An effective therapeutic strategy to treat tendon or ligament injury continues to be a clinical challenge due to the limited natural healing capacity of these tissues. Furthermore, the repaired tendons or ligaments usually possess inferior mechanical properties and impaired functions. Tissue engineering can restore the physiological functions of tissues using biomaterials, cells, and suitable biochemical signals. It has produced encouraging clinical outcomes, forming tendon or ligament-like tissues with similar compositional, structural, and functional attributes to the native tissues. This paper starts by reviewing tendon/ligament structure and healing mechanisms, followed by describing the bioactive nanostructured scaffolds used in tendon and ligament tissue engineering, with emphasis on electrospun fibrous scaffolds. The natural and synthetic polymers for scaffold preparation, as well as the biological and physical cues offered by incorporating growth factors in the scaffolds or by dynamic cyclic stretching of the scaffolds, are also covered. It is expected to present a comprehensive clinical, biological, and biomaterial insight into advanced tissue engineering-based therapeutics for tendon and ligament repair. Tissue engineering is an evolving multidisciplinary field for regenerating damaged tissue/organs by transplanting a cell-seeded functional scaffold. Using converged knowledges from biology, materials science, chemistry, and engineering, tissue engineering has combined the use of cells, growth factors, and scaffolds to make remarkable progress over the last decade  1]. Wit. Wit1]. The tendons and ligaments are fibrous, dense, regular connective tissue, allowing for movement and maintenance of body posture. The main functions of tendons and ligaments are to connect and transmit forces from muscles to bones and from one bone to another, respectively. They share a comparable composition and hierarchical structure. The ECM of tendons is composed predominantly of collagen, which accounts for up to 85% of the dry weight of a tendon tissue. Within different types of collagen in tendon ECM, collagen type I represents ~95% of the dry weight, with the rest being collagen type III, V, XI, XII, and XIV. The tendon is composed of two primary cellular components: tenocytes that are fully differentiated cells and account for 90–95% of cellular content in a healthy mature tendons, and tendon stem/progenitor cells that are located within the ECM of the tendon. Additional cellular components include synovial cells located on the surface and vascular cells present in the endotenon and epitenon regions. In normal circumstances, the maintenance and repair of tendons are carried out by tenocytes, but tendon stem/progenitor cells also perform a crucial function in this process by engaging themselves in self-renewal and differentiation into tenocytes ,11. The The structure and composition of a tendon leads to its unique ability to withstand a high tensile strength, and this distinct mechanical characteristic distinguishes it from other tissues in the body. Indeed, in order to play a key function in joint stability during movement and physical activity, the tendon and ligament need to display superior mechanical strength and flexibility ,14,15. TThe musculoskeletal tissues contain both soft and hard tissues, which provide a gradient of mechanical properties with progressive transition from one end to the other. To meet this need, material gradients existed at the junctions for reducing stress concentrations found at these sites. At the interface of tendon/ligament to muscle or bone, the junctions are called entheses and myotendinous junctions, which enable a physiological transmission of load over the junction over a wide area ,20. The As tendons and ligaments have a unique structure and function, their repair after injury remains a challenging task for clinicians. The low cellularity and hypovascularity in these tissues usually leads to ineffective treatment and reduced healing ability . Indeed,There are three main stages during tendon healing post-injury, including inflammation, proliferation, and remodeling  33]. Af. Af33]. Tendon and ligament injuries can be treated with extracorporeal shockwave therapy, eccentric exercise therapy, ultrasound, and low-intensity laser therapy, all of which are considered conservative and unsatisfactory . AdditioVarious polymers have been employed as scaffold materials for tendon and ligament tissue engineering ,50,51,52Synthetic polymers have been widely used to produce tendon/ligament scaffolds due to their availability, ease of processing, and reproducibility ,14. In aPoly(caprolactone) (PCL) is a linear hydrophobic polymer with good mechanical properties, a low melting point, and good processability ,63. It i2. However, it undergoes slow degradation within a period of 10 months to 4 years . Th. Th56]. +) provides the best mechanical properties compared with aligned nanofibers prepared without PRP (Random) and random nanofibers prepared with PRP (Random+). The combined effects from growth factors in PRP and fiber alignment in the Align+ nanofibrous membrane also led to enhanced proliferation of rabbit tenocytes as well as up-regulated tendon-specific gene expression and increased tenogenic marker protein synthesis. Besides biochemical cues from PRP, the cell-seeded Align+ scaffold was mechanically stimulated in vitro under cyclic tensile loading in a bioreactor, by which a shorter tendon maturation time and a higher cell proliferation rate were found with well-preserved tendon phenotype when compared to non-mechanically loaded cell culture conditions. Therefore, topographical cues from nanofibers can be facilely combined with mechanical stimulation to ameliorate the cellular response of tenocytes in a core–sheath nanofiber membrane scaffold for tendon tissue engineering.Co-axial electrospinning technology was used to create core–shell nanofibers and was disclosed by Sun et al. in 2003, where a spinneret made up of two co-axial needles was employed separately to deliver two immiscible spinning solutions during electrospinning  Figure A. Full eA variety of methods to fabricate a three-dimensional (3D) amalgamated fibrous scaffold using electrospinning have been attempted to mimic the natural ECM structure of a tendon or ligament, which is made up of a hierarchal structure of aligned collagen fibers at both the micro- and nanoscales . Among tThe bioactive scaffolds utilized in tendon tissue engineering should be able to withstand excessive stresses in addition to encouraging the healing process of injured tendons . AlignedGrowth factors (GFs) represent the largest group of biomolecules that can induce tenogenesis, and considerable studies have been undertaken to elucidate their roles during tendon healing. GFs can belong to several families, including fibrous growth factor-2 (FGF-2 or bFGF), transforming growth factors beta , vascular endothelial growth factor (VEGF), connective tissue growth factors (CTGF), platelet-derived growth factor (PDGF), and insulin-like growth factors-1 (IGF-1) ,173,174.Basic fibroblast growth factor (bFGF), which belongs to the family of heparin-binding growth factors, is well recognized for being a strong inducer of angiogenesis and cellular migration. Although in vivo bFGF supplementation can affect early stage rat patellar tendon healing, the prompt inactivation and limited plasma half-life have hindered this effect at the healing site . ConsideTransforming growth factor beta (TGF-β) has been found to be active in almost all phases of tendon healing by guiding fibroblast migration, neovascularization, and ECM protein production . There aPlatelet-derived growth factors (PDGFs) are a class of dimeric polypeptide isoforms that are made up of three structurally identical subunits. Because of their well-known chemotactic, mitogenic, and angiogenic properties, PDGFs have been studied as a GF to help tendon healing after damage or rupture to tendons . The PDGA summary of the scaffold-based delivery of growth factors for tendon and ligament tissue engineering is provided in In tendon and ligament tissue engineering, a growing emphasis is placed on dynamic mechanical stimulation during cell culture, by culturing the cell/scaffold construct in a bioreactor under cyclic tensile loading. It is reported that mechanical stimulation is one of the most important physical cues affecting cell proliferation, gene expression, ECM formation, collagen fiber alignment, and tissue remodeling in tendons and ligaments . MoreoveWang et al. studied the effect of uniaxial and biaxial mechanical loading on tendon-derived stem cells (TDSCs) by applying a 6% biaxial or uniaxial cyclic strain at 0.25 Hz, 8 h/day, for 6 days to enhance tenogenic differentiation . They reA PCL nanofibrous woven scaffold was used for the tri-culture of human ADSCs/human tenocytes (HTs)/human umbilical vein endothelial cells (HUVECs) under cyclic uniaxial elongation along the direction of nanofibers using 4% strain at 0.5 Hz, 2 h/day, for a total of 12 days. The mechanically stimulated cell/scaffold constructs under dynamic stretch can significantly enhance tenogenic differentiation with increased production of tendon-related proteins and upregulated expression of tendon-specific genes . Using uIndeed, a collective finding from previous studies underlines that a mechanical stretching frequency of 1 Hz may be the optimal value to generate a favorable cellular response, such as an exceptionally high degree of cell proliferation and tenogenic differentiation, and a diminished beneficial effect was found beyond this value. Nevertheless, a lower frequency may be better when considering the quality of regenerated tendons or ligaments. Additionally, cells can be progressively adapted to the stimulus during the rest intervals, resulting in a reduction in the impact of the applied mechanical stimulation. By including a rest interval, the mechanical sensitivity of stretched cells may be restored and result in a more favorable impact. Several studies found that shorter duration and lower frequency were associated with higher cell proliferation rates. The highest cell proliferation rate was found with mechanical stretching at 0.5 or 1 Hz and 2 or 3 h/day, which resulted in upregulated tenogenic marker expression and high-quality neo-tendon tissue formation under mechanically stimulated in vitro ,200,206.Regeneration of tendon and ligament tissues using the tissue engineering principle remains a challenging issue in orthopedic research. Current treatment strategies are unable to fully restore the functions of injured tendons and ligaments to their native states, and repair of injured tendons and ligaments continues to be a clinical problem. Using seeded cells in scaffolds supplemented with scaffold-based biological and physical cues, the tendon/ligament tissue engineering approach may provide a solution to this problem, by providing a milieu for cell proliferation as well as for phenotype maintenance of tendon-derived cells or for tenogenic differentiation of stem cells. However, the tissue engineered tendon or ligament should be endowed with improved mechanical properties and functions over naturally healed tendons or ligaments. By combining biomimicry and manufacturing flexibility, electrospinning is undoubtedly one of the most promising methods to fabricate scaffolds for tendon or ligament tissue engineering. Although nano- to macro-scale scaffolds are discussed in this paper without clear distinction, a novel electrospun 3D scaffold mimicking the hierarchical structure of a tendon or ligament must be developed by integrating the beneficial physico–chemical properties offered by natural and synthetic polymers. The growth factors play a crucial role during regeneration of tendons/tendons; therefore, growth factors related to the development of these tissues must be introduced into the scaffold with controlled release characteristics to provide biochemical cues during the regenerative process. Furthermore, a novel scaffold design for scaffold-based gene therapeutics or delivery of exosome may be a promising approach toward this end and is expected to produce positive outcomes in the future. Mechanical stimulation can provide physical cues to cells loaded in a scaffold, which appears to be an important route to generating functional tendon or ligament tissue in a bioreactor under dynamic culture. However, the operation parameters during cyclic tensile loading, such as strain, frequency, and duration time, must be investigated and optimized. With additional refinement and the combination of these components, tissue engineering will undoubtedly be a very convincing option for tendon and ligament repair. However, the type of cells for seeding in a scaffold should be carefully chosen based on the types of tissue to be regenerated, which is expected not only to enhance tissue healing but also to provide acceptable mechanical performance at the tissue level. The development of a feasible cell delivery system that can temporally and spatially reproduce the normal physiology of native tendons or ligaments may require further investigation; however, the inception of new techniques followed by substantial research for optimization will undoubtedly direct them toward clinical applications in due course.


Sepsis is the most common cause of admission to intensive care units worldwide. Sepsis patients frequently suffer from sepsis-associated encephalopathy (SAE) reflecting acute brain dysfunction. SAE may result in increased mortality, extended length of hospital stay, and long-term cognitive dysfunction. The diagnosis of SAE is based on clinical assessments, but a valid biomarker to identify and confirm SAE and to assess SAE severity is missing. Several blood-based biomarkers indicating neuronal injury have been evaluated in sepsis and their potential role as early diagnosis and prognostic markers has been studied. Among those, the neuroaxonal injury marker neurofilament light chain (NfL) was identified to potentially serve as a prognostic biomarker for SAE and to predict long-term cognitive impairment. In this review, we summarize the current knowledge of biomarkers, especially NfL, in SAE and discuss a possible future clinical application considering existing limitations. Sepsis is a potentially life-threatening organ dysfunction caused by a dysregulated host response to severe infection , 2. Due Sepsis-associated encephalopathy (SAE) is one of the most common organ dysfunctions in sepsis and is also associated with significantly higher mortality rates , 16–18. Due to inconsistent diagnostic criteria in clinical studies and diverging daily clinical practice, the estimated prevalence of delirium in SAE varies from 9 to 71% in sepsis patients . As an eIn addition to acute changes in mental state during the acute phase, sepsis is associated with long-term cognitive dysfunction following hospital discharge. According to a study of long-term cognitive outcomes in patients admitted to ICUs with acute respiratory failure, septic or cardiogenic shock, 40% (after three months) and 34% (after twelve months) of patients had persisting cognitive impairment after hospital discharge . The sevIn the ICU, delirium severity is routinely measured using the CAM-ICU and Intensive Care Delirium Screening Checklist (ICDSC), both showing high reliability and validity in patients who are able to interact with the investigator. According to CAM-ICU, a patient is rated as delirious when (a) the mental status acutely changes or fluctuates and (b) the patient fails to pay attention and either (c) the patient exhibits disorganized thinking or (d) has an altered level of consciousness. To evaluate the level of consciousness, the Richmond Agitation-Sedation Scale (RASS) is used . AnotherThe major disadvantage of the CAM-ICU and the other scores is the reliance on patient interaction. Therefore, these clinical tools cannot be used in deeply sedated patients . Furthermore, patients with hypoactive delirium might also be underrecognized. Thus, the delirium rates in the ICU are likely to be underestimated in severely ill patients.Besides challenges in the practical use of delirium tests itself in SAE patients, a recent study evaluated the current practice of clinical SAE diagnostics in the ICU and demonstrated a great heterogeneity in the application of diagnostic tests in Germany .in-vivo data indicate neuronal and synaptic damage in sepsis alongside with activation of immune cells in the CNS. Analyses of brain autopsies from patients who died of sepsis showed diffuse cerebral damage with neuronal apoptosis, axonal damage and ischemic lesions ..21].Biomarkers should provide objective and quantitative results. In SAE, an ideal biomarker would provide high sensitivity and specificity independent of the effects of sedatives. It should enable an early diagnosis as well as a reliable outcome assessment. Several potential biomarkers have been proposed and studied in the course of SAE, such as neuron- and glia-derived proteins , 56, butIn the last decade, neurofilament light chain (NfL) has been intensively investigated as a biomarker in several neurological diseases . NfL is Neurofilaments are cylindrical proteins found in the neuronal cytoplasm . TogetheDue to its proven role as a biomarker directly reflecting neuronal damage with the opportunity of blood measurements, NfL has been considered an ideal candidate for the diagnosis and prognostic assessment in SAE . HoweverVery recently, in a gender and age-matched series of patients with community-acquired pneumonia we demonstrated that serum NfL levels were associated with the occurrence of SAE as determined by confusion or delirium but not with overall disease severity, thus supporting the specificity of Nfl as a marker for CNS involvement in infectious and inflammatory disease . These fConsidering these results, blood NfL levels could serve as a biomarker for SAE and may have potential to predict long-term cognitive impairment after sepsis. In addition to the evidence provided by the above-mentioned first studies with rather small sample size there are several arguments that NfL might have a larger potential as compared to other biomarkers. It has already proven to be directly associated with long-term cognitive impairment and even predicting worsening of cognition over time in other neurological diseases, such as multiple sclerosis, cardiac surgery, Alzheimers’ disease and mild cognitive impairment –101. MorTogether, an increase of NfL levels at a defined time point during sepsis or changes in serum NfL levels over time during SAE might be suitable and clinically useful to predict long-term cognitive outcome in patients with sepsis. An NfL increase might enable ICU clinicians to identify patients at high risk for structural brain damage and therefore to prioritize brain imaging and protection during the hospital stay , 56. TheThere are several factors that may influence serum levels of NfL in the setting of severely ill sepsis patients Fig. . Here, NIn general, NfL values show also interindividual variability in healthy individuals and in patients with certain comorbidities , 106. ThSeveral immunoassays  are currently available to reliably quantify NfL in blood at very low concentrations . To dateIn this regard, NfL might be valuable by providing information on long-term prognosis, as repeated NfL measurements might help to differentiate between reversible brain dysfunction  and structured brain damage  . FurtherIn 2001, Pepe and colleagues published a five-phase framework for cancer biomarker development, which has been modified by the Geneva Task Force for the Roadmap of Alzheimer’s Biomarkers for the development of biomarkers , 115. Ac


To identify demographic, premorbid and injury-related factors, or biomarkers associated with long-term (≥3 months) adverse outcomes in children after mild traumatic brain injury (mTBI).Scoping review of literature.Children and adolescents with mTBI.Any demographic, premorbid and injury-related factors, or biomarkers were included. We excluded genetic and treatment-related factors.Postconcussion syndrome (PCS), recovery.Seventy-three publications were included, reporting 12 long-term adverse outcomes, including PCS in 12 studies and recovery in 29 studies. Additional outcomes studied were symptom scores/severity (n=22), quality of life (n=9) and cognitive function (n=9). Forty-nine risk factors were identified across studies. Risk factors most often assessed were sex (n=28), followed by age (n=23), injury mechanism = (n=22) and prior mTBI (n=18). The influence of these and other risk factors on outcomes of mTBI were inconsistent across the reviewed literature.The most researched risk factors are sex, age and mechanism of injury, but their effects have been estimated inconsistently and did not show a clear pattern. The most studied outcomes are recovery patterns and symptom severity. However, these may not be the most important outcomes for clinicians and patients. Future primary studies in this area should focus on patient-important outcomes. Population-based prospective studies are needed that address prespecified hypotheses on the relationship of risk factors with given outcomes to enable reliable prediction of long-term adverse outcomes for childhood mTBI. Mild traumatic brain injury (mTBI) is common in childhood and can lead to prolonged symptoms in about one-third of children.Persisting symptoms can hinder development and reduce quality of life.There is a dearth of predictive tools and limited evidence on factors placing a child at risk of developing prolonged symptoms.This study collated potential demographic, premorbid and injury-related factors, or biomarkers for long-term adverse outcomes of childhood mTBI.Forty-nine risk factors for 12 different outcomes were identified across 73 studies.The associations between any of the risk factors and adverse outcomes were not consistent.The inconsistency of findings indicates a need for consensus on definitions underpinning measurement.Robust primary studies that follow-up children with mTBI long-term are required to reliably predict adverse outcomes.Almost half a million children attend hospital annually after a traumatic brain injury (TBI) in the UK.Research on mTBI pathophysiology has explored links between symptoms and potential individual or environmental factors.There is no widely accepted, validated prediction tool to identify children at risk of developing long-term sequelae of mTBI. Limited evidence on syndrome characterisation precludes developing interventions for PCS.In this review, we aimed to identify factors associated with long-term adverse outcomes of mTBI from published research and identify key areas for future research.To identify from the literature the demographic, premorbid and injury-related factors, or biomarkers associated with long-term (≥3 months) adverse outcomes in children after mTBI.We followed accepted methods for scoping reviews and used an iterative process to define research questions, extract data and summarise results.We included observational studies reporting any demographic, premorbid and injury-related factors, or biomarker risk factors for adverse outcomes 3 months or longer after mTBI in children under 18 years. We searched three electronic databases and references lists of included studies and published systematic reviews to identify peer reviewed and grey literature in January 2022. Screening of titles and abstracts and full texts was done in duplicate. Data extraction was done by one author, and the data items included study design, author, location, year of publication, participants, risk factors identified or studied and outcome(s). We did not extract effect estimates and did not perform risk of bias assessments. Findings were summarised into a table of risk factors studied for each outcome and in figures presenting long-term adverse outcomes and risk factors studied in literature respectively. A stakeholder consultation helped refine the synthesis and findings. Detailed methods are available in 10.1136/archdischild-2022-325202.supp1Supplementary dataOf 8039 unique references, 678 underwent full-text assessment, and 73 publications were included  in 46 studies. Median age was 13.6 years (IQR 12–15) across the 64% of included studies reporting mean age. Half the studies reported race, in which participants were mostly white .Our primary outcome PCS was reported in 12 studies only, though descriptions and definitions of PCS differed .Symptom severity or scores (rather than presence of a set of symptoms) were reported in 22 studies, using various scales. Recovery was reported in 29 studies. Other outcomes were reported less frequently .Follow-up schedules varied, with 3-month outcomes reported most often (n=43); the longest follow-up was 7 years.Forty-nine risk factors were reported across 73 studies, of which sex , age  and injury mechanism  were most frequently assessed. Fourteen factors were assessed in single studies only .Twelve studies assessed effect of risk factors on PCS occurrence. Evidence was inconsistent for age and sex, assessed in three and four studies, respectively. Premorbid anxiety and depression were assessed in two studies each and were unrelated to PCS in both. All other factors were assessed in single studies , prior cognitive problems, absence of headache at presentation and higher serum S100B after mTBI were linked to poor cognitive outcome in single studies . There were inconsistent effects from different mechanisms of mTBI, although road traffic injuries were found by some to be predictive of poorer outcome. Prior mTBI was unrelated to poor outcomes in 12 out of 18 studies assessing this, and the only outcome it consistently predicted was persistent headaches (n=3).Evidence on all other risk factors was also inconsistent; presence or absence of these factors did not always predict similar outcome patterns across studies. Several injury-related factors are easily measurable at presentation postinjury. However, measurement is often variable, for example, proxy versus self-rated symptoms versus clinician assessment, which may explain inconsistent findings.Blood biomarkers have been increasingly suggested as potential predictors for recovery from mTBI.Most studies relied on retrospective accounts of preinjury difficulties, which have inherent potential for recall bias. From included studies and stakeholder consultations, it seems symptoms commonly reported after mTBI  may already be present prior to injury. Baseline (preseason) testing, as undertaken in some sports in regions such as the USA, allows assessment of change in symptoms on comparable measures and recording of any existing risk factors. Such prospective surveillance  in school level sports and its use in future research can improve reliability of post mTBI findings as new or worse symptoms, facilitating reliable relating of postinjury findings to baseline risk factors. Healthcare services in many settings do not currently follow-up children long-term post-mTBI; were this to happen, the understanding of the natural progression of outcomes following mTBI would be greatly enriched. These measurements could be part of a core outcome set for implementation in the UK and other healthcare systems – either collated by the clinician in Electronic Health Records or by patients/families in a mobile device application (as was done during COVID).We found 15 systematic reviews of one or more risk factors for various mTBI outcomes.This scoping review explored evidence reporting associations of demographic, premorbid and injury-related factors with adverse outcomes following mTBI and whether biomarkers are potential predictors. The inconsistency of findings indicates a need for consensus on definitions underpinning measurement of potential risk factors and outcomes and for studies specifying a priori hypotheses and including baseline measures where feasible. The role of biomarkers appears under-researched as does our understanding of behavioural responses of children, their parents and healthcare providers to post-mTBI symptoms, which may improve our understanding of why such variation has been found to date.This was not a systematic review. As such, we did not perform study bias assessments or pooling of effects across studies. Our aim was to scope existing literature for all factors studied to date as potential risk factors for specific outcomes. While we identified 49 potential factors, the evidence is limited for any of these, and several prespecified potentially relevant factors are missing from existing research. We included all ‘author-defined mTBI’ to scope the full breadth of the evidence, but a disadvantage of this is substantial heterogeneity across studies . We did not address moderate or severe TBI as these often require active management, whereas mTBI is expected to resolve spontaneously. mTBI is especially important to study as this is the severity ascribed to most children, and identifying those who will experience long-term symptoms is challenging for clinicians.In the substantial research on risk factors associated with poor long-term outcomes of mTBI, the three most researched are sex, age and mechanism of injury. However, their effects have been measured variably and do not show a clear pattern. The most commonly reported outcomes of recovery and symptom severity may not be the most important outcomes for clinicians and patients, and a collaborative core outcome set should be developed. Future studies should correlate risk factors with prioritised outcomes in high-quality primary observational studies with follow-up of several months duration. True quantification of the impact of mTBI in childhood will only be possible if preinjury data are routinely collected, either by healthcare systems, organised sports or self-report. Research is also needed to clarify the severity of some risk factor categories, such as some age groups or some injury mechanisms for relationship with worse outcomes.


The eye has anatomical structures that function as robust static and dynamic barriers, limiting the penetration, residence time, and bioavailability of medications administered topically. The development of polymeric nano-based drug-delivery systems (DDS) could be the solution to these challenges: it can pass through ocular barriers, offering higher bioavailability of administered drugs to targeted tissues that are otherwise inaccessible; it can stay in ocular tissues for longer periods of time, requiring fewer drug administrations; and it can be made up of polymers that are biodegradable and nano-sized, minimizing the undesirable effects of the administered molecules. Therefore, therapeutic innovations in polymeric nano-based DDS have been widely explored for ophthalmic drug-delivery applications. In this review, we will give a comprehensive overview of polymeric nano-based drug-delivery systems (DDS) used in the treatment of ocular diseases. We will then examine the current therapeutic challenges of various ocular diseases and analyze how different types of biopolymers can potentially enhance our therapeutic options. A literature review of the preclinical and clinical studies published between 2017 and 2022 was conducted. Thanks to the advances in polymer science, the ocular DDS has rapidly evolved, showing great promise to help clinicians better manage patients. The eye is a complex and delicate organ that is protected by robust anatomical barriers that limit the penetration, bioavailability, and residence time of drugs administered topically. To overcome these challenges, the development of polymeric nano-based drug-delivery systems (DDS) has emerged as a promising solution. These systems can pass through ocular barriers and provide higher bioavailability of administered drugs to targeted tissues, leading to improved therapeutic outcomes. Furthermore, the use of biodegradable polymers minimizes the adverse effects of administered drugs that are not able to decompose naturally, such as the risk of infection, tissue damage, or reaction to toxic byproducts.In recent years, there has been a growing body of research focused on exploring the therapeutic potential of polymeric nano-based DDS for ocular diseases. This review article provides a comprehensive overview of the current state of the field, including the material science aspects of the biopolymers used in DDS. It also highlights the key findings of preclinical and clinical studies conducted between 2017 and 2022. Our review highlights the therapeutic innovations and advances in polymer science that have contributed to the rapid evolution of ocular DDS, and how these systems are well positioned to help clinicians better manage patients with anterior segment diseases and glaucoma particularly. To provide a well-rounded review, this article will also cover non-polymeric nano-based DDS for ocular diseases, comparing and contrasting their features with those of polymeric nano-based DDS.By providing a comprehensive overview of the latest findings in the field, this article provides insights into the current state of the art and highlights the future direction of research in this area.Repetitive drug administrations with high dosages are often required for conventional formulations due to their extremely low bioavailability and fast clearance. This results in reduced patient compliance and can increase systemic side effects. Nano-based drug-delivery systems have the potential to reduce the frequency of administration for eye drops, as well as combine the administration of multiple molecules, resulting in improved patient compliance and better long-term clinical control of the disease. Nanocarriers can incorporate different polymers to increase ocular drug bioavailability. For example, cellulose derivatives are commonly used as viscosity enhancers to increase the retention time of drugs in the tear film without causing blurred vision. Additionally, mucoadhesive polymers can electrostatically bind to negatively charged mucin and reduce their lacrimal clearance. Nanocarrier DDS can transverse the ocular barriers to reach the target site. Some permeation enhancers enable the nanocarriers to open tight junctions between epithelial cells temporarily, while others form highly soluble host-guest complexes that increase hydrophobic and hydrophilic membrane permeability. To prevent the non-specific distribution of ocular drugs, nanocarrier platforms have incorporated targeting moieties to direct their delivery. Moreover, targeted drug-delivery strategies can be responsive to a disease-specific stimulus, which prevents them from releasing the drugs in non-target tissues. Finally, nanocarrier delivery systems can increase the stability of drugs in the eye by reducing their interactions with tear proteins, and also reduce their electrostatic modification by the different pH levels in different eye structures.(1)Uniform nano-size distribution.(2)High stability in biological media.(3)High payload capacity.(4)Advanced bioavailability.(5)Biodegradability and high biocompatibility.(6)Controlled release.(7)Controlled cellular uptake and improved pharmacodynamic effect.(8)Ease of upscaling to bulk manufacturing.(9)Cost-effectiveness.Ideally, nanoparticles are designed to have the following properties :(1)UnifoWhen synthesizing drug-delivery systems, it is challenging to develop a system with all the desired properties for application in different diseases. A key strategy for obtaining such nanocarriers with optimized physiochemical properties  is combining multiple polymers with nano assemblies. Using copolymers has proven to be more advantageous for nanocarrier DDS synthesis compared to homopolymers, proteins, or lipid-based carriers due to their highly tunable association properties, lower toxicity, and ability to functionalize.Many chemical strategies are used to blend polymers into miscible nanostructures. Supramolecular assemblies can be formed by activating functional groups on one polymer and controlling their interaction with other host-guest complexing polymers. This results in the formation of nanocarriers with sponge-like morphologies that can non-covalently interact with guest drug molecules. Using cross-linkers, such as dihydrides, genipin, crown ethers, boronic acids, etc., to hyperlink polymers is an important strategy to form hydrogels. Block copolymerization is a common approach for nanomicelle and nanocapsule synthesis. It usually relies on self-assembly by the unfavorable mixing enthalpy of the polymers in the solution. It is important to note that the morphologies  direct the properties of the nanocarriers. Therefore, maximizing the effectiveness of nanocarriers as drug-delivery systems is crucial to managing their creation.The biodegradability of the polymers used in nanocarrier DDS results in biocompatible metabolites and prevents the adverse effects accompanying surgical removal of non-biodegradable DDS. The morphology of the biodegradable DDS plays an important role in polymer design given its effect on drug release, cell uptake, and diffusion in cell media . FirstlyThe use of biocompatible and biodegradable polymers in ocular drug delivery is becoming increasingly popular. Surface properties such as size and charge can affect the binding of these polymers and differ with each region of the eye. Below are the biopolymers used in ocular drug delivery. Hyaluronic acid is an anionic polymer and one of the main components of the Eukaryotic extracellular matrix. Given their negatively charged surface, this polymer can permeate the retina by not aggregating in the vitreous humor which also contains negatively charged proteins . HyaluroCellulose nanocrystals are stable colloidal dispersions that are rod-shaped and extracted from cellulose fibers. Cellulose-based liquid crystals can self-assemble into nanorods, nanospheres, nanosponges, and nanorods upon functionalization with a copolymer and have shown great potential for ocular drug delivery . Hairy nChitosan is derived from Chitin, which is commonly found in the exoskeletons of many animals. Chitosan requires chemical modification such as acylation, hydroxylation, or esterification to solubilize them in aqueous solutions. Chitosan derivatives are mucoadhesive and possess unique in situ gelling properties, making them suitable for ocular drug-delivery applications with a high potential for advancing glaucoma DDS . It is aAlginate is an anionic copolymer composed of an M unit of β-d-mannuronic acid and a G unit of α-l-guluronic acid units conjugated into a polymer with different GG, MM, and GM proportions. Alginate and chitosan are commonly used in ocular drug delivery as copolymeric nanoparticles since the functional groups on the chitosan derivatives can interact with the eye membranes and can enhance the encapsulation efficiency of alginate . AlginatPoly(lactide-co-glycolic acid) is among the most common polymers used in drug delivery since they are subject to abundant modifications. Their size and surface potential can be enhanced, which selectively alters their membrane permeability. Jiang et al. compared several commonly used PLGA copolymeric nanoparticles and identified that copolymers consisting of hydroxypropyl-β-cyclodextrin and PLGA had the highest entrapment efficiency and trans-ocular permeation . PLGA caPoloxamers are a class of biodegradable, mucomimetic, non-ionic surfactants that are made up of a central block of polyoxyethylene molecules surrounded by two outer blocks of polyoxypropylene molecules. Poloxamer 407 has been approved by FDA as a vehicle for ocular drug delivery and has been used in various ocular formulations such as eye drops, gels, and solutions.Cyclodextrins are cyclic oligosaccharides that consist of glucopyranose units which can form hydrophobic cavities with externally hydrophilic surfaces. Cyclodextrin nanoparticles for drug delivery have been shown to increase the bioavailability of many guests, primarily due to the advantage of using the guest-host chemistry of isolated for unique complexation of different guests. Functionalizing the alcohol groups on the hydrophilic surfaces of cyclodextrins with several molecules can enable their crosslinking and is known to enhance their physiochemical properties. A wide range of cyclodextrin-based formulations has been shown to have great potential for ocular drug delivery .Nano-based DDS have been designed to improve sustained and targeted drug delivery to various targets within the eye. The characteristics of these systems are outlined in Nanomicelles are spherical structures formed by surfactant molecules that self-assemble in polar solvents such as water. With the hydrophobic tails of the surfactant pointing inward and the hydrophilic heads facing outward, nanomicelles are ideal for encapsulating hydrophobic compounds and targeted delivery to specific locations in the body. Higher encapsulation capacity is achieved by increasing the concentration of amphiphilic polymers, while polymeric micelles exhibit a lower critical micelle concentration and a more stable shape. Enhancing ocular micro adhesion through the addition of mucin-targeting moieties (such as cyclic peptide ligand and phenylboronic acid) has been demonstrated . The shrNanomicelles have been developed not only to enhance corneal penetration but also to target the posterior segments of the eye. In vivo studies have demonstrated the efficacy of chitosan oligosaccharide-valylvaline-stearic acid nanomicelles in reaching the posterior segments through the conjunctival route .Liposomes are a commonly used formulation in ocular drug delivery, known for their advantageous precorneal penetration and rapid conjunctival uptake ,26. ThesNanoparticles have gained significant attention as a strategy for solubilizing host molecules due to their ability to form supramolecular assemblies. These assemblies are made up of molecular subunits held together by various forces such as van der Waals forces, hydrophobic interactions, electrostatic interactions, hydrogen bonding, and cation–π interactions .The reduced size and lack of aggregation in dispersed nanoparticles increase their carrying efficiency, enabling them to transport a greater number of drugs to the target tissue . AdditioNanoparticles can be designed with various self-assembling topologies, such as nanospheres, nanorod assemblies , and nanNanocapsules offer a promising solution for ocular drug delivery. Their core consisting of the drug and the protective polymer coating enables them to penetrate the eye’s barriers effectively and reach the target tissue. This enhances the drug’s efficacy and extends its residence time in the eye. The versatility of nanocapsules has been demonstrated in the successful delivery of various drugs, including anti-inflammatory and anti-glaucoma agents . With thSolid Lipid Nanoparticles (SLNPs) are a promising drug-delivery system composed of a solid lipid core surrounded by a stabilizing surfactant. This unique structure offers several advantages over traditional liposomes and microemulsions, including improved stability, increased drug loading capacity, and an easier manufacturing process. SLNPs also show higher thermal stability and longer shelf life compared to other types of nanoparticles .Dendrimers are a type of repeating multibranched polymers that feature a dense core and functional groups attached to the surface. Dendrimers are formed of radially symmetric and branched molecules that cross-link several spherical layers. Growing outwards, the core interacts with monomers containing one reactive and two dormant groups, which activates a cascade reaction to form peripheral branches. They can encapsulate different drugs in their large central core. Due to their structure, dendrimers exhibit a high encapsulation efficiency and well-defined biodistribution, making them a promising candidate for ocular drug-delivery systems (DDS). Their core-shell architecture and narrow polydispersity allow for the creation of dendrimer hydrogels, which can be adjusted for crosslinking and gel properties by controlling reactant concentration or functional group density on the dendrimer surface. These hydrogels have been shown to have large internal hydrophobic pores and high loading capacity, making them a valuable tool in ocular drug delivery ,36,37.Hydrogels are attracting attention for their potential in ocular drug delivery. Various chemical and physical crosslinking between copolymers allow for the formation of molecules with large water-accommodating pores. The surface polarity and solubility of the chosen polymers typically influence the morphology of the pores. To match the body’s physiological needs, polyacrylic acid is used in combination with pH-responsive polymers that allow for controlled and sustained drug release at a pH of 5.5. Different chemical modifications, such as amine, ortho ester, imine, and hydrazone, can alter the pH sensitivity of these hydrogels. Other polymers, such as cellulose, chitosan, N-isopropylacrylamide, poloxamers, PLGAs, and PEGs, are used to create thermo-responsive hydrogels that are injectable at room temperature and turn into gels at higher temperatures . UltrasoThe extended drug release profile of hydrogels reduces the frequency of intravitreal injections and allows for targeted delivery to the site of action in the posterior segments of the eye. By incorporating targeted moieties and drugs into the hydrogel in its sol state, the risks associated with frequent injections are minimized.Nanosuspensions and nanoemulsions have been widely accepted as DDS for ocular drug delivery. According to Nagai and Otake (2022), they can effectively deliver poorly soluble and permeable drugs. Among nano-based biodegradable DDS, nanoemulsions have been widely approved for ocular drug delivery. Nanoemulsions are small droplets of one liquid dispersed in another liquid, which can improve the solubility and stability of poorly soluble drugs and make them suitable for ocular administration. The use of amphiphilic salts of cholesterol in nanoemulsions has been found to greatly stabilize the formulations and make them effective for delivering antiglaucoma, anti-inflammatory, and antiviral drugs . By incrNanosuspensions, on the other hand, are aqueous dispersions of insoluble drug particles stabilized by surfactants. They are especially useful for delivering drugs with large molecular weights and high melting points or drugs that are unable to form salts . NanosusMicroneedles have shown their potential to deliver ocular drugs to specific eye segments, such as the subarachnoid and posterior regions. This method offers several benefits compared to subconjunctival injections, such as improved accuracy in target delivery, ease of self-administration, and reduced risk of complications that can affect the integrity of the eye barriers. Furthermore, by using hollow microneedles, higher concentrations of drug molecules can be delivered, which can be controlled by adjusting the copolymer grafting ratios .Ocular drugs can be administered via several routes, including topical, subconjunctival periocular, intravitreal, and systemic delivery. The three main routes for delivering drugs to the back of the eye are topical, systemic, and intravitreal. Topical application is the simplest method and is commonly used, but only about 5% of the applied dose can penetrate the internal structures of the eye due to barriers such as the tear film, cornea, conjunctiva, vitreous, blood–aqueous barrier, and blood–retina barrier   management is the cornerstone of treatment for glaucoma. With the aim of reducing intraocular pressure (IOP), there has been a recent surge in the use of nanocarriers to enhance ocular drug delivery. This development is particularly significant as the long-term use of conventional IOP-lowering agents, which are based on poorly penetrating molecules, can cause frequent ocular toxicity and intolerance due to their adverse effects on the corneal epithelium .One advantage of nanoparticles is the ability to modify them with biodegradable polymers, which can enhance the bioavailability of the drug they are delivering. This is especially important for glaucoma drugs such as brinzolamide, which has low solubility and thereby limits its therapeutic efficacy. Various studies have formulated PLGA-modified (Polylactic-co-glycolic acid) nanoparticles to have a sustained release of brinzolamide that significantly reduced IOP in animal models with minimal toxicity ,46,47. SOther polymers recently used for forming nanoparticles are γ-cyclodextrin  and chitAlthough Mesoporous Silica Nanoparticles (MSNs) have poor degradability given a pure silica framework, some studies have recently modified MSNs to achieve biodegradation suitable for clinical application. Fan et al. (2021) used biodegradable hollow mesoporous organosilica (HOS) nanocapsules to deliver NO in a stimulus-responsive manner for improved penetration and bioavailability . AlthougNiosomes are lipid-based vesicular systems, providing improved residence time and corneal permeation as a DDS. Zafar et al. (2021) created a chitosan-coated niosome, improving biodegradability and bioadhesion, to deliver carteolol (CT) . SimilarCubosomes are formed by a continuous lipid bilayer, similar to the structure of cell membranes of the corneal epithelium. It has therefore been investigated as a possible DDS for ocular delivery. Teba et al. (2021) used a novel cubosome system to deliver acetazolamide, with improved corneal permeation, ocular residence time, and no signs of ocular irritation . SimilarNanoemulsions are nanoscale droplets capable of carrying both hydrophilic and hydrophobic materials. They have been reported to be feasible carriers of travoprost and brinzolamide, enhancing drug absorption and prolonging IOP-lowering effects ,64. HoweTo improve treatment adherence and decrease the frequency of administration, optimizing ocular inserts using nano-based carriers has been a common focus of research in ocular pharmacology. Several studies have used chitosan, a highly biodegradable polymer, to develop ocular inserts and films for topical delivery. Modifications were carried out to improve the solubility of chitosan, such as the addition of chondroitin sulfate and hydroxyethyl cellulose ,66; thesNanomicelles have been used to co-deliver latanoprost and timolol through a drug-laden contact lens developed by Xu et al. (2019) . The autHydrogels have been extensively researched as a promising ocular delivery system, given their properties of in situ sol-to-gel formation triggered by environmental factors such as pH, temperature, etc. . HoweverLiposomes can carry both hydrophilic and hydrophobic drugs and are highly biodegradable nanocarriers. Jin et al. (2018) presented a TPGS-modified (tocopheryl polyethylene glycol succinate) liposome carrier for brinzolamide with a greater sustained release and maintained IOP reduction, with no significant side effects . HoweverPAMAM (polyamidoamine) dendrimers have been used for the sustained release of timolol with no signs of cytotoxicity or ocular irritation in vitro. Further studies with in vivo models for safety and pharmacokinetic profiling are required to optimize drug loading as well as investigate the effects of chronic application . LancinaOther notable DDS systems include self-assembly drug nanostructures (SADN)  and phasInterestingly, a drug-free, non-surgical method of reducing IOP was proposed by Chae et al. (2020), where they use a hyaluronic acid hydrogel microneedle injection to expand the suprachoroidal space . This meSeveral studies have recently modified existing DDS such as microspheres ,93, soliAlthough solid formulations  for ocular delivery are beneficial in terms of prolonged ocular residence, there is a need to avoid having them interfere with patients’ vision and improve comfort. Recent DDS studies propose the use of electrospinning biodegradable polymers that are more adaptable and rapidly dissolve in the cornea due to their highly porous structure. Andreadis et al. (2022) created an in situ electrospun film gel for the delivery of timolol maleate , and simTM). Notably, 16 patients with Primary Open Angle Glaucoma (POAG) and 13 patients with ocular hypertension were enrolled; however, the control group had a small sample size of 5. Given the biodegradability of chitosan, the insert did not need to be removed from the patients afterwards. This was a safety study, where the insert did not cause any major side effects, visual acuity changes, or central corneal thickness. The insert provided an IOP reduction of 30% by the third week, compared to the 35% reduction with eye drops. This study confirmed a better therapeutic regime, changing from daily dosage to using inserts in 3-week intervals, improving patient compliance [To improve sustained release while limiting systemic exposure, Rubiao et al. (2021) conducted a Phase 2 controlled study comparing a bimatoprost topical chitosan-based insert to conventional bimatoprost eyedrops  [FDA-approved in 2020, Durystaettings) . It is pettings) . It has ettings) . There iettings) ,103, impThe sustained release of bimatoprost was also investigated through an ocular ring in double-masked randomized Phase 2 clinical trials by Brandt et al. (2017) . The lonTM). Assessed at days 14 and 28, a greater reduction in IOP was found in the DRZ-nanoliposomes group with extended release and higher intensity postulated to be due to increased adhesion and corneal permeation with the liposome delivery system. Any irritation or redness reported was similar between both groups, commonly caused by dorzolamide itself. This can possibly improve treatment outcomes by reducing the frequency of administration without reducing efficacy.A randomized controlled trial was conducted by Kouchak et al. (2017) on patients with OAG and OH to investigate the effects of dorzolamide nanoliposomes (DRZ-nanoliposome) on IOP . Twenty Although conventional therapeutic strategies towards treating glaucoma are decreasing IOP, this remains inadequate in addressing the permanent damage to retinal ganglion cells (RGCs) and the optic nerve in advanced diseases. There are also forms of normotensive glaucoma, and cases of controlled IOP where visual loss progresses . TherefoTM synthetic clay, composed of nanoscale crystals and capable of controlled release of drugs [Beginning with a drug treatment previously discussed, in addition to its clinical use in reducing IOP, brimonidine also exhibits neuroprotective effects by regulating excitatory NMDA receptors in RGCs . To improf drugs . Both syGiven that neurotrophic factors cannot cross the blood–retinal barrier and degrade rapidly, some studies investigate the delivery of neurotrophic factors (NFs) to prevent retina damage in glaucoma models. Yang et al. (2021) delivered CTNF and oncostatin M (OSM) successfully with nanoparticles, improving RGC survival and preservation of vision and photoreceptors . SimilarHydrogels have also been used to provide a sustained release and improve the bioavailability of neuroprotective drugs. The use of biodegradable chitosan thermogel was used to deliver pilocarpine and RGFP966, an HDAC inhibitor known to protect RGCs from apoptosis and optic nerve damage . The theCannabinoids have also exhibited a neuroprotective effect; however, poor delivery to the posterior eye limits their therapeutic efficacy. Kabiri et al. (2018), used an HA-MC thermosensitive hydrogel laden with cannabigerolic acid (CBGA) nanoparticles . This meVarious studies have used nanoparticles as their DDS for neuroprotective agents. Memantine, an NMDA antagonist, was loaded on biodegradable PEGylated nanoparticles, reporting enhanced delivery and reduced RGC loss . An admiLi et al. (2020) used biodegradable PEG-based nanoparticles for the co-delivery of brinzolamide and miR-124, a miRNA known for its anti-inflammatory and neuronal differentiation effects . This coAnother notable DDS-delivering neuroprotective agent is a microcrystal proposed by Hsueh et al. (2021), which contained sunitinib, an FDA-approved multi-kinase inhibitor that promotes the survival of RGCs . They acCurrent therapeutic trials targeting neuroprotection for glaucoma have been finding difficulty in replicating the in vivo efficacy in humans. Primarily, this could be due to the use of acute damage animal models injuring the optic nerve and RGCs, whereas the progression of glaucoma in humans is chronic and prolonged, yielding differing neuronal dysfunction . CurrentTM was recently used in a beagle in vivo model to investigate whether the sustained release of bimatoprost aided in IOP-lowering post-selective laser trabeculoplasty (SLT) in the study performed by Ghosn et al., 2022 [Nano-based DDS can also be used to improve anti-fibrotic, anti-inflammatory, and sustained IOP-lowering effects after glaucoma filtration surgeries and laser trabeculoplasty (SLT). As previously mentioned, an FDA-approved bimatoprost implant, Durystal., 2022 . This stAnother implant considered for use after glaucoma surgery is a collagen matrix implant loaded with bevacizumab and sodium hyaluronate developed by Andres-Guerrero et al. (2021) . This imMitomycin C (MMC) and 5-Fluorouracil (5-FU) are commonly applied after filtration surgery to prevent scarring. A PLGA film containing MMC, and 5-FU was formulated by Swann et al. (2019). This provided anti-fibrotic treatment post-trabeculectomy, with a sustained release of both drugs in low dosages. Long-term studies to further elucidate the safety of this system are required. Vildanova et al. (2022) developed a biodegradable modified chitosan and HA hydrogel to improve sustained delivery of MMC and 5-FU . CurrentThe gelatin-based hydrogel was used by Chun et al. (2021) to deliver siRNA (siSPARC) to reduce subconjunctival scarring post-trabeculectomy . siSPARCTM eye drops. Some limitations include their small sample size and patients being unmasked toward treatment type. Altogether, given the risks and complications associated with MMC administration, this nanoparticle system was able to localize and limit the exposure within the eye, providing a potentially safer alternative to MMC post-glaucoma surgery.The literature search yielded one recent clinical study pertaining to improving drug-delivery post-glaucoma surgery. Johannesson et al. (2020) used dexamethasone nanoparticles (DexNP) to deliver MMC post-trabeculectomy in a randomized, single-masked clinical trial . With a Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial condition characterized by insufficient or poor-quality tears that result in discomfort, visual disturbances, and instability of the tear film. This can lead to inflammation of the eye surface and cause damage to the ocular surface. It is often accompanied by an increased osmolarity in the tear film. Dry eye disease can be caused by a number of factors, including aging, certain medical conditions such as Sjogren’s syndrome, medications, environmental factors, lifestyle habits, and hormonal changes. Pharmacologic therapies for DED can range from mild cases, such as artificial tears and ointments, to more severe cases requiring topical corticosteroids, immunosuppressants, and autologous tear therapies. The pharmacological treatment options for dry eye disease (DED) vary depending on the severity of the condition. Mild cases may be managed with artificial tears and ointments, while more severe cases may require the use of topical steroids, immunosuppressants, or autologous tear therapy. Each of these treatments has its own limitations and drawbacks. For example, artificial tears need to be applied multiple times per day and rely on the compliance of the patient. Long-term use of topical steroids can cause side effects such as increased intraocular pressure and cataracts, and autologous tear therapy is both costly and involves multiple visits to a healthcare setting for blood draws. Moreover, DED itself can affect ocular drug delivery by reducing the residence time of topically applied drugs and increasing the risk of systemic absorption. DED can also increase the rate of tear turnover which can further reduce the efficacy of topical medications. To maintain a healthy ocular surface and improve drug delivery, other therapeutic strategies have been developed.TM and RestasisTM have also been approved for dry eye disease due to their highly solubilized state and their stability improvement. The delivery of the drug to ocular tissue remains hampered by its high molecular weight and its higher affinity with the oil phase of the nanoemulsion. Recently, the use of CequaTM, a nanomicelle solution containing cyclosporine A, has been shown to treat dry eye diseases. After 84 days of treatment, patients have reported increased tear production and improved ocular surface integrity [TM nanomicelles are amphiphilic surfactants that can increase the dissolution of the hydrophobic cyclosporine A, and its penetration through the tear film and other anatomical barriers of the eye. Recently, KPI-121, a mucin-penetrating particle (MPP) for the delivery of loteprednol etabonate has been approved by the FDA for the treatment of dry eye disease. The nanosuspension (roughly 300 nm) was developed by a milling procedure containing loteprednol etabonate and Pluronic F127 polymer. This delivery system showed a significant advantage over the conventional loteprednol formulation in a New Zealand white rabbit model. KPI-121 achieved a higher ocular exposure with peak concentrations of approximately threefold higher in ocular tissues than the conventional formulation with a single topical delivery [Currently, nanoemulsions encapsulating cyclosporine A such as Cyclokatntegrity . CequaTMdelivery ,146. Thedelivery . The phadelivery . The F12delivery .Several novel biodegradable nano-sized DDS have recently been investigated in clinical trials. They aim to reduce the frequent administration times of currently used DDS and to increase the bioavailability of guest drugs at the target site of action. To achieve long-term controlled drug delivery of cyclosporine A, Mun et al. (2019) have synthesized cholesterol-hyaluronate nanomicelles. Crosslinking the nanomicelles using ethylene glycol dimethacrylate and hydroxyethyl methacrylate resulted in the formation of contact lenses that showed a prolonged therapeutic effect on a dry eye disease rabbit model . Novel nRebamipide has been demonstrated to increase mucin and lipid layers of the tear film and reduce ocular surface dryness. Clinically, rebamipide eye drops have been found to treat tear deficiency and corneal epithelial damage caused by a lack of mucin. Novel drug-delivery systems are being investigated to evade nasolacrimal clearance and increase drug compliance by altering its opaque and turbid appearance. Copolymeric nanoparticles have been developed by Nagai et al., from 2-hydroxypropyl-β-cyclodextrin and methylcellulose and had a more sustained release compared to the commercially available formulation. The use of nanoparticles allows for improved delivery to the goblet cells and meibomian glands, leading to increased stimulation of mucin and lipid production . AnotherRecently, Wang et al. have reported the synthesis of rapamycin nanospheres based on 3- hydroxybutyrate-co-3-hydroxyvalerate copolymers. Unlike the currently available rapamycin ocular formulations, these nanospheres can penetrate the tear film barrier effectively. They have been shown to increase tear meniscal height, decrease tear break-up time, and improve Schirmer’s test scores, suggesting that they may be advantageous for Sjögren-associated dry eye disease . HoweverLuo et al. synthesized a novel thermo-responsive in situ gel by functionalizing poly(N-isopropylacrylamide) with mucoadhesive gelatin and helix pomatia. One-time use of the gel in a rabbit dry eye disease model increased the drug  bioavailability on the ocular surface beyond the therapeutic level for 14 days .Mucolytic agents are a class of drugs that typically function by reducing mucus viscosity and inhibiting inflammatory cascades. Typically, mucolytic agents are synthetic polymers that have a thiol group, enabling them to break the disulfide bonds in mucoprotein complexes. Other types of mucolytic agents include enzymes such as papain or bromelain, which have been used as they can cleave the cross-links of mucus glycoproteins. By modifying nanocarriers with mucolytic agents, a controlled drug release, enhanced permeation, and improved mucoadhesion can be achieved. Although there has been research on the development of mucolytic enzyme-loaded nanoparticles for penetrating intestinal mucous layers, studies for ocular delivery are currently limited .TM) for patients with dry eye disease and found a sustained improvement over a 1-month period of treatment. This was indicated by an increase in intact corneas by 64%, an increase in Schirmer’s score by 68%, and an increase in tear break-up time by 50%. Thiolated polymers also have the advantage of being able to bind with positively charged glucosamine as well as negatively charged carboxylic acids in mucosal proteins. This is because they can form amidine bonds in the case of cationic targets as well as sulfhydryl bonds in the case of anionic targets [N-acetylcysteine (NAC) is a mucolytic agent that has been used to treat various anterior segment diseases including cataracts, DED, and filamentous keratitis. NAC is administered via intracorneal injections and is associated with side effects including edema, sloughing, and corneal haze due to the rapid mucolytic activity of NAC. Therefore, integrating them with biodegradable polymers (thiolated polymers) may improve this by achieving a controlled, sustained release. For example, the functionalization of NAC with chitosan has been an attractive strategy for forming highly mucoadhesive copolymers for ocular drug-delivery systems. By optimizing the concentration of NAC on the surface of chitosan, the thiol groups of NAC can form covalent bonds with cysteine-rich mucosal glycoproteins . Nepp et targets . This ma targets . However targets .TM) and its nanomicelle form (CequaTM) are the two most used topical medications by ophthalmologists in North America. Overall, these novel DDS offer promising results in increasing drug bioavailability and reducing the need for frequent administration. This translates clinically into improved symptom management, greater compliance, and fewer side effects.In short, there are several novel drug-delivery systems (DDS) that have been developed to treat dry eye disease. Among these DDS, the nanoemulsions encapsulating cyclosporine A (RestasisMeibomian gland dysfunction (MGD) is a condition characterized by decreased secretion or blockage of the meibomian glands. This disruption of meibomian gland function can negatively impact both the quality and quantity of the meibum secreted, leading to changes in tear film composition, particularly the lipid layer of the tear film, and subsequent issues such as increased tear evaporation, hyperosmolarity, inflammation, and damage to the ocular surface. Currently, the main treatment strategies for MGD involve a combination of heat therapy, massage, and lid margin hygiene. Artificial tears and topical steroids can provide relief for symptoms of dry eye and ocular irritation, but their effectiveness may be limited by low patient compliance.2O2 concentrations. Moreover, in vivo experiments demonstrated that contact lenses had protective effects in a mouse model when 3% H2O2 eyedrops were administered [Chronic inflammation and oxidative stress play a critical role in the development and progression of MGD . Thus, pnistered .TM, Taejoon, Korea) have been investigated in Phase 3 clinical trials for the treatment of MGD. Nanoemulsions maintain optical transparency and are considered more thermodynamically stable compared to normal emulsions. The trial concludes that cyclosporine nanoemulsions show significant improvement in dry eye disease progression secondary to MGD compared to the control group. The group receiving cyclosporine nanoemulsions had better corneal staining and increased lipid layer thickness after one month of treatment compared to the group receiving the conventional cyclosporine formulation [Recently, nanoemulsions encapsulating cyclosporine A  are advantageous for encapsulating lipophilic molecules inside the lipid matrix, which improves drug solubility. The solid lipid nanoparticle in situ gels demonstrated thermo-responsive gelation at 32 degrees and had advantageous therapeutic effects in vivo compared to conventional conjunctivitis eye drops .To prolong the release of topical antibiotics in the treatment of bacterial conjunctivitis, several novel DDS are being investigated in vitro and in vivo. Chitosan and PVA nanofibers have been designed to encapsulate ofloxacin. The linking of the nanofibers by glutaraldehyde vapor could reduce the burst release of ofloxacin and significantly increase its bioavailability compared to the currently available suspensions . AnotherKeratoconus is a progressive eye condition in which the normally round cornea becomes thin and cone-shaped. This shape change can lead to distorted vision, nearsightedness, and irregular astigmatism. Early treatment, such as rigid contact lenses or corneal crosslinking (CXL), can help slow the disease process. Corneal crosslinking (CXL) is a surgical procedure that aims to strengthen the cornea by creating new chemical bonds within the cornea’s collagen fibers. It involves performing an epithelial debridement with a blade, applying riboflavin drops to the eye, and subsequently exposing the cornea to ultraviolet light. The traditional CXL technique has a limitation in that the cornea must be of a certain thickness to avoid making the cornea even thinner during the epithelial debridement step, which can lead to postoperative corneal ectasia. Fortunately, advanced drug-delivery systems can potentially eliminate the need for mechanical epithelial debridement, reducing the risk of complications and making the procedure safer, especially in patients with thin corneal thickness. In fact, the advanced nano-sized DDS can penetrate the cornea and target the photosensitizing agent directly to the cornea’s deeper layers.Nanocarriers loaded with riboflavin have been studied for their ability to penetrate the tear film and corneal epithelium and reach the corneal stroma. Nanostructured lipid carriers, consisting of a solid lipid matrix with liquid lipid, have advantages over solid lipid nanoparticles, such as improved stability and loading capacity. These nanostructured lipid carriers have been loaded with riboflavin and displayed advantageous sustained release compared to eye drops and solid lipid nanoparticle formulations . AnotherThe delivery of certain peptides might be important for modifying keratoconus disease mechanisms. However, with the lack of appropriate DDS, the rate of diffusion and residence time of peptides in the cornea are the major barriers to their therapeutic efficacy. Copolymeric nanoparticles from chitosan-tripolyphosphate and chitosan-Sulfobutylether-β-cyclodextrin have been synthesized for the delivery of lactoferrin, a peptide that can potentially promote corneal healing. The nanoparticles displayed advantageous mucoadhesive properties that allowed them to achieve an ocular retention time of more than 240 min .Keratitis is an inflammation of the cornea. The causes of keratitis can range from infectious origins  to autoimmune etiologies . In severe cases, it can lead to corneal melting, perforation, or scarring resulting in severe vision loss, making prompt and proper treatment important. The treatment of keratitis varies according to its etiology, with options including but not limited to topical corticosteroids, antibiotics, and immunomodulatory agents.The only polymeric DDS approved for the treatment of keratitis is a gel formulation synthesized from sodium hydroxide, mannitol, and benzalkonium chloride for the delivery of ganciclovir . The gelTM eye drops with minimal in vivo toxicity [Levofloxacin is a broad-spectrum antibiotic used to treat infectious keratitis. To enhance its precorneal residence time, Jain et al. designed an in situ gel from hydroxypropyl methylcellulose and sodium alginate. The hydrogels spontaneously self-assemble at corneal pH and had a higher permeation compared to marketed Quixintoxicity .Amphotericin B is a polyene antibiotic that can self-aggregate, resulting in reduced bioavailability and reduced biocompatibility. Poly(vinylpyrrolidone) and polyvinyl alcohol microneedles have recently been developed for the ocular delivery of amphotericin B. Microneedles offer an improved solution for amphotericin B ocular treatment as they do not contain deoxycholate, eliminating the painful side effects associated with current options. Moreover, the microneedles were more effective in targeting Candida species compared to the liposomal amphotericin B formulation . AnotherCataract surgery, the replacement of the diseased lens with a synthetic intraocular lens, remains the treatment of choice for cataracts. It is a commonly performed procedure with a high success rate. However, like all surgical procedures, it can carry certain risks and complications, such as corneal edema, cystoid macular edema, endophthalmitis, and retinal detachment. The FDA has approved the use of topical NSAIDs for the prevention of postoperative cystoid macular edema . However3 that can potentially reduce the reactive oxygen species around the lens. Mesoporous silica nanoparticles have several advantages in drug-delivery applications due to their highly tunable pore characteristic. However, the formulations were designed as systemic injections and the non-biodegradable nature of silica would result in the persistence of toxic metabolites in the blood [The use of silver moieties in the synthesis of nanoparticles has been explored for enhancing the topical delivery of drugs, including antioxidants. This approach aims to improve the bioavailability of the antioxidants, thereby potentially offering a new avenue for the treatment of cataracts ,181. Thihe blood ,184. TheA PLGA-based nanoformulation was recently prepared by Liu et al., to combine antioxidant curcumin and cerium oxide nanoparticles. The prepared nanoformulation could have effective antioxidant and anti-glycation potential to protect lens epithelial cells. Interestingly, the nanoformulations showed lower in vivo toxicity and increased cerium nanoparticle bioavailability in the rat eye compared to subcutaneous injections . AnotherRecently, chitosan conjugated with NAC has been used as a biodegradable nanocarrier for the delivery of drugs to the anterior segment. Lan et al. have developed nanoparticles that incorporate chitosan-NAC with hydroxypropyl β-CD. The inclusion complexes of β-CD were used to encapsulate and deliver quercetin, which has been used in the treatment of cataracts. The nanoparticles enhanced the permeability of quercetin and allowed for its delivery deeper into the corneal epithelium .The use of biodegradable gels is also an attractive DDS for cataracts due to their prolonged contact with the target membrane allowing for the build-up of significantly higher amounts of permeated drug at the site of administration while maintaining the drug in its bioactive form. Bodoki et al. have used biodegradable nanoparticles composed of zein and PLGA to deliver the antioxidant Lutein to prevent the progression of cataract disease. In vivo experiments showed a significant reduction in cataract severity in rats topically treated with lutein-loaded NPs compared to the positive control .In conclusion, the development of polymeric nano-based drug-delivery systems (DDS) offers promising solutions to the challenges posed by the anatomical barriers of the eye in the treatment of anterior segment diseases and glaucoma. Our literature review of the latest published studies highlights the advances in polymer science and the key findings that have contributed to the progress of these systems.The use of biopolymers in the design of DDS offers the potential to enhance therapeutic options and better manage patients with anterior and glaucomatous diseases. The high bioavailability and longer residence time of these polymeric nanocarriers in ocular tissues, combined with their biodegradable nature, make them an attractive alternative to conventional treatments for ocular pathologies.This review highlights the current state of the field and provides insights into the future direction of research in this area. As the field continues to advance, we can expect to see further therapeutic innovations in polymeric nano-based DDS and a greater understanding of the material science aspects that are crucial for their design and development. The potential benefits of polymeric nano-based DDS in improving patient outcomes make them an exciting area of ongoing research and development.