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Jongkhajornpong P, Lekhanont K, Rattanasiri S, Numthavaj P, McKay G, Attia J, Thakkinstian A. Efficacy of 100% autologous platelet-rich plasma and 100% autologous serum in dry eye disease: a randomised controlled trial. BMJ Open Ophthalmol 2024; 9:e001857. [PMID: 39384222 PMCID: PMC11474780 DOI: 10.1136/bmjophth-2024-001857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/21/2024] [Indexed: 10/11/2024] Open
Abstract
OBJECTIVE The 0bjective is to compare treatment effects between undiluted autologous platelet-rich plasma (APRP) and autologous serum (AS) in patients with moderate-to-severe dry eye disease (DED). METHODS AND ANALYSIS A single-centre, randomised, double-masked, non-inferiority clinical trial was conducted. 96 adult DED patients with an Ocular Surface Disease Index (OSDI) Score of ≥23 and/or Oxford staining grade of ≥2 were randomised to receive either 100% APRP (n=48) or 100% AS (n=48) for 4 weeks. Primary outcomes included OSDI Score and ocular surface staining measured by Oxford grading scale at 4 weeks. Secondary outcomes included fluorescein tear break-up time, Schirmer's test, meibum quality and expressibility, and adverse events. The 95% CI for the mean difference in OSDI scores between groups was estimated to assess non-inferiority of the OSDI score at a prespecified margin of 4.18 points. RESULTS At week 4, there was no significant difference in decreased OSDI scores between groups, with the mean difference (100% APRP-100% AS) of 1.41 (95% CI -1.26, 4.08, p=0.299). The upper limit was less than the prespecified margin, indicating non-inferiority of 100% APRP vs 100% AS. The probabilities of achieving an Oxford grade 0-1 after treatment were not significantly different between groups, with an OR of 0.61 (95% CI 0.25, 1.52, p=0.288). No significant differences in secondary outcomes were observed between groups. CONCLUSION In the short-term, 100% APRP was not inferior to 100% AS in reducing dry eye symptoms and ocular surface staining in moderate-to-severe DED. TRIAL REGISTRATION NUMBER NCT04683796.
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Affiliation(s)
- Passara Jongkhajornpong
- Department of Ophthalmology, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
| | - Kaevalin Lekhanont
- Department of Ophthalmology, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
| | - Sasivimol Rattanasiri
- Department of Clinical Epidemiology and Biostatistics, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
| | - Pawin Numthavaj
- Department of Clinical Epidemiology and Biostatistics, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
| | | | - John Attia
- Centre for Clinical Ophthalmology and Biostatistics and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia
- Department of Medicine, John Hunter Hospital, University of Newcastle Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Ammarin Thakkinstian
- Department of Clinical Epidemiology and Biostatistics, Mahidol University Faculty of Medicine Ramathibodi Hospital, Bangkok, Thailand
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Anam A, Liu C, Tong L, Liu YC. Blood-Derived Eye Drops for the Treatment of Corneal Neuropathic Pain. J Ocul Pharmacol Ther 2024; 40:281-292. [PMID: 38648544 PMCID: PMC11296151 DOI: 10.1089/jop.2023.0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
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.
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Affiliation(s)
- Ansa Anam
- Department of Ophthalmology, MTI Khyber Teaching Hospital, Peshawar, Pakistan
| | - Chang Liu
- Cornea and Refractive Surgery Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Louis Tong
- Department of Corneal and External Eye Disease, Singapore National Eye Centre, Singapore, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
- Ocular Surface Group, Singapore Eye Research Institute, Singapore, Singapore
| | - Yu-Chi Liu
- Cornea and Refractive Surgery Group, Singapore Eye Research Institute, Singapore, Singapore
- Department of Corneal and External Eye Disease, Singapore National Eye Centre, Singapore, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore
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Leonhard M, Turner C, Langenbucher A, Flockerzi E, Seitz B. [Comparison of the Effect of Autologous Serum on Therapy Resistant Corneal Erosions and Ulcers on the Corneal Graft vs. the Patient's Own Cornea]. Klin Monbl Augenheilkd 2024; 241:102-109. [PMID: 37164338 DOI: 10.1055/a-2091-0111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
PURPOSE The aim of this study is to compare the healing of corneal epithelial defects or ulcers on the corneal graft in comparison with the patient's own cornea after treatment with 100%, undiluted autologous serum eye drops. METHODS In a retrospective study over 7 years, we analysed 263 treatments with autologous serum eye drops of persistent corneal epithelial defects (erosions [88%] vs. ulcers [12%]). We compared the epithelial healing tendency of patients with defects on their own cornea (51.9%) vs. patients who had previously undergone penetrating keratoplasty (48.1%). Complete epithelial healing during the 28 days of treatment was considered as therapeutic success. In addition, the recurrence rate of the epithelial defects after finishing the therapy was analysed. RESULTS 88.2% of the epithelial defects healed during 28 days of therapy. The recurrence rate during follow-up was 5.1%. There was no significant difference with respect to success rate between corneal defects on the patient's own cornea (87.8%) and on the graft (88.6%; p = 0.137). There was a significantly lower success rate for corneal ulcers (74.2%) than for erosions (90.3%; p < 0.001). The recurrence rate of erosions was 4.4%, vs. 4.3% in ulcers during follow-up. CONCLUSION The results of our study suggest that autologous serum eye drops are a non-invasive and safe alternative treatment for persistent corneal epithelial defects - with no significant difference in patients with a defect on their own cornea vs. defects on the corneal graft. The success rate, but not the recurrence rate, is significantly worse in ulcers than in erosions.
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Affiliation(s)
- Marie Leonhard
- Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes (UKS), Homburg/Saar, Deutschland
| | - Christina Turner
- Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes (UKS), Homburg/Saar, Deutschland
| | - Achim Langenbucher
- Institut für Experimentelle Ophthalmologie, Universitätsklinikum des Saarlandes, Homburg/Saar, Deutschland
| | - Elias Flockerzi
- Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes (UKS), Homburg/Saar, Deutschland
| | - Berthold Seitz
- Klinik für Augenheilkunde, Universitätsklinikum des Saarlandes (UKS), Homburg/Saar, Deutschland
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Møller-Hansen M, Utheim TP, Heegaard S. Surgical Procedures in the Treatment of Dry Eye Disease. J Ocul Pharmacol Ther 2023; 39:692-698. [PMID: 37566528 DOI: 10.1089/jop.2023.0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023] Open
Abstract
Dry eye disease (DED) is a multifactorial disease affecting 5% to 50% in different populations. The most severe cases of DED are often caused by aqueous deficient dry eye disease (ADDE) due to lacrimal gland (LG) hypofunction. Many patients with severe ADDE do not experience adequate symptom relief from topical treatment, severely reducing their quality of life. The focus of this review is to describe the surgical interventions presently being used or investigated when topical treatment with eye drops is insufficient. The conventional surgical approach is to proceed to punctal occlusion or partial or total tarsorrhaphy. However, novel surgical procedures have been reported to have higher efficacy and patient satisfaction than conventional treatments. These procedures include amniotic membrane transplantation, transposition or transplantation of the salivary glands, and cell-based injections into the LG, each with strengths and weaknesses. Further development of these treatment modalities might prove pivotal in treating dry eye patients in the future.
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Affiliation(s)
- Michael Møller-Hansen
- Department of Ophthalmology, Copenhagen University Hospital-Rigshospitalet, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Tor Paaske Utheim
- Departmernt of Ophthalmology, Oslo University Hospital, Oslo, Norway
| | - Steffen Heegaard
- Department of Ophthalmology, Copenhagen University Hospital-Rigshospitalet, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Zheng N, Zhu SQ. Randomized controlled trial on the efficacy and safety of autologous serum eye drops in dry eye syndrome. World J Clin Cases 2023; 11:6774-6781. [PMID: 37901024 PMCID: PMC10600870 DOI: 10.12998/wjcc.v11.i28.6774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/31/2023] [Accepted: 09/14/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Autologous serum eye drops (ASEDs), a novel treatment derived from blood serum, have emerged as a groundbreaking solution for managing dry eye syndrome (DES). These drops have shown significant promise in relieving the distressing symptoms of DES. This study aimed to evaluate the safety and effectiveness of ASEDs compared to traditional treatments, which often prove inadequate or result in unwanted side effects, particularly in individuals with moderate-to-severe DES. AIM To evaluate whether ASEDs are safer and more effective than conventional artificial tears in the treatment of moderate-to-severe DES. METHODS This multi-centered randomized controlled trial included 240 patients with moderate-to-severe DES from three ophthalmology clinics in China. They were randomly assigned to receive either ASEDs or artificial tears for 12 wk. The primary outcome was the change in the ocular surface disease index (OSDI) score, with secondary outcomes including tear break-up time (TBUT), Schirmer I test, corneal fluorescein staining (CFS), and conjunctival impression cytology (CIC). Statistics analysis was performed using an analysis of covariance with adjustments made for baseline values. RESULTS Our findings revealed that both ASEDs and artificial tears significantly improved the OSDI score, TBUT, Schirmer I test, CFS, and CIC from baseline to week 12. The ASEDs group showed significantly greater improvement in all these measures than the artificial tears group (all P values < 0.05). The average difference in the OSDI score between the two cohorts was -10.3 (95% confidence interval: -13.6 to -7.0), indicating a substantial improvement in the ASEDs group. The occurrence of adverse events was comparable between cohorts, with no reports of severe adverse events. CONCLUSION ASEDs are more effective and safer than artificial tears for mitigating symptoms of moderate-to-severe DES. ASEDs could be an alternative/supplementary therapy for patients with DES less responsive to traditional treatments.
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Affiliation(s)
- Na Zheng
- Department of Ophthalmology, Chengdu University of Traditional Chinese Medicine, Chengdu 610032, Sichuan Province, China
| | - Si-Quan Zhu
- Department of Ophthalmology, Beijing Anzhen Hospital Affiliated to China Medical University, Beijing 100029, China
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Mancini M, Postorino EI, Gargiulo L, Aragona P. Use of allogeneic platelet-rich plasma for the treatment of autoimmune ocular surface disorders: case series. FRONTIERS IN OPHTHALMOLOGY 2023; 3:1215848. [PMID: 38983003 PMCID: PMC11182103 DOI: 10.3389/fopht.2023.1215848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/06/2023] [Indexed: 07/11/2024]
Abstract
Purpose To assess the effectiveness of topical allogeneic platelet-rich plasma (PRP) eye drops for the treatment of symptoms and clinical signs in patients with severe dry eye disease as a secondary condition caused by Sjögren's syndrome (SS). Design Case series and literature review. Methods Six eyes from three consecutive patients with severe dry eye from SS were evaluated. The eyes were treated with allogeneic topical PRP eye drops, with one drop applied six times daily for 3 months. A post-treatment follow-up evaluation was conducted 3 months after treatment suspension. We evaluated subjective symptoms, visual acuity, tear breakup time, the results of Schirmer's I test, fluorescein corneal and conjunctival staining, and corneal sensitivity. Results The symptoms and visual acuity improved significantly in all patients. There was a significant improvement in corneal sensitivity and a decrease or disappearance of fluorescein corneal staining. Conclusion The treatment with allogenic PRP eye drops of patients with SS-related severe dry eye disease has proven to be very effective, with an improvement in symptoms and main clinical signs.
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Affiliation(s)
- Maura Mancini
- Department of Biomedical Sciences, Ophthalmology Clinic, University of Messina, Messina, Italy
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Lozano-Sanroma J, Barros A, Alcalde I, Sánchez-Ávila RM, Queiruga-Piñeiro J, Fernández-Vega Cueto L, Merayo-Lloves J. Impact of Plasma Rich in Growth Factors (PRGF) Eye Drops on Ocular Redness and Symptomatology in Patients with Dry Eye Disease. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59050928. [PMID: 37241160 DOI: 10.3390/medicina59050928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/19/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023]
Abstract
Background and Objectives: Dry eye disease (DED) is a common and very symptomatic pathology that affects normal daily activity. The aim of the study was to evaluate the efficacy of plasma rich in growth factors (PRGF) added to one routine treatment protocol for DED (artificial tears substitutes, lid hygiene, and anti-inflammatory therapy). Materials and Methods: Patients were divided into two groups of treatment: standard treatment group (n = 43 eyes) and PRGF group (n = 59). Patients' symptomatology (inferred from OSDI and SANDE questionnaires), ocular inflammation, tear stability, and ocular surface damage were analyzed at baseline and after 3 months of treatment. Results: OSDI test scores were significantly lower in both groups (p < 0.001). SANDE frequency test scores also improved statistically, with differences between groups (p = 0.0089 SANDE frequency and p < 0.0119 SANDE severity). There was a greater reduction in ocular redness (ocular inflammation) in the PRGF group (p < 0.0001) and fluorescein tear break-up time was significantly improved in the PRGF group (p = 0.0006). No significant changes were found in terms of ocular surface damage. No adverse events were obtained in either group. Conclusions: The addition of PRGF to the standard treatment of DED, according to the results obtained, proved to be safe and produced an improvement in ocular symptomatology and signs of inflammation, particularly in moderate and severe cases, when compared to standard treatment.
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Affiliation(s)
| | - Alberto Barros
- Instituto Oftalmológico Fernández-Vega, 33012 Oviedo, Spain
| | - Ignacio Alcalde
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | | | | | - Luis Fernández-Vega Cueto
- Instituto Oftalmológico Fernández-Vega, 33012 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Department of Surgery and Medical-Surgical Specialties, Universidad de Oviedo, 33006 Oviedo, Spain
| | - Jesús Merayo-Lloves
- Instituto Oftalmológico Fernández-Vega, 33012 Oviedo, Spain
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Department of Surgery and Medical-Surgical Specialties, Universidad de Oviedo, 33006 Oviedo, Spain
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Development of In Vitro Dry Eye Models to Study Proliferative and Anti-Inflammatory Effects of Allogeneic Serum Eye Drops. Int J Mol Sci 2023; 24:ijms24021567. [PMID: 36675083 PMCID: PMC9864688 DOI: 10.3390/ijms24021567] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
This study aimed to develop valid in vitro models for preclinical evaluation of proliferative and anti-inflammatory effects of human allogeneic serum eye drops for dry eye disease (DED) treatment. A DED wound healing model was developed by analyzing the influence of coating and serum concentrations on human corneal epithelial (HCE-T) wound closure. Further, intralaboratory variance, freeze-thaw cycle effects, donor variability and stability assays were conducted. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) were used to induce the gene expression of matrix metalloproteinase 9 (MMP9), cyclooxygenase 2 (COX2), transforming growth factor-β (TGFβ) and IL-1β. MMP9 induction was optimized using a design-of-experiments (DoE) approach and applied to examine serum under static and dynamic conditions. MMP9 protein expression was analyzed by ELISA. The DED wound healing model detected proliferative effects of serum down to 1% with a small intralaboratory variance. Serum stability was shown over six months, donor variance could be detected, and freeze-thaw cycle effects did not affect wound closure. Serum decreased MMP9 expression on the gene and protein levels. The induction method was successfully optimized using DoE modeling and transferred to a dynamic setting mimicking tear film fluidics. The DED wound healing and inflammatory DED model present useful in vitro models for the preclinical evaluation of allogeneic serum eye drops without the use of animal experiments.
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Rawat P, Agrawal R, Bhaisare V, Walia S, Kori N, Gupta R. Autologous platelet-rich plasma eye drop versus artificial tear eye drop for symptomatic dry eye disease: A prospective comparative interventional study. Indian J Ophthalmol 2022; 70:1549-1553. [PMID: 35502024 PMCID: PMC9333043 DOI: 10.4103/ijo.ijo_2595_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/02/2021] [Accepted: 01/24/2022] [Indexed: 11/24/2022] Open
Abstract
Purpose To evaluate and compare the efficacy of autologous platelet-rich plasma (aPRP) eye drop and artificial tear (AT) eye drop in moderate to severe symptomatic dry eye disease (DED). Methods This prospective interventional study included 121 eyes of 61 patients of moderate to severe DED. Patients were divided into aPRP (31 patients) and AT (30 patients) group. Ocular Surface Disease Index (OSDI) score, tear film breakup time (TBUT) (s), corneal fluorescein staining (CFS) score, and Schirmer test score (mm) of both the groups were evaluated and compared pre-treatment and post-treatment at the end of 3 months. Results The mean age of the aPRP group and AT group was 52.8 ± 12.8 years and 55.5 ± 13.4 years, respectively. At the end of 3 months, OSDI score reduced more in the aPRP group as compared to AT group, and the mean difference (-22.7) was statistically significant (P < 0.001). There was no significant difference in post-treatment Schirmer test score between the two groups (P = 0.44). Post-treatment improvement in TBUT and CFS score in the aPRP group was significantly higher in the aPRP group as compared to that in the AT group (P < 0.05). Bruising at the site of blood withdrawal was noted in two patients in the aPRP group. Conclusion aPRP is safe and more effective than AT in treating patients with moderate to severe symptomatic DED.
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Affiliation(s)
- Preeti Rawat
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
| | - Ritika Agrawal
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
| | - Vijay Bhaisare
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
| | - Shweta Walia
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
| | - Neetu Kori
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
| | - Rishi Gupta
- Department of Ophthalmology, Mahatma Gandhi Memorial Medical College, M. Y. Hospital, Indore, Madhya Pradesh, India
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Elhusseiny AM, Soleimani M, Eleiwa TK, ElSheikh RH, Frank CR, Naderan M, Yazdanpanah G, Rosenblatt MI, Djalilian AR. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:259-268. [PMID: 35303110 PMCID: PMC8968724 DOI: 10.1093/stcltm/szab028] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/06/2021] [Indexed: 11/24/2022] Open
Abstract
The corneal epithelium serves to protect the underlying cornea from the external environment and is essential for corneal transparency and optimal visual function. Regeneration of this epithelium is dependent on a population of stem cells residing in the basal layer of the limbus, the junction between the cornea and the sclera. The limbus provides the limbal epithelial stem cells (LESCs) with an optimal microenvironment, the limbal niche, which strictly regulates their proliferation and differentiation. Disturbances to the LESCs and/or their niche can lead to the pathologic condition known as limbal stem cell deficiency (LSCD) whereby the corneal epithelium is not generated effectively. This has deleterious effects on the corneal and visual function, due to impaired healing and secondary corneal opacification. In this concise review, we summarize the characteristics of LESCs and their niche, and present the current and future perspectives in the management of LSCD with an emphasis on restoring the function of the limbal niche.
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Affiliation(s)
- Abdelrahman M Elhusseiny
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Department of Ophthalmology, Harvey and Bernice Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Mohammad Soleimani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Taher K Eleiwa
- Department of Ophthalmology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Reem H ElSheikh
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Charles R Frank
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Morteza Naderan
- Department of Ophthalmology, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghasem Yazdanpanah
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
- Corresponding author: Ali R. Djalilian, Cornea Service, Stem Cell Therapy and Corneal Tissue Engineering Laboratory, Illinois Eye and Ear Infirmary, 1855 W. Taylor Street, M/C 648, Chicago, IL 60612, USA.
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Preparation and growth factor characterization of cord blood-derived plasma, serum, growth factor-rich plasma and induced serum. Cytokine 2021; 149:155756. [PMID: 34763157 DOI: 10.1016/j.cyto.2021.155756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND In recent years, there has been a significant decline in the demand for cord blood units (CBUs). This trend has led to cord blood banks (CBBs) exploring complementary uses of CBUs in order to exploit the full potential of this unique, valuable, and readily available product. The aim of this study was to establish standardized protocols for the preparation of four cord blood (CB) derivatives: plasma (CB-P), serum (CB-S), induced-serum (CB-IS) and growth factor-rich plasma (GFRP); to measure their respective growth-factor content and their potential as cell culture supplements, and finally, to identify the characteristics of each derivative beyond their growth-factor composition, in the context of optimizing CBBs resources. STUDY DESIGN AND METHOD To this end, CB plasma and serum were prepared and their concentrations for ten growth factors (TGF-β1, TGF-β2, TGF-β3, EGF, HGF, PDGF-BB, VEGF-A, VEGF-D, IGF-I, IGF-II) were determined using a multiplex bead array, and compared to adult plasma and serum. Protocols for the preparation of CB-IS and GFRP with reverse anticoagulation using CaCl2·2H2O were also established, and all four derivatives were compared for their EGF and TGF-β1 content by enzyme-linked immunosorbent assay (ELISA), and also for their cell culture supplement capacity. RESULTS CB plasma was shown to be richer than adult plasma for TGF-β2 and TGF-β3, with a lower concentration of IGF-I and IGF-II. CB serum was shown to be richer than adult serum for TGF-β2, TGF-β3, EGF, HGF, PDGF-BB, and VEGF-A and D, and poorer in IGF-I and II. The measure of EGF and TGF-β1 concentrations has shown that CB serum is the most concentrated (1874 pg/ml and 41 094 pg/ml) of the CB derivatives, followed by induced-serum (405 pg/ml and 16 735 pg/ml), growth factor-rich plasma (131 and 7947 pg/ml) and plasma (8 and 2845 pg/ml). All four CB derivatives were shown to be superior to FBS in sustaining cell growth at low doses. CONCLUSION Our study shows that four CB derivatives can be easily prepared and pooled to provide significant volume of products that vary in their growth factor composition. A cord blood bank interested in introducing such manufacturing will need to evaluate the financial and processing characteristics of each derivative. The use of standardized manufacturing protocols such as the ones we suggest could help research initiatives exploring the potential therapeutic uses of such rich and high-quality starting material.
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Panda BB, Mohapatra S, Parida S. Update on the role of Eye platelet-rich plasma (E-PRP) in the treatment of ocular surface disorders. INDIAN JOURNAL OF CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 2020; 6:487-496. [DOI: 10.18231/j.ijceo.2020.106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2024]
Abstract
Platelet rich plasma is the highly concentrated form of autologous human platelets in a small amount of plasma which contains important growth factors and plasma proteins that plays a significant role in wound healing process by epithelial differentiation and collagen bundle organization. In this article, we aim to provide an update on the current literature regarding the eye platelet rich plasma, its methods of preparation, physiological and biochemical properties, its clinical applications, safety and efficacy as compared to other blood derived products etc. In ophthalmology, this product is being used in the management of symptomatic dry eyes, corneal ulcers, periocular chemical and thermal burns, Idiopathic macular hole, Skin rejuvenation post Blepharoplasties and more recently actinic elastosis in the lower eyelid regions. The role of eye platelet rich plasma in ocular surface disorders has been sparsely studied in literature with more studies and reports on the application of autologous and allogeneic serum eye drops and therefore, it becomes very important to update ourselves with more studies in this topic to prove the efficiency of this blood derived product. Moreover, the role of other platelet derived products like platelet rich growth factors, platelet lysate in ocular surface disorders have also been discussed.
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Management of Ocular Surface Disease in Glaucoma: A Survey of Canadian Glaucoma Specialists. J Glaucoma 2020; 29:1162-1172. [PMID: 33264166 DOI: 10.1097/ijg.0000000000001659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PRéCIS:: Ocular surface disease (OSD) in glaucoma is an area for improvement in the management of patients with glaucoma. This study explores the knowledge of glaucoma subspecialists toward OSD in glaucoma, then provides a suggested treatment algorithm. PURPOSE To assess the attitudes, knowledge, and level of comfort of Canadian glaucoma specialists with respect to the assessment and management of OSD among patients with glaucoma. METHODS Ophthalmologist members of the Canadian Glaucoma Society with fellowship training in glaucoma were contacted to participate in this cross-sectional survey study. Responses were recorded to statements regarding attitudes toward OSD in glaucoma, and assessment and management modalities. These were recorded primarily in the form of a Likert scale rated 1 to 7 from "strongly disagree" to "strongly agree." Descriptive statistics were generated, and mean and SD for responses on Likert scales. RESULTS Thirty-six responses were included. All respondents agreed that comprehensive management of OSD could improve quality of life, 97% agreed it could lead to better glaucoma outcomes, whereas only 22% agreed it is presently being adequately managed in glaucoma practices. Respondents were asked to list all treatment modalities they felt knowledgeable about, ranging from 100% for optimizing topical glaucoma therapies to 31% for serum tears. Nearly all respondents (92%) agreed that a suggested algorithm for the treatment of OSD in glaucoma could improve their approach to management. CONCLUSION OSD is a common comorbidity of glaucoma. Although respondents overwhelmingly agreed that comprehensive management of OSD may lead to improved quality of life and glaucoma-related outcomes, only a small percentage felt it was presently adequately managed. Increasing knowledge related to the assessment and management of OSD in glaucoma may in the future improve patient care.
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Bernabei F, Roda M, Buzzi M, Pellegrini M, Giannaccare G, Versura P. Blood-Based Treatments for Severe Dry Eye Disease: The Need of a Consensus. J Clin Med 2019; 8:E1478. [PMID: 31533289 PMCID: PMC6780616 DOI: 10.3390/jcm8091478] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/05/2019] [Accepted: 09/12/2019] [Indexed: 01/08/2023] Open
Abstract
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.
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Affiliation(s)
- Federico Bernabei
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.
| | - Matilde Roda
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.
| | - Marina Buzzi
- Emilia Romagna Cord Blood Bank-Transfusion Service, S.Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.
| | - Marco Pellegrini
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.
| | - Giuseppe Giannaccare
- Department of Ophthalmology, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.
| | - Piera Versura
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, S.Orsola-Malpighi Teaching Hospital, 40138 Bologna, Italy.
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Labetoulle M, Baudouin C, Calonge M, Merayo‐Lloves J, Boboridis KG, Akova YA, Aragona P, Geerling G, Messmer EM, Benítez‐del‐Castillo J. Role of corneal nerves in ocular surface homeostasis and disease. Acta Ophthalmol 2019; 97:137-145. [PMID: 30225941 DOI: 10.1111/aos.13844] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 05/14/2018] [Indexed: 12/11/2022]
Abstract
Corneal nerves are key components of the physiological system that controls ocular surface homeostasis. The cornea is primarily innervated by the ophthalmic branch of the trigeminal nerves (cranial nerve V), which distend bilaterally from the pons. The nasociliary branch (afferent) of the ophthalmic nerve is sensory for cornea, eyelid and conjunctiva. These nerve fibres play a role in sensing temperature, chemical and mechanical stimuli, and pain, whereas, branches of the facial nerve (cranial nerve VII) contain motor nerves that control blinking and autonomic (sympathetic and a paucity of parasympathetic) fibres that stimulate tear production and secretion via feedback loops between the ocular surface, lacrimal glands and brain. Disruption of these nerves with interruption of neural feedback loops between the ocular surface and lacrimal glands can lead to corneal diseases such as dry eye disease (DED) and neurotrophic keratopathy (NK). Inversely, hypersensitivity of the nerve fibres and/or dysregulation of pain-controlling nervous centres may lead to neuropathic pain. Recently, medications that specifically target regeneration of corneal nerves have started to become available - and considering the high prevalence of diseases associated with corneal nerve dysfunction, these agents promise to fulfil a hitherto important unmet need. In this review, we explore the physiology of corneal nerves, the pathology of corneal nerve diseases and how these relate to neuropathic pain, NK and DED. We also discuss what novel treatments may be useful against diseases involving corneal nerves.
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Affiliation(s)
- Marc Labetoulle
- Ophthalmology South Paris University Hospital‐APHP Le Kremlin‐Bicêtre France
| | - Christophe Baudouin
- Quinze‐Vingts National Ophthalmology Hospital Paris France
- INSERM UMRS968 CNRS UMR7210 Paris 6 Vision Institute UPMC University Paris France
- University of Versailles Saint‐Quentin en Yvelines Versaille France
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Strategies for reconstructing the limbal stem cell niche. Ocul Surf 2019; 17:230-240. [PMID: 30633966 DOI: 10.1016/j.jtos.2019.01.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 10/21/2018] [Accepted: 01/07/2019] [Indexed: 12/19/2022]
Abstract
The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of these epithelial cells depends, in part, on the limbal epithelial stem cells (LESCs) located in a specialized microenvironment known as the limbal niche. Many disorders affecting the regeneration of the corneal epithelium are related to deficiency and/or dysfunction of LESCs and the limbal niche. Current approaches for regenerating the corneal epithelium following significant injuries such as burns and inflammatory attacks are primarily aimed at repopulating the LESCs. This review summarizes and assesses the clinical feasibility and efficacy of current and emerging approaches for reconstruction of the limbal niche. In particular, the application of mesenchymal stem cells along with appropriate biological scaffolds appear to be promising strategies for long-term revitalization of the limbal niche.
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Buzzi M, Versura P, Grigolo B, Cavallo C, Terzi A, Pellegrini M, Giannaccare G, Randi V, Campos EC. Comparison of growth factor and interleukin content of adult peripheral blood and cord blood serum eye drops for cornea and ocular surface diseases. Transfus Apher Sci 2018; 57:549-555. [PMID: 29929885 DOI: 10.1016/j.transci.2018.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 05/31/2018] [Accepted: 06/05/2018] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Various blood-derived products have been proposed for the topical treatment of ocular surface diseases. The aim of the study was to compare the different content of Growth Factors (GFs) and Interleukins (ILs) in peripheral blood (PB-S) and Cord Blood (CB-S) sera. MATERIALS AND METHODS Sera were obtained from 105 healthy adult donors (PB-S) and 107 umbilical/placental veins at the time of delivery (CB-S). The levels of epithelial-GF (EGF), fibroblast-GF (FGF), platelet-derived-GF (PDGF), insulin-GF (IGF), transforming-GF alpha (TGF-α,) and beta 1-2-3 (TGF-β1-β2-β3), vascular endothelial-GF (VEGF), nerve-GF (NGF), Interleukin (IL)-1β,IL-4,IL-6,IL-10, and IL-13 were assessed by Bio-Plex Protein Array System (Bio-Rad Laboratories, CA, USA). The Mann-Whitney test for unpaired data was applied to compare GFs and ILs levels in the two sources. The associations among each GF/IL level and the obstetric data for CB-S and hematological characteristics for PB-S were also investigated. RESULTS The levels of EGF, TGF-α, TGF-β2, FGF, PDGF, VEGF, NGF, IL-1B, IL-4, IL-6, IL-10, and IL-13 were significantly higher in CB-S compared to PB-S. Conversely, the levels of IGF-1, IGF-2, and TGF-β1 were significantly higher in PB-S. The female sex and the weight of the child showed a significant association in predicting EGF and PDGF levels. CONCLUSION A significantly different content in those GFs and ILs was demonstrated in the two blood sources. Since each GF/IL selectively regulates different cellular processes involved in corneal healing, the use of PB-S or CB-S should be chosen on the basis of the cellular mechanism to be promoted in each clinical case.
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Affiliation(s)
- M Buzzi
- Emilia Romagna Cord Blood Bank-Transfusion Service, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - P Versura
- Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy.
| | - B Grigolo
- RAMSES Laboratory, Department of Research & Innovation, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - C Cavallo
- RAMSES Laboratory, Department of Research & Innovation, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - A Terzi
- Emilia Romagna Cord Blood Bank-Transfusion Service, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - M Pellegrini
- Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - G Giannaccare
- Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - V Randi
- Emilia Romagna Cord Blood Bank-Transfusion Service, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
| | - E C Campos
- Ophthalmology Unit, DIMES, Alma Mater Studiorum University of Bologna and S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
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Marchand M, Harissi-Dagher M, Germain M, Thompson P, Robert MC. Serum drops for ocular surface disease: national survey of Canadian cornea specialists. Can J Ophthalmol 2018; 53:266-271. [DOI: 10.1016/j.jcjo.2017.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 08/04/2017] [Accepted: 09/05/2017] [Indexed: 10/18/2022]
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Han SB, Liu YC, Mohamed-Noriega K, Mehta JS. Application of Novel Drugs for Corneal Cell Regeneration. J Ophthalmol 2018; 2018:1215868. [PMID: 29854423 PMCID: PMC5954904 DOI: 10.1155/2018/1215868] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 02/26/2018] [Accepted: 03/27/2018] [Indexed: 11/18/2022] Open
Abstract
Corneal transplantation has been the only treatment method for corneal blindness, which is the major cause of reversible blindness. However, despite the advancement of surgical techniques for corneal transplantation, demand for the surgery can never be met due to a global shortage of donor cornea. The development of bioengineering and pharmaceutical technology provided us with novel drugs and biomaterials that can be used for innovative treatment methods for corneal diseases. In this review, the authors will discuss the efficacy and safety of pharmacologic therapies, such as Rho-kinase (ROCK) inhibitors, blood-derived products, growth factors, and regenerating agent on corneal cell regeneration. The promising results of these agents suggest that these can be viable options for corneal reconstruction and visual rehabilitation.
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Affiliation(s)
- Sang Beom Han
- Department of Ophthalmology, Kangwon National University Hospital, Kangwon National University, Chuncheon, Republic of Korea
| | - Yu-Chi Liu
- Singapore National Eye Centre, Singapore
- Singapore Eye Research Institute, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Karim Mohamed-Noriega
- Department of Ophthalmology, Faculty of Medicine, University Hospital “Jose E. Gonzalez”, Autonomous University of Nuevo Leon, Monterrey, NL, Mexico
| | - Jodhbir S. Mehta
- Singapore National Eye Centre, Singapore
- Singapore Eye Research Institute, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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De Aracena Del Cid RM, De Espinosa Escoriaza IM. Subconjunctival application of regenerative factor-rich plasma for the treatment of ocular alkali burns. Eur J Ophthalmol 2018; 19:909-15. [DOI: 10.1177/112067210901900603] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Ziaei M, Greene C, Green CR. Wound healing in the eye: Therapeutic prospects. Adv Drug Deliv Rev 2018; 126:162-176. [PMID: 29355667 DOI: 10.1016/j.addr.2018.01.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/06/2017] [Accepted: 01/10/2018] [Indexed: 02/07/2023]
Abstract
In order to maintain a smooth optical surface the corneal epithelium has to continuously renew itself so as to maintain its function as a barrier to fluctuating external surroundings and various environmental insults. After trauma, the cornea typically re-epithelializes promptly thereby minimizing the risk of infection, opacification or perforation. A persistent epithelial defect (PED) is usually referred to as a non-healing epithelial lesion after approximately two weeks of treatment with standard therapies to no avail. They occur following exposure to toxic agents, mechanical injury, and ocular surface infections and are associated with significant clinical morbidity in patients, resulting in discomfort or visual loss. In the case of deeper corneal injury and corneal pathology the wound healing cascade can also extend to the corneal stroma, the layer below the epithelium. Although significant progress has been made in recent years, pharmaco-therapeutic agents that promote corneal healing remain limited. This article serves as a review of current standard therapies, recently introduced alternative therapies gaining in popularity, and a look into the newest developments into ocular wound healing.
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Etxebarria J, Sanz-Lázaro S, Hernáez-Moya R, Freire V, Durán JA, Morales MC, Andollo N. Serum from plasma rich in growth factors regenerates rabbit corneas by promoting cell proliferation, migration, differentiation, adhesion and limbal stemness. Acta Ophthalmol 2017; 95:e693-e705. [PMID: 28266180 DOI: 10.1111/aos.13371] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 11/18/2016] [Indexed: 12/22/2022]
Abstract
PURPOSE To evaluate the regenerating potential and the mechanisms through which the autologous serum derived from plasma rich in growth factors (s-PRGF) favours corneal wound healing in vitro and in vivo. METHODS We compared the effect of various concentrations of s-PRGF versus fetal bovine serum (FBS) and control treatment in rabbit primary corneal epithelial and stromal cells and wounded rabbit corneas. Cell proliferation was measured using an enzymatic colorimetric assay. In vitro and in vivo wound-healing progression was assessed by image-analysis software. Migration and invasion were evaluated using transfilter assays. Histological structure was analysed in stained sections. Protein expression was evaluated by immunohistochemistry. RESULTS s-PRGF promoted the robust proliferation of epithelial cultures at any concentration, similar to FBS. Likewise, s-PRGF and FBS produced similar re-epithelialization rates in in vitro wound-healing assays. In vivo, s-PRGF treatment accelerated corneal wound healing in comparison with control treatment. This difference was significant only for 100% s-PRGF treatment in our healthy rabbit model. Histological analysis confirmed normal epithelialization in all cases. Immunohistochemistry showed a higher expression of cytokeratins 3/76 and 15, zonula occludens-1 and alpha-smooth muscle actin proteins as a function of s-PRGF concentration. Notably, keratocyte density in the anterior third of the stroma increased with increase in s-PRGF concentration, suggesting an in vivo chemotactic effect of s-PRGF on keratocytes that was further confirmed in vitro. CONCLUSION s-PRGF promotes proliferation and migration and influences limbal stemness, adhesion and fibrosis during corneal healing.
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Affiliation(s)
- Jaime Etxebarria
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
- Department of Ophthalmology; BioCruces Health Research Institute; University Hospital of Cruces; Begiker; Barakaldo Spain
| | - Sara Sanz-Lázaro
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
| | - Raquel Hernáez-Moya
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
| | - Vanesa Freire
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
- R & D Department; Instituto Clínico-Quirúrgico de Oftalmología; Bilbao Spain
| | - Juan A. Durán
- R & D Department; Instituto Clínico-Quirúrgico de Oftalmología; Bilbao Spain
- Department of Ophthalmology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
| | - María-Celia Morales
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
| | - Noelia Andollo
- Department of Cell Biology and Histology; School of Medicine and Nursing; BioCruces Health Research Institute; University of the Basque Country; Begiker; Leioa Spain
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Treatment of Dry Eye Disease with Autologous Platelet-Rich Plasma: A Prospective, Interventional, Non-Randomized Study. Ophthalmol Ther 2017; 6:285-293. [PMID: 28791607 PMCID: PMC5693817 DOI: 10.1007/s40123-017-0100-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Indexed: 11/16/2022] Open
Abstract
Introduction The objective of this study was to evaluate the use of autologous platelet-rich plasma (PRP) eye drops as monotherapy for the treatment of moderate to severe cases of dry eye disease. Methods Three hundred and sixty-eight patients with moderate to severe dry eye disease (DED) were included in this prospective case series. Subjects were classified as evaporative DED (EDED) or aqueous deficient DED (ADDED). Improvement of the DED subjective symptoms, corneal fluorescein staining (CFS), and corrected distance visual acuity (BCVA) were evaluated. We also analysed how many rounds of PRP therapy were used. Results Two hundred and ninety-seven (80.7%) patients were women, and 71 (19.3%) were men. Two hundred and thirty-two (63%) patients had EDED, while 136 (37%) had ADDED. After 6 weeks of monotherapy treatment with autologous PRP, dry eye symptoms improved in 322 (87.5%) cases. A decrease of CFS was observed in 280 (76.1%) patients. One hundred and six (28.8%) patients improved at least 1 line of BCVA. The scores in the ocular Surface Disease Index and the Oxford scale of corneal fluorescein staining decreased statistically after the treatment (p < 0.05). Conclusion The topical use of autologous platelet-rich plasma as monotherapy is an effective treatment to improve signs and symptoms in patients suffering from moderate to severe chronic DED.
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Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, Dana R, Deng SX, Dong PN, Geerling G, Hida RY, Liu Y, Seo KY, Tauber J, Wakamatsu TH, Xu J, Wolffsohn JS, Craig JP. TFOS DEWS II Management and Therapy Report. Ocul Surf 2017; 15:575-628. [DOI: 10.1016/j.jtos.2017.05.006] [Citation(s) in RCA: 578] [Impact Index Per Article: 72.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/03/2017] [Indexed: 02/06/2023]
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Wu MF, Stachon T, Seitz B, Langenbucher A, Szentmáry N. Effect of human autologous serum and fetal bovine serum on human corneal epithelial cell viability, migration and proliferation in vitro. Int J Ophthalmol 2017; 10:908-913. [PMID: 28730081 DOI: 10.18240/ijo.2017.06.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 02/06/2017] [Indexed: 12/14/2022] Open
Abstract
AIM To analyze the concentration-dependent effects of autologous serum (AS) and fetal bovine serum (FBS) on human corneal epithelial cell (HCEC) viability, migration and proliferation. METHODS AS was prepared from 13 patients with non-healing epithelial defects Dulbecco's modified eagle medium/Ham's F12 (DMEM/F12) with 5% FBS, 0.5% dimethyl sulphoxide (DMSO), 10 ng/mL human epidermal growth factor, 1% insulin-transferrin-selenium, then were incubated in serum media: DMEM/F12 supplemented by 5%, 10%, 15% or 30% AS or FBS. HCEC viability was analyzed using cell proliferation kit XTT, migration using a wound healing assay, proliferation by the cell proliferation enzyme-linked immunosorbent assay (ELISA) BrdU kit. Statistical analysis was performed using the generalized linear model, the values at 30% AS or 30% FBS were used as the baselines. RESULTS HCEC viability was the highest at 30% AS or 15% FBS and the lowest at 10% AS or 30% FBS application. HCEC migration was the quickest through 30% AS or 30% FBS and the slowest through 5% AS or 5% FBS concentrations. Proliferation was the most increased through 15% AS or 5% FBS and the least increased through 30% AS or 30% FBS concentrations. HCEC viability at 10% and 15% AS was significantly worse (P=0.001, P=0.023) compared to baseline and significantly better at 15% FBS (P=0.003) concentrations. HCEC migration was significantly worse (P≤0.007) and HCEC proliferation significantly better (P<0.001) in all concentration groups compared to baseline. CONCLUSION For the best viability of HCEC 30% AS or 15% FBS, for HCEC migration 30% AS or 30% FBS, for proliferation 15% AS or 5% FBS should be used. Therefore, we suggest the use of 30% AS in clinical practice.
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Affiliation(s)
- Ming-Feng Wu
- Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar 66424, Germany
| | - Tanja Stachon
- Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar 66424, Germany
| | - Berthold Seitz
- Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar 66424, Germany
| | - Achim Langenbucher
- Experimental Ophthalmology, Saarland University, Homburg/Saar 66424, Germany
| | - Nóra Szentmáry
- Department of Ophthalmology, Saarland University Medical Center, Homburg/Saar 66424, Germany.,Department of Ophthalmology, Semmelweis University, Budapest 1085, Hungary
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Nassiri N, Rodriguez Torres Y, Meyer Z, Beyer MA, Vellaichamy G, Dhaliwal AS, Chungfat N, Hwang FS. Current and emerging therapy of dry eye disease. Part A: pharmacological modalities. EXPERT REVIEW OF OPHTHALMOLOGY 2017. [DOI: 10.1080/17469899.2017.1327350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Nariman Nassiri
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Yasaira Rodriguez Torres
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Zachary Meyer
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Michael A. Beyer
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Gautham Vellaichamy
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Amar S. Dhaliwal
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Neil Chungfat
- Department of Ophthalmology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Frank S. Hwang
- Kresge Eye Institute - Department of Ophthalmology, School of Medicine, Wayne State University, Detroit, MI, USA
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Safety of Cultivated Limbal Epithelial Stem Cell Transplantation for Human Corneal Regeneration. Stem Cells Int 2017; 2017:6978253. [PMID: 28465692 PMCID: PMC5390601 DOI: 10.1155/2017/6978253] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/08/2017] [Indexed: 12/13/2022] Open
Abstract
Ex vivo cultivated limbal stem cell transplantation is a promising technique for the treatment of limbal stem cell deficiency. While the results of the clinical trials have been extensively reported since the introduction of the technique in 1997, little has been reported regarding the potential health risks associated with production processes and transplantation techniques. Culture procedures require the use of animal and/or human-derived products, which carry the potential of introducing toxic or infectious agents through contamination with known or unknown additives. Protocols vary widely, and the risks depend on the local institutional methods. Good manufacturing practice and xeno-free culture protocols could reduce potential health risks but are not yet a common practice worldwide. In this review, we focus on the safety of both autologous- and allogeneic-cultivated limbal stem cell transplantation, with respect to culture processes, surgical approaches, and postoperative strategies.
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Autologous method for ex vivo expansion of human limbal epithelial progenitor cells based on plasma rich in growth factors technology. Ocul Surf 2017; 15:248-256. [PMID: 28115245 DOI: 10.1016/j.jtos.2017.01.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/17/2017] [Accepted: 01/18/2017] [Indexed: 01/05/2023]
Abstract
PURPOSE Develop an autologous culture method for ex vivo expansion of human limbal epithelial progenitor cells (LEPCs) using Plasma Rich in Growth Factors (PRGF) as a growth supplement and as a scaffold for the culture of LEPCs. METHODS LEPCs were cultivated in different media supplemented with 10% fetal bovine serum (FBS) or 10% PRGF. The outgrowths, total number of cells, colony forming efficiency (CFE), morphology and immunocytochemistry against p63- α and cytokeratins 3 and 12 (CK3-CK12) were analyzed. PRGF was also used to elaborate a fibrin membrane. The effects of the scaffold on the preservation of stemness and the phenotypic characterization of LEPCs were investigated through analysis of CK3-CK12, ABCG-2 and p63. RESULTS LEPCs cultivated with PRGF showed a significantly higher growth area than FBS cultures. Moreover, the number of cells were also higher in PRGF than FBS, while displaying a better morphology overall. CFE was found to be also higher in PRGF groups compared to FBS, and the p63-α expression also differed between groups. LEPCs cultivated on PRGF membranes appeared as a confluent monolayer of cells and still retained p63 and ABCG-2 expression, being negative for CK3-CK12. CONCLUSIONS PRGF can be used in corneal tissue engineering, supplementing the culture media, even in a basal media without any other additives, as well as providing a scaffold for the culture.
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Ma IH, Chen LW, Tu WH, Lu CJ, Huang CJ, Chen WL. Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome. Taiwan J Ophthalmol 2017; 7:213-220. [PMID: 29296554 PMCID: PMC5747232 DOI: 10.4103/tjo.tjo_102_17] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
PURPOSE: Autologous serum eye drops are considered safe and efficient for the treatment of various ocular surface disorders, including dry eye diseases (DED) caused by the primary and secondary Sjogren syndrome (SS). However, the serum components in patients of SS may be different from those of normal patients and can thus lead to unpredictable therapeutic effects. This study divided the SS patients into active and inactive types based on the erythrocyte sedimentation rate and the presence or absence of active rheumatoid arthritis. METHODS: We compared the serum components of these two groups with standard and multiplex enzyme linked immunosorbent assay arrays and predicted the therapeutic effects of topical autologous serum for the treatment of DED with ocular surface disease index (OSDI) and Oxford Schema scale (OSS). RESULTS: Hyaluronic acid and transforming growth factor b1 levels were significantly higher in the active SS group compared to the inactive SS group (P < 0.01), whereas epidermal growth factors, insulin growth factor 1, and fibroblast growth factor b had no significant differences between these two groups. Active SS group had significantly higher expressions of interleukin (IL) 1 beta, IL 6, and tumor necrosis factor alpha compared to inactive SS patients (P < 0.05). There were no statistical differences in therapeutic effects between these two groups, as measured with the OSDI or OSS. CONCLUSION: Dividing the Sjogren dry eye patients into active and inactive groups may appear as a reasonable method to predict the quality of autologous serum eye drops, but there seems to be no significant predictability to the therapeutic effects.
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Affiliation(s)
- I-Hsin Ma
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Lily Wei Chen
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Hui Tu
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Ju Lu
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Jung Huang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Li Chen
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan.,Center of Corneal Tissue Engineering and Stem Cell Biology, National Taiwan University Hospital, Taipei, Taiwan
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Undiluted Serum Eye Drops for the Treatment of Persistent Corneal Epitheilal Defects. Sci Rep 2016; 6:38143. [PMID: 27909310 PMCID: PMC5133461 DOI: 10.1038/srep38143] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/04/2016] [Indexed: 12/02/2022] Open
Abstract
Several studies found that 50–100% serum eye drops provided greater benefits without inducing detrimental effects on the corneal epithelial healing. This study assessed the efficacy of undiluted serum eye drops for the treatment of persistent corneal epithelial defects (PED). A total of 109 eyes received 100% serum eye drops for PED were recruited into this study. The data were compared with an historical control group of 79 eyes with PED who received conventional treatments from 2006–2011 at the same institution. Main outcome measures were complete healing of PED and incidence of adverse events. No significant difference in demographics between the 2 groups was noted. The success rate of the treatment and control groups were 87.16% (95% CI 0.79–0.93) and 69.62% (95% CI 0.59–0.80) (P = 0.001), respectively. The median time to complete epithelialization was 14 days (95% CI 12–21) in the treatment group and 28 days (95% CI 21–59) in the control group (P = 0.001). Serum treatment, primary diagnosis of non-limbal stem cell deficiency etiology, and prior contact lens wear significantly correlated with the corneal re-epithelialization. There were no serious side effects encountered during the study period. In conclusion, undiluted serum therapy is effective and safe for treating PED.
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Lee YK, Lin YC, Tsai SH, Chen WL, Chen YM. Therapeutic outcomes of combined topical autologous serum eye drops with silicone–hydrogel soft contact lenses in the treatment of corneal persistent epithelial defects: A preliminary study. Cont Lens Anterior Eye 2016; 39:425-430. [DOI: 10.1016/j.clae.2016.06.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/08/2016] [Accepted: 06/10/2016] [Indexed: 11/28/2022]
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Riestra AC, Alonso-Herreros JM, Merayo-Lloves J. Platelet rich plasma in ocular surface. ARCHIVOS DE LA SOCIEDAD ESPANOLA DE OFTALMOLOGIA 2016; 91:475-490. [PMID: 27062018 DOI: 10.1016/j.oftal.2016.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/28/2016] [Accepted: 03/01/2016] [Indexed: 06/05/2023]
Abstract
The use of platelet-rich preparations has experienced a significant increase in recent years due to its role in tissue-repair and regeneration. The aim of this study is to examine the available evidence regarding the application of plasma rich in growth factors, and its variations, on the ocular surface. A review is also presented on the effects of platelet-derived growth factors, the implications of the preparation methods, and the existing literature on the safety and efficacy of these therapies in ocular surface diseases. Despite the widespread use of platelet preparations there is no consensus on the most appropriate preparation method, and growth factors concentration vary with different systems. These preparations have been used in the treatment of ocular surface diseases, such as dry eye or persistent epithelial defects, among others, with good safety and efficacy profiles, but further studies are needed to compare to the currently available alternatives.
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Affiliation(s)
- A C Riestra
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, Oviedo, España.
| | | | - J Merayo-Lloves
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, Oviedo, España
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Conway ED, Stiles J, Townsend WM, Weng HY. Comparison of the in vitro anticollagenase efficacy of homologous serum and plasma on degradation of corneas of cats, dogs, and horses. Am J Vet Res 2016; 77:627-33. [DOI: 10.2460/ajvr.77.6.627] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Arnalich F, Rodriguez AE, Luque-Rio A, Alio JL. Solid Platelet Rich Plasma in Corneal Surgery. Ophthalmol Ther 2016; 5:31-45. [PMID: 27179661 PMCID: PMC4909678 DOI: 10.1007/s40123-016-0051-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Indexed: 02/07/2023] Open
Abstract
Abstract Solid eye platelet-rich plasma (E-PRP) concentrates platelets in a small volume of plasma which contains a high concentration of important growth factors and cell adhesion molecules. These cell adhesion molecules and growth factors occupy a major role in wound healing and enhance the physiological procedure at the site of the injury or the surgery. There are different materials used to tectonically maintain the solid clot attached at the site where treatment is necessary. Although AM may be used for this purpose, other biomaterials such a bovine pericardium or autologous fibrin membrane are at least as effective with less interdonor variations, no biological hazards, providing a better surgical alternative than the biologically so variable amniotic membrane patch. Solid platelet-rich plasma in the form obtained in ophthalmology, E-PRP, is a reliable and effective surgical coadjuvant to promote corneal wound healing in severe corneal ulcers and corneal perforations, and may be associated with other ocular surface reconstruction procedures. Funding Supported in part by a grant from the Spanish Ministry of Science and Innovation, Centro para el Desarrollo Tecnológico Industrial (CDTI), CENIT: “Customized Eye Care”, CeyeC (CEN-20091021).
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Affiliation(s)
| | | | | | - Jorge L Alio
- Department of Cornea and Refractive Surgery, VISSUM, Alicante, Spain. .,School of Medicine, Miguel Hernandez University, Alicante, Spain.
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Suri K, Gong HK, Yuan C, Kaufman SC. Human Platelet Lysate as a Replacement for Fetal Bovine Serum in Limbal Stem Cell Therapy. Curr Eye Res 2016; 41:1266-1273. [PMID: 26863375 DOI: 10.3109/02713683.2015.1116586] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE To evaluate the use of human platelet lysate (HPL) as an alternative supplement for limbal explant culture. METHODS Culture media were prepared using either 10% pooled HPL (PHPL), single donor HPL, or fetal bovine serum (FBS). Limbal tissues, obtained from the Minnesota Lions Eye Bank, were cultured in each medium on plastic plates or on denuded amniotic membrane (AM). Immunofluorescence staining was performed for ABCG2, tumor protein p63α, and cytokeratin 3 (K3). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to evaluate the expression of ABCG2 and p63. Limbal explants grown in each medium were labeled with bromodeoxyuridine (BrdU) to assess the proliferative capacity in each medium. Concentration of growth factors including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and platelet derived growth factor (PDGF) in HPL and PHPL was compared to that in human serum (HS). RESULTS Immunofluorescence staining on AM showed prominent expression of ABCG2, p63α but sparse expression of K3 in HPL and PHPL supplemented medium. Real time-PCR showed 1.7 fold higher expression of ABCG2 in PHPL supplemented medium (p = 0.03), and similar expression of p63 in HPL and PHPL supplemented medium compared to FBS medium. The proliferation assay showed that LSCs retained their proliferative potential in HPL supplemented medium. Higher concentration of growth factors were found in HPL, compared to HS. CONCLUSIONS Human platelet lysate has higher concentration of grown factors and is effective in maintaining growth and stem cell phenotype of corneal limbal explant cultures.
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Affiliation(s)
- Kunal Suri
- a Department of Ophthalmology , University of Minnesota , Minneapolis , MN , USA
| | - Hwee K Gong
- a Department of Ophthalmology , University of Minnesota , Minneapolis , MN , USA
| | - Ching Yuan
- a Department of Ophthalmology , University of Minnesota , Minneapolis , MN , USA
| | - Stephen C Kaufman
- a Department of Ophthalmology , University of Minnesota , Minneapolis , MN , USA.,b State University of New York-Downstate Medical Center , Brooklyn , NY , USA
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Perches C, Pellizzon C, Ranzani J, Donatti C, Padovani C, Merlini N, Fonzar J, Beserra H, Rocha N, Brandão C. Expressão de metaloproteinases de matriz e PCNA em úlceras de córnea profundas, induzidas em coelhos, tratadas com plasma rico em plaquetas. ARQ BRAS MED VET ZOO 2015. [DOI: 10.1590/1678-4162-8142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
O objetivo deste estudo foi avaliar a influência do plasma rico (PRP) e pobre (PPP) em plaquetas na proliferação celular e expressão de metaloproteinases de matriz (MMPs), durante a reparação de úlceras corneais profundas. Foram utilizadas 45 coelhas, distribuídas em 3 grupos (G) experimentais (n=15), designados como grupos PRP (GR), PPP (GP) e Controle (GC), de acordo com o tratamento. Todos os animais foram submetidos à indução cirúrgica unilateral de úlcera corneal. No GR e GP, o sangue autólogo foi centrifugado, utilizando-se protocolo padronizado, e foram confeccionados os colírios de PRP e PPP, e instilados cinco vezes ao dia. No GC, foi utilizado colírio lubrificante. Cada grupo foi subdividido (n=5), segundo o momento final de avaliação, sendo 4 (M4), 7 (M7) e 30 dias (M30). As córneas dos animais foram processadas para avaliação morfológica e imuno-histoquímica para PCNA, MMP1, MMP2, MMP9, MT1-MMP e TIMP1. No M4, os níveis de MMP2 foram maiores no GP e GR, sendo que, no M7, esse comportamento foi observado apenas no GP. No M30, no GR, verificou-se maior número de células epiteliais e marcação para MMP1 que o GP. No GR, a proliferação celular foi maior no M4 que nos demais momentos, e a marcação para MMP2 foi maior no M4 que no M30. O PRP estimula a proliferação celular na fase inicial (M4) do tratamento quando comparado aos demais momentos, diferentemente dos demais tratamentos. O uso de colírios de plasma rico e pobre em plaquetas influencia a expressão de metaloproteinases de matriz envolvidas no processo de reparação corneal.
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Anitua E, Muruzabal F, Tayebba A, Riestra A, Perez VL, Merayo-Lloves J, Orive G. Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies. Acta Ophthalmol 2015; 93:e605-14. [PMID: 25832910 DOI: 10.1111/aos.12710] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 02/06/2015] [Indexed: 01/22/2023]
Abstract
The use of blood derivatives represents an alternative therapeutic approach that is gaining interest in regenerative medicine due to its potential to stimulate and accelerate tissue healing. Autologous serum eye drops and platelet-enriched plasma eye drops are being used in the treatment of different ophthalmological disorders. In this review, we summarize the different blood-derived formulations used in the treatment and care of ocular surface disorders. The biological basis and use of autologous serum and plasma rich in growth factors are deeply evaluated as well as the challenges to be addressed in the future in this new generation of blood-derived therapies.
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Affiliation(s)
| | | | - Ali Tayebba
- Microbiology & Immunology; Walter G. Ross Chair in Ophthalmic Research; Ocular Surface Center; Bascom Palmer Eye Institute; University of Miami Miller School of Medicine; Miami Florida USA
| | - Ana Riestra
- Fernandez-Vega Ophthalmological Institute; Eye Research Foundation; University of Oviedo; Oviedo Spain
| | - Victor L. Perez
- Microbiology & Immunology; Walter G. Ross Chair in Ophthalmic Research; Ocular Surface Center; Bascom Palmer Eye Institute; University of Miami Miller School of Medicine; Miami Florida USA
| | - Jesus Merayo-Lloves
- Fernandez-Vega Ophthalmological Institute; Eye Research Foundation; University of Oviedo; Oviedo Spain
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van der Meer PF, Seghatchian J, de Korte D. Autologous and allogeneic serum eye drops. The Dutch perspective. Transfus Apher Sci 2015; 53:99-100. [DOI: 10.1016/j.transci.2015.05.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Soni NG, Jeng BH. Blood-derived topical therapy for ocular surface diseases. Br J Ophthalmol 2015; 100:22-7. [DOI: 10.1136/bjophthalmol-2015-306842] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 06/21/2015] [Indexed: 11/03/2022]
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Targeting growth factor supply in keratopathy treatment: comparison between maternal peripheral blood and cord blood as sources for the preparation of topical eye drops. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2015; 14:145-51. [PMID: 26192781 DOI: 10.2450/2015.0020-15] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 03/05/2015] [Indexed: 11/21/2022]
Abstract
BACKGROUND Epitheliotrophic growth factors (GF) can be supplied topically to patients with severe keratopathy through a variety of blood-derived products. We compared GF content in adult peripheral blood serum (PB-S) and cord blood serum (CB-S) as potential sources of GF. To limit inter-individual variability the assessment was performed in maternal-child pairs at the time of delivery. MATERIAL AND METHODS The amounts of epidermal GF (EGF), insulin-like GF (IGF), transforming GF-beta (TGF-β), vascular endothelial GF (VEGF) in CB units collected from the umbilical vein and PB from mothers (each group n=30) were estimated by enzyme-linked immunosorbent assays. Obstetric characteristics and haematological data were recorded from the archives of the Emilia Romagna Cord Blood Bank. Statistical evaluations were performed by Wilcoxon's test and correlations between variables were determined using Spearman's (ρ) coefficient; p-values <0.05 were considered statistically significant. RESULTS EGF, TGF-β and VEGF levels were significantly higher in CB-S than in PB-S (median 1,254.4 vs 646.0 pg/mL, 51.3 vs 38.4 μg/mL and 686.8 vs 30 pg/mL, respectively; all p<0.0001) whereas IGF content was significantly higher in PB-S than in CB-S (159.9 vs 53.5 pg/mL, respectively; p<0.0001). In CB-S, the CD34(+) cell concentration appeared to be related to EGF, IGF and TGF-β levels whereas white blood cell count appeared to be related to EGF and TGF-β levels. VEGF levels showed no relation to the haematological parameters considered. Platelet counts were not related to GF level in either CB or PB. DISCUSSION The GF content in the two blood sources was different, with CB containing larger amounts. Each GF selectively regulates cellular processes involved in corneal healing, so the use of PB or CB should be targeted to supply specific GF on the basis of the type and severity of the keratopathy.
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Kang NH, Lee S, Jun RM. Comparison of epitheliotrophic factors in autologous serum eyedrops from sera of chronic renal failure patients vs. normal controls. Graefes Arch Clin Exp Ophthalmol 2015; 253:1705-12. [DOI: 10.1007/s00417-015-3056-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 05/08/2015] [Accepted: 05/11/2015] [Indexed: 10/23/2022] Open
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Nugent RB, Lee GA. Ophthalmic use of blood-derived products. Surv Ophthalmol 2015; 60:406-34. [PMID: 26077627 DOI: 10.1016/j.survophthal.2015.03.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 03/23/2015] [Accepted: 03/25/2015] [Indexed: 12/23/2022]
Abstract
There is a wide spectrum of blood-derived products that have been used in many different medical and surgical specialties with success. Blood-derived products for clinical use can be extracted from autologous or allogeneic specimens of blood, but recombinant products are also commonly used. A number of blood derivatives have been used for a wide range of ocular conditions, from the ocular surface to the retina. With stringent preparation guidelines, the potential risk of transmission of blood-borne diseases is minimized. We review blood-derived products and how they are improving the management of ocular disease.
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Affiliation(s)
| | - Graham A Lee
- City Eye Centre, Brisbane, Queensland, Australia; Department of Ophthalmology, University of Queensland, Brisbane, Queensland, Australia.
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De Pascale MR, Sommese L, Casamassimi A, Napoli C. Platelet derivatives in regenerative medicine: an update. Transfus Med Rev 2015; 29:52-61. [PMID: 25544600 DOI: 10.1016/j.tmrv.2014.11.001] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 11/03/2014] [Accepted: 11/09/2014] [Indexed: 12/26/2022]
Abstract
Prior preclinical and clinical studies support the use of platelet-derived products for the treatment of soft and hard tissue lesions. These regenerative effects are controlled by autocrine and paracrine biomolecules including growth factors and cytokines contained in platelet alpha granules. Each growth factor is involved in a phase of the healing process, such as inflammation, collagen synthesis, tissue granulation, and angiogenesis collectively promoting tissue restitution. Platelet derivatives have been prepared as platelet-rich plasma, platelet gel, platelet-rich fibrin, and platelet eye drops. These products vary in their structure, growth factors, composition, and cytokine concentrations. Here, we review the current use of platelet-derived biological products focusing on the rationale for their use and the main requirements for their preparation. Variation in the apparent therapeutic efficacy may have resulted from a lack of reproducible, standardized protocols for preparation. Despite several individual studies showing favorable treatment effects, some randomized controlled trials as well as meta-analyses have found no constant clinical benefit from the application of platelet-derived products for prevention of tissue lesions. Recently, 3 published studies in dentistry showed an improvement in bone density. Seven published studies showed positive results in joint regeneration. Five published studies demonstrated an improvement in the wound healing, and an improvement of eye epithelial healing was observed in 2 reports. Currently, at least 14 ongoing clinical trials in phase 3 or 4 have been designed with large groups of treated patients (n > 100). Because the rationale of the therapy with platelet-derived compounds is still debated, a definitive insight can be acquired only when these large randomized trials will be completed.
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Affiliation(s)
- Maria Rosaria De Pascale
- UOC Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Ospedaliera Universitaria (AOU), Second University of Naples, Naples, Italy
| | - Linda Sommese
- UOC Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Ospedaliera Universitaria (AOU), Second University of Naples, Naples, Italy
| | - Amelia Casamassimi
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
| | - Claudio Napoli
- UOC Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Ospedaliera Universitaria (AOU), Second University of Naples, Naples, Italy; Institute of Diagnostic and Nuclear Development, IRCCS, Naples, Italy
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Corneal wound healing promoted by 3 blood derivatives: an in vitro and in vivo comparative study. Cornea 2014; 33:614-20. [PMID: 24727633 DOI: 10.1097/ico.0000000000000109] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE The aim of this study was to compare the effect on corneal wound healing of 3 differently manufactured blood derivatives [autologous serum (AS), platelet-rich plasma, and serum derived from plasma rich in growth factors (s-PRGF)]. METHODS Scratch wound-healing assays were performed on rabbit primary corneal epithelial cultures and human corneal epithelial cells. Additionally, mechanical debridement of rabbit corneal epithelium was performed. Wound-healing progression was assessed by measuring the denuded areas remaining over time after treatment with each of the 3 blood derivatives or a control treatment. RESULTS In vitro data show statistically significant differences in the healing process with all the derivatives compared with the control, but 2 of them (AS and s-PRGF) induced markedly faster wound healing. In contrast, although the mean time required to complete in vivo reepithelization was similar to that of AS and s-PRGF treatment, only wounds treated with s-PRGF were significantly smaller in size from 2.5 days onward with respect to the control treatment. CONCLUSIONS All 3 blood derivatives studied are promoters of corneal reepithelization. However, the corneal wound-healing progresses differently with each derivative, being faster in vitro under AS and s-PRGF treatment and producing in vivo the greatest decrease in wound size under s-PRGF treatment. These findings highlight that the manufacturing process of the blood derivatives may modulate the efficacy of the final product.
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Semeraro F, Forbice E, Braga O, Bova A, Di Salvatore A, Azzolini C. Evaluation of the efficacy of 50% autologous serum eye drops in different ocular surface pathologies. BIOMED RESEARCH INTERNATIONAL 2014; 2014:826970. [PMID: 25136628 PMCID: PMC4130192 DOI: 10.1155/2014/826970] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 05/18/2014] [Indexed: 12/04/2022]
Abstract
PURPOSE This study evaluated the efficacy of 50% autologous serum eye drops in ocular surface diseases not improved by conventional therapy. METHODS We analyzed two groups: (1) acute eye pathologies (e.g., chemical burns) and (2) chronic eye pathologies (e.g., recurrent corneal erosion, neurotropic keratitis, and keratoconjunctivitis sicca). The patients were treated for surface instability after conventional therapy. The patients received therapy 5 times a day until stabilization of the framework; they then reduced therapy to 3 times a day for at least 3 months. We analyzed the best corrected visual acuity, epithelial defects, inflammation, corneal opacity, and corneal neovascularization. We also analyzed symptoms such as tearing, burning, sense of foreign body or sand, photophobia, blurred vision, and difficulty opening the eyelids. RESULTS We enrolled 15 eyes in group 1 and 11 eyes in group 2. The average therapy period was 16 ± 5.86 weeks in group 1 and 30.54 ± 20.33 weeks in group 2. The epithelial defects all resolved. Signs and symptoms improved in both groups. In group 2, the defect recurred after the suspension of therapy in 2 (18%) patients; in group 1, no defects recurred. CONCLUSIONS Autologous serum eye drops effectively stabilize and improve signs and symptoms in eyes previously treated with conventional therapy.
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Affiliation(s)
- Francesco Semeraro
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili 1, 25123 Brescia, Italy
| | - Eliana Forbice
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili 1, 25123 Brescia, Italy
| | - Osvaldo Braga
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili 1, 25123 Brescia, Italy
| | - Alessandro Bova
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili 1, 25123 Brescia, Italy
| | - Attilio Di Salvatore
- Eye Clinic, Department of Neurological and Vision Sciences, University of Brescia, Piazzale Spedale Civili 1, 25123 Brescia, Italy
| | - Claudio Azzolini
- Department of Surgical and Morphological Sciences, Section of Ophthalmology, University of Insubria, Ospedale di Circolo, Via F. Guicciardini 9, 21100 Varese, Italy
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Topical 100% serum eye drops for treating corneal epithelial defect after ocular surgery. BIOMED RESEARCH INTERNATIONAL 2013; 2013:521315. [PMID: 23984378 PMCID: PMC3745890 DOI: 10.1155/2013/521315] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/05/2013] [Accepted: 07/09/2013] [Indexed: 11/17/2022]
Abstract
The purpose of this study was to investigate the efficacy and safety of topical 100% serum eye drops for corneal epithelial defect after ocular surgery. A total of 181 patients who received topical 100% serum therapy for the treatment of corneal epithelial defect following several different types of ocular surgery were recruited into this study. Each patient already failed conventional medical therapy before being prescribed 100% serum eye drops. Slit-lamp biomicroscopic examination with fluorescein staining was performed at baseline and all follow-up visits. The main outcome measures were the rate of complete healing of the corneal epithelial defect and incidence of adverse events. One hundred and seventy-eight eyes (98.34%) received autologous serum eye drops, and 3 (1.66%) received allogeneic serum eye drops. The overall success rate of treating persistent postoperative epithelial defect using 100% serum eye drops was 93.92% (95% CI 0.88-0.98). The median time to complete corneal epithelialization was 4 days (95% CI 4-5). Adverse reactions were observed in 3 patients (1.66%), including sticky sensation with minimal eye discomfort and asymptomatic trace corneal subepithelial infiltration. No serious complications were reported. In conclusion, 100% serum eye drops are effective, safe, and tolerable for treating postoperative corneal epithelial defect following ocular surgeries.
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Cho YK, Huang W, Kim GY, Lim BS. Comparison of Autologous Serum Eye Drops with Different Diluents. Curr Eye Res 2012; 38:9-17. [DOI: 10.3109/02713683.2012.720340] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Vitali C, Palombi G, Cataleta P. Treating Sjögren's Syndrome: Insights for the Clinician. Ther Adv Musculoskelet Dis 2012; 2:155-66. [PMID: 22870445 DOI: 10.1177/1759720x10363246] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disease that affects the exocrine glands, mainly the salivary and lachrymal glands, with consequent persistent dryness of the mouth and eyes. In addition to the clinical manifestations related to the exocrine gland involvement, a consistent prevalence of patients may present systemic manifestations. Some of these can be ascribed to the periepithelial extension of lymphocytic infiltration whilst others are determined by an immunomediated process affecting small- or medium-size vessels. While the use of tear and saliva substitutes and local or systemic stimulation of residual secretions represent the mainstays of the therapy of sicca component, different immunomodulating or immunosuppressive agents are usually required to treat extraglandular features, similarly to what happens in other connective tissue diseases. In the last few years, the advancement in the understanding the pathogenetic mechanisms of this disorder and the availability of new biologic target therapies seem to offer completely new therapeutic options. The use of B cell depleting or modulating therapies has achieved promising results.
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Affiliation(s)
- Claudio Vitali
- Department of Internal Medicine and Section of Rheumatology, 'Villamarina' Hospital, Piombino, Italy
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Human platelet-rich plasma- and extracellular matrix-derived peptides promote impaired cutaneous wound healing in vivo. PLoS One 2012; 7:e32146. [PMID: 22384158 PMCID: PMC3285658 DOI: 10.1371/journal.pone.0032146] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 01/24/2012] [Indexed: 01/03/2023] Open
Abstract
Previous work in our laboratory has described several pro-angiogenic short peptides derived from endothelial extracellular matrices degraded by bacterial collagenase. Here we tested whether these peptides could stimulate wound healing in vivo. Our experiments demonstrated that a peptide created as combination of fragments of tenascin X and fibrillin 1 (comb1) applied into cranial dermal wounds created in mice treated with cyclophosphamide to impair wound healing, can improve the rate of wound closure. Furthermore, we identify and characterize a novel peptide (UN3) created and modified from two naturally-occurring peptides, which are present in human platelet-rich plasma. In vitro testing of UN3 demonstrates that it causes a 50% increase in endothelial proliferation, 250% increase in angiogenic response and a tripling of epithelial cell migration in response to injury. Results of in vivo experiments where comb1 and UN3 peptides were added together to cranial wounds in cyclophosphamide-treated mice leads to improvement of wound vascularization as shown by an increase of the number of blood vessels present in the wound beds. Application of the peptides markedly promotes cellular responses to injury and essentially restores wound healing dynamics to those of normal, acute wounds in the absence of cyclophosphamide impairment. Our current work is aimed at understanding the mechanisms underlying the stimulatory effects of these peptides as well as identification of the cellular receptors mediating these effects.
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