Article

Application of Umbilical Cord Serum Eyedrops for the Treatment of Neurotrophic Keratitis

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Abstract

To investigate the efficacy of umbilical cord serum eyedrops for the treatment of neurotrophic keratitis. Prospective noncomparative case series. Twenty-eight eyes of 28 patients with neurotrophic keratitis who were refractory to conventional treatment. The patients with neurotrophic keraitis were treated with 20% umbilical cord serum eyedrops 6 to 10 times a day. Ophthalmic examinations including best-corrected visual acuity (VA) measurement, corneal sensitivity test, corneal fluorescein staining, and anterior segment photography were performed before and after the treatment. Concentrations of substance P, insulinlike growth factor 1 (IGF-1), and nerve growth factor (NGF) in umbilical cord serum, normal peripheral blood serum, and tears were measured. Epithelial healing time; changes of VA and corneal sensitivity after treatment; and levels of substance P, IGF-1, and NGF in umbilical cord serum, normal peripheral blood serum, and tears. The epithelial defect healed completely in all eyes, with a mean healing time of 4.4+/-4.0 weeks. The epithelial defect healed within 2 weeks in 8 eyes (28.6%), between 2 and 4 weeks in 14 eyes (50.0%), and after 4 weeks in 6 eyes (21.4%). After treatment, VA improved by >2 lines in 17 eyes (60.7%). Mean pretreatment corneal sensitivity was 21.1+/-10.5 mm, and mean posttreatment corneal sensitivity was 24.3+/-11.7 mm (P<0.01). Mean concentrations of substance P, IGF-1, and NGF were 245.3+/-53.9 pg/ml, 239.0+/-77.1 ng/ml, and 729.7+/-72.0 pg/ml in umbilical cord serum; 169.5+/-81.0 pg/ml, 375.5+/-51.3 ng/ml, and 401.7+/-98.1 pg/ml in peripheral blood serum; and 69.8+/-24.9 pg/ml, 75.7+/-50.5 ng/ml, and 107.5+/-70.9 pg/ml in tears, respectively. Umbilical cord serum contains many neurotrophic factors, and umbilical cord serum eyedrops appeared to be effective for the treatment of neurotrophic keratitis.

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... Among them, umbilical cord serum boasts their regenerative efficacy due to the presence of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), plateletderived growth factor (PDGF), fibroblast growth factor (FGF), transforming growth factor (TGF), hepatocyte growth factor (HGF), insulin like-growth factor (IGF) and nerve growth factor (NGF) etc. In addition to these growth factors, it has different cytokine/chemokine molecules, neurotrophic factors and biologically active substances (4,14) and their biological roles have discussed in Tables I and II. Thus, the application of UCS has increased in various regenerative approaches and cell culturing techniques. ...
... Initially, autologous serum eyedrops were assumed to provide essential tear elements and growth factors in the treatment of persistent corneal epithelial defect (15). Later, researchers found that cord serum contains more growth factors and neurotrophic factors than autologous serum (14,16). The first trial of cord serum established in persistent corneal epithelial defects patients by Vajpayee et al. ...
... In that trial, most of the UCS treated patients exhibited higher healing rates in the defect areas than the autologous serum-treated group (17). The reason may be that presence of growth factors are probably higher in the UCS than autologous serum, which may enhance significant migration and proliferation of epithelial cells that consequently lead to a faster re-epithelialization. Yoon et al. first confirmed that cord blood serum comprises a higher level of crucial tear elements, neurotrophic factors, biological substances and growth factors than autologous serum and they are effectively used to improve the symptoms of neurotrophic keratitis, severe dry eye syndrome and persistent corneal defects (14,16,18,19). To assess the efficacy and safety of UCS eye drops in dry eye associated graft-versus-host-disease (GVHD), recruited patients were treated with 20% cord serum eye drops. ...
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Regenerative medicine is a branch of medicine that incorporates tissue-engineering, biomaterials, and cell therapy approaches to replace or repair damaged cells and tissues. Umbilical cord serum (UCS) is an important liquid component of cord blood, which has a reliable source of innumerable growth factors and biologically active molecules. Usually, serum can be prepared from different sources of blood. In therapeutic application, cord serum can be prepared and used in the form of eye drops for the treatment of severe dry eye diseases, ocular burns, glaucoma, persistent corneal epithelial defects and neurotrophic keratitis. In addition, cord serum combined with synthetic bio scaffold materials is used to regenerate different types of tissues including tympanic membrane regeneration, bone regeneration and nerve regeneration. Absence of animal origin viruses and bacteria, lack of xenoproteins and cost-effective features make cord serum a feasible choice as replacement of fetal bovine serum in cell culture techniques. Thus, this review emphasizes the role of cord serum in regenerative therapy and clinical uses.
... Recently, this technology has advanced and extended to umbilical cord blood as a derivative source as well. Compared to autologous blood, umbilical cord blood-derived serum (UCS) and platelet-rich plasma (UCPRP) contain higher levels of growth factors, are readily available, and are more sterile (Yoon et al. 2007;Nadelmann et al. 2021;Rhéaume et al. 2022;Roura et al. 2015). Importantly, they have been utilized in various disease treatments (Wang et al. 2021a;Mazzotta et al. 2022), among which eye disease is one of the most prominent ones. ...
... Lastly, there are some limitations to using UCS, UCPRP, or any other blood-derived biologics for corneal treatment. Firstly, vascular endothelial growth factor (VEGF) is one of the known factors in UCS and UCPRP and a main driver of angiogenesis and neovascularization (Yoon et al. 2007;Murphy et al. 2012). Using UCS or UCPRP for cornea treatment would therefore be illadvised as it may lead to corneal neovascularization, a condition where blood vessels form on the cornea and cause vision loss. ...
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Background Umbilical cord blood-derived therapeutics, such as serum (UCS) and platelet-rich plasma (UCPRP), are popular treatment options in clinical trials and can potentially be utilized to address a clinically unmet need caused by preservatives, specifically benzalkonium chloride (BAK), present in ophthalmic formulations. As current clinical interventions for secondary injuries caused by BAK are suboptimal, this study will explore the feasibility of utilizing UCS and UCPRP for cornea treatment and investigate the underlying mechanisms associated with this approach. Methods Mice’s corneas were administered BAK to induce damage. UCS and UCPRP were then utilized to attempt to treat the injuries. Ocular tests were performed on the animals to evaluate recovery, while immunostaining, RNA-seq, and subsequent bioinformatics analysis were conducted to investigate the treatment mechanism. Results BAK administration led to widespread inflammatory responses in the cornea. Subsequent treatment with UCS and UCPRP led to the downregulation of immune-related ‘interactions between cytokine receptors’ and ‘IL-17 signaling’ pathways. Although axonal enhancers such as Ngf, Rac2, Robo2, Srgap1, and Rock2 were found to be present in the injured group, robust axonal regeneration was observed only in the UCS and UCPRP treatment groups. Further analysis revealed that, as compared to normal corneas, inflammation was not restored to pre-injury levels post-treatment. Importantly, Neuropeptide Y (Npy) was also involved in regulating immune responses, indicating neuroimmune axis interactions. Conclusions Cord blood-derived therapeutics are feasible options for overcoming the sustained injuries induced by BAK in the cornea. They also have potential applications in areas where axonal regeneration is required.
... Higher growth factors components have been reported by several studies. [9][10][11] These components such as epidermal growth factor, nerve growth factor, insulin-like growth factor (IGF), Substance P, vitamin A, and transforming growth factor (TGF)-β are essential for ocular surface health and are common constituents of tear film. Umbilical cord serum eye drops are considered effective and safe in treating patients with dry eye disease. ...
... 27 UCS includes a high level of nerve growth factor, and this may explain previously reported improvement in corneal sensitivity after UCS use in a neurotrophic keratitis patient. 11 This result suggests that corneal nerve endings were repaired after UCS therapy, thus improving positive feedback to and increased aqueous secretion by the lacrimal gland. 30 Unfortunately, our study did not include a corneal sensitivity test. ...
Article
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Purpose: To evaluate the efficacy and safety of umbilical cord serum eye drops for dry eyes in ocular Stevens-Johnson Syndrome (SJS). Patients and methods: A pre-post test study with umbilical cord serum (UCS) eye drop for ocular SJS patient with moderate to severe dry eyes. Study was conducted at Kirana Cipto Mangunkusumo General Hospital from June 2020 to December 2020. A total of five patients (five eyes) with a diagnosis of SJS more than 6 months, dry eye symptoms, and abnormal tear stability test results were included in the study. Each patient was asked to instill UCS drop into the affected eye six times daily. Evaluation of ocular symptoms with ocular surface disease index (OSDI) questionnaires, non-invasive tear break-up time (NIBUT), Schirmer I, and keratoepitheliopathy scores was administered before applying UCS drop and at week 2 and 4 of eye drop use. Results: From June 2020 to December 2020, five eyes of five patients were evaluated in this study. Patients were aged from 22 to 71 years old with history of SJS over periods from 1 to 35 years. Three patients underwent ocular surgeries prior to the study. After four weeks of treatment, symptoms score, Schirmer I, and keratoepitheliopathy scores improved significantly, while NIBUT scores improved insignificantly. No side effects were noted during treatment. Conclusion: Administration of UCS eye drop was effective in improving symptoms and signs of dry eye in chronic SJS patients.
... Human umbilical cord serum has been shown to contain higher concentrations of EGF, NGF and TGF-β compared to peripheral blood serum (Yoon et al., 2006;Yoon et al., 2007). Vajpayee et al. (Vajpayee et al., 2003) reported that umbilical cord serum has been reported to lead to a faster median percentage decrease in the size of PEDs at 7, 14 and 21 days (p < 0.05) compared to peripheral blood serum. ...
... Vajpayee et al. (Vajpayee et al., 2003) reported that umbilical cord serum has been reported to lead to a faster median percentage decrease in the size of PEDs at 7, 14 and 21 days (p < 0.05) compared to peripheral blood serum. Yoon et al. (Yoon et al., 2007) treated 28 NK eyes with 20% umbilical serum reported complete epithelial defect healing in all eyes, with a mean healing time of 4.4 ± 4.0 weeks. Umbilical serum has also been shown to improve corneal nerve morphology (assessed with IVCM), with an increase of total nerve number and a decrease of nerve tortuosity (Giannaccare et al., 2017). ...
Article
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Neurotrophic keratitis (NK) is a rare degenerative condition that is caused by damage to the trigeminal nerve, with partial or complete loss of corneal sensory innervation. The loss of innervation leads to impaired healing of corneal epithelium, which subsequently results in punctate epithelial erosions, persistent epithelial defects, corneal ulcers and corneal perforation. Management of NK is often supportive and aims to promote epithelial healing and prevent progression of disease. Multiple novel pharmacological approaches have been proposed to address the underlying pathophysiology of NK, which are discussed in this paper.
... The current available noninvasive conventional treatments for PEDs include the administration of lubricating agents, hyperosmotic agents, autologous serum, and umbilical cord serum, as well as the application of therapeutic contact lenses [4][5][6][7][8]. Surgical treatments include debridement, keratectomy, and amniotic membrane transplantation [9][10][11]. ...
... Serum treatment is widely used for many ocular surface diseases such as PEDs, and contains several substances that aid regeneration of the keratoconjunctival epithelium, such as epidermal growth factor (EGF), transforming growth factor-β, vitamin A, fibroblast growth factor and insulin-like growth factor-I [4][5][6][7]. In particular, EGF is known to stimulate proliferation, migration, and differentiation of epithelial cells, endothelial cells, and fibroblasts during wound healing and [12][13][14]. ...
Article
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Background: Healthy corneal epithelium acts as a barrier against damage to the deeper structures in the eye. Failure in the mechanisms of corneal epithelization can lead to persistent epithelial defects of the cornea (PEDs) and can compromise its function. Epidermal growth factor (EGF) promotes the proliferation, migration, and differentiation of epithelial cells, endothelial cells, and fibroblasts during wound healing and may be beneficial in treating patients with PEDs. We, therefore, investigated the effect of EGF ointment on patients with PEDs. Methods: Fifteen patients with PEDs refractory to conventional treatment were treated twice a day with EGF ointment. Patient demographics and comorbidities were noted. The epithelial healing time was determined along with the primary outcome measures in the areas of the epithelial defects, visual acuity, visual analog scale (VAS) scores, and esthesiometer scores 1 month and 2 months after treatment. Results: Five eyes of herpetic keratitis (33.3%), 3 eyes of dry eye disease (20.0%), 3 eyes of bacterial keratitis (20.0%), 2 eyes of limbal stem cell deficiency (13.3%), 1 eye of diabetic neurotrophic keratitis (6.7%), and 1 eye of filamentary keratitis (6.7%) were associated with PEDs, respectively. Two months following treatment with EGF ointment, there was a reduction in the area of the epithelial defects (5.7 ± 3.9 to 0.1 ± 0.3 mm2) as well as a significant improvement in best-corrected visual acuity (0.9 ± 0.8 to 0.6 ± 0.5 LogMAR) and VAS scores (4.5 ± 1.2 to 2.5 ± 0.7) in 12 eyes (80%). Among these cases, the mean epithelial healing time was 5.5 ± 1.8 weeks. Amniotic membrane transplantation was performed on the remaining 3 (20.0%) patients that did not respond to EGF treatment. Conclusions: EGF ointment could reduce symptoms and promotes corneal epithelialization of refractory PEDs. It may, therefore, be well-tolerated and a potentially beneficial addition in the management of refractory PEDs.
... The rationale for applying serum to the ocular surface is that, compared to conventional lubricant treatments, it more closely resembles natural tears due to several of its biochemical constituents [3]. UCBS has been extensively used in the setting of ocular surface diseases and has produced satisfactory results in terms of efficacy and safety [3,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. Yoon and coauthors were among the first to test the use of UCBS in the management of several ocular surface disorders, such as dry eye with or without SS, oGVHD, persistent epithelial defects, neurotrophic keratitis, and ocular chemical injury. ...
... Treated patients showed a faster epithelial healing rate, greater improvement in symptoms, and increased goblet cell density and corneal sensitivity when compared to healthy subjects. In particular, patients with neurotrophic keratitis experienced a 100% healing rate after approximately 1 month of therapy [26][27][28][29][30][31][32][33]. Furthermore, a significant improvement in corneal epitheliopathy (as indicated by a decreased Oxford staining score) and a higher number of nerves with improved morphology and lower tortuosity were reported by our group, who successfully treated moderate-tosevere forms of dry eye disease with UCBS [6]. ...
Article
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Several blood derivatives have been proposed for the treatment of various ocular diseases that affect either the anterior or the posterior segment of the eye. Blood sources may range from the patient’s own peripheral blood (autologous) to donor tissues, mainly allogeneic peripheral blood and umbilical cord blood (UCB). The utilization of the latter permits the collection of a large amount of serum all at once, and is characterized by therapeutic feasibility in patients with a poor general condition or anemia and blood dyscrasia. Products derived from UCB have two potential uses. First, serum in the form of eye drops can be applied topically onto the ocular surface to efficiently treat anterior segment disorders such as dry eye syndrome or corneal epithelial defects with different etiologies. The rationale for and efficacy of this application derive from the high concentrations of biologically active components and growth factors in UCB, which can nourish the ocular surface. Second, UCB is a source of stem cells, which are used in the field of regenerative medicine because they differentiate into various mature cells, including corneal and retinal cells. Therefore, UCB-derived stem cells have been proposed as a replacement therapy for the treatment of retinal and optic nerve diseases, given that current standard treatments often fail. The present review explores the clinical results that have been obtained using UCB-derived products in the field of ophthalmology, as well as the current limitations of those products in this field. Furthermore, given the promising development of UCB-based therapies, possible future directions in this area are discussed.
... UCBS eye drops were investigated as possible therapy of DED [46,82,86], PED [87][88][89][90], acute chemical burns [91,92], oGVHD [93], RCE [94], after PK [95], laser epithelial keratomileusis (LASEK) [96], Hansen's disease [97], and NK [98,99] (Table 3). A significant reduction of subjective discomfort symptoms associated with an improvement of tear stability, and recovery of the corneal sensitivity and keratopathy after UCBS treatment was shown in all studies in severe DED patients, with a high degree of satisfaction upon instillation. ...
... UCBS seems to be useful in the treatment of NK as it contains high levels of neurotrophic factors such as substance P, IGF-1, and NGF. In particular, a study on 28 eyes with NK reported complete epithelial defect healing in all eyes, with a mean healing time of 4.4 ± 4.0 weeks [98]. UCBS was also used in adjunct to conventional treatments after LASEK and was successful in reducing the early postoperative corneal haze and in improving tear film and ocular surface parameters [96]. ...
Article
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The use of blood-based eye drops as therapy for various diseases of the ocular surface has become increasingly popular in ophthalmic practice during recent years. The rationale for their use is based on the promotion of cellular proliferation and migration thanks to the supply of metabolically active substances, in particular growth factors. Blood-derived eye drops have been used for the treatment of several ocular surface disorders, such as dry eye disease, corneal ulcer, persistent epithelial defect, neurotrophic keratitis, ocular surface burn, recurrent corneal erosion, and limbal stem-cell deficiency. Both autologous (from patients themselves) and heterologous (from adult donors or from cord blood sampled at birth)-derived products exist, and each source has specific pros and cons. Despite an extensive literature, several issues are still under debate and the aim of this manuscript is to review the indications, preparation methods and storage, characterization of content, rationale for clinical outcomes, patient stratification, length of treatment, and rationale for repeated treatments at disease relapse. A rationale based on a "5 Ws and 2 Hs" protocol is proposed as a way of thinking, with the attempt to clarify Who, Why, When, Where, What, and How to use these treatment options.
... e most accepted theory that explains that response is "X, Y, and Z theory" [8], where it suggests the replication of stem cells, then a horizontal migration to fill up the defect, and finally a vertical growth in order to end up with a matured, five-layered, stratified squamous, nonkeratinized epithelium. Different factors, both internal and external, may contribute, positively or negatively, to this process [9][10][11][12][13][14][15][16]. While agents like corticosteroids [9] and antimetabolites [10] are well known to hinder epithelial regeneration; others like autologous serum [11], umbilical cord serum [12], and various growth factors [13] were found to promote it. ...
... Different factors, both internal and external, may contribute, positively or negatively, to this process [9][10][11][12][13][14][15][16]. While agents like corticosteroids [9] and antimetabolites [10] are well known to hinder epithelial regeneration; others like autologous serum [11], umbilical cord serum [12], and various growth factors [13] were found to promote it. D-Panthenol, the precursor of vitamin B5, possesses an established positive effect on epithelium healing in general [17,18]. ...
Article
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Purpose: To study the effect of D-panthenol (provitamin B5) on corneal epithelial healing, in cases of surface laser ablation. Patients and Methods: 45 eyes, of 45 patients undergoing laser surface ablation, received D-panthenol 2% in one eye and artificial tear drops of similar composition not containing D-panthenol in the other eye, postoperatively, for 2 months. Patients were examined daily for 3 days after the procedure. They were then examined weekly for 1 month. An additional examination was made after 2 months. Visual acuity (Log MAR) was assessed at every visit. Rate of healing (% of covered area) and subjective sensation of discomfort (scale 0-5) were assessed in the 1st 3 visits. Residual manifest cylinder (D) (as a parameter of corneal irregularity) and corneal clarity (epithelial and stromal haze) were assessed from week 1 to month 2. Results: During the first 3 days, both groups showed statistically nonsignificant (P > 0.05) results. From week 1 to month 2, eyes receiving D-panthenol showed better vision and less residual cylinder (P < 0.05) at week 1. For all other parameters, and at different examinations, both groups showed a statistically nonsignificant (P > 0.05) difference. Still, eyes receiving D-panthenol showed better values at the majority of the parameters tested. Conclusion: D-Panthenol effect on corneal epithelial regeneration is of minimal clinical relevance. A different dosage and a larger sample of patients might reveal a statistical relevance. This trial is registered with https://doi.org/10.1186/ISRCTN81441126.
... Human blood-derived and plasma-derived eye drops have been used for the treatment of several ocular surface disorders intractable to conventional therapy, such as dry eye disease, persistent epithelial defect, and NK. 64,179,194,207 Blood-derived eye drops are formulated from either the patient's own peripheral blood serum (autologous source), including autologous serum, platelet-rich plasma, plasma rich in growth factors, and platelet lysate, or from donors (homologous source), such as allogeneic peripheral blood serum and umbilical cord blood serum. ...
... Observations revealed a significant reduction in the OSDI score (60.9%) and improvement in BCDVA (52.8%) [54]. Yoon et al. [31], evaluated 28 eyes of 28 patients with neurotrophic keratitis refractory to conventional medical treatment. PED healed completely in all eyes, with a mean (SD) healing time of 4.4 (4.0) weeks. ...
Article
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Background: Umbilical cord blood (UCB) is a novel treatment of resistant corneal ulcers owing to the unique anti-inflammatory molecules and growth factors it contains. Platelet lysates are a potential future alternative. The aim of the present study was to assess the role of human UCB platelet lysate in treating resistant corneal ulcers. Methods: This was prospective, non-comparative, interventional case series involving 40 eyes of patients aged 6 - 65 years with persistent corneal ulcers from the Mansoura Ophthalmic Center and Mansoura Research Center for Cord Stem Cells. Patients were classified according to the cause of persistent corneal ulcer into four groups: group I, including 14 eyes with dry eye disease; group II, including six eyes post-keratoplasty; group III, including four eyes with corneal chemical burn; and group IV, including 16 eyes with persistent corneal ulcer from other causes. All participants underwent detailed ophthalmic examinations, and baseline and final best-corrected distance visual acuity (BCDVA) were recorded. Eye drops were prepared from UCB platelet lysate and administered to all patients along with detailed meticulous instructions for the method of use. Clinical progression of wound healing was continuously observed. The treatment response was identified as complete healing, improvement, or treatment failure. Results: BCDVA improved significantly in all studied groups (all P < 0.05). In group I, complete healing, improvement, and treatment failure occurred in 71%, 29%, and 0% of cases. In group II, complete healing, improvement, and treatment failure occurred in 67%, 33%, and 0% of cases. In group III, complete healing, improvement, and treatment failure occurred in 50%, 50%, and 0% of cases. In group IV, complete healing, improvement, and treatment failure occurred in 63%, 12%, and 25% of cases. No adverse events associated with the treatment were observed or subjectively self-reports in the study period. Conclusions: Eye drops from UCB platelet lysate were a novel therapeutic blood component with unique growth factors and anti-inflammatory compounds that could be an effective and safe treatment option in managing persistent corneal ulcers of different causes. A future randomized clinical trial with a large sample size and a longer follow-up is required to confirm these preliminary outcomes.
... Autologous serum (AS) eye drops are effective in the treatment of NK, severe dry eye, persistent epithelial defects/recurrent corneal erosion, GVHD, and superior limbic keratoconjunctivitis. [2][3][4][5][6][7] Human umbilical cord serum (UCBS) has been found to be a safe and effective adjunct in the management of DED, Stevens-Johnson syndrome, recurrent corneal erosions, GVHD, and ocular chemical injuries, by virtue of its intrinsic property to promote-proliferation, differentiation, and maturation of surface epithelium, owing to the presence of high concentration of growth factors. [8][9][10][11][12][13][14] Additionally, UCBS serves as a strong anti-inflammatory agent. Both AS and UCBS exert this action due to the presence of growth factors like epidermal growth factors (EGFs), acidic and basic fibroblast growth factor (FGF), plateletderived growth factor (PDGF), hepatocyte growth factor (HGF), vitamins, transforming growth factor (TGF), substance P, insulin-like growth factor (IGF), etc. ...
Article
Purpose: Umbilical cord blood serum (UCBS) is an effective adjunctive treatment along with conventional therapy in ocular surface disorders (OSDs). It aids in rapid ocular surface restoration thereby achieving epithelial integrity, in addition to improvement in subjective and objective parameters. The study aims to compare the efficacy of human umbilical cord blood serum and autologous serum (AS) in treatment of OSD. Methods: A prospective randomized study was conducted on 101 eyes diagnosed with OSD resulting from dry eye disease (DED; n = 40), acute chemical burn (ACB; n = 21), and ocular allergy (OA; n = 40). Randomization was done in Group I, administered with AS, and Group II with UCBS. Outcomes evaluated were visual acuity (VA), eye sensation score (ESS), ocular surface disease index (OSDI), tear break-up time (TBUT), Schirmer's value, Corneal Fluorescein Score, epithelial defect, limbal ischemia, corneal clarity (CC), and improvement in grade of severity. Statistical analysis was done using Wilcoxon signed-rank, Wilcoxon rank sum, Chi-square, and Z-test with a significance level (P ≤ 0.05). Results: In DED, Group II showed significant improvement in VA, ESS, and OSDI by the 7th day, whereas the mean Schirmer, TBUT, and corneal fluorescein staining score improved by 3 months. In ACB, Group II showed improvement in VA, reepithelialization, reduction in limbal ischemia, and CC by 3 months. In OA, Group II showed improvement in ESS by day 7. Conclusion: Human umbilical cord blood serum is more effective than AS in restoring ocular surface.
... There are isolated reports of secondary corneal infections from contaminated serum. [44] Umbilical cord serum for epithelialization has higher promotional growth factor content. [45,46] However, the lack of ease of access limits its use in general practice. ...
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We present a comprehensive review of existing literature on surgical corneal neurotization (SCN) as a treatment modality for neurotrophic keratopathy (NK) with an interim report of seven cases where SCN was performed using the indirect approach and followed up till 18 months postoperatively to look for improvement in ocular surface, corneal sensations, and nerve regeneration by using in vivo confocal microscopy (IVCM). A literature search was performed for publications with keywords "corneal nerves," "neurotization," "esthesiometry," "corneal anesthesia," and "neurotrophic keratopathy." All literature available till December 31, 2020 was reviewed and included to describe NK and its management options, particularly SCN. NK is associated with absent or reduced corneal sensations and is managed using a step-ladder algorithm ranging from medical management for symptomatic relief to surgical corneal neurotization. Both direct and indirect approaches of SCN have a favorable outcome with reduced surgical morbidity in the indirect approach using sural nerve graft. Post neurotization, corneal sensation recovery may take up to 3-6 months, while nerve regeneration on confocal microscopy can take as long as 6 months-1 year.
... In our study, these properties are supported by a decrease in the proportion of patients using adjuvant anti inflammatory therapy on PRGF. The inclusion of concentrated growth factors and lack of pro-inflammatory components may be especially helpful for our neurotrophic keratitis [23,[37][38][39][40] and GVHD patients [41][42][43]. ...
Article
Purpose: To investigate the efficacy and safety of plasma rich in growth factors (PRGF) eyedrops in the management of patients with ocular surface diseases in North America. Methods: Multicenter interventional case series of patients using PRGF eyedrops for the first time. A cohort of patients was analyzed for corneal staining score at initial visit and at 3 months of therapy with PRGF. Another cohort responded to a 10-item questionnaire that evaluated patients' satisfaction and safety, which included the symptom assessment questionnaire in dry eye (SANDE) score, after 6 months of PRGF treatment. Results: A total of 153 patients were analyzed. Of these, 102 were reviewed for corneal epitheliopathy and 99 patients responded to the questionnaire. The mean (±SD) age of the population was 63.7 ± 17 years and 72.5% were female. The clinical indications for PRGF usage were dry eye (60%), neurotrophic keratopathy (15%), dormant corneal ulcers (12%), limbal stem cell deficiency (10%), and cicatrizing conjunctivitis (4%). At the final visit, 74.3% of patients showed an improvement of their corneal staining. Those who had punctate epithelial erosions or epithelial defects were reduced from 76.5% to 47% and 23.5%-7.8% respectively (p < 0.0001). Symptoms, measured via SANDE score, significantly decreased from a median of 90 to 34.6 out of 100 points on follow-up (p < 0.0001). Only one patient (0.98%) complained of ocular burning sensation as a side effect. Conclusions: This multicentric study demonstrates the safety and efficacy of the use of PRGF for treating signs and symptoms in patients with significant ocular surface diseases.
... Horses 1 and 6, exhibiting the longest history of corneal epithelial defect, had been previously treated topically with AS without success, for 10 and 60 days, BID to TID, respectively (and was stopped 7 and 42 days, respectively, before initiating eUCS therapy). hUCS eyedrops have shown beneficial effects in treating recurrent and persistent corneal defects in humans associated with several primary conditions such as dry eye syndrome, neuropathic keratophathies, or idiopathic non-healing ulcers (15,18,30,(52)(53)(54)(55) and were more effective compared with hAS (56). Considering our cases, healing times and rates were variable among horses. ...
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Background Human autologous serum (AS) and umbilical cord serum (UCS) both contain growth and neurotrophic factors that promote corneal healing. Aim Our objectives were to compare equine AS and UCS cytokine and growth factor profiles and to assess the safety and clinical feasibility of the therapeutic use of UCS eye drops in cases of spontaneous complex ulcers. Study Design Prospective clinical trial. Methods Vitamin A insulin growth factor, platelet-derived growth factor-BB, transforming growth factor (TGF)-β1 (enzyme-linked immunosorbent assay), interleukin (IL)-1β, IL-6, interferon-γ, and monocyte chemoattractant protein 1 concentrations were determined in 10 AS collected from different horses and 10 UCS sampled at delivery. Six client-owned horses presenting with complex non-healing corneal defects of >5 mm² were included in a clinical trial and treated with conventional therapy and conditioned UCS drops for 8–15 days. Ulcer surface and time to complete epithelialization were recorded. Results Median concentrations of vitamin A, insulin growth factor, and platelet-derived growth factor-BB were not significantly different in AS compared with UCS (respectively, 14.5 vs. 12.05 μg/ml; 107.8 vs. 107.3 pg/ml; and 369.1 vs. 924.2 pg/ml). TGF-β1 median concentration in UCS was significantly higher than in AS (3,245 vs. 2571pg/ml) (p = 0.04). IL-1β, IL-6, interferon-γ, and monocyte chemoattractant protein 1 concentrations were variable in AS and undetectable in UCS. The corneal median ulcerative area was 37.2 mm² (6.28–57.14 mm²) and had a duration of 4–186 days (median 19 days). All lesions healed within 13–42 days (median 17 days). No adverse effects nor recurrences within 1 month were noticed. Limitations The sample size was small. Spontaneous corneal epithelial defects presented with variable clinical characteristics. There were no age-matched control horses to assess corneal healing time and rate. Conclusion and Clinical Significance Equine UCS may be beneficial, as it contains no pro-inflammatory cytokines and a greater concentration of TGF-β1 compared with AS. Topical UCS appears safe and may potentially be used as adjunctive therapy for equine complex non-healing ulcers.
... In order to improve quality and availability of cryopreserved grafts, new preparation techniques have been developed such as lyophilization or low-temperature vacuum evaporation [71][72][73][74]. As an alternative to surgery, AS is rich in neurotrophin and neuropeptides playing a crucial role in corneal regeneration process [75][76][77][78][79]. Topical use of umbilical cord serum [80][81][82][83], substance P and insulin-like growth factor [84][85][86], insulin [87], and thymosin beta 4 [88] have been considered as an alternative to AS with promising results. In association with specific Content courtesy of Springer Nature, terms of use apply. ...
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Purpose Management of NK can be difficult, involving a range of treatments with variable efficacy. We conducted a systematic review and meta-analysis to evaluate the efficacy of medical and surgical treatments for neurotrophic keratitis (NK). Method PubMed, Cochrane Library, Embase, ClinicalTrial.gov, and ScienceDirect were searched for studies assessing efficacy of NK treatments. We computed random-effect meta-analyses on corneal healing, time to complete healing, and visual acuity changes between baselines and after treatment, stratified on treatment classes. We followed the PRISMA guidelines (registration number CRD42021225721). Results We included 20 studies: 571 patients and 5 treatment classes (2 surgical and 3 non-surgical). The percentage of patients with complete corneal healing did not differ between specific treatments (nerve growth factor eyedrops (NGF), 75%, 95CI 46 to 104%; autologous serum (AS), 92%, 86 to 98%; neurotization, 99%, 95 to 103%; amniotic membrane transplantation (AMT), 86%, 78 to 94%). All specific treatments had better percentage of complete healing (p < 0.001) than non-specific treatment groups, i.e., mainly lubricants (23%, 14 to 32). Time to complete healing was 24.2 days (5.4 to 43.1) with NGF, 27.6 days (15.2 to 40.0) with AS, 117 days (28.8 to 205.2) with neurotization, and 16.4 days (11.1 to 21.7) with AMT. Only NGF and AMT improved visual acuity. Efficacy outcomes were not affected by sociodemographic (age, sex) nor severity of disease (Mackie stages). Conclusion We confirmed the efficacy of specific treatments in NK. Further comparative trials are needed to investigate the medical and economic benefits of innovative therapies.
... Allogeneic serum is used in patients with contraindications to autologous serum, such as inaccessible peripheral venous access and hematological pathology [24]. In a study by Yoon et al., application of 20% concentrated umbilical cord serum resulted in complete resolution of epithelial defects in 28 eyes (100%) and significant improvement in mean corneal sensitivity [25]. Healing of the epithelial defect occurred within four weeks in 22 eyes (78.6%). ...
Article
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Neurotrophic keratopathy (NK), or neurotrophic keratitis, is a degenerative condition that results from decreased innervation to the cornea. The cornea is innervated by the ophthalmic branch of the trigeminal nerve. Neurotrophic keratopathy is most commonly caused by herpes keratitis however, any condition that disrupts the normal corneal innervation can cause NK. Neurotrophic keratopathy is a clinical diagnosis and is classified into three stages based on the disease severity. Stage 1 has mild epithelial defects, such as punctate keratopathy, stage 2 disease has persistent epithelial defects, and stage 3 is defined by the presence of ulcers. Current treatment modalities consist of medical and surgical options. Stage 1 is treated with lubrication through artificial tears, eyelid taping, and punctal plug/cautery. Stage 2 treatment can involve therapeutic contact lenses, topical autologous or allogenic serum, tarsorrhaphy, botulinum toxin injections, and possibly anti-inflammatory medications. Stage 3 disease may require human nerve growth factor, amniotic membrane transplantation, conjunctival flap, or corneal neurotization. New therapies, such as matrix regenerating therapy, plasma rich in growth factors, Thymosin β4, Substance P/Insulin like growth factor-1, and nicergoline represent exciting future options. KEY MESSAGES Neurotrophic keratopathy is a rare degenerative disease defined by decreased innervation to the cornea that is associated with significant morbidity. Treatment options range from lubrication alone to various medical and surgical treatments. Matrix regenerating therapy, plasma rich in growth factors, Thymosin β4, Substance P/Insulin like growth factor-1, and nicergoline are exciting novel therapies that will influence how neurotrophic keratopathy is treated in the future.
... Treatments included in the panel's recommendations have been shown to be effective in treating NK. For example, autologous serum eye drops have been shown to be effective in retrospective, noncomparative case series [37] and there is evidence that human umbilical cord serum and platelet rich plasma drops can be used to treat ocular surface conditions [38][39][40]. Cenegermin is currently the only US Food and Drug Administration approved treatment for NK. Its efficacy and safety have been demonstrated in patients with Stage 2-3 NK in two Phase II trials [19,20] and one case series [41]. ...
Article
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Background Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. Methods An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. Results There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. Conclusions These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK.
... The treatment of this condition is based on the severity of the clinical picture: in early stages, supportive treatment with preservative-free tear substitutes and lubricant ointments is used to prevent epithelial breakdown and improve ocular surface conditions. As the severity of NK progresses, topical antibiotics, blood-derived eye drops, and therapeutic contact lens are indicated [6,7]. The welcomed advent of the recombinant nerve growth factor (Cenegermin, Dompè Farmaceutici, Milan, Italy) with specific target on the root pathology has determined a paradigm shift in medical management of NK. ...
Article
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Introduction Neurotrophic keratopathy (NK) is a degenerative corneal disease originating from a damage to the trigeminal innervation. Corneal neurotization (CN) is a recently introduced surgical procedure consisting of the transfer of normally functioning nerves into the anesthetic cornea. Two main approaches are feasible: i) direct nerve transfer of an healthy nerve branch; ii) interpositional nerve graft coapted to a healthy donor nerve. Areas Covered In this review, we present an overview of the current literature about CN for the treatment of NK. We discuss all the surgical approaches with specific advantages and disadvantages for each technique along with the results of published clinical studies in terms of both efficacy and safety. Expert Opinion CN is a safe and effective treatment for NK. This procedure has shown the ability to improve corneal sensitivity, epithelial integrity and visual acuity. Postoperative corneal re-innervation has been also detected by in vivo confocal microscopy. To date, no conclusive data are available about the technique of choice. In our practice, we perform direct nerve transfer techniques in patients with severe NK in order to take advantage of the presumed immediate sprouting from the transferred nerves; in the other cases, we use interpositional sural nerve graft.
... A prospective, noncomparative case series study applied 20% UCS eye drops to patients with NK, who were not responding to conventional treatment, observing that the epithelial defect healed completely in all patients (100%) within a mean time-frame of just 4 weeks. Visual acuity improved by >2 lines in 60% of cases, and corneal sensitivity also improved after treatment [23][24][25][26]. ...
Article
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Blood derived products have become a valuable source of tissue for the treatment of ocular surface diseases that are refractory to conventional treatments. These can be obtained from autologous or allogeneic sources (patient’s own blood or from healthy adult donors/umbilical cord blood, respectively). Allogeneic cord blood demonstrates practical advantages over alternatives and these advantages will be discussed herein. Umbilical cord blood (UCB) can be divided, generally speaking, into two distinct products: first, mononuclear cells, which can be used in regenerative ophthalmology, and second, the plasma/serum (an acellular fraction), which may be used in the form of eyedrops administered directly to the damaged ocular surface. The rationale for using umbilical cord serum (UCS) to treat ocular surface diseases such as severe dry eye syndrome (DES), persistent epithelial defects (PED), recurrent epithelial erosions, ocular chemical burns, graft versus host disease (GVHD), among others, is the considerably high concentration of growth factors and cytokines, mimicking the natural healing properties of human tears. Allogeneic serum also offers the opportunity for therapeutic treatment to patients who, due to poor heath, cannot provide autologous serum. The mechanism of action involves the stimulation of endogenous cellular proliferation, differentiation and maturation, which is highly efficient in promoting and enhancing corneal epithelial healing where other therapies have previously failed.
... One optional treatment is the recombinant human collagen (RHC), which has been shown to promote partial regeneration of subbasal nerves . Additional treatments, which have been shown to ameliorate nerve insult, may consist of autologous serum eye drops (Matsumoto et al., 2004), umbilical cord serum eye drops (Yoon et al., 2007), platelet-rich plasma (Farrag et al., 2007) or neuronal growth factor (NGF) (Bonini et al., 2000). These treatments may contribute to the regeneration of nerve fibers following SM ocular exposure. ...
Article
The use of sulfur mustard (SM) in global terrorism is still a relevant threat to both civilian population and military personnel. Casualties exposed to SM may present mild, moderate or severe acute ocular lesions followed by a complete ocular resolution, chronic lesions or re-emerged ocular pathologies after a latent period. Current treatment for SM-induced ocular injury is based mainly on the clinical manifestation at the different stages of the injury and includes pharmaceutical and surgical interventions. These therapeutic measures are beneficial but not sufficient, and the ocular injury remains a continuous challenge for medical professionals. This review focuses on treatment experience carried out in humans and studied in animal models, for both SM-induced ocular acute injury and late pathology. In general, therapeutic measures are based on clinical features of the ocular injury or on the involvement of specific factors during the ocular injury that point out towards potential treatments. Anti-inflammatory treatments and limbal stem cell transplantation techniques were developed based on the clinical manifestation of the ocular injury. Optional therapies for impaired corneal innervation and endothelium are suggested for future research. Additionally, studies on potential treatments with anti-matrix metalloproteinase (MMP), anti-vascular endothelial growth factor (VEGF) and anti-IL-6 agents are discussed. Consequently, future studies may reveal the potential of additional pharmacological and biological treatments or advanced cellular and molecular biology methods to serve as novel therapeutic measures and techniques for this complicated ocular injury.
... CBED at 20% serum dilution were also used in 33 eyes with chemical burns, demonstrating the safety and lack of toxicity of this treatment. Complete epithelialisation was achieved in 12 of 18 cases in shorter times compared to the times taken by artificial tears and autologous serum 18 . Additional positive results with CB serum were reported from patients with severe dry eye syndrome associated with neurotrophic keratitis 18 and GVHD 19 . ...
Article
Background: Current treatments for several corneal lesions show limited efficacy. Here we report the clinical evaluation of the efficacy of a novel eye drop preparation produced in a public cord blood (CB) bank. Material and methods: In a multicentre, retrospective, consecutive case study we evaluated 33 patients (46 eyes) unresponsive to conventional treatments who required urgent intervention. The patients were given allogeneic eye drops obtained from cord blood platelet lysate (CBED) to treat severe ocular surface lesions under a compassionate use protocol. The CBED were prepared from CB units donated for haematopoietic stem cell transplantation that did not contain the minimum stem cell dose required for this use. Patients were grouped by acute conditions (neurotrophic ulcers: group I; other corneal ulcers: group II; corneal burns: group III), and chronic conditions (ocular graft-versus-host disease: group IV; severe dry eye syndrome: group V). The patients received one or two drops of the product to the affected eye four to six times per day for 19 days. A further 19-day cycle of treatment could be repeated according to the initial clinical response. Results: Patients received a median of 19 CBED vials (interquartile range 19-57, range 19-442) to complete the therapy. Group I-II-III patients showed full and partial ulcer recovery in 25 (78%) and six (19%) eyes respectively. One eye (3%) did not respond to treatment. For groups IV-V improvement was reported for 12 (85%) eyes and lesions worsened on treatment in both eyes (15%) of one patient. No severe adverse events were directly attributed to CBED. Discussion: Promptly available CBED resulted in a well-tolerated allogeneic treatment that showed evidence of efficacy in this cohort of patients. These positive results support further studies on CBED from platelet lysate as a novel product of CB banks. A prospective clinical trial in neurotrophic keratitis (NCT03084861) is ongoing to confirm these preliminary data.
... Umbilical cord serum eye drops (UCSEDs) can be prepared using umbilical cord blood collected during delivery, which contains numerous growth factors including substance P, IGF-1, NGF, EGF and TGF-β. UCSEDs are effective for corneal nerve reconstruction and epithelial healing in the persistent corneal epithelial defect [49,50]. The results of an in vitro study showed that hepatocyte growth factor (HGF) protected corneal epithelial cells from apoptosis and improved cell survival in homeostatic conditions. ...
... Fetal sığır serumu, allojenik serum ve göbek kordon serumu da büyüme faktörlerinin kayna-ğı olarak kullanılmaktadır, ancak alerjik reaksiyon ve enfeksiyon riski yüksek olan heterolog ürünler olması dezavantajlarındandır. (22,23) Otolog preparatlar ise immünojenik reaksiyonlar ve hastalık bulaşımı ile ilgili endişeleri ortadan kaldırmaktadır. ...
Chapter
DEJENERATİF RETİNA HASTALIKLARINDA OTOLOG KAN ÜRÜNLERİ KAYNAKLI BÜYÜME FAKTÖRLERİ VE KÖK HÜCRE UYGULAMALARI
... These are concentrates of growth factors that are normally present in patients' autologous serum or umbilical cord serum. 45,46 There is a good body of evidence in humans that these preparations are superior to conventional -Remove any particulate material: lid eversion (even double eversion) may be necessary; ...
Article
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Ocular chemical burns are absolute ophthalmic emergencies and require immediate management to minimize devastating sequelae. Management of alkali and acid burns is started at the scene of the accident by copious irrigation. Treatment is directed at improving epithelial integrity and stromal stability, reduction of undue inflammation, and prevention or timely management of complications. To ascertain the best possible outcome, numerous biological medications and surgical interventions have been merged into conventional therapeutic regimens. These include autologous and umbilical cord serum preparations, platelet-rich plasma, amniotic membrane transplantation, limbal stem-cell transplantation, and anti-angiogenic agents.
... [11][12][13] Cord blood serum (CBS, collected at birth from placenta umbilical veins) based eye drops have also been proposed. [14][15][16][17][18] Both sources were demonstrated to be efficient in the healing of epithelial defects, in the course of clinical trials having conventional therapies as control, and only one controlled study compared the effectiveness of autologous PBS versus allogeneic CBS. 19 One major criticism may be that these studies had not characterised the content of each source for trophic substances, which was demonstrated to be different. ...
Article
Aim To compare the efficacy of cord blood and peripheral adult donor blood serum eyedrops, controlled for growth factor content, in the treatment of severe dry eye diseases (DED) resistant to conventional therapy. Methods This was a multicentre randomised, double-masked, cross-over clinical trial. Sixty patients diagnosed as severe DED, associated to persistent corneal epithelial defects were randomised and equally assigned to group A (treated with cord blood serum (CBS)) or group B (treated with PBS), eyedrops administered eight times/day for 1 month. Primary outcome was the pretreatment and post-treatment change in corneal fluorescein staining. Secondary outcomes included the pretreatment and post-treatment change in Ocular Surface Disease Index (OSDI) questionnaire and Visual Analogue Score (VAS) of subjective symptoms, Schirmer I test, tear break-up time and conjunctival staining. Patients with relapse in signs or symptoms after further 2 months switched to the remaining group for one additional month. Data were statistically analysed (p<0.05). Results Corneal staining was more significantly reduced after the CBS treatment, both VAS and OSDI score reduction was observed in both groups, but group A reported significantly less grittiness and pain. Nineteen patients shifted in the crossover period, the within individual comparison confirmed a better recovery in the CBS treatment period. Reduction in epithelial damage was positively associated with epidermal growth factor, transforming growth factorα and platelet-derived growth factor content. Levels of interleukins (IL-13) were positively associated with symptom decrease. Conclusions Overall, DED signs improved after both CBS and PBS treatments, with potential advantages of CBS for subjective symptoms and corneal damage reduction. Clinical trial registration NCT03064984 .
... The rationale for their use is based on several advantages over autologous sources (eg, feasibility in patients with poor venous access or coexisting systemic diseases, such as anemia and blood dyscrasia; higher content of growth factor levels; and possibility of selection of a pool with proper content of the desired growth factor). 1 Allo-PBS and CBS contain different concentrations of growth factors, and, in particular, the latter has higher levels of nerve growth factor, a neurotrophin that stimulates the proliferation and survival of corneal nerves. 38,39 Therefore, we hypothesized that these 2 sera might determine different effects on corneal nerves and separately analyzed patients according to the 2 types of therapies. Among the analyzed IVCM parameters, only CNFrD showed a statistically higher improvement in patients treated with CBS compared with those treated with allo-PBS. ...
Article
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Purpose: To investigate the comparative effect of allogeneic peripheral blood serum (allo-PBS) and cord blood serum (CBS) eye drops on the status of the corneal subbasal nerve plexus in patients with dry eye disease by using an automated analysis system of in vivo confocal microscopy images. Methods: This prospective, randomized, double-blind study included 30 patients with severe dry eye disease assigned to receive allo-PBS (group 1) or CBS (group 2) eye drops 8 times a day for 30 days. The following in vivo confocal microscopy parameters were calculated with ACCMetrics before (visit 1 [V1]) and after treatment (visit 2 [V2]): corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve total branch density, corneal nerve fiber area, corneal nerve fiber width, and corneal nerve fractal dimension (CNFrD). Results: In overall patients, the values of corneal nerve fiber density, corneal nerve fiber length, and CNFrD significantly increased, whereas the value of corneal nerve fiber width significantly decreased at V2 compared with V1 (respectively, 20.4 ± 7.9 vs. 17.4 ± 10.1 n/mm; 13.5 ± 4.0 vs. 12.0 ± 5.1 mm/mm; 1.466 ± 0.046 vs. 1.475 ± 0.033; and 0.022 ± 0.002 vs. 0.023 ± 0.002; all P < 0.05). In the subanalysis according to the treatment type, the increase of CNFrD value from V1 to V2 was higher in group 2 compared with group 1 (respectively, from 1.455 ± 0.041 to 1.471 ± 0.030 and from 1.479 ± 0.050 to 1.481 ± 0.035; P = 0.030). Conclusions: Overall, both treatments significantly improved corneal subbasal nerve plexus parameters, and in particular, nerve density, length, width, and fractal dimension. Treatment with CBS eye drops was associated with a higher increase of CNFrD compared with allo-PBS.
Article
Neurotrophic keratitis is a rare eye condition characterised by reduced or absent corneal sensation. This leads to impaired corneal healing through a loss of protective mechanisms such as blinking. The cornea becomes vulnerable to persistent epithelial defects, ulceration, infection and ultimately, vision loss or loss of the eye. Treatment strategies aim to protect the corneal surface and promote re-epithelialisation. Established treatments include specialised eye drops such as blood serum eye drops and topical nerve growth factor. In some cases, surgical interventions or procedures such as amniotic membrane transplantation or corneal neurotisation may be necessary. Emerging therapeutic drug options include insulin drops, BRM424, CSB-001 and varenicline. The aim of this Current Opinion is to introduce and review this field for the general reader, paying particular attention to emerging drug therapies for neurotrophic keratitis.
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Pediatric facial nerve paralysis can present significant challenges based on its various etiologies, unique approach to treatment options, and overall outcomes. It can impact both the child and parent when regarding function, appearance, and psychosocial implications. The etiology of facial nerve palsy can include congenital, traumatic, iatrogenic, and idiopathic causes. In some, the paralysis is transient while others have permanent loss of function. A thorough evaluation and differential diagnosis are essential to guide treatment planning. The purpose of this paper is to review facial paralysis in children with a focus on surgical management.
Article
Background Corneal wound healing involves several complex pathways that can be targeted by drugs with varying mechanisms of action. Infected corneal ulcers represent a special challenging situation facing ophthalmologists due to resistance to treatment and visual impairing complications. Purpose The aim of this study was to evaluate the efficacy of umbilical cord blood serum (CBS) as an adjunctive therapy for resistant infected corneal ulcers. Patients and methods This prospective cohort study included 40 eyes having infected corneal ulcer resistant to specific medical treatment for 2 weeks. The patients were recruited from the Cornea Unit at Tanta University Hospital, Tanta, Egypt. They were divided into two groups, 20 cases each. Group A cases were treated with umbilical CBS as an adjunctive therapy together with medical treatment based on culture and sensitivity testing, while group B cases continued the conventional medical treatment only till the complete healing was achieved. The results of the two groups were compared regarding the duration of healing and best-corrected visual acuity improvement. Results Visual acuity improvement was achieved with one or more line gain in 14 (70%) cases in group A compared to 6 (30%) cases in group B, with a statistically significant difference ( P = 0.008). Healing was achieved in 16 (80%) cases of group A in 2–4 weeks compared to 14 (70%) cases of group B that achieved healing in a longer duration of 3–6 weeks, with a statistically significant difference ( P = 0.001). Amniotic membrane transplantation AMT was required in 4 (20%) cases in group A due to thinning compared to 6 (30%) cases in group B. Conclusion Umbilical CBS was safe and effective when applied to the cornea as an adjunctive therapy in cases of resistant infected corneal ulcers where it accelerated healing with better visual outcome results.
Article
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Blood-derived preparations, including autologous or allogenic serum, umbilical cord serum/plasma, and platelet-rich plasma eye drops, contain various growth factors, cytokines, and immunoglobulins that resemble natural tears. These components play important roles in corneal cell migration, proliferation, and wound healing. Blood-derived eye drops have demonstrated clinical effectiveness across a spectrum of ocular surface conditions, encompassing dry eye disease, Sjögren's syndrome, graft-versus-host disease, and neuropathic corneal pain (NCP). Currently, management of NCP remains challenging. The emergence of blood-derived eye drops represents a promising therapeutic approach. In this review, we discuss the benefits and limitations of different blood-derived eye drops, their mechanisms of action, and treatment efficacy in patients with NCP. Several studies have demonstrated the clinical efficacy of autologous serum eye drops in relieving pain and pain-like symptoms, such as allodynia and photoallodynia. Corneal nerve parameters were also significantly improved, as evidenced by increased nerve fiber density, length, nerve reflectivity, and tortuosity, as well as a decreased occurrence of beading and neuromas after the treatment. The extent of nerve regeneration correlated with improvement in patient-reported photoallodynia. Cord plasma eye drops also show potential for symptom alleviation and corneal nerve regeneration. Future directions for clinical practice and research involve standardizing preparation protocols , establishing treatment guidelines, elucidating underlying mechanisms, conducting long-term clinical trials, and implementing cost-effective measures such as scaling up manufacturing. With ongoing advancements, blood-derived eye drops hold promise as a valuable therapeutic option for patients suffering from NCP.
Article
Purpose The purpose of this study was to assess potential corneal reinnervation and recovery of corneal sensation in patients with severe neurotrophic keratopathy (NK) secondary to herpes zoster ophthalmicus (HZO) after treatment with topical autologous serum tears (AST). Method Four cases of HZO with severe NK were followed clinically and by serial laser in vivo confocal microscopy (IVCM, HRT3/RCM, Heidelberg Engineering GmbH) before and during treatment with 20% AST drops 8 times a day. Two masked observers reviewed the IVCM images and assessed corneal nerve alterations. Results At baseline, all patients had complete loss of corneal sensation. In addition, IVCM showed complete lack of the subbasal corneal nerve plexus in all patients. All 4 patients were refractory to conventional therapies and were treated with AST drops. All patients demonstrated significant nerve regeneration by IVCM within 3 to 7 months of treatment. The total nerve density increased to a mean ± SEM of 10,085.88 ± 2,542.74 μm/mm ² at the last follow-up. Corneal sensation measured by Cochet–Bonnet esthesiometry improved to a mean ± SEM of 3.50 ± 1.30 cm. Interestingly, 3 of 4 patients developed stromal keratitis with stromal thinning within weeks of corneal reinnervation, which was reversed by adding topical steroids. Conclusions Autologous serum tears are effective in restoring corneal subbasal nerves and sensation in patients with severe NK secondary to HZO. However, this group of patients may require concurrent topical immunomodulation and antiviral therapy while on AST to prevent stromal keratitis.
Article
Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Non-surgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure’s novelty and varied recovery timelines after CN. Regardless of the chosen approach, corneal neurotization has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with neurotrophic keratopathy.
Article
This study aimed to evaluate the effects of platelet-rich plasma (PRP), autologous blood serum (ABS), and umbilical cord serum (UCS) on corneal healing following penetrating keratoplasty (PK). A total of 120 New Zealand white rabbits, forty were designated as donors, while the remaining eighty rabbits were randomly divided into four groups after undergoing PRP Group (n = 20), ABS Group (n = 20), UCS Group (n = 20) and Control Group (n = 20). Corneal opacity score, corneal vascularization, corneal staining, histopathological analysis, and immunohistochemical analysis (including CD4+, CD8+, and major histocompatibility complex [MHC] II) were assessed at postoperative 1, 2, 3, and 12 weeks. The results showed that corneal opacity score and corneal vascularization did not differ significantly among the groups. However, corneal staining was found to be statistically higher in the PRP group (0.40 ± 0.60) compared to the other groups (p = 0.011). Immunohistochemical examination revealed no significant differences in CD4+, CD8+, and MHC II levels among the groups. Notably, in all groups, CD4+, CD8+, and MHC II levels were significantly higher at 12 weeks compared to other time points. PRP, ABS, and UCS demonstrated positive effects on corneal healing after PK. However, among the three products, PRP exhibited a superior healing effect compared to ABS and UCS crucial in the postoperative period following PK procedures, as they significantly impact visual quality, graft transparency, graft survival, and prevention of stromal resorption caused by infections. Despite the avascular nature of the cornea and its immune privilege, failure to resolve epithelial defects (ED) commonly observed after PK can result in irreversible scarring and ulceration, leading to graft rejection. While epithelial defects are observed in 14–100% of cases on the first postoperative day, approximately 3–7% of them persist as non-healing ED in subsequent periods. In conclusion, our study demonstrated that PRP, ABS, and UCS have a positive effect on corneal healing after PK.
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Background/Aims: Neurotrophic keratitis (NK) is a neurodegenerative disease that can lead to corneal hypoesthesia, decreased tear production, and epitheliopathy. Based on the severity of ocular surface damage, NK is classified into 3 stages. Stage 1 NK is characterized by superficial punctate keratopathy, tear film instability, and reduced corneal sensation. The therapeutic efficacy of PRGF eye drops for NK stages 2 and 3 has been previously reported. In this study, we evaluated the efficacy and safety of autologous PRGF eye drops in improving corneal sensitivity and other ocular surface clinical signs in patients with stage 1 NK. Methods: Retrospective chart review Results: 26 eyes of 15 stage 1 NK patients (seven males, eight females), aged 76.3 ± 12.1 years, were included in the study. The mean treatment duration was 2 ± 1.8 months. With PRGF treatment, corneal sensitivity increased from 2.8 to 4.5 cm in 53.8% (14/26) (p < 0.01), TBUT increased from 3.6 to 5.0 s in 69.2% (18/26) (p < 0.01), and Schirmer score increased from 13.7 to 16.8 mm in 80.7% (21/26) of treated eyes (p < 0.01). Similarly, an improvement in corneal staining (punctate epithelial erosions) and MMP-9 levels was seen in 80.7% (n = 21) and 65.4% (n = 17) of treated eyes, respectively. BCVA improvement was seen in 26.9% of treated eyes (n = 7). Conclusions:This study demonstrates the effective role of PRGF therapy in recovering corneal sensation and tear film function and in the healing of corneal erosions in stage 1 NK patients.
Article
Zusammenfassung Hintergrund Ziel dieser Arbeit war es, die Wirkung von 100% autologen Serumaugentropfen bei therapieresistenten Erosiones und Ulcera corneae auf der eigenen Hornhaut vs. transplantierter Hornhaut zu vergleichen. Patienten und Methoden In einer retrospektiven Studie über 7 Jahre wurden 263 Behandlungen mit autologen Serumaugentropfen bei therapieresistenten Epitheldefekten untersucht, die zwischen 2007 und 2014 auftraten. Unterschieden wurde, ob der Epitheldefekt (Erosio [88%] vs. Ulcus corneae [12%]) sich auf dem Hornhauttransplantat (48,1%) oder auf der eigenen Hornhaut (51,9%) befand. Zielgröße war der komplette Epithelschluss innerhalb von 28 Tagen Therapie. Die Rezidivrate im Verlauf wurde ebenfalls untersucht. Ergebnisse Bei 88,2% der behandelten Defekte kam es innerhalb von 28 Behandlungstagen zu einem kompletten Epithelschluss. Bei 5,1% der erfolgreich geschlossenen Defekte kam es nach Abschluss der 1-monatigen Therapie zu einem Rezidiv. Es zeigte sich kein signifikanter Unterschied zwischen der Erfolgsrate von transplantiertem Hornhautgewebe (88,6%) oder eigenem Hornhautgewebe (87,8%; p = 0,137). Die Rezidivrate lag bei transplantierter Hornhaut bei 6,4%, bei der eigenen Hornhaut bei 1,7%. Bei Ulcera (74,2%) zeigte sich eine signifikant reduzierte Erfolgsrate im Vergleich zu den Erosiones (90,3%; p < 0,001). 4,4% der Erosiones und 4,3% der Ulcera rezidivierten im Verlauf. Schlussfolgerungen Die autologen Serumaugentropfen stellen eine gute, nicht invasive und sichere Therapiealternative bei therapieresistenten Epitheldefekten dar, ohne signifikanten Unterschied der Wirkung bei Epitheldefekten auf der eigenen Hornhaut und transplantierter Hornhaut. Die Erfolgsrate, aber nicht die Rezidivrate ist bei Hornhautulcera signifikant geringer als bei Erosiones corneae.
Article
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Background Neurotrophic keratopathy (NK) is an orphan disease, with an estimated prevalence of 1–5/10,000. No data regarding the incidence exists. The primary aim was to evaluate incidence and prevalence of NK at a tertiary referral center in Germany, and the secondary aim was to analyze demographic parameters, etiology, and clinical features and therapeutic outcomes. Methods and material All patients treated for NK with serum eye drops (SED), amnionic membrane transplantation (AMT), or penetrating keratoplasty (PK) in 2013–2017 were identified. Age, sex, etiology of NK, visual acuity, disease stage, treatment, and visual acuity were analyzed. Incidence and prevalence of NK in our hospital and the overall population of the city were calculated. Results In 63 eyes of 60 patients (56.7% male; 68 ± 16 years), the most common underlying diseases were herpetic infections (23.8%), neurological causes (19%), and diabetes mellitus (14.3%). The annual incidence of NK in our tertiary referral center ranges between 5/10,000 and 3/10,000, the prevalence between 9/10,00 and 22/10,000. In all patients treated with corneal ulcers, the prevalence was up to 27% (2706/10,000). The incidence in the overall population is estimated at 0.1–0.3/10,000, the prevalence at 0.2–0.5/10,000 to 0.5/10,000. Conclusion Based on our assessment, the prevalence of NK in the overall population is lower than estimated before. However, in patients with corneal ulcers, the percentage of NK is comparably high. The disease may still be underdiagnosed due to the variety of underlying disorders and unknown comorbidities. Thus, in cases of therapy-refractive superficial keratopathy or ulcerations, NK should be considered more frequently.
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Purpose: To evaluate the clinical efficacy of amniotic membrane extract eye drops (AMEEDs) in patients with persistent epithelial defects (PEDs) of the cornea.Methods: Sixteen patients with PEDs refractory to the conventional treatment were further treated with AMEEDs six times a day. Visual acuity, visual analog scale (VAS), esthesiometer score, and areas of the epithelial defects before and after 1 and 2 months of treatment were evaluated. After 2 months, AMEEDs were considered effective if all epithelial defects were healed, partially effective if the epithelial defects decreased in size compared with the baseline, and ineffective if the epithelial defects increased in size and required additional treatment.Results: After 2 months of treatment with AMEEDs, there was a reduction in the area of epithelial defects (5.2 ± 3.1 mm2 vs. 0.1 ± 0.1 mm2, respectively, p = 0.01), as well as a significant improvement in best-corrected visual acuity (0.8 ± 0.5 logarithm of minimal angle of resolution [LogMAR] vs. 0.6 ± 0.3 LogMAR, respectively, p = 0.03), and VAS scores (4.3 ± 1.0 vs. 2.8 ± 0.7, respectively, p = 0.04) compared with the baseline values. Treatment with AMEEDs was effective in 13 (81.3%) patients and partially effective in three (18.8%) patients.Conclusions: AMEEDs could stimulate epithelial wound healing and improve ocular symptoms in patients with refractory PED. Therefore, AMEEDs could be considered an effective treatment option for refractory PEDs.
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With the recent development of bioprinting technology, various attempts have been made to replace bioprinting technologies and regenerative medicine are more directed towards transplantation/reconstructive surgeries only with the implantation of scaffolds. The purpose of this study is to determine whether the growth factors, human umbilical cord serum (hUCS) and bFGF (basic fibroblast growth factor), have a synergistic effect on eardrum regeneration, when used with a cell-printed scaffold in a chronic tympanic membrane perforation (TMP) model. In this study, in vitro cellular activities for bioprinted cell-laden collagen scaffolds using human adipose stem cells (hASCs) and supplemented with 10 μg\mu \text{g} /mL hUCS and 10 ng/mL bFGF were performed. The mixture of the growth factors in the cell-laden structures effectively affects various in vitro cellular responses including the proliferation of hASCs and the migration of keratinocytes due to the synergistic effect of the growth factors and hASCs. For the in vivo evaluation, a rat TMP model was used, and the TMP regeneration was assessed by otoscopic examination, hearing threshold measurement, and histologic examination. Although the cell-laden structure containing hUCS was more enhancing effect compared to the structure with bFGF, more synergistic effect in the structure using hUCS/bFGF was observed. Based on the results, we believe that the cell-laden structure incorporating hUCS and bFGF can induce significant regeneration of chronic tympanic membrane perforation.
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Purpose of review: The corneal epithelium is a crucial barrier against pathogens, and when disrupted in the setting of certain underlying risk factors such as neurotrophic keratopathy (NK), may result in persistent epithelial defects (PEDs) of the cornea. Management is challenging and may require a variety of different approaches ranging from conservative medical therapy to surgical intervention. The purpose of this review is to provide an update on current and potential future therapeutic options for PEDs and NK. Recent findings: Recent research has yielded promising results for numerous novel therapies aimed at treating PEDs. Many of these attempt to stimulate healing at the cellular level, via signaling of corneal epithelial differentiation, migration, and proliferation. Considerable advances have also been made regarding medical and surgical promotion of corneal re-innervation and restoration of corneal sensitivity to directly address the underlying NK condition. Summary: Together with the current well established therapeutic options available for PEDs and NK, growing research on newer alternatives suggest increasing potential for both more effective and more convenient therapies for these difficult situations.
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Purpose of Review Neurotrophic keratopathy (NK) is a degenerative corneal disease characterized by decreased corneal sensibility and impaired corneal healing. In this article, we review surgical techniques for corneal neurotization (CN) and novel medical therapies for the treatment of NK. Recent Findings In recent decades, there has been a paradigm shift in the treatment strategies for NK. New minimally invasive direct and indirect CN approaches have demonstrated efficacy at improving best-corrected visual acuity and central corneal sensation while decreasing surgical morbidity. In addition, several targeted medical therapies, such as recombinant human nerve growth factor (rhNGF), regenerating agents (RGTA), and nicergoline, have shown promise in improving corneal epithelial healing. Of these options, cenegermin (Oxervate®, Dompé), a topical biologic medication, has emerged as an approved medical treatment for moderate to severe NK. Summary NK is a challenging condition caused by alterations in corneal nerves, leading to impairment in sensory and trophic function with subsequent breakdown of the cornea. Conventional therapy for NK depends on the severity of disease and focuses primarily on protecting the ocular surface. In recent years, numerous CN techniques and novel medical treatments have been developed that aim to restore proper corneal innervation and promote ocular surface healing. Further studies are needed to better understand the long-term efficacy of these treatment options, their target populations, and the potential synergistic efficacy of combined medical and surgical treatments.
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The past 20 years of experience with umbilical cord blood transplantation have demonstrated that cord blood is effective in the treatment of a spectrum of diseases, including hematological malignancies, bone marrow failure, hemoglobinopathies, and inborn errors of metabolism. However, only a few number of umbilical cord blood units collected have a cell content adequate for an allogenic hematopoietic stem cell transplantation. In the meanwhile, there is an increasing interest in exploiting cord blood derivatives in different fields. In this review, we will summarize the most recent updates on clinical applications of umbilical cord blood platelet derivatives for regenerative medicine, and we will revise the literature concerning the use of umbilical cord blood for autologous or allogeneic transfusion purposes. The methodological aspect and the biological characteristics of these products also will be discussed.
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Background: Several therapeutics have been proposed for neurotrophic keratitis, but no direct comparison among different approaches is available. Objective: To compare treatment-related problems and outcomes of both traditional and novel therapeutics for neurotrophic keratopathy, focusing on resolution rate, healing time, and recurrence rate. Data sources: Literature search of published studies between 1980 and 2019 on neurotrophic keratopathy available on PubMed was made without any language constraints but limited to human study participants. Study selection: All published peer-reviewed open, blinded and randomized clinical trials, case series and case reports, divided according to evidence level, were reviewed and resolution rate, healing time, relapses of the disease, and visual outcomes were evaluated. Data extraction and synthesis: Single observer data extraction. MAIN OUTCOMES AND MEASURES: resolution rate, healing time, recurrence rate. Results: Human recombinant Nerve Growth Factor eye drops, Serum Tears and Substance P showed comparable resolution rate in patients with neurotrophic keratopathy. Amniotic membrane transplantation and Nerve Growth Factor eye drops are associated with a faster healing time among available treatments. Nerve Growth Factor eye drops clinical trial are the only study with evidence level 1, hence randomized and controlled. Conclusions and relevance: Several new treatment options are available for patients with neurotrophic keratitis with adequate safety.
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Neurotrophic keratopathy (NK) is a degenerative corneal disease caused by damage of trigeminal innervation. This leads to epithelial defects, ulceration and, eventually, perforation. Both herpes simplex and varicella zoster keratitis are reported to be the main causes of NK. Furthermore, prognosis in this type of NK is poor. Classic clinical findings in post-herpes NK are spontaneous epithelial breakdown, round and central epithelial defects with smooth edges, stromal melting and thinning, scarring, and neovascularisation. Although several medical and surgical treatments have been reported, no therapies are currently available to definitely restore corneal sensitivity. Therefore, NK remains a challenging disease to treat. In this review a summary is presented of the pathogenesis, manifestations, and current management of post-herpes NK. The role of antiviral treatment and varicella-zoster vaccination is also discussed. A description is also presented on both medical and surgical novel therapies, such as regenerative drugs and corneal neurotization.
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Purpose: To compare the therapeutic effects of human derivatives in a mouse alkali burn model. Methods: The right eyes of mice were injured using NaOH. After alkali injury, one of the following agents was topically administered for 7 days: human amniotic membrane (hAM) suspension, human umbilical cord serum (hUCS), and human peripheral blood serum (hPBS), or saline. The epithelial defect areas on days 1, 2, and 3, degrees of opacity on days 2, 3, and 7, and corneal neovascularization (NV) areas on day 7 were evaluated. Histologic examination and mRNA expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-8, and MMP-9 were also evaluated on day 7. Results: The epithelial defect areas in the hUCS group were smaller than those in the control and hPBS groups on day 3 (p < 0.05, respectively). The epithelial defect areas in the hAM suspension group showed smaller than those in the control and hPBS groups on days 1 and 2 (p < 0.05, respectively). The degrees of opacity were lower in all treatment groups than that of the saline control group on day 7 (p < 0.05, respectively). Corneal NV areas were not different among groups on day 7 (p=0.20). The expression levels of TNF-α, IL-6, MMP-8, and MMP-9 mRNA and the infiltration of the inflammatory cells in all treatment groups were lesser than those in the control group on day 7 (p<0.05, respectively). Conclusion: All treatments reduced inflammatory reactions and corneal opacity development. Corneal reepithelialization was faster in the hUCS group.
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Resumen La queratopatía neurotrófica (QN) es una enfermedad corneal degenerativa causada por un daño en la inervación del nervio trigémino. Esta situación produce defectos epiteliales, ulceración y, eventualmente, perforación. Tanto la queratitis por herpes simple como por varicela zoster constituyen la principal causa de QN. Además, el pronóstico en este tipo de QN es pobre. Los hallazgos clínicos clásicos en la QN postherpética incluyen la rotura epitelial espontánea, defectos epiteliales ovalados y centrales de bordes suaves, queratolisis con adelgazamiento del estroma, cicatrización y neovascularización. Aunque se han descrito tratamientos médicos y quirúrgicos prometedores, actualmente no hay un tratamiento definitivo para restaurar la sensibilidad de la córnea. Por tanto, la QN sigue siendo un reto terapéutico. En esta revisión resumimos la patogenia, la clínica y el tratamiento actual de la QN postherpética. Se discute el papel del tratamiento antiviral y de las vacunas contra el virus de la varicela-zoster. Se describen nuevas terapias médicas y quirúrgicas, como los agentes regenerativos y la neurotización corneal.
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Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been used widely in bone tissue regeneration; however, the use of rhBMP‐2 can be limited clinically because extremely high doses can cause opposing effects on bone formation, such as high inflammation, edema, and even uncontrollable bone growth. To overcome the limitation of using BMP-2, we used an umbilical cord serum (UCS) that exhibits various growth factors (epidermal growth factor, transforming growth factor-β nerve growth factor, etc.). To evaluate the effect of the UCS, we studied the synergistic effect of the composite scaffold using BMP-2/UCS/alginate coated on three-dimensional mesh-structured poly-ε-caprolactone (PCL), both in vitro and in vivo, using a rat mastoid obliteration model. The newly suggested biocomposite scaffold (BMP-2/UCS/alginate) demonstrates significantly rapid new bone formation (particularly, in the interstitial area of the scaffold) compared to those of two controls: PCL mesh structure coated with alginate, and BMP-2/alginate-coated PCL scaffold. Based on the in vitro and in vivo works, the present study demonstrates that the simultaneous use of low‐dose BMP‐2 and UCS increases osteogenesis significantly in a rat model compared to the control that uses only BMP‐2. © 2019 The Korean Society of Industrial and Engineering Chemistry
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Aim: To evaluate the efficacy of autologous serum application for the treatment of dry eye in Sjögren's syndrome. Methods: The stability of essential components (EGF, vitamin A, and TGF-beta) in preserved serum were examined following preservation at 4 degrees C and -20 degrees C. In a primary clinical trial, 12 patients with Sjögren's syndrome were treated with autologous serum (diluted to 20% with sterile saline) for 4 weeks, and vital staining of the ocular surface was compared before and after treatment. The effects of serum on mucin (MUC-1) expression were observed in cultured conjunctival epithelial cells in vitro. Results: EGF, vitamin A, and TGF-beta were well preserved for up to 1 month in the refrigerator at 4 degrees C and up to 3 months in the freezer at -20 degrees C. Rose bengal and fluorescein scores improved significantly from the initial scores of 5.3 and 5.6 to 1.7 and 2.5 after 4 weeks, respectively. The additive effect of human serum for cultured conjunctival epithelial cells showed significant MUC-1 upregulation on the cell surface. Conclusion: Autologous serum application is a safe and efficient way to provide essential components to the ocular surface in the treatment of dry eye associated with Sjögren's syndrome.
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A recent clinical report demonstrated that topical nerve growth factor (NGF) treatment in patients affected by corneal neurotrophic ulcers induced epithelial and stromal healing restoring corneal integrity. Mechanisms(s) undergoing these clinical NGF actions are still unclear. The aim of this study was to investigate the role of NGF in human and rat cornea physiopathology. Expression of high-affinity NGF receptors, NGF-mRNA, and NGF protein was evaluated in human and rat normal corneas, in human and rat corneal epithelial cell cultures, in human corneal organ culture, and in the rat cornea after an experimental model of epithelial injury, by means of immunohistochemistry, in situ hybridization reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay. The resultant data demonstrated that NGF is a constitutive molecule present and produced in normal human and rat corneas. In vitro human and rat corneal epithelial cells produce, store, and release NGF and also express high-affinity NGF receptors (TrkA). In human organ culture, epithelium, keratocytes, and endothelium have been shown to bind exogenous radiolabeled NGF, and the epithelial cells' binding was increased after epithelium injury. In vivo, after rat corneal epithelial injury, a transient increase of corneal NGF levels was observed. Inhibition of endogenous NGF activity by neutralizing anti-NGF antibodies delayed the corneal epithelial healing rate, whereas exogenous administration of NGF accelerated healing. Taken together, the above findings show that NGF plays an important role in corneal physiopathology and suggest that this neurotrophin may exert therapeutic action in wide-spectrum corneal diseases.
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To evaluate whether amniotic membrane transplantation can be an effective alternative treatment for neurotrophic corneal ulcers. Amniotic membrane transplantation was performed in 16 eyes of 15 patients with neurotrophic corneal ulcers and vision equal to or worse than 20/200. The neurotrophic state was developed following keratoplasty (four eyes), herpes zoster ophthalmicus (four eyes), diabetes mellitus (four eyes), radiation (two eyes), removal of acoustic neuroma with neuroparalysis (one eye), and herpes simplex keratitis (one eye). During a mean follow up period of 18.8 (SD 13.0) months, one to three layers of amniotic membrane with or without additional membrane as a patch were used for 17 procedures in 16 eyes for persistent neurotrophic corneal ulcers. All but four (76.4%) instances of amniotic membrane transplantation achieved rapid epithelialisation in 16.6 (9.0) days. Of the four eyes showing delayed healing, three eyes healed by tarsorrhaphy, and the remaining one eye with corneal perforation required penetrating keratoplasty and tarsorrhaphy. Two eyes gained vision better than 20/200. The healed corneal surface was accompanied by reduced inflammation. Amniotic membrane transplantation can be considered an effective alternative for treating severe neurotrophic corneal ulcers.
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Autologous serum drops have been reported to be beneficial in keratoconjunctivitis sicca (KCS) and persistent epithelial defects (PED). A clinical pilot study was carried out to examine these potential uses and in vitro toxicity testing on corneal epithelial cell cultures was performed to compare the effect of serum drops with unpreserved hypromellose (hydroxypropylmethylcellulose 0.3%). Patients with KCS and PED, unresponsive to conventional treatment were recruited. Patients were examined before treatment, at 1 and 2 weeks after initiation, and then 2 weekly until treatment ceased. Symptoms were assessed at each visit. Clinical examination included Schirmer's test without anaesthesia, rose bengal staining, and fluorescein staining. Epithelial defects were measured with the slit beam. In the laboratory, cultured human corneal epithelial cells were exposed to serum drops and hypromellose, and their viability evaluated with fluorescent viability staining (Calcein AM ethidium homodimer) and an ATP assay. Autologous serum was used in 15 eyes of 13 patients with PED and 11 eyes of nine patients with KCS. In two patients serum drops were started after penetrating keratoplasty (PK). The PKs were performed for perforations secondary to PEDs. Of the 15 eyes with PED, nine healed at a mean of 29 days and six failed. The mean duration of PED before the use of serum drops was 48.2 days. Of the 11 eyes with KCS, six had improved subjective scores and fluorescein scores, and five had improved rose bengal scores after the use of serum drops. For the two patients who used serum eyedrops post-PK, there was a stable and intact epithelium at 1 week. Cessation of serum drops during the postoperative period led to deterioration in the subjective and objective scores in both patients. One developed a PED that responded to reinstitution of serum drops. The morphology and ATP levels of cultured epithelial cells exposed to serum were better maintained than those exposed to hypromellose. Autologous serum drops are useful for PED and KCS. This effect may be related to a number of active factors in serum including growth factors, fibronectin, vitamin A, and anti-proteases. In vitro toxicity testing demonstrated that serum drops have reduced toxicity compared with unpreserved hypromellose. Currently regulatory restrictions in the UK have prevented the establishment of a prospective randomised controlled trial examining the efficacy of autologous serum drops for the management of this group of ocular surface disorders.
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To investigate the effects of topical application of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and epithelial wound closure in rats with capsaicin-induced neurotrophic keratopathy. Neonatal rats were injected subcutaneously with a single dose of capsaicin to induce neurotrophic keratopathy. Corneal epithelial barrier function was evaluated with an anterior fluorophotometer. Tear fluid secretion was measured by the Schirmer test. Corneal epithelial wound healing was determined by measurement of the size of the epithelial defect after debridement of the entire epithelium. The combination of SP (1 mM) and IGF-1 (1 micro g/mL) in phosphate-buffered saline was administered in eye drops six times daily. Corneal epithelial barrier function was impaired and corneal epithelial wound healing was delayed in rats injected with capsaicin. The application of eye drops containing the combination of SP and IGF-1 to capsaicin-injected rats resulted in a significant improvement in corneal epithelial barrier function compared with that apparent in capsaicin-injected animals that received eye drops containing vehicle alone. Such treatment with SP and IGF-1 also significantly increased the rate of corneal epithelial wound closure in capsaicin-injected animals. Topical application of the combination of SP and IGF-1 improved both corneal epithelial barrier function and epithelial wound healing in an animal model of neurotrophic keratopathy.
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To establish a rat model of neurotrophic keratopathy and to examine the effects of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and wound healing in this model. Corneal denervation was achieved by thermocoagulation of the ophthalmic branch of the trigeminal nerve. A modified Schirmer test was performed without topical anesthesia. Corneal epithelial barrier function was assessed by measurement of fluorescein permeability with an anterior fluorophotometer. Epithelial wound healing was evaluated by measurement of the area of the defect at various times after removal of the entire epithelium. Eye drops containing both 1 mM SP and IGF-1 (1 micro g/mL) were administered six times daily. The Schirmer test result in eyes subjected to trigeminal denervation was lower than that in control eyes. The fluorescein permeability of the corneal epithelium of denervated eyes was increased relative to that of control eyes. Furthermore, trigeminal denervation induced a delay in corneal epithelial wound healing. Application of eye drops containing SP and IGF-1 to denervated corneas restored the fluorescein permeability of the corneal epithelium to control levels and abolished the delay in epithelial wound healing. A rat model of neurotrophic keratopathy, characterized by reduced tear secretion, loss of corneal sensation, impaired epithelial barrier function, and delayed epithelial wound healing, was established by trigeminal denervation. Treatment with both SP and IGF-1 improved corneal epithelial barrier function and stimulated corneal epithelial wound healing in this model.
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To evaluate umbilical cord serum therapy as a means of promoting the healing of persistent corneal epithelial defects. Umbilical cord serum or autologous serum drops were used to promote the healing of persistent epithelial defects. The study design was a prospective randomised controlled clinical trial. 60 eyes of 59 patients were divided into two groups, 31 in the cord serum group and 29 in the autologous serum control group. Epithelial defects measuring at least 2 mm in linear dimension resistant to conventional medical management were included. Serial measurements of the size of the epithelial defects-namely, two maximum linear dimensions perpendicular to each other, and the area and perimeter was done at start of therapy and follow up days 3, 7, 14, 21. Rate of healing of the epithelial defects were measured as percentage decrease from the baseline parameter at each subsequent follow up. The data were analysed by the non-parametric Wilcoxon rank sum test using STATA 7.0. The median percentage decrease in the size of the epithelial defect was significantly greater in the cord serum group at days 7, 14 and 21 (p<0.05) when measured in terms of the area and perimeter. A greater number of patients showed complete re-epithelialisation with umbilical cord serum (n = 18) than with autologous serum (n = 11) (Pearson chi = 0.19). None of the patients reported any side effects or discomfort with either treatment. Umbilical cord serum leads to faster healing of the persistent corneal epithelial defects refractory to all medical management compared to autologous serum.
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Neurotrophic keratopathy is a degenerative corneal disease induced by an impairment of trigeminal nerve. Impairment of loss of corneal sensory innervation is responsible for corneal epithelial defects, ulcer, and perforation. In the present report, we reviewed the pathogenesis, diagnosis, and therapeutic aspects of this disease. An accurate history and clinical examination, including the function of cranial nerves, together with the clinical features of the ocular surface are essential for a prompt diagnosis. The evaluation of the corneal sensitivity and tear film function are important diagnostic steps as well. Specific medical and surgical treatments, based on the clinical staging of the disease, are often able to halt its progression. Future developments in the medical treatment including the administration of neuropeptide and growth factors are presented.
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Persistent corneal epithelial defects (PED) present a very challenging problem to anterior segment surgeons. Autologous serum tears had been demonstrated to be beneficial in the treatment of PED. The current study was conducted to review the local spectrum of indications and to examine the outcome of autologous serum tear usage. All cases of PED treated with autologous serum tears at a tertiary referral centre for the period August 1999 - July 2001 were identified and reviewed. A total of 10 eyes from 10 patients were identified (5OD : 5OS). The gender ratio was 7M : 3F and the mean age was 36.8 (range 17-73) years old. The mean duration of PED before the usage of autologous serum tears was 22.4+/-69.6 days. Six eyes healed within 2 weeks, but two eyes failed to heal after 1 month of treatment and two patients defaulted follow-up. No adverse effects were observed with the addition of autoserum tears. The results of the current study correlated well with previous reported studies. Autologous serum tears may be considered as a valuable adjunct in the management of recalcitrant cases of PED.
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Tears have antimicrobial, nourishing, mechanical, and optical properties. They contain components such as growth factors, fibronectin, and vitamins to support proliferation, migration, and differentiation of the corneal and conjunctival epithelium. A lack of these epitheliotrophic factors--for example, in dry eye, can result in severe ocular surface disorders such as persistent epithelial defects. Recently, the use of autologous serum in the form of eye drops has been reported as a new treatment for severe ocular surface disorders. Serum eye drops may be produced as an unpreserved blood preparation. They are by nature non-allergenic and their biomechanical and biochemical properties are similar to normal tears. In vitro cell culture experiments showed that corneal epithelial cell morphology and function are better maintained by serum than by pharmaceutical tear substitutes. Clinical cohort studies have reported its successful use for severe dry eyes and persistent epithelial defects. However, the protocols to prepare and use autologous serum eye drops varied considerably between the studies. As this can result in different biochemical properties protocol variations may also influence the epitheliotrophic effect of the product. Before the definitive role of serum eye drops in the management of severe ocular surface disease can be established in a large randomised controlled trial this has to be evaluated in more detail. In view of legislative restrictions and based upon the literature reviewed here a preliminary standard operating procedure for the manufacture of serum eye drops is proposed.
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To evaluate the therapeutic effect of umbilical cord serum in the treatment of persistent epithelial defect of the cornea. Fourteen eyes of 14 patients with persistent epithelial defect that had persisted for at least 2 weeks despite conventional treatment were treated with 20% umbilical cord serum eyedrops six times a day. The images of the epithelial defects were captured using a camera attached to a slit lamp biomicroscope and the areas of the epithelial defects were calculated. Treatment was considered effective for epithelial defect healing within 2 weeks, partially effective for healing within 2 to 4 weeks, and ineffective for healing requiring either more than 1 month or additional measures. Mean duration of epithelial defect before treatment was 7.2 +/- 6.3 weeks, and mean area was 7.86 +/- 7.32 mm2. Umbilical cord serum therapy was effective in 6 eyes (42.9%), partially effective in 6 (42.9%), and ineffective in 2 (14.2%). Nevertheless, the epithelial defects in both the ineffective eyes were eventually healed within 8 weeks. Mean healing time in effective or partially effective cases was 2.75 +/- 1.06 weeks. The use of umbilical cord serum eyedrops for the treatment of persistent epithelial defect is effective.
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Purpose: This study was designed to compare and evaluate the efficacy of amniotic membrane transplantation with the conventional management (tarsorrhaphy and bandage contact lens) in eyes with refractory neurotrophic corneal ulcers. Methods: Thirty eyes of 30 patients (14 females and 16 males) with neurotrophic corneal ulcers refractory to medical management were included and divided randomly into group 1 (n = 15), who received conventional management with a tarsorrhaphy (n = 11) or bandage contact lens (n = 4), and group 2 (n = 15), who underwent Amniotic Membrane Transplantation. The outcome parameters evaluated were epithelialization time, duration of healing of corneal ulcers, and improvement in best corrected visual acuity. Results: The mean age in our study was 37 +/- 14.71 years. At the end of 3 months follow-up, 10 of 15 patients (66.67%) in group 1 showed complete epithelialization and subsequent healing and 11f 15 patients (73.33%) in group 2 showed complete epithelialization and healing (P > 0.05). The median time for complete epithelialization was 21 days in both groups. Both groups showed an improvement in the best-corrected visual acuity. Conclusions: Both amniotic membrane transplantation and conventional management (tarsorrhaphy or bandage contact lens) are effective treatment modalities for refractory neurotrophic corneal ulcers.
Article
AIMS To evaluate whether amniotic membrane transplantation can be an effective alternative treatment for neurotrophic corneal ulcers. METHODS Amniotic membrane transplantation was performed in 16 eyes of 15 patients with neurotrophic corneal ulcers and vision equal to or worse than 20/200. The neurotrophic state was developed following keratoplasty (four eyes), herpes zoster ophthalmicus (four eyes), diabetes mellitus (four eyes), radiation (two eyes), removal of acoustic neuroma with neuroparalysis (one eye), and herpes simplex keratitis (one eye). RESULTS During a mean follow up period of 18.8 (SD 13.0) months, one to three layers of amniotic membrane with or without additional membrane as a patch were used for 17 procedures in 16 eyes for persistent neurotrophic corneal ulcers. All but four (76.4%) instances of amniotic membrane transplantation achieved rapid epithelialisation in 16.6 (9.0) days. Of the four eyes showing delayed healing, three eyes healed by tarsorrhaphy, and the remaining one eye with corneal perforation required penetrating keratoplasty and tarsorrhaphy. Two eyes gained vision better than 20/200. The healed corneal surface was accompanied by reduced inflammation. CONCLUSION Amniotic membrane transplantation can be considered an effective alternative for treating severe neurotrophic corneal ulcers.
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purpose. To investigate the effects of topical application of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and epithelial wound closure in rats with capsaicin-induced neurotrophic keratopathy. methods. Neonatal rats were injected subcutaneously with a single dose of capsaicin to induce neurotrophic keratopathy. Corneal epithelial barrier function was evaluated with an anterior fluorophotometer. Tear fluid secretion was measured by the Schirmer test. Corneal epithelial wound healing was determined by measurement of the size of the epithelial defect after debridement of the entire epithelium. The combination of SP (1 mM) and IGF-1 (1 μg/mL) in phosphate-buffered saline was administered in eye drops six times daily. results. Corneal epithelial barrier function was impaired and corneal epithelial wound healing was delayed in rats injected with capsaicin. The application of eye drops containing the combination of SP and IGF-1 to capsaicin-injected rats resulted in a significant improvement in corneal epithelial barrier function compared with that apparent in capsaicin-injected animals that received eye drops containing vehicle alone. Such treatment with SP and IGF-1 also significantly increased the rate of corneal epithelial wound closure in capsaicin-injected animals. conclusions. Topical application of the combination of SP and IGF-1 improved both corneal epithelial barrier function and epithelial wound healing in an animal model of neurotrophic keratopathy.
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We describe the use of topical substance P (SP) and insulinlike growth factor 1 (IGF-1) in the treatment of severe neurotrophic and anhidrotic keratopathy in a young child. These compounds may provide a medical therapy for patients with keratopathy due to corneal anesthesia or dry eyes unresponsive to lubrication. Report of a Case. A 16-month-old white girl was referred to 1 of us (D.W.L.) for the evaluation of bilateral nonhealing corneal epithelial defects. She had difficulty swallowing since birth and developmental delay. She never produced tears when crying. An ocular examination revealed bilateral central epithelial defects (~5×5) mm) in both eyes; there was no evidence of infection or uveitis. There were no visible tear lakes. The child had no blink response to a cotton wisp or to instillation of eyedrops. Despite intensive lubrication and bandage contact lens treatment, rapid stromal melting occurred bilaterally (Figure 1), leading to a central descemetocele
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Serumaugentropfen stellen eine neue Möglichkeit zur Behandlung von Oberflächenerkrankungen des Auges dar. Wir untersuchten den Einfluss der Präparation von Blutprodukten anhand eines Zellkulturmodells. Zusätzlich evaluierten wir, ob Plasma eine Alternative für die Behandlung von Augenoberflächenerkrankungen darstellen könnte.Aus Vollblut von 10 Probanden wurden Serum- und Plasmaproben bei 500 und 3000 G zentrifugiert. Die hierin enthaltenen Wachstumsfaktoren EGF, PDGF, TGF-1, Fibronektin und Vitamin A wurden quantifiziert. Kulturen humaner Hornhautepithelzellen wurden mit allen 4 Blutprodukten in Dosiswirkungsexperimenten inkubiert und der zelluläre ATP-Gehalt als Maß für die Zellproliferation bestimmt.Serum enthielt signifikant höhere Konzentrationen an EGF, PDGF und Vitamin A als Plasma. Die Fibronektinkonzentration war in allen Präparaten gleich. Die Zellproliferation wurde am besten durch 25%iges, plättchenarmes Serum unterstützt. Auch die Differenzierung und Migration wurden durch Serumpräparate besser als durch Plasma gefördert.Der biochemische Charakter von Serumaugentropfen wird durch die Wahl der Präparationsparameter beeinflusst. Plasma scheint kein geeigneter Ersatz für Serumaugentropfen zu sein. Ihre Produktion sollte weiter optimiert werden, bevor klinische Studien zu ihrer Effektivität durchgeführt werden.
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Growth factors—for nerves and for epidermal tissue—are the areas of research of last year's recipients of the Nobel Prizes for Medicine. The growth of nerves and of epidermal tissue requires a chemical stimulant. Nerve growth factor (NGF) proved to be a freely diffusing protein that is essential for the normal development of embryos, but which, in excess, results in major disruption of neurogenic processes. NGF has been isolated from several sources, including the salivary glands of mice. Crude extracts of NGF had unexpected side effects, the systematic investigation of which led to the discovery of epidermal growth factor (EGF). EGF, like NGF, is a protein, whose sequence has been determined. The primary signal mediated by EGF is thought, at present, to involve the tyrosine kinase activity of its receptor. Abstract Growth factors—for nerves and for epidermal tissue—are the areas of research of last year's recipients of the Nobel Prizes for Medicine. The growth of nerves and of epidermal tissue requires a chemical stimulant. Nerve growth factor (NGF) proved to be a freely diffusing protein that is essential for the normal development of embryos, but which, in excess, results in major disruption of neurogenic processes. NGF has been isolated from several sources, including the salivary glands of mice. Crude extracts of NGF had unexpected side effects, the systematic investigation of which led to the discovery of epidermal growth factor (EGF). EGF, like NGF, is a protein, whose sequence has been determined. The primary signal mediated by EGF is thought, at present, to involve the tyrosine kinase activity of its receptor.
Article
Objective: To evaluate the efficacy of autologous serum application for the treatment of persistent epithelial defect. Design: Prospective, clinical, noncomparative case series. Participants: A total of 16 eyes were studied. Intervention: Autologous serum was prepared from the patients and diluted to 20% by saline. The patients were instructed to use the autologous serum six to ten times a day. The concentration of vitamin A, epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta) was measured at 1 week and 1 month stored in the refrigerator and 1 month and 3 months in the freezer. Main outcome measures: Time to closure of epithelial defect. Results: Vitamin A, EGF, and TGF-beta were stable during the 1 month in the refrigerator and 3 months in the freezer. Among 16 persistent epithelial defects, 7 (43.8%) healed within 2 weeks, 3 (18.8%) healed within 1 month, and the remaining 6 (37.5%) did not respond within 1 month. No apparent side effect of autologous serum application was observed. Conclusions: Autologous serum application healed 43.8% of persistent defect within 2 weeks and 62.5% within 1 month.
Article
We find that substance P (SP) and insulin-like growth factor-1 (IGF-1) demonstrate a synergistic effect on the stimulation of rabbit corneal epithelial migration in an organ culture. The addition of either SP or IGF-1 alone did not affect epithelial migration, while the combination of SP and IGF-1 stimulated epithelial migration in a dose-dependent fashion. The synergistic effects of SP and IGF-1 on corneal epithelial migration were nulled by the addition of a SP antagonist or enkephalinase. Among neurotransmitters (vasoactive intestinal peptide, calcitonin gene-related peptide, acethylcholine chloride, norepinephrine, serotonin) or tachykinins (neurokinin A, neurokinin B, kassinin, eledoisin, physalaemin), only SP demonstrated a synergistic effect with IGF-1 on cellular migration. In contrast, the combination of SP and IGF-1 did not affect the incorporation of 3H-thymidine into corneal epithelial cells. The attachment of the corneal epithelial cells to fibronectin, collagen type IV, and laminin matrices increased after treatment of the cells with SP and IGF-1, but SP or IGF-1 by themselves did not affect the attachment of the cells to these extracellular matrix proteins. An identical synergistic effect on corneal epithelial migration was observed when an NK-1 receptor agonist was used in place of SP, suggesting the synergistic effect of SP and IGF-1 might be mediated through the NK-1 receptor system. These results suggest that the maintenance of the normal integrity of the corneal epithelium might be regulated by both humoral and neural factors.
Article
The purpose of this study was to determine whether corneal epithelial defects and epitheliopathy in patients with unilateral dysfunction of the ophthalmic division of the trigeminal nerve (neurotrophic keratitis) is associated with reduced aqueous tear production. Sensation of the skin, cornea, and nasal mucosa, aqueous tear production by Schirmer 1 testing, nasal-lacrimal reflex, and exposure zone rose bengal staining were evaluated in the affected and fellow eyes of subjects with neurotrophic keratitis (n = 5), eyes of subjects who had recent herpes zoster ophthalmicus (HZO) and who did not develop neurotrophic keratitis (n = 4), and normal controls (n = 10). Sensation in the brow and upper lid skin and nasal mucosa was absent on the affected side of patients with neurotrophic keratitis, but was intact in all other groups. Corneal sensation and Schirmer 1 test values were significantly reduced (p < or = 0.05) in eyes with neurotrophic keratitis compared with the other groups. The nasal-lacrimal reflex was absent on the involved side of subjects with neurotrophic keratitis but was intact in subjects with HZO without keratopathy, and in normal controls (p < 0.008). Rose bengal keratitis staining scores were significantly increased in eyes with neurotrophic keratitis compared with the other groups (p < 0.05). We conclude that neurotrophic keratitis is associated with reduced cutaneous, nasal mucosal, and corneal sensation on the affected side, as well as marked reduction in aqueous tear production with loss of the nasal-lacrimal reflex. It is possible that the corneal epithelial pathology in neurotrophic keratitis is due in part to aqueous tear deficiency.
Article
We investigated the combined effects of substance P (SP) and insulin-like growth factor-1 (IGF-1) on corneal epithelial wound closure in vivo. The corneal epithelium of 16 rabbits was debrided by n-heptyl alcohol treatment; SP (1 mg/ml) and/or IGF-1 (1 microgram/ml) in phosphate-buffered saline (PBS) were administered immediately and at 2, 4, 6, 8, 10, 24, 26, 28, 30, 32, and 34 hours after debridement. Controls received PBS alone. The eyes were stained with fluorescein and photographed at baseline and at 6, 12, 18, 24, 30, 36, and 48 hours after debridement. The wound radii of the epithelial defects were recorded from hour 12 to hour 30, and the rate of healing was calculated by linear regression analysis. The mean (+/-SD) healing rate in the control group was 57.03 +/- 7.88 microns/h. The administration of SP or IGF-1 alone did not affect the healing rates, which were 55.49 +/- 2.49 and 55.57 +/- 7.14 microns/hr, respectively. However, when SP and IGF-1 were combined, the mean healing rate was significantly higher (75.16 +/- 6.68 microns/hr) than that of the control, SP-treated, or IGF-1-treated groups (p < 0.05). These results demonstrated that SP and IGF-1 synergistically affect corneal epithelial wound closure.
Article
To determine whether substance P is present in human tears. Tear samples (1-2 microliters) were collected from one eye of each of 12 subjects. Two of the eyes had dry eye syndrome, two wore contact lenses and had dry eye syndrome, and eight were normal. Five of the eight normal eyes were scheduled to undergo excimer laser refractive surgery, and tears were collected from these eyes before and after surgery. Tear samples were analyzed by laser desorption mass spectrometry. Pooled samples from one individual were subjected to enzyme-linked immunoabsorbent assay. Laser desorption mass spectra of the 18 tear samples displayed well defined peaks with mass to charge (m/z) ratios ranging from 1343.7 to 1355.9 and/or 1356.9 to 1364.7, corresponding to an average m/z of 1349.8 +/- 1.13 for protonated substance P and 1361.2 +/- 0.54 for oxidized substance P obtained from 14 mass spectra of standards formulated with substance P concentrations ranging from 10(-4) M to 10(-12) M. As confirmation, an enzyme-linked immunoabsorbent assay performed twice on pooled tears from one eye detected substance P in both replicates at a concentration of 125 pg/ml (9.26 x 10(-11) M). These findings demonstrate that substance P is a component of tears obtained from normal eyes of men and women ranging in age from 26 to 60 years, from eyes fitted with contact lenses, from eyes with dry eye syndrome, and from eyes 1 and 2 days after excimer laser refractive surgery. Whether the concentration of substance P in tears varies with sex, age, or eye condition, the source of substance P in tears, and its role in tears remains to be discovered.
Article
Corneal neurotrophic ulcers associated with impairment of sensory innervation of the cornea may lead to loss of vision, and there is no effective treatment for these ulcers. We evaluated the effects of nerve growth factor in patients with this disorder. Twelve patients (14 eyes) with severe neurotrophic corneal ulcers associated with corneal anesthesia were treated with topical nerve growth factor 10 times daily for two days and then 6 times daily until the ulcers healed. Treatment continued for 2 weeks after the ulcers healed, and the patients were then followed for up to 12 months. The evolution of the corneal disease during treatment and follow-up was evaluated by slit-lamp examination, photography, fluorescein-dye testing, and tests of corneal sensitivity and best corrected visual acuity. Corneal healing began 2 to 14 days after the initiation of treatment with nerve growth factor, and all patients had complete healing of their corneal ulcers after 10 days to 6 weeks of treatment. Corneal sensitivity improved in 13 eyes, and returned to normal in 2 of the 13 eyes. Corneal integrity and sensitivity were maintained during the follow-up period (range, 3 to 12 months). Best corrected visual acuity increased progressively during treatment and follow-up in all patients. There were no systemic or local side effects of treatment. In this preliminary, uncontrolled study, topically applied exogenous nerve growth factor restored corneal integrity in patients with corneal neurotrophic ulcers.
Article
Recent studies have suggested the involvement of nerve growth factor (NGF) in the conjunctival inflammatory process and in corneal epithelium proliferation and differentiation. To verify the hypothesis that NGF could locally modulate the inflammatory and reparative processes, the authors evaluated the expression of NGF high-affinity receptor on the ocular surface in normal and pathologic conditions. Ten conjunctival biopsies (obtained from three healthy subjects, five patients affected by vernal keratoconjunctivitis [VKC], and two patients with cicatricial pemphigoid [CP]) and five corneal specimens obtained from the Eye Bank of Veneto (Italy) were evaluated. All specimens were histologically stained, and immunohistochemistry was performed to identify the NGF high-affinity receptor (TrkA). All tissues expressed immunoreactivity for NGF receptors. In conjunctival specimens of healthy subjects, basal epithelial cells strongly expressed immunoreactivity and, in the stroma, rare cells were immunopositive for TrkA. No significant difference in immunoreactivity was observed in the conjunctival epithelium between healthy subjects and patients with inflammatory conjunctival diseases, whereas there were more immunopositive cells observed in the conjunctival stroma of VKC and CP patients than in the controls. The immunoreactivity in the cornea was confined to basal epithelial cells and endothelium. The NGF receptor is present on the human ocular surface. The authors' data support the possibility that NGF modulates ocular inflammation and corneal epithelial proliferation and differentiation through its receptors.
Article
Neurotrophic keratopathy is a degenerative corneal disease caused by an impairment of corneal sensitivity. Lack of the sensory nerve's trophic effect is responsible for the impairment in corneal healing and for the changes on the ocular surface that lead to corneal epithelial deficit, ulcer, and perforation. The etiology and recent advances in understanding of the pathogenetic mechanisms of neurotrophic keratopathy are reviewed here. An accurate history and a clinical examination that covers the function of cranial nerves often identify the cause of the disease. Clinical features and guidelines for the differential diagnosis and treatment are presented. Specific medical and surgical treatments, selected on the basis of clinical staging of the disease, can often halt disease progression. Future developments in medical treatment, including the use of neuropeptide and growth factors, are discussed. The identification of corneal anesthesia associated with an epithelial defect allows appropriate treatment and prevention of progression to stromal lysis and perforation.
Article
In a previous report we showed that substance P (SP) and insulin-like growth factor-1 (IGF-1) or epidermal growth factor (EGF) synergistically stimulate corneal epithelial migration. In this study, we used an organ culture system of rabbit cornea to identify which signal transduction system affects corneal epithelial migration. Rabbit corneal blocks were cultured in TC-199 culture medium containing various reagents for 24 hours. After the end of cultivation, the length of the path of epithelial migration was measured. Acting alone, protein kinase C (PKC) inhibitors, calphostin C and H-7, each reduced the length of epithelial migration. Tyrosine kinase (TK) inhibitors, genistein and herbimycin A, also acted individually to inhibit epithelial migration. The synergistic stimulatory effects of SP and IGF-1 on corneal epithelial migration were eliminated when PKC inhibitors or TK inhibitors were added. The synergistic effect of SP and EGF was eliminated by TK inhibitors, but only partly suppressed by PKC inhibitors. These results suggest that the synergistic effect of SP and EGF might require a TK pathway, and that the synergistic effect of SP and IGF-1 might require both PKC and TK pathways.
Article
To evaluate the efficacy of nerve growth factor (NGF) in patients with neurotrophic keratitis. Prospective, noncomparative, interventional case series. Forty-five eyes of 43 consecutive patients with moderate (stage 2, n = 17) to severe (stage 3, n = 28) neurotrophic keratitis unresponsive to other nonsurgical therapies. After a 10-day washout with preservative-free artificial tears, 45 eyes with neurotrophic keratitis received murine NGF (200 microg/ml) every 2 hours for 2 days followed by one drop six times daily until the ulcer healed. A maintenance dose of one drop NGF (100 microg/ml) was administered four times daily for the 2 weeks subsequent to ulcer healing. Size and depth of the ulcer or the epithelial defect, corneal sensitivity, best corrected visual acuity, side effects, and relapse of the disease in the follow-up period. All patients had a complete resolution of the persistent epithelial defect (with or without an ulcer) after 12 days to 6 weeks of treatment with NGF. Patients affected by both stages of the disease demonstrated both improved corneal sensitivity and visual acuity (P<0.001). No significant differences were observed in the time to complete corneal healing between stage 2 and stage 3 patients. Hyperemia and ocular and periocular pain were side effects reported during the first days of treatment. No relapse of the disease was observed during the follow-up period, with the exception of three patients with trigeminal nerve resection, who required a single retreatment. Nerve growth factor eye drops improved corneal sensitivity and promoted corneal epithelial healing in both moderate and severe neurotrophic keratitis. Although performed in an uncontrolled and nonrandomized series of patients, this therapy shows promise for the restoration of ocular surface integrity and visual function in neurotrophic corneal disease.