expert testimony or patent-licensing arrangements), or non- subcommittee on anatomy, physiology, and pathophysi-
financial interest (such as personal or professional relationships, ology of the meibomian gland. Invest Ophthalmol Vis
affiliations, knowledge or beliefs) in the subject matter or mate- Sci 4:1938–1978
rials discussed in this manuscript. 16. Zhou L, Zhao SZ, Koh SK et al (2012) In-depth analysis
of the human tear proteome. J Proteom 13:3877–3885
Ethical approval This article does not contain any studies 17. Azkargorta M, Soria J, Ojeda C et al (2015) Human basal
with human participants or animals performed by any of the tear peptidome characterization by CID, HCD, and ETD
authors. followed by in silico and in vitro analyses for antimicro-
bial peptide identification. J Proteome Res 6:2649–2658
Consent for publication Not applicable. 18. Dartt DA, Willcox MDP (2013) Complexity of the tear
film: importance in homeostasis and dysfunction during
disease. Exp Eye Res 117:1–3
19. Mantelli F, Mauris J, Argüeso P (2013) The ocular sur-
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