Research Progress of Polymer Biomaterials as Scaffolds for Corneal Endothelium Tissue Engineering.

Nowadays, treating corneal diseases arising from injury to the corneal endothelium necessitates donor tissue, but these corneas are extremely scarce. As a result, researchers are dedicating significant efforts to exploring alternative approaches that do not rely on donor tissues. Among these, creating a tissue-engineered scaffold on which corneal endothelial cells can be transplanted holds particular fascination. Numerous functional materials, encompassing natural, semi-synthetic, and synthetic polymers, have already been studied in this regard. In this review, we present a comprehensive overview of recent advancements in using polymer biomaterials as scaffolds for corneal endothelium tissue engineering. Initially, we analyze and present the key properties necessary for an effective corneal endothelial implant utilizing polymer biomaterials. Subsequently, we focus on various emerging biomaterials as scaffolds for corneal endothelium tissue engineering. We discuss their modifications (including natural and synthetic composites) and analyze the effect of micro- and nano-topological morphology on corneal endothelial scaffolds. Lastly, we highlight the challenges and prospects of these materials in corneal endothelium tissue engineering.

TIPE2 Inhibits MGD Inflammation by Regulating Macrophage Polarization.

BACKGROUND: The aim of this study was to decide the role of the polarization of macrophages regulated by tumor necrosis factor-α (TNF-α)-induced protein 8-like 2 (TIPE2) in meibomian gland dysfunction (MGD). METHODS: Firstly, the secretory function of the meibomian gland (MG) in apolipoprotein E knockout (ApoE-/-) MGD mice and normal mice was detected by oil red staining. Then, the expression levels of markers of M1 and M2 macrophages were detected by immunofluorescence staining in MGD, normal mice, and mild and severe MGD corpses to decide the role of M1 and M2 macrophages in MGD inflammation. Meanwhile, the expression levels of TIPE2 in MGD mice and MGD patients were detected by immunofluorescence staining, and the correlations among TIPE2, M1 and M2 macrophages were analyzed by immunofluorescence double staining in MGD mice and MGD patients. Furthermore, lipopolysaccharide (LPS) and interleulkin-4 (IL-4) were used to induce M1 and M2 polarization of macrophages, and the mRNA level of TIPE2 was detected in M1 and M2 macrophages. RESULTS: Oil red staining showed that eyelid fat congestion was more severe in (ApoE-/-) MGD mice than in normal mice, and the M1 macrophage was the primary inflammatory cell infiltrated in (ApoE-/-) MGD mice (p < 0.05). The results of the immunofluorescence staining showed that the infiltration of macrophages in MGD mice was more obvious than that in the normal group, and M1 macrophage was the dominant group (p < 0.05). Similar to the results of the MGD mouse model, more macrophage infiltration was observed in MGD patients' MG tissues, and there were more M1 cells in the severe group than in the mild group (p < 0.05). Moreover, the expression of TIPE2 was positively correlated with the expression of M2 macrophages in MGD patients and mice MG tissues (p < 0.05). The expression of TIPE2 mRNA in LPS-induced M1 macrophages declined, while the expression of TIPE2 mRNA in IL-4-induced M2 macrophages increased (p < 0.05). CONCLUSION: M1 macrophage was the dominant group infiltrated in the MG tissue of MGD, and TIPE2 is a potential anti-inflammatory target for preventing the development of MGD by promoting the M2 polarization of macrophages.

WNT16b promotes the proliferation and self-renewal of human limbal epithelial stem/progenitor cells via activating the calcium/calcineurin A/NFATC2 pathway.

Our previous finding revealed that WNT16b promoted the proliferation of human limbal epithelial stem cells (hLESCs) through a ß-catenin independent pathway. Here, we aimed to explore its underlying molecular mechanism and evaluate its potential in the treatment of limbal stem cell deficiency (LSCD). Based on the findings of mRNA-sequencing, the expression of key molecules in WNT/calcineurin A/NFATC2 signalling pathway was investigated in WNT16b-co-incubated hLESCs and control hLESCs. An epithelial wound healing model was established on Wnt16b-KO mice to confirm the regulatory effect of WNT16b in vivo. The therapeutic potential of WNT16b-co-incubated hLESCs was also evaluated in mice with LSCD. Our findings showed that WNT16b bound with Frizzled7, promoted the release of Ca2+ and activated calcineurin A and NFATC2. With the translocation of NFATC2 into cell nucleus and the activation of HDAC3, WDR5 and GCN5L2, the expression of H3K4me3, H3K14ac and H3K27ac in the promoter regions of FoxM1 and c-MYC increased, which led to hLESC proliferation. The effect of the WNT16b/calcium/calcineurin A/NFATC2 pathway on LESC homeostasis maintenance and corneal epithelial repair was confirmed in Wnt16b-KO mice. Moreover, WNT16b-coincubated hLESCs could reconstruct a stable ocular surface and inhibit corneal neovascularization in mice with LSCD. In conclusion, WNT16b enhances the proliferation and maintains the stemness of hLESCs by activating the non-canonical calcium/calcineurin A/NFATC2 pathway in vitro and in vivo, and accelerates corneal epithelial wound healing.

WNT16B enhances the proliferation and self-renewal of limbal epithelial cells via CXCR4/MEK/ERK signaling.

Culture of limbal epithelial cells (LECs) provides the principal source of transplanted limbal stem cells (LESCs) for treatment of limbal-stem-cell deficiency. Optimization of the culture conditions for in-vitro-expanded LECs will help to create a graft with an optimized quality and quantity of LESCs. This study aimed to investigate the effects of WNT16B on LECs and corneal wound healing and the underlying mechanism. Treatment with exogenous WNT16B increased the proliferative capacity and self-renewal of LECs in the cultures. We further revealed that C-X-C chemokine receptor type 4 (CXCR4) was vital for the effects of WNT16B, and activation of CXCR4/MEK/ERK signaling was pivotal in mediating the effects of WNT16B on LECs enriched for LESCs. The stimulatory effect of WNT16B on corneal epithelial repair was confirmed in a mouse corneal-wound-healing model. In summary, WNT16B enhances proliferation and self-renewal of LECs via the CXCR4/MEK/ERK signaling cascade and accelerates corneal-epithelial wound healing.

Analysis of the first tear film break-up point in Sjögren's syndrome and non-Sjögren's syndrome dry eye patients.

BACKGROUND: Tear film instability plays an important role in the course of Sjögren's Syndrome dry eye (SSDE) even though it is generally classified as aqueous-deficient dry eye. The measurement of the first tear film break-up point (FTBUP) helps to evaluate the most unstable position of the tear film on ocular surface. We aim to investigate FTBUP in Sjögren's Syndrome dry eye (SSDE) and non-Sjögren's Syndrome dry eye (NSSDE) patients, and explore its correlation with dry eye indices. METHODS: Twenty-two SSDE patients (44 eyes) and 22 NSSDE patients (44 eyes) were enrolled in the study. Oculus Keratograph K5M was used to measure FTBUP, the first and average non-invasive keratographic breakup time (f-NIKBUT and av-NIKBUT), the tear meniscus height, and meibomian gland dropout. Other tests of tear film were also performed including Ocular Surface Dryness Index (OSDI), Schirmer I test, fluorescein break-up time and corneal fluorescein staining. Dry eye indices and the locations of the FTBUP were compared between SSDE and NSSDE patients. Generalized estimating equation (GEE) was used to ajusted the correlations between right and left eyes. The correlations between the FTBUP and ocular symptoms and signs were investigated using Pearson's correlation coefficient test. RESULTS: The FTBUP occurred at the supranasal quadrant in 12/88 eyes, supratemporal quadrant in 8/88 eyes, inferonasal quadrant in 34/88 eyes, and inferotemporal quadrant in 34/88 eyes. The percentage eyes with inferior FTBUP was significantly higher in the SSDE than in the NSSDE subjects (86.3% vs 68.1%, P = .049). Moreover, in SSDE subjects, temporal breakup point was seen more often in those who presented corneal fluorescein staining in any location, while nasal breakup point was more frequent in those who did not present any corneal fluorescein staining (P = .045). CONCLUSION: The location of the FTBUP in SSDE patients had specific characteristics. However, the diagnostic potential of FTBUP in early recognition of SSDE needs further validation.

Evaluation of Meibomian Gland Function after Therapy of Eyelid Tumors at Palpebral Margin with Super Pulse CO2 Laser.

PURPOSE: To investigate the effect on meibomian gland function of super pulse carbon dioxide (CO2) laser excision in the treatment of eyelid tumors at palpebral margin. METHODS: 36 patients with 36 eyelid tumor size ≤ 1 cm and within 1 mm to palpebral margin were recruited in this study. Of which, 16 cases with tumors in the upper eyelid and 20 cases in the lower eyelid were involved. The eyelid tumors of all the patients were treated by super pulse CO2 laser with its power density varied between 0.6 and 21.1 W/mm2 and in repeat mode. The laser spot size ranged from 120 to 200 µm. Ocular surface parameters including tear film break-up time (BUT) and meibograde, meibum expressibility, and meibum quality were evaluated at pretherapy, 1 week, 1 month, and 3 months posttherapy in all 36 patients. RESULT: All the patients were satisfied with the therapy. No infective complications and recurrence occurred in any of the 36 patients at the following period. The eyelid wound recovered well with nearly normal appearing after 2 to 3 weeks. The morphology of limbi palpebralis, BUT, meibograde, meibum expressibility, and meibum quality of all the 36 patients showed no significant difference before and after the therapy. CONCLUSIONS: Super pulse CO2 laser had no effect on meibomian gland function and morphology in the excision of tumors at palpebral margins, which was an efficacy and well-tolerated therapy with lower complications and recurrence.

Trends of Corneal Transplantation in Adults from 2010 to 2019 in East China: A 10-Year Experience.

INTRODUCTION: The aim of the study was to provide an overview of trends in the indications and surgical techniques for corneal transplantation in adults in East China from 2010 to 2019. METHODS: The medical charts of all patients (aged ≥18 years old) undergoing keratoplasty at the Eye, Ear, Nose and Throat Hospital of Fudan University between January 2010 and December 2019 were retrospectively reviewed. The indications for keratoplasty and the surgical techniques were collected. RESULTS: A total of 2,929 cases were included. Acquired nontraumatic corneal diseases (n = 1,927, 65.8%) have been the leading indication for corneal transplantation during the past decade. Although infectious keratitis was still the leading indication among acquired nontraumatic diseases, its absolute number and proportion gradually decreased during this decade (p < 0.001). In contrast, the proportion of endothelial dysfunction/bullous keratopathy increased from 7.8% in 2010 to 12.4% in 2019 (p = 0.029). Penetrating keratoplasty (PKP) has been the predominant surgical technique (n = 1,854, 63.3%), followed by deep anterior lamellar keratoplasty (DALK) (n = 361, 12.3%) and endothelial keratoplasty (EK) (n = 305, 10.4%). Nevertheless, the proportion of PKP decreased from 77.6% in 2010 to 56.9% in 2019 (p = 0.002) and was gradually replaced by DALK (from 7.8% to 16.3%, p < 0.001) and EK (from 3.4% to 10.4%, p = 0.009). CONCLUSIONS: Over the past decade, infectious keratitis and endothelial dysfunction/bullous keratopathy have been the leading indications for keratoplasty in adults. Preferred surgical techniques for keratoplasty have been shifting from PKP to more customized lamellar keratoplasties.

Changes of Dry Eye Related Markers and Tear Inflammatory Cytokines After Upper Blepharoplasty.

Objectives: To investigate the changes of dry eye-related clinical manifestations, ocular surface parameters, and tear inflammatory cytokines after upper blepharoplasty. Methods: Forty eyes of 20 who underwent upper blepharoplasty were divided into either the group with or the group without preexisting dry eye before upper blepharoplasty. Ocular Surface Disease Index (OSDI), Schirmer I test, tear meniscus height, lipid layer thickness, non-invasive tear break-up time (NIKBUT), fluorescein tear film break-up time (FBUT), corneal fluorescein staining, meibum expression, lid margin changes, and tear inflammatory cytokines were assessed preoperatively and at 1, 3, and 6 months postoperatively. Correlations between inflammatory cytokines and dry eye-related parameters were determined. Results: The OSDI scores increased significantly at 1 month (p = 0.040) and subsequently decreased to the preoperative levels at 6 months postoperatively in subjects with dry eye. First (f)-NIKBUT and FBUT were significantly shortened at 1, 3, and 6 months postoperatively in subjects with dry eye (f-NIKBUT: p <0.001, p = 0.010, p = 0.042; FBUT: p = 0.002, p = 0.005, p = 0.037, respectively), but were only shortened at 1 month (p = 0.028, p = 0.005) and returned to baseline levels at 6 months postoperatively in subjects without preexisting dry eye. A significant increasing trend of interleukin (IL)-6 was found in both dry eye and subjects without preexisting dry eye (p = 0.016, p = 0.008), while IL-8 and tumor necrosis factor alpha (TNF-α) were only found to be increased in subjects with dry eye postoperatively (p = 0.031, p = 0.031). The levels of IL-8 and TNF-α were positively correlated with OSDI scores (p = 0.046, p = 0.043, respectively) and negatively correlated with f-NIKBUT and FBUT (p = 0.026, p = 0.006, respectively). Conclusions: Upper blepharoplasty might increase the release of tear inflammatory cytokines and tear film instability that contribute to the development of postoperative dry eye in the early postoperative period and the changes most relieved in 6 months. Preexisting dry eye is a higher risk factor for worse and persistent ocular surface damage after upper blepharoplasty.

Indications and Surgical Techniques for Repeat Corneal Transplantation in Eastern China: A Twelve-Year Study.

PURPOSE: To analyze the indications and surgical procedures for repeat keratoplasty in eastern China from 2008 to 2019. METHODS: This retrospective descriptive study included 418 eyes of 411 patients who underwent no less than 2 keratoplasties at the Eye, Ear, Nose and Throat Hospital of Fudan University from 2008 to 2019. Medical charts were reviewed. The primary indications for repeat keratoplasty, the reasons for regrafting, and the surgical techniques used in the treatment were collected and analyzed. RESULTS: Among 418 eyes, 337 eyes (80.6%) had one repeat keratoplasty, and 81 eyes (19.4%) had multiple repeat keratoplasties (≥2 repeat keratoplasties). The median interval between the initial keratoplasty and the first repeat keratoplasty was 25 months, and that between two keratoplasties after the first repeat keratoplasty was 27.5 months. Infectious keratitis was the leading primary indication for single repeat keratoplasty (80 cases, 23.7%) and multiple repeat keratoplasties (19 cases, 23.5%). The second most common primary indication was bullous keratopathy for single repeat keratoplasty (49 eyes, 14.5%) and chemical injury for multiple repeat keratoplasties (14 eyes, 17.3%). The main reason for regrafting was allograft rejection (262 cases, 49.3%), followed by endothelial dysfunction (92 cases, 17.3%), and for vision improvement after tectonic keratoplasty (60 cases, 11.3%). Penetrating keratoplasty (PKP) was the major technique used in repeat keratoplasty (447 cases, 84.2%). However, Descemet stripping endothelial keratoplasty was more frequently used than PKP (72.4% vs. 27.6%, P < 0.001) in the treatment of failed endothelial keratoplasty. CONCLUSION: Infectious keratitis was still the leading cause of repeat keratoplasty in eastern China. Although PKP remains the major technique of repeat keratoplasty, the application of customized lamellar keratoplasty has greatly expanded in the last decade. Cautious selection of indications, surgical techniques, and timing for surgery is crucial for a good prognosis after repeat keratoplasty.

Indications and Techniques of Pediatric Keratoplasty in Eastern China From 2008 to 2017.

PURPOSE: To explore the transition of indications and surgical techniques of pediatric keratoplasty in Eastern China in the past 10 years. METHODS: Medical charts of 1026 pediatric patients (1059 eyes) who underwent keratoplasties at the Eye, Ear, Nose and Throat Hospital of Fudan University from 2008 to 2017 were retrospectively reviewed. The indications for keratoplasty and the surgical techniques were collected and analyzed. RESULTS: A total of 634 infants (≤3 years) (661 eyes), 207 toddlers and older children (4-12 years) (211 eyes), and 185 adolescents (13-18 years) (187 eyes) were included. The median age at the time of surgery was 2 years. The surgical indications were composed of congenital abnormalities (74.6%), acquired nontraumatic diseases (16.5%), acquired traumatic diseases (3.6%), and regraft (5.3%). Only congenital abnormality had a significant growing trend during this decade (P = 0.023). Keratoconus (67.2%) exceeded infectious keratitis (14.9%) and was the most common acquired nontraumatic cause in our study. The annual number of pediatric keratoplasties increased significantly from 40 cases in 2008 to 190 cases in 2017 (P < 0.001). Although penetrating keratoplasty was performed in 414 eyes (39.1%), its application in the treatment of keratoconus decreased significantly during this decade (P = 0.04). By contrast, deep anterior lamellar keratoplasty showed an increasing trend because of its popularization in the treatment of keratoconus (P = 0.003). CONCLUSIONS: Congenital abnormalities have replaced infectious keratitis and have been the leading indications of pediatric keratoplasty in the past 10 years. Although the using of penetrating keratoplasty was still the predominant procedure to treat pediatric corneal pathologies, the adoption of deep anterior lamellar keratoplasty showed a significant increasing trend during the past decade.

Postoperative chemotherapy had no prognostic effect on early-staged young ovarian cancer with unilateral resection.

Postoperative chemotherapy has been widely used in the treatment of early-staged ovarian cancer patients underwent unilateral resection, but the clinical decision mainly depends on the doctor's experience without a well-defined guideline. This study used propensity score matching to analyze the effect of postoperative chemotherapy for early-staged ovarian cancer patients underwent unilateral resection on prognosis. Patients of age 50 or younger than 50 with early-staged ovarian cancer were explored from the Surveillance, Epidemiology, and End Results program database during 2000-2018. Propensity score matching was used to randomize the dataset and reduce the selection biases. Univariate and multivariate cox proportional hazards models were utilized to estimate the necessity of chemotherapy. In univariate analysis of matched population, both the overall survival and cancer-specific survival analysis showed that chemotherapy had no effect on the prognosis of early-staged young ovarian cancer patients (Overall survival, P = 0.477; Cancer-specific survival, P = 0.950). In propensity-adjusted multivariate analysis, chemotherapy still had no effect on both the overall and cancer-specific survival probability after excluding the effect of all the confounding factors (HR = 0.863, CI = 0.587-1.269, P = 0.455; HR = 1.009, CI = 0.633-1.607, P = 0.970). Our study suggested that postoperative chemotherapy is not necessary for early-staged young ovarian cancer patients with unilateral resection, as indicated by both the overall survival and cancer-specific survival.