Open Clinical Study of Eye Drops Containing the Fibronectin-Derived Peptide PHSRN for Treatment of Persistent Corneal Epithelial Defects

Yamada, Naoyuki; Morishige, Naoyuki; Yanai, Ryoji; Morita, Yukiko; Kimura, Kazuhiro; Chikama, T.–I.; Nomizu, Motoyoshi; Sonoda, Koh Hei; Nishida, Teruo

doi:10.1097/ico.0b013e31824afd6c

Cited by 16 publications

(11 citation statements)

References 27 publications

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“…Taking advantage of the improved mechanical stability of the RHCIII-MPC hydrogel, we printed and analysed micropatterns that used human fibronectin (FN) as ''ink''. FN is a cell-interactive protein in the ECM that promotes adhesion and migration of corneal epithelial cells during wound healing [21,22] and has been successfully tested therapeutically for the repair of persistent epithelial defects in human corneas [23]. We quantitatively evaluated the effect of the printed FN micropatterns on the growth of human corneal epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications

Islam

Cėpla

et al. 2015

Acta Biomaterialia

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The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes for the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500μm thick RHCIII-MPC constructs comprising over 85% water are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, unlike the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30μm wide fibronectin stripes enhanced cell attachment and showed the highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

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Section: Introductionmentioning

confidence: 99%

Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications

Islam

Cėpla

et al. 2015

Acta Biomaterialia

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“…We previously showed that FGLM-NH 2 + SSSR eyedrops [17] and PHSRN eyedrops [18] facilitated corneal epithelial migration in a rat model of diabetes. Furthermore, both types of eyedrops promoted corneal epithelial wound closure in patients with PEDs [12, 19, 20]. However, treatment of PEDs in diabetic patients with such peptide eyedrops is likely to be insufficient in the presence of other abnormalities of the cornea that impede epithelial migration in response to such drugs.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we have previously shown that eyedrops containing the substance P-derived peptide FGLM-NH 2 plus IGF-1 [17] or PHSRN [18] facilitated corneal epithelial wound closure in diabetic rats. In addition to the effectiveness of PHSRN eyedrops for the treatment of PEDs in patients with diabetic keratopathy [12], we also found that eyedrops containing FGLM-NH 2 and either IGF-1 [19] or the IGF-1-derived peptide SSSR [20] were effective for the treatment of PEDs in patients with neurotrophic keratopathy. Despite the potential of these various peptides for the treatment of PEDs associated with diabetic keratopathy, however, we encountered some cases that responded with incomplete epithelial resurfacing.…”

Section: Introductionmentioning

confidence: 93%

“…The peptides FGLM-NH 2 , SSSR, and Ac-PHSRN-NH 2 were obtained from Protein Research Foundation (Osaka, Japan). The eyedrops contained either FGLM-NH 2 plus SSSR at 1 mg/mL and 0.05629 µg/mL, respectively, in phosphate-buffered saline [20] or 0.02% Ac-PHSRN-NH 2 in phosphate-buffered saline [12, 21], as previously described.…”

Section: Case Presentationmentioning

confidence: 99%

“…Conventional treatments in the first category include administration of artificial tears, hyaluronate eyedrops, or oily ointment, insertion of punctal plugs, and application of a bandage soft contact lens. More novel treatment options in the second category include topical application of autologous serum [9], nerve growth factor [10], the substance P-derived peptide FGLM-NH 2 plus insulin-like growth factor-1 (IGF-1) [11], or the fibronectin-derived peptide PHSRN [12]. Finally, treatments in the third category include topical application of fibronectin [13] and surgical removal of a degenerated Bowman’s layer.…”

Section: Introductionmentioning

confidence: 99%

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Remodeling of the Corneal Epithelial Scaffold for Treatment of Persistent Epithelial Defects in Diabetic Keratopathy

Ohta

Morita

Yamada

et al. 2018

Case Rep Ophthalmol

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Background: To develop a strategy based on surgical removal of a degenerated corneal epithelial scaffold for treatment of persistent epithelial defects (PEDs) in diabetic keratopathy. Case Presentation: Three diabetic patients with PEDs were initially treated with eyedrops containing the fibronectin-based peptide PHSRN (Pro-His-Ser-Arg-Asn) or both the substance P-derived peptide FGLM-NH₂ and the insulin-like growth factor-1-derived peptide SSSR. A degenerated Bowman’s layer or calcified lesion thought to be responsible for incomplete healing was surgically removed after confirmation of reactivity to the peptide eyedrops. All three patients achieved complete epithelial wound closure after surgery. Two cases treated by phototherapeutic keratectomy or lamellar keratoplasty did not show PED recurrence during 6 or 36 months of follow-up, respectively. One case treated by mechanical removal of a degenerated Bowman’s layer manifested recurrence after 1 month, but resurfacing of the defect was again achieved after repeat surgery. Conclusion: We propose a new strategy for treatment of diabetic PEDs based on surgical remodeling of the corneal epithelial scaffold for patients who respond to peptide eyedrops but fail to achieve wound closure.

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The role of fibronectin in corneal wound healing explored by a physician–scientist

Nishida

2012

Jpn J Ophthalmol

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For the past 30 years, I have worked as a physician-scientist in both the clinic and laboratory setting at a number of university medical schools. Encountering patients in the clinic for whom treatment was not available led me to the laboratory in an attempt to develop the appropriate treatment for future patients. The main focus of my translational research has been the role of fibronectin in corneal epithelial wound healing and the development of fibronectin eyedrops for the treatment of patients with persistent corneal epithelial defects. An extension of this research led to the development of eyedrops containing the synthetic peptide proline-histidine-serine-arginine-asparagine (PHSRN), which corresponds to the second cell-binding site of fibronectin. My clinical experience with fibronectin eyedrops also prompted me to examine the role of the sensory neurotransmitter substance P and insulin-like growth factor-1 (IGF-1) in corneal wound healing, leading to the development of eyedrops containing peptides derived from these agents (peptides FGLM-amide and SSSR, respectively). Although the path from the laboratory to the clinic in these instances has been relatively short, the time required to establish the newly identified treatment modalities in the wider community has been long. In this review, I relate the trajectory of my translational research career.

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Open Clinical Study of Eye Drops Containing the Fibronectin-Derived Peptide PHSRN for Treatment of Persistent Corneal Epithelial Defects

Abstract: Eye drops containing the fibronectin-derived PHSRN peptide are clinically efficacious for the treatment of PEDs.

Cited by 16 publications

References 27 publications

Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications

Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications

Remodeling of the Corneal Epithelial Scaffold for Treatment of Persistent Epithelial Defects in Diabetic Keratopathy

The role of fibronectin in corneal wound healing explored by a physician–scientist

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