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The concentrations of epidermal growth factor (EGF) (A), fibronectin (B), transforming growth factor-beta1 (TGF-β1) (C) and transforming growth factor-beta2 (TGF-β2) (D) in 20% autologous serum eye drops (diluted with Balanced Salt Solution, BSS) derived from SJS and non-autoimmune (control) dry eye patients, after storage at different temperature and duration. The white bars (the last bar of each cluster) represent the sera which had been stored in an undiluted form at −20°C for 6 months before being diluted with BSS to make 20% sera just prior to the assay. This was used as an experiment backup for the concentrations of the epitheliotrophic factors at the 6-month period and was not engaged in statistical calculations. Each bar represents a mean with an error bar showing a standard deviation. *p < 0.05 compared to baseline; **p < 0.01 compared to baseline and was considered statistically significant (threshold significant p value = 0.01, after Bonferroni correction of multiple comparisons).
Source publication
To compare the concentrations of epitheliotrophic factors in autologous serum eye drops (ASE) prepared from sera of chronic Stevens-Johnson syndrome (SJS) patients with dry eyes to those prepared from non-autoimmune dry eye controls and to study the stability of the epitheliotrophic factors in different storage conditions.
Twenty-percent ASE were p...
Citations
... Research has indicated that epitheliotrophic factors within autologous SEDs remain stable for up to 6 months when properly stored at -20°C. 17 This complex mixture provides essential nutritional elements crucial for maintaining cellular tropism and epithelial migration, reducing the risk of infection, and suppressing apoptotic reactions during epithelial repair processes. 18 Moreover, autologous SEDs harbor immunoglobulins (Ig) such as IgG, IgA, and lysozyme, imparting bactericidal and bacteriostatic effects. ...
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.
... The instillation of preservative-free artificial tears is necessary and recommended to increase their volume while preserving the ocular surface [3,[10][11][12]. Instillation of eye drops containing non-steroidal anti-inflammatory drugs is contraindicated as they are known to worsen corneal damage (ulceration, keratitis) that can lead to corneal perforation [13,14]. Artificial tears should be used as required. ...
... Therefore, autologous serum eye drops could be useful in the treatment of ocular surface disease with cell damage. Their effectiveness has been demonstrated in the treatment of dry eye syndrome or in the persistence of corneal epithelial defects [10,14]. In vitro toxicity tests showed that autologous serum eyedrops reduced toxicity compared to hypromellose, a substance forming the texture of eyedrops, present in preservative-free eye drops [22]. ...
Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are serious and rare diseases, most often drug-induced, and their incidence has been estimated at 6 cases/million/year in France. SJS and TEN belong to the same spectrum of disease known as epidermal necrolysis (EN). They are characterized by more or less extensive epidermal detachment, associated with mucous membrane involvement, and may be complicated during the acute phase by fatal multiorgan failure. SJS and TEN can lead to severe ophthalmologic sequelae. There are no recommendations for ocular management during the chronic phase. We conducted a national audit of current practice in the 11 sites of the French reference center for toxic bullous dermatoses and a review of the literature to establish therapeutic consensus guidelines. Ophthalmologists and dermatologists from the French reference center for epidermal necrolysis were asked to complete a questionnaire on management practices in the chronic phase of SJS/TEN. The survey focused on the presence of a referent ophthalmologist at the center, the use of local treatments (artificial tears, corticosteroid eye drops, antibiotic-corticosteroids, antiseptics, vitamin A ointment (VA), cyclosporine, tacrolimus), the management of trichiatic eyelashes, meibomian dysfunction, symblepharons, and corneal neovascularization, as well as the contactologic solutions implemented. Eleven ophthalmologists and 9 dermatologists from 9 of the 11 centers responded to the questionnaire. Based on questionnaire results, 10/11 ophthalmologists systematically prescribed preservative-free artificial tears, and 11/11 administered VA. Antiseptic or antibiotic eye drops or antibiotic-corticosteroid eye drops were recommended as needed by 8/11 and 7/11 ophthalmologists, respectively. In case of chronic inflammation, topical cyclosporine was consistently proposed by 11/11 ophthalmologists. The removal of trichiatic eyelashes was mainly performed by 10/11 ophthalmologists. Patients were referred to a reference center for fitting of scleral lenses (10/10,100%). Based on this practice audit and literature review, we propose an evaluation form to facilitate ophthalmic data collection in the chronic phase of EN and we also propose an algorithm for the ophthalmologic management of ocular sequelae.
... 23 Regular use of non-preserved artificial tears can reduce complaints of dry eye-related ocular surface discomfort. 1 Several other studies have reported the beneficial effects of topical autologous serum as an adjunctive treatment in ocular SJS patients with reduced symptoms and inflammation. 24,25 Yoon et al compared the components of plasma serum and UCS with those of tears, and found higher levels of tear components in UCS than in plasma serum that gave better results. Therefore, application of UCS is currently being developed. ...
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.
... www.nature.com/scientificreports/ techniques might also affect the concentration of epitheliotrophic factors [20][21][22][23][24][25] . Stability of the epitheliotrophic factors in autologous serum and platelet-rich plasma over a long period of storage time is also one of the major concerns regarding their uses. ...
... Stability of the epitheliotrophic factors in autologous serum and platelet-rich plasma over a long period of storage time is also one of the major concerns regarding their uses. Phasukkijwatana et al. 24 reported that epitheliotrophic factors in autologous serum were stable for up to 6 months, if stored properly at − 20 °C. Another study focused on the stability of plasma rich in growth factors (PRGF) eye drops and demonstrated that PDGF-AB, VEGF, EGF, and vitamin A stored at − 20 °C for 15, 30, and 90 days were stable, but fibronectin and TGF-β1 stored in the same condition were not 22 . ...
Current treatment of severe dry eye disease (DED) includes blood-derived eye drops, such as autologous serum (AS), which lubricate the eyes and provide factors that improve ocular surface and aid in wound healing. Recent studies indicated that platelet-rich plasma (PRP) was also effective. This study aims to compare the concentration and stability of epitheliotrophic factors in AS and PRP and their efficacy in DED patients. Epitheliotrophic factors of interest are epidermal growth factor (EGF), fibronectin, platelet-derived growth factor-AB (PDGF-AB), and transforming growth factor-beta1 (TGF-β1). We determined that all epitheliotrophic factors were present in AS and PRP at baseline and did not decrease in concentrations in all storage conditions (4 °C for 1 week and at − 20 °C for 1 and 3 months). However, differences in concentrations in AS and PRP were observed. PRP was also shown not to be inferior to AS in terms of efficacy in DED treatment in a prospective randomized control trial which evaluated ocular surface disease index, dry eye questionnaire, ocular surface staining, tear breakup time, and Schirmer test at baseline and at 1-month follow-up. Therefore, with its shorter preparation time, PRP could be considered as an alternative to AS for the treatment of DED.
... 20,21 However, differences in preparation techniques might also affect the concentration of epitheliotrophic growth factors. [20][21][22][23][24][25] Stability of the epitheliotrophic growth factors in autologous serum and platelet-rich plasma over a long period of storage time is also one of the major concerns regarding their uses. ...
... Phasukkijwatana et al 24 reported that epitheliotrophic growth factors in autologous serum were stable for up to 6 months, if stored properly at -20°C. Another study focused on the stability of plasma rich in growth factors (PRGF) eye drops and demonstrated that PDGF-AB, VEGF, EGF, and vitamin A stored at -20°C for 15, 30, and 90 days were stable, but bronectin and TGF-β1 stored in the same condition were not. ...
... This result is consistent with previous studies which showed that EGF and bronectin were stable in PRP and AS at -20°C for 3 months. 24,28 However, one study reported contrasting ndings, in which they found that after storage at -20°C for up to 3 months, only EGF was stable in PRGF but bronectin was not. 29 This might suggest that different preparations of blood-derived eye drop is the cause of the differences in stability and might indicate the superiority of PRP over PRGF. ...
Current treatment of severe dry eye disease (DED) includes blood-derived eye drops, such as autologous serum (AS), which lubricate the eyes and provide factors that improve ocular surface and aid in wound healing. Recent studies indicated that platelet-rich plasma (PRP) was also effective. This study aims to compare the concentration and stability of epitheliotrophic growth factors in AS and PRP and their efficacy in DED patients. Growth factors of interest are epidermal growth factor (EGF), fibronectin, platelet-derived growth factor-AB (PDGF-AB), and transforming growth factor-beta1 (TGF-β1). We determined that all growth factors were present in AS and PRP at baseline and did not decrease in levels in all storage conditions (4ºC for 1 week and at -20ºC for 1 and 3 months.) However, differences in growth factor concentrations in AS and PRP were observed. PRP was also shown not to be inferior to AS in terms of efficacy in DED treatment in a prospective randomized control trial which evaluated ocular surface disease index, dry eye questionnaire, ocular surface staining, tear breakup time, and Schirmer test at baseline and at 1-month follow-up. Therefore, with its shorter preparation time, PRP could be considered as an alternative to AS for the treatment of DED.
... Besides these two growth factors, fibronectin also plays an essential role in epithelium wound healing, promoting migration and attachment of cells to the defect (Nishida et al., 1983). TGF-β and EGF are considered the two main GFs attributed to the qualitative parameters of ASEDs (Geerling et al., 2004;Bradley et al., 2009), and therefore their concentration and stability are frequently monitored (Tsubota et al., 1999a, b;Bradley et al., 2009;Phasukkijwatana et al., 2011;Lopez-Garcia et al., 2014, 2016. IGF-1, NGF and other neurotrophic factors also influence epithelial proliferation, migration and differentiation (Lambiase et al., 2009;Wirostko et al., 2015). ...
... Although the effect of storage conditions on the stability of various GFs in ASEDs has been studied frequently, data from all storage periods and temperatures used in practice are not complete. In particular, the results concerning the stability of TGF-β after 6 months are contradictory; whereas Lopez-Garcia et al. (2016) did not detect any TGF-β level decrease, Phasukkijwatana et al. (2011) found a significant decline. ...
... The decreased TGF-β1 and IGF-1 levels after 8-day storage support the previously stated recommendation to store ASEDs in the refrigerator for a maximum of 7 days (Geerling et al., 2004;Jirsova et al., 2014). Although the stability of EGF and TGF-β at 4 °C for up to 7 days has been documented in some studies (Tsubota et al., 1999a;Phasukkijwatana et al., 2011;Lopez-Garcia et al., 2014), and one month in others (Tsubota et al., 1999a;Phasukkijwatana et al., 2011), it should be taken into consideration that the average temperature of domestic refrigerators in everyday use may normally be higher than this value. Up to now, only the study of Fischer et al. (2012) evaluated the stability of EGF, fibronectin, vitamins A and E and albumin in 20, 50 and 100% serum after 7 days at 6 °C, a temperature more typical in a patient's refrigerator. ...
Autologous serum eye drops (ASEDs) are used as a treatment for severe dry eye disease. The concentration and stability of various growth factors in ASEDs is determinative for their efficiency. We therefore assessed the concentrations of transforming growth factor beta 1 (TGF-β1), epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) in ASEDs following storage at 4-8, -20, -80 and -156 °C. Twenty % and 100% sera from eight healthy volunteers were analysed by the sandwich enzyme immunoassay at different time intervals up to seven months. The mean levels of TGF-β1 and EGF in undiluted and 20% serum did not differ significantly from the baseline levels in fresh serum for any storage conditions after 7 days at 4-8 °C, as well as after 4- and 7-month preservation at sub-zero temperatures. In 20% serum, no IGF-1 concentration decrease was found following 7 days of preservation at 4-8 °C. However, a decrease to 78 % and 81 % (P < 0.01) of baseline values was found in 20% serum after 4-month storage at -20 °C and 7-month storage at -156 °C, respectively. A more pronounced decrease in IGF-1 was observed in undiluted serum. All assessed growth factors present in 20% frozen serum remained stable for up to 7 months. The highest stability was achieved at -80 °C. At -20 and -156 °C, some decrease in IGF-1 occurred. Our results indicate that 20% ASEDs can be stored frozen up to 7 months under proper conditions.
... Corneal infection and perforation are severe consequences that can occur as a result of persistent, untreated corneal epithelial defects during the acute and subacute phase of SJS/TEN. Recommended standard treatments for persistent defects include those that modulate tear film (lubrication with artificial tears and ointment, serum tears, punctal occlusion), those that protect the ocular surface [discontinuation of toxic medications, bandage contact lens, AMT (ProKera)], and those that correct eyelid abnormalities (tarsorrhaphy) (19,62,(65)(66)(67). ...
Stevens Johnson syndrome and toxic epidermal necrolysis are on a spectrum of a severe, immune-mediated, mucocutaneous disease. Ocular involvement occurs in the vast majority of cases and severe involvement can lead to corneal blindness. Treatment in the acute phase is imperative in mitigating the severity of chronic disease. Advances in acute treatment such as amniotic membrane transplantation have shown to significantly reduce the severity of chronic disease. However, AMT is not a panacea and severe chronic ocular disease can and does still occur even with aggressive acute treatment. Management of chronic disease is equally critical as timely intervention can prevent worsening of disease and preserve vision. This mini-review describes the acute and chronic findings in SJS/TEN and discusses medical and surgical management strategies.
... Similarly in 2011, a study that compared the levels of GF in the serum of patients with SJS and in patients without systemic disease demonstrated that there were no statistically significant differences in the levels of any of the epitheliotropic factors among the groups. Although they did not report the therapeutic outcomes, the results suggested that the epitheliotropic capacity of ASTs from SJS patients could be comparable to those from patients without autoimmune or inflammatory diseases [32]. In the case of cGVHD-related KCS, several studies have also corroborated the safety and effectiveness of ASTs [33][34][35]. ...
Purpose of Review
In this article, we review the latest clinical outcomes of the treatment of ocular surface diseases with autologous blood products.
Recent Findings
Besides their well-known use in the treatment of severe dry eye disease, these products have recently been successfully used in the management of other conditions such as post-crosslinking surgery in patients with keratoconus. Also, new and easier-to-preserve presentations of these products are discussed.
Summary
Autologous blood eye drops have become an interesting, well-known, and widely used therapeutic option for many ocular surface diseases since their introduction into the ophthalmologic field 46 years ago. The foundation for their use in the treatment of pathologies, such as severe keratoconjunctivitis sicca, persistent epithelial defects, ocular chemical burns, recurrent epithelial erosions, Stevens-Johnson syndrome, ocular graft versus host disease, and, lately, in many other ocular surface conditions, relies on the fact that they contain proteins, vitamins, cytokines, and growth factors that participate in the signaling pathways of corneal epithelial healing in similar amounts to those found in normal, healthy tear films. These molecules confer on them a huge advantage over conventional artificial tears that can only lubricate the eyes but lack epitheliotropic properties. Despite some reported controversy regarding their composition and safety, the versatility of autologous blood eye drops in terms of source and final products and their proven efficacy in the treatment of ocular surface diseases resistant to conventional therapy have slowly but steadily granted them recognition and acceptance in the modern clinical ophthalmologic practice.
... The use of human autologous serum has been suggested to be advantageous over other currently available medications since it has multiple components similar to human tears [7] that are diminished in patients with dry eye [8]. Among the elements present in autologous serum are Epidermal growth factor (EGF), vitamin A and Transforming growth factor β (TGF-β) and Fibronectin [9], the same three factors have been described to be among the most critical components of human tears [10]. EGF promotes corneal epithelial cell migration and proliferation, accelerating the wound healing process while TGF-β1 and TGF-β2 inhibit epithelial proliferation in a dose-dependent manner [7,[11][12][13]. ...
... This study has some limitations; the rst one is the sample size; however, our sample size is similar to that of other studies [10,16,17,21,[39][40][41][42]; since, due to the cost of supplies, it is di cult to include more patients. In addition, our study population it´s mainly of young adults, and according to Liu et al. age of the donors has an impact on Fibronectin and TGF-β1 concentrations [21], we cannot ensure that the effect of coagulation time is similar in all age groups. ...
Background: To know the influence of coagulation time on the concentration of epitheliotropic factors of autologous serum.
Methods: A prospective, cross-sectional and experimental study was conducted evaluating the concentrations of epitheliotropic factors in the serum of 20 healthy volunteers over 18 years of age, who did not suffer from diseases or took any medication or with a history of blood transfusion in the last year, those with diagnosis of anemia, coagulation diseases or another situation that contraindicates the sampling were excluded. Epidermal growth factor (EGF), Transforming growth factor β1 (TGF-β1) and Fibronectin were quantified in the various undiluted serum samples by an enzyme-linked immunosorbent assay.
Results: 65% were male with an average age of 22.7 ± 5.47 years (range 19 to 45 years). Age was similar in both groups (p = 0.87), men had an average age of 22.85 ± 6.84 years and women 22.43 ± 1.13 years. Vitamin A and Fibronectin did not have a statistically significant difference of concentration at 2 and 24 hours, while the concentration of TGF-β1 had a statistically significant decrease as the clot formation time increased (average 0.22 range, 0.003,0.451), opposite, the EGF increased its concentration statistically significantly with the longer coagulation time (average -0.39 range, -0.60, -0.18).
Conclusions: a prolonged clotting time (24 hours) have a significant impact on the composition and epitheliotrophic factors of the serum, increasing the EGF concentrations, and lowering the TGF-β1.
... Nonetheless, the response to AS in the treatment of corneal ulcers was dose-dependent, thus advocating more frequent blood collection so as to obtain a denser AS with a 50% concentration, which would enable better sealing of the corneal ulcer. In our study, we used 20% AS because this is the concentration that the majority of authors recommend as clinically effective and well tolerated by patients, allowing us to reduce the possible appearance of adverse effects and, thereby, achieving better adherence to treatment 7,8,17,[21][22][23][24] . ...
... Harloff et al. 23 demonstrated that the AS of the patients who had rheumatoid arthritis in the active phase and who were subjected to immunosuppressive treatment had lower concentrations of both fibronectin and transforming growth factor-β. Pasukkijwatama et al. 24 , however, compared the epitheliotropic effects of the AS of patients with autoimmune DED versus the AS of patients with non-autoimmune DED, without finding any significant differences 24 . They concluded that the use of AS eye drops is not contraindicated in patients with autoimmune diseases, such as rheumatoid arthritis. ...
... Harloff et al. 23 demonstrated that the AS of the patients who had rheumatoid arthritis in the active phase and who were subjected to immunosuppressive treatment had lower concentrations of both fibronectin and transforming growth factor-β. Pasukkijwatama et al. 24 , however, compared the epitheliotropic effects of the AS of patients with autoimmune DED versus the AS of patients with non-autoimmune DED, without finding any significant differences 24 . They concluded that the use of AS eye drops is not contraindicated in patients with autoimmune diseases, such as rheumatoid arthritis. ...
Background:
Autologous serum eye drops, produced by separation of liquid and cellular components of the patient's blood, contain biological nutrients present in natural tears. The aim of this study was to analyse changes in conjunctival impression cytology with transfer and both lachrymal stability and flow tests in patients with dry eye disease after treatment with autologous serum eye drops.
Materials and methods:
Conjunctival impression cytology and lachrymal flow and stability tests, namely Schirmer's and tear break-up time, were prospectively studied in patients with dry eye disease before and 1 month after treatment with autologous serum eye drops.
Results:
Twenty-four patients (23 women, mean age 53.8±12.6 years) were included in the study. Ten patients (41.7%) had moderate and six (25.0%) had severe dry eye disease. Five patients had rheumatoid arthritis. After treatment, the number and density of conjunctival goblet cells, their size, the size of their nuclei and the nucleus/cytoplasm ratio increased significantly (202.3±107.5 vs 210.1±100.9 cells/mm2, p<0.01). Seven of ten patients with grade 3 or 4 metaplasia had an improvement in the degree of metaplasia. Both Schirmer's test and tear break-up time improved significantly in this subgroup of patients. In the multivariate study, the increase in conjunctival goblet cells was associated with the number of goblet cells and the size of the cytoplasm at baseline. No adverse reactions were noted.
Discussion:
Treatment with autologous serum eye drops for 1 month was well tolerated and improved tear production, lachrymal flow and stability tests and conjunctival impression cytology with transfer, increasing the density of the goblet cells.
