Original Article
Topical Treatment with Nerve Growth Factor for Corneal Neurotrophic Ulcers
N Engl J Med 1998; 338:1174-1180April 23, 1998
- Abstract
Background
Corneal neurotrophic ulcers associated with impairment of sensory innervation of the cornea may lead to loss of vision, and there is no effective treatment for these ulcers. We evaluated the effects of nerve growth factor in patients with this disorder.
Methods
Twelve patients (14 eyes) with severe corneal neurotrophic ulcers associated with corneal anesthesia were treated with topical nerve growth factor 10 times daily for two days and then 6 times daily until the ulcers healed. Treatment continued for 2 weeks after the ulcers healed, and the patients were then followed for up to 15 months. The evolution of the corneal disease during treatment and follow-up was evaluated by slit-lamp examination, photography, fluorescein-dye testing, and tests of corneal sensitivity and best corrected visual acuity.
Results
Corneal healing began 2 to 14 days after the initiation of treatment with nerve growth factor, and all patients had complete healing of their corneal ulcers after 10 days to 6 weeks of treatment. Corneal sensitivity improved in 13 eyes, and returned to normal in 2 of the 13 eyes. Corneal integrity and sensitivity were maintained during the follow-up period (range, 3 to 15 months). Best corrected visual acuity increased progressively during treatment and follow-up in all patients. There were no systemic or local side effects of treatment.
Conclusions
In this preliminary, uncontrolled study, topically applied exogenous nerve growth factor restored corneal integrity in patients with corneal neurotrophic ulcers.
Media in This Article
Figure 3
Best Corrected Visual Acuity before, during, and after Treatment with Nerve Growth Factor in 12 Patients (14 Eyes) with Corneal Neurotrophic Ulcers from Various Causes.Figure 2
Effects of Treatment with Nerve Growth Factor on Ulcer Size in 12 Patients (14 Eyes) with Corneal Neurotrophic Ulcers from Various Causes.Article Activity
- Article
Several ocular and systemic diseases and circumstances, including fifth-nerve palsy, viral infections, chemical burns, corneal surgery, abuse of topical anesthetics, neurotrophic keratitis, diabetes mellitus, and multiple sclerosis, can cause corneal neurotrophic ulcers.1 These ulcers result from loss of the sensory innervation of the cornea, which leads to a decrease in the number of corneal stem cells,2 decreased metabolic and mitotic rates in the corneal epithelium (which increases cell permeability),3,4 and reduced acetylcholine and choline acetyltransferase concentrations.5 The result is progressive corneal damage, with epithelial defects, vascularization, opacification, ulceration, and ultimately, perforation, even in the absence of injury or infection. The standard treatments consist of covering the eye with a patch or a soft contact lens, tarsorrhaphy, and constructing a conjunctival flap, but they are often ineffective, and the outcome is often loss or severe impairment of vision.
Nerve growth factor is a well-characterized neurotrophin that is required for the development and survival of selected neurons, including sympathetic and sensory neurons.6 It provides trophic support after neuronal injuries and reverses pathologic changes induced by peripheral-nerve injury.7 In denervated skin, nerve growth factor induces sensory-neuron sprouting and restores the density of nerve growth factor receptors.8,9 Skin ulcers caused by the impairment of sensory innervation, such as in patients with diabetes mellitus and leprosy and after trauma, may be the result of decreased concentrations of local nerve growth factor.10,11
Nerve growth factor receptors have been found on the normal and abnormal cornea and conjunctiva.12,13 In this study, we evaluated the efficacy of topical application of nerve growth factor in patients with severe noninfectious corneal ulcers due to corneal anesthesia that were unresponsive to conventional therapy.
Methods
Patients
We studied 12 patients (14 eyes) who had noninfectious corneal ulcers associated with impaired corneal sensitivity, caused by essential neurotrophic keratitis (5 eyes), chemical burns (3 eyes), abuse of topical anesthetics (2 eyes), surgery for orbital tumor (1 eye), surgery for acoustic neuroma (1 eye), penetrating keratoplasty for unknown reasons (1 eye), and lamellar keratoplasty for a herpetic vascularized scar (1 eye) (Table 1Table 1
Base-Line Characteristics of the 12 Patients with Corneal Neurotrophic Ulcers and Corneal Anesthesia.). The mean age of the patients was 31 years (range, 4 to 56); six were female and six male. All the patients presented with corneal ulcer without ocular pain and photophobia or other signs of active inflammation (Figure 1AFigure 1
Photographs of the Eye of a Patient with a Corneal Neurotrophic Ulcer before, during, and after Treatment with Nerve Growth Factor.). Corneal ulceration had been present for a mean (±SD) of 45±24 days. All had received conventional treatment, such as artificial tears and covering the eye with a patch or a soft contact lens,1 and antibiotics with little or no benefit, and were referred to our center because of progressive worsening of the ulcer. The criteria for enrollment in the study were clinical evidence of corneal ulcer that was unresponsive to conventional therapy and the presence of corneal and conjunctival anesthesia. The exclusion criteria were the presence of corneal infection and the presence of other ocular diseases.Before starting treatment with nerve growth factor, the patients were treated with preservative-free artificial tears (one drop every two hours) for 10 days. If no tendency to heal was observed or if the ulcer progressed toward ocular perforation, all topical and systemic treatments were discontinued and topical treatment with nerve growth factor was commenced. The study protocol was approved by the ethics committee of the Hospital of Venice, and written informed consent was obtained from all patients.
Study Protocol
The patients were evaluated at base line, daily for 1 week during treatment with nerve growth factor and then weekly until the corneal ulcer was completely healed, and thereafter every month for up to 12 months after treatment was discontinued. The treatment used was murine nerve growth factor (200 μg in 1 ml of balanced salt solution), purified from submaxillary glands according to the method of Bocchini and Angeletti.14 Each patient was treated in the hospital until corneal healing began (after 2 to 14 days). The patients received one drop (approximately 50 μl) of nerve growth factor in the conjunctival fornix of the affected eye every two hours from 6 a.m. to midnight for two days, followed by a dose of one drop six times a day until the ulcer healed. After the ulcer healed, one drop of a lower concentration of nerve growth factor (100 μg per milliliter) was administered four times daily for two weeks.
Procedures
All patients were evaluated at base line by a complete eye examination (slit-lamp evaluation, tonometry, fundus oculi evaluation when possible, photography, fluorescein-dye test, corneal-sensitivity tests, estimation of best corrected visual acuity, and Schirmer's test). A general history was obtained and physical examination and routine hematologic and chemical tests were performed to rule out systemic disease. Cranial magnetic resonance imaging was also performed in the patients with essential neurotrophic keratitis to rule out anatomical lesions of the central nervous system or the cranial nerves.
The best corrected visual acuity was defined as the best vision that the eye can achieve after correction of its refractive error. Visual acuity was measured by having the patient read the smallest-possible line on a visual chart and expressed as a fraction of the normal value (normal vision is defined as 1.0, or 20/20). Corneal culture was performed to rule out bacterial and fungal infection, and corneal scrapings were analyzed with the polymerase chain reaction to rule out herpesvirus infection.
Corneal ulcers were classified according to their widest diameter and depth on slit-lamp examination. To test corneal sensitivity, we removed and twisted the tip of a cotton swab and then slowly advanced it until it touched the central corneal zone of the patient.15 All tests of corneal sensitivity were performed between 9 and 11 a.m. Corneal sensitivity was considered to be normal if there was a blink reflex when the cornea was touched. If the patient felt contact but had no blink reflex, corneal hypoesthesia was diagnosed, and if no response was present, corneal anesthesia was diagnosed. To test for the presence of sensitivity to chemical stimulation, we determined whether the patient noted a burning sensation after conjunctival instillation of a pungent substance15 (a commercial mydriatic drug [Visumidriatic 1 percent, Merck Sharp & Dohme]).
The eye examinations were repeated daily while the patient was hospitalized, weekly during treatment, and then monthly during follow-up. To assess the efficacy of nerve growth factor, we evaluated the results of the slit-lamp examinations, changes in ulcer size, best corrected visual acuity, and changes in corneal sensitivity. The effects of treatment on best corrected visual acuity were compared with paired t-tests at base line, at the time of discontinuation of therapy, and 6 and 12 months later.
Results
All patients had complete resolution of the corneal ulcer after 10 days to 6 weeks of treatment with nerve growth factor (Figure 1A, Figure 1B, Figure 1C, Figure 1D, and Figure 2Figure 2
Effects of Treatment with Nerve Growth Factor on Ulcer Size in 12 Patients (14 Eyes) with Corneal Neurotrophic Ulcers from Various Causes.), at which time the dosage was reduced for 2 weeks and then discontinued. The mean duration of treatment was 34 days (range, 24 to 56). The healing process began two days after the initiation of treatment in three patients and within two weeks in the other patients (Table 2Table 2
Effects of Treatment with Nerve Growth Factor in 12 Patients with Corneal Neurotrophic Ulcers.). The rate of healing was not related to the severity of the ulcer, its depth in the stroma, the age of the patient, or the cause of the ulcer. The first signs of healing were an advancement of epithelial cells from the margin toward the center of the ulcer and the occurrence of mild-to-moderate conjunctival hyperemia and were accompanied by pain and photophobia in all patients. Subsequently, superficial or deep corneal neovascularization occurred in 9 of the 14 treated eyes. All ocular symptoms disappeared once the corneal ulcer was completely healed. Corneal sensitivity improved after ulcer healing in 13 of the 14 eyes (sensitivity returned to normal in 2 eyes and improved to hypoesthesia in 11 eyes), and after healing, all patients reported a burning sensation after conjunctival instillation of a mydriatic drug.After healing of the ulcer, all patients had a corneal scar; both the scarring and the corneal neovascularization disappeared during follow-up. The improvements in corneal sensitivity and visual acuity were maintained throughout the follow-up period (Figure 3Figure 3
Best Corrected Visual Acuity before, during, and after Treatment with Nerve Growth Factor in 12 Patients (14 Eyes) with Corneal Neurotrophic Ulcers from Various Causes.). Follow-up lasted 3 months in the case of three patients, 4 months in four patients, 8 months in two patients, 12 months in two patients, and 15 months in one patient. After three months, all patients had photophobia during slit-lamp examination. One patient had no corneal contact sensitivity despite the presence of photophobia during slit-lamp examination and a burning sensation after the instillation of a mydriatic drug, both of which had been absent before treatment.When compared with the values at base line (mean, 0.03±0.02), best corrected visual acuity significantly improved after healing of the corneal ulcer in all 14 eyes (mean, 0.20±0.02; P<0.001). The improvement was even more evident after 6 months (mean of six eyes, 0.40±0.18; P = 0.002) and 12 months (mean of three eyes, 0.63±0.06; P = 0.002) (Figure 3).
None of the patients had systemic or ocular side effects during treatment with nerve growth factor or follow-up. Moreover, none had a relapse of their eye disease, and corneal integrity and sensitivity were maintained during follow-up.
Discussion
The results of this study indicate that topical administration of nerve growth factor is effective therapy for patients with severe corneal ulcers with sensory-nerve impairment and corneal anesthesia. These ulcers, although uncommon, have devastating effects on the cornea, frequently leading to ocular perforation and visual loss. There is no effective medical treatment. The only treatment is surgical, with the use of such procedures as tarsorrhaphy, construction of a conjunctival flap, or lamellar or penetrating keratoplasty.1 The main goal of these procedures is to preserve the anatomical integrity of the eye; they do not restore visual function. In most cases, the prognosis regarding visual function is very poor, and relapses of the ulcer are frequent.
Topical administration of nerve growth factor healed the ulcer in all the patients and improved corneal sensitivity in most within 10 days to 6 weeks, and no patient had a relapse during follow-up. The first sign of corneal healing was a line of epithelial cells advancing from the border of the ulcer in association with conjunctival hyperemia. These findings suggest that the nerve growth factor had a direct action on the epithelium, in agreement with the results of a previous in vitro study in which nerve growth factor as well as other growth factors stimulated the proliferation and differentiation of rabbit corneal epithelial cells16 and the evidence that human corneal epithelium has high-affinity receptors for nerve growth factor.13 Nerve growth factor may also act indirectly by inducing neurogenic inflammation. There is increasing evidence that nerve growth factor stimulates the release of several neuropeptides and growth factors that can stimulate the healing process.17-20
During epithelial proliferation, all patients had photophobia and burning of their eyes during slit-lamp examinations, and most patients had improvement of corneal sensitivity, which suggests functional recovery of corneal innervation. This finding may be related to the well-known ability of nerve growth factor to induce neuritic sprouting by neuronal cells in vitro and nerve regeneration in vivo in denervated skin, as well as in the central and peripheral nervous systems after surgical, chemical, or ischemic injury.6-9,21 Systemic treatment with nerve growth factor also induces hyperalgesia in animals and healthy subjects.22,23
The murine nerve growth factor that we used is closely homologous to human nerve growth factor.24 Because of its trophic and regenerative actions on the central and peripheral nervous system,6 nerve growth factor has been proposed for the treatment of several neurologic diseases.25 In two clinical studies, intracerebral administration of murine nerve growth factor in patients with Parkinson's disease26 and Alzheimer's disease27 was of some benefit and caused no side effects. In our study, ophthalmic administration of murine nerve growth factor produced no local or systemic side effects.
The maintenance of corneal sensitivity after treatment with nerve growth factor suggests that such treatment completely restores sensory innervation of the cornea. This possibility is consistent with the known pathophysiologic role of sensory innervation in corneal wound healing. The cornea is a virtually avascular tissue, but it has very dense innervation (40 times more than the tooth pulp and 400 times more than skin). Thus, any inflammatory reaction and subsequent healing are controlled by this neuronal innervation.28 Experimentally, corneal-nerve damage induces severe alterations in the metabolism and vitality of the epithelium, and clinically, surgical damage (as may occur during trigeminal-nerve manipulation or penetrating keratoplasty) or chemical damage (such as that caused by abuse of local anesthetics) of corneal innervation impairs epithelial healing and induces trophic ulcers.29-31
Our results are in line with the current hypothesis of the pathogenesis of corneal neurotrophic ulcers. It has been thought that corneal nerves release a trophic factor that maintains the integrity of the corneal epithelium and that nerve damage compromises the integrity.32,33 The finding that exogenous nerve growth factor restored corneal integrity and sensitivity suggests that the progressive corneal damage that occurs in some patients with corneal sensory-nerve deficits could be due to a deficit of endogenous nerve growth factor. This hypothesis is in agreement with the effects of this factor in other biologic systems. For example, in animals with a targeted mutation of the gene coding for the low-affinity nerve growth factor receptor, ulcers and lesions of the feet occur,34 and exogenous nerve growth factor accelerates the rate of wound contraction in mice.35 Moreover, concentrations of nerve growth factor are decreased in ulcerative tissue from patients with systemic conditions such as diabetes mellitus, leprosy, and nerve trauma.10,11
In conclusion, in a preliminary, uncontrolled study, treatment with nerve growth factor induced prompt healing and restoration of corneal sensitivity with no local or systemic side effects in patients with corneal neurotrophic ulcers.
We are indebted to Prof. Rita Levi-Montalcini for her encouragement during the study and helpful suggestions and discussion.
Source Information
From the Department of Ophthalmology, University of Rome Tor Vergata, Rome (A.L., S.B.); the Division of Ophthalmology, Hospital of Venice SS. Giovanni e Paolo, Venice (A.L., P.R., G.C.); the Institute of Neurobiology, National Research Council, Rome (A.L., L.A.); and the G.B. Bietti Eye Foundation, Rome (S.B.) — all in Italy.
Address reprint requests to Dr. Aloe at the Institute of Neurobiology, National Research Council, Viale Marx 15, 00132 Rome, Italy.
- References
References
1
Mackie IA. Neuroparalytic keratitis. In: Fraunfelder FT, Roy FH, eds. Current ocular therapy 4. Philadelphia: W.B. Saunders, 1995:506-8.
2
Puangsricharern V ,Tseng SCG . Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology 1995;102:1476-1485
Web of Science | Medline3
Simone S . De Ricerche sul contenuto in acqua totale ed in azoto totale della cornea di coniglio in condizioni di cheratite neuroparalitica sperimentale. Arch Oftalmol 1958;62:151-1514
Sigelman S ,Friedenwald JS . Mitotic and wound-healing activities of the corneal epithelium: effect of sensory denervation. Arch Ophthalmol 1954;52:46-57
Web of Science | Medline5
Mittag TW ,Mindel JS ,Green JP . Trophic functions of the neuron.V. Familial dysautonomia: choline acetyltransferase in familial dysautonomia. Ann N Y Acad Sci 1974;228:301-306
CrossRef | Web of Science | Medline6
Levi-Montalcini R . The nerve growth factor 35 years later. Science 1987;237:1154-1162
CrossRef | Web of Science | Medline7
Riaz SS ,Tomlinson DR . Neurotrophic factors in peripheral neuropathies: pharmacological strategies. Prog Neurobiol 1996;49:125-143
CrossRef | Web of Science | Medline8
Mearow KM ,Kril Y ,Diamond J . Increased NGF mRNA expression in denervated rat skin. Neuroreport 1993;4:351-354
CrossRef | Web of Science | Medline9
Verge VMK ,Merlio J-P ,Grondin J , et al. Colocalization of NGF binding sites, trk mRNA, and low-affinity NGF receptor mRNA in primary sensory neurons: responses to injury and infusion of NGF. J Neurosci 1992;12:4011-4022
Web of Science | Medline10
Anand P . Neurotrophins and peripheral neuropathy. Philos Trans R Soc Lond B Biol Sci 1996;351:449-454
CrossRef | Web of Science | Medline11
Anand P ,Pandya S ,Ladiwala U ,Singhal B ,Sinicropi DV ,Williams-Chestnut RE . Depletion of nerve growth factor in leprosy. Lancet 1994;344:129-130
CrossRef | Web of Science | Medline12
Lambiase A ,Bonini S ,Bonini S , et al. Increased plasma levels of nerve growth factor in vernal keratoconjunctivitis and relationship to conjunctival mast cells. Invest Ophthalmol Vis Sci 1995;36:2127-2132
Web of Science | Medline13
Lambiase A ,Bonini S ,Aloe L ,Carito G ,Rama P . Expression of nerve growth factor receptors on human ocular surface. Invest Ophthalmol Vis Sci 1997;38:S1078-S1078 abstract.14
Bocchini V ,Angeletti PU . The nerve growth factor: purification as a 30,000-molecular-weight protein. Proc Natl Acad Sci U S A 1969;64:787-794
CrossRef | Web of Science | Medline15
Faulkner WJ, Varley GA. Corneal diagnostic technique. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea: fundamentals of cornea and external disease. St. Louis: Mosby–Year Book, 1997:275-81.
16
Kruse FE ,Tseng SCG . Growth factors modulate clonal growth and differentiation of cultured rabbit limbal and corneal epithelium. Invest Ophthalmol Vis Sci 1993;34:1963-1976
Web of Science | Medline17
Stead RH ,Bienenstock J ,Stanisz AM . Neuropeptide regulation of mucosal immunity. Immunol Rev 1987;100:333-359
CrossRef | Web of Science | Medline18
Donnerer J ,Schuligoi R ,Stein C . Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 1992;49:693-698
CrossRef | Web of Science | Medline19
Brown SM ,Lamberts DW ,Reid TW ,Nishida T ,Murphy CJ . Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1. Arch Ophthalmol 1997;115:926-927
Web of Science | Medline20
Tripathi BJ ,Kwait PS ,Tripathi RC . Corneal growth factors: a new generation of ophthalmic pharmaceuticals. Cornea 1990;9:2-9
CrossRef | Web of Science | Medline21
Hefti F . Neurotrophic factor therapy for nervous system degenerative diseases. J Neurobiol 1994;25:1418-1435
CrossRef | Medline22
Lewin GR ,Ritter AM ,Mendell LM . Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci 1993;13:2136-2148
Web of Science | Medline23
Petty BG ,Cornblath DR ,Adornato BT , et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994;36:244-246
CrossRef | Web of Science | Medline24
Ebendal T . Function and evolution in the NGF family and its receptors. J Neurosci Res 1992;32:461-470
CrossRef | Web of Science | Medline25
Liberini P ,Cuello AC . Effects of nerve growth factor in primate models of neurodegeneration: potential relevance in clinical neurology. Rev Neurosci 1994;5:89-104
CrossRef | Medline26
Olson L ,Backlund EO ,Ebendal T , et al. Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease: one-year follow-up of first clinical trial. Arch Neurol 1991;48:373-381
Web of Science | Medline27
Olson L . NGF and the treatment of Alzheimer's disease. Exp Neurol 1993;124:5-15
CrossRef | Web of Science | Medline28
Tervo K ,Latvala TM ,Tervo TM . Recovery of corneal innervation following photorefractive keratoablation. Arch Ophthalmol 1994;112:1466-1470
Web of Science | Medline29
Paton L . The trigeminal and its ocular lesions. Br J Ophthalmol 1926;10:305-342
CrossRef | Medline30
Price FW Jr ,Whitson WE ,Marks RG . Graft survival in four common groups of patients undergoing penetrating keratoplasty. Ophthalmology 1991;98:322-328
Web of Science | Medline31
Epstein DL ,Paton D . Keratitis from misuse of corneal anesthetics. N Engl J Med 1968;279:396-399
Full Text | Web of Science | Medline32
Beuerman RW ,Schimmelpfennig B . Sensory denervation of the rabbit cornea affects epithelial properties. Exp Neurol 1980;69:196-201
CrossRef | Web of Science | Medline33
Verhoeff FH . The cause of keratitis after gasserian ganglion operations. Am J Ophthalmol 1925;8:273-27534
Lee KF ,Li E ,Huber LJ , et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 1992;69:737-749
CrossRef | Web of Science | Medline35
Li AKC ,Koroly MJ ,Schattenkerk ME ,Malt RA ,Young M . Nerve growth factor: acceleration of the rate of wound healing in mice. Proc Natl Acad Sci U S A 1980;77:4379-4381
CrossRef | Web of Science | Medline
- Citing Articles (89)
Citing Articles
1
Jiucheng He, Haydee E.P. Bazan. (2012) Mapping the Nerve Architecture of Diabetic Human Corneas. Ophthalmology
CrossRef2
Masahiko Mori, Toshiro Yamamoto, Takeshi Amemiya, Narisato Kanamura, Tetsunari Nishikawa, Tomoharu Okamura, Akio Tanaka, Shinichiro Sumitomo, Michio Shikimori. (2012) The functions of nerve growth factor and nerve growth factor receptor in wound healing. Oral Medicine & Pathology 16:3/4, 51-65
CrossRef3
Kristina Kurbanyan, Kathryn Colby. (2011) Cataract and Refractive Surgery in Herpetic Eye Disease. International Ophthalmology Clinics 50:1, 13-24
CrossRef4
Teruo Nishida, Tai-Ichiro Chikama, Mitsuru Sawa, Kazunori Miyata, Takaaki Matsui, Kyoko Shigeta. (2011) Differential contributions of impaired corneal sensitivity and reduced tear secretion to corneal epithelial disorders. Japanese Journal of Ophthalmology
CrossRef5
Ulf Westerlund, Bengt Linderoth, Tiit Mathiesen. (2011) Trigeminal complications arising after surgery of cranial base meningiomas. Neurosurgical Review
CrossRef6
Pooja Jain, Ruihong Li, Teresa Lama, H. Uri Saragovi, Garth Cumberlidge, Karen Meerovitch. (2011) An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye. Experimental Eye Research 93:4, 503-512
CrossRef7
Arianna Calza, Fulvio Florenzano, Daniela Pellegrini, Paola Tirassa. (2011) Time-Dependent Activation of c-fos in Limbic Brain Areas by Ocular Administration of Nerve Growth Factor in Adult Rats. Journal of Ocular Pharmacology and Therapeutics 27:3, 209-218
CrossRef8
Timothy Jerome Echevarria, Nick Girolamo. (2011) Tissue-Regenerating, Vision-Restoring Corneal Epithelial Stem Cells. Stem Cell Reviews and Reports 7:2, 256-268
CrossRef9
Hamdy Abdelkader, Dipika V Patel, Charles NJ McGhee, Raid G Alany. (2011) New therapeutic approaches in the treatment of diabetic keratopathy: a review. Clinical & Experimental Ophthalmology 39:3, 259-270
CrossRef10
Hye Young Shin, Ji Wook Yang, Young Chun Lee, Su Young Kim. (2011) Expression of Nerve Growth Factor during Corneal Epithelial Wound Healing in Rats. Journal of the Korean Ophthalmological Society 52:5, 597
CrossRef11
Su-Young Kim, Jiwook Yang, Young-Chun Lee. (2011) The Effects of Nicergoline on Corneal Nerve Regeneration in Rat Corneas after Photorefractive Keratectomy. Current Eye Research 36:1, 29-33
CrossRef12
Koray Gumus, Anisa Gire, Stephen C Pflugfelder. (2010) The Successful Use of Boston Ocular Surface Prosthesis in the Treatment of Persistent Corneal Epithelial Defect After Herpes Zoster Ophthalmicus. Cornea 29:12, 1465-1468
CrossRef13
Sabina Muzi, Valeria Colafrancesco, Federica Sornelli, Flavio Mantelli, Alessandro Lambiase, Luigi Aloe. (2010) Nerve Growth Factor in the Developing and Adult Lacrimal Glands of Rat With and Without Inherited Retinitis Pigmentosa. Cornea 29:10, 1163-1168
CrossRef14
Matthias F. Seidel, Marjeta Herguijuela, Randolf Forkert, Uwe Otten. (2010) Nerve Growth Factor in Rheumatic Diseases. Seminars in Arthritis and Rheumatism 40:2, 109-126
CrossRef15
Silvia López-Plandolit, María-Celia Morales, Vanessa Freire, Jaime Etxebarría, Juan A Durán. (2010) Plasma Rich in Growth Factors as a Therapeutic Agent for Persistent Corneal Epithelial Defects. Cornea 29:8, 843-848
CrossRef16
Steven P. Dunn, David G. Heidemann, Christopher Y. C. Chow, David Crockford, Nabila Turjman, Janet Angel, Christian B. Allan, Gabriel Sosne. (2010) Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin β4. Annals of the New York Academy of Sciences 1194:1, 199-206
CrossRef17
Jiucheng He, Haydee E.P. Bazan. (2010) Omega-3 fatty acids in dry eye and corneal nerve regeneration after refractive surgery. Prostaglandins, Leukotrienes and Essential Fatty Acids 82:4-6, 319-325
CrossRef18
Fabricio Witzel de Medeiros, Steven E Wilson. 2010. Wound healing after laser in situ keratomileusis and photorefractive keratectomy. , 16-21.
CrossRef19
Audrey M Bernstein. 2010. Abnormalities of corneal wound healing. , 9-15.
CrossRef20
Xialin Liu, Yongjun Li, Yizhi Liu, Yan Luo, Dingding Wang, Brian H. Annex, Pascal J. Goldschmidt-Clermont. (2010) Endothelial Progenitor Cells (EPCs) Mobilized and Activated by Neurotrophic Factors May Contribute to Pathologic Neovascularization in Diabetic Retinopathy. The American Journal of Pathology 176:1, 504-515
CrossRef21
J.D. Unterlauft, M. Kohlhaas, I. Hofbauer, K. Kasper, G. Geerling. (2009) Albumin-Augentropfen zur Behandlung von Augenoberflächenerkrankungen. Der Ophthalmologe 106:10, 932-937
CrossRef22
A. Lambiase, L. Aloe, M. Centofanti, V. Parisi, F. Mantelli, V. Colafrancesco, G. L. Manni, M. G. Bucci, S. Bonini, R. Levi-Montalcini. (2009) Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proceedings of the National Academy of Sciences 106:32, 13469-13474
CrossRef23
Youngnam Cho, Riyi Shi, Albena Ivanisevic, Richard Ben Borgens. (2009) A mesoporous silica nanosphere-based drug delivery system using an electrically conducting polymer. Nanotechnology 20:27, 275102
CrossRef24
Teruo Nishida, Ryoji Yanai. (2009) Advances in treatment for neurotrophic keratopathy. Current Opinion in Ophthalmology 20:4, 276-281
CrossRef25
Nick Di Girolamo, Maria Sarris, Jeanie Chui, Haroon Cheema, Minas T. Coroneo, Denis Wakefield. (2008) Localization of the low-affinity nerve growth factor receptor p75 in human limbal epithelial cells. Journal of Cellular and Molecular Medicine 12:6b, 2799-2811
CrossRef26
V SPOSATO, M BUCCI, M COASSIN, M RUSSO, A LAMBIASE, L ALOE. (2008) Reduced NGF level and TrkA protein and TrkA gene expression in the optic nerve of rats with experimentally induced glaucoma. Neuroscience Letters 446:1, 20-24
CrossRef27
Eun-Ju Chang, Young Sun Im, EunDuck P. Kay, Jong Youl Kim, Jong Eun Lee, Hyung Keun Lee. (2008) The role of nerve growth factor in hyperosmolar stress induced apoptosis. Journal of Cellular Physiology 216:1, 69-77
CrossRef28
Takeo Mammoto, Ruth A. Seerattan, Kent D. Paulson, Catherine A. Leonard, Robert C. Bray, Paul T. Salo. (2008) Nerve growth factor improves ligament healing. Journal of Orthopaedic Research 26:7, 957-964
CrossRef29
Chisa Yamada, Karen E. King, Paul M. Ness. (2008) Autologous serum eyedrops: literature review and implications for transfusion medicine specialists. Transfusion 48:6, 1245-1255
CrossRef30
Samar A. Al-Swailem. (2008) Graft failure: II. Ocular surface complications. International Ophthalmology 28:3, 175-189
CrossRef31
AJAY SHAH, JAMIE BRUGNANO, STACY SUN, AJOY VASE, ELIZABETH ORWIN. (2008) The Development of a Tissue-Engineered Cornea: Biomaterials and Culture Methods. Pediatric Research 63:5, 535-544
CrossRef32
Hong Qi, De-Quan Li, H. David Shine, Zhuo Chen, Kyung-Chul Yoon, Dan B. Jones, Stephen C. Pflugfelder. (2008) Nerve growth factor and its receptor TrkA serve as potential markers for human corneal epithelial progenitor cells. Experimental Eye Research 86:1, 34-40
CrossRef33
Alessandro Lambiase, Marco Coassin, Nicola Costa, Paolo Lauretti, Alessandra Micera, Emiliano Ghinelli, Luigi Aloe, Paolo Rama, Stefano Bonini. (2007) Topical treatment with nerve growth factor in an animal model of herpetic keratitis. Graefe's Archive for Clinical and Experimental Ophthalmology 246:1, 121-127
CrossRef34
Veronica Di Fausto, Marco Fiore, Paola Tirassa, Alessandro Lambiase, Luigi Aloe. (2007) Eye drop NGF administration promotes the recovery of chemically injured cholinergic neurons of adult mouse forebrain. European Journal of Neuroscience 26:9, 2473-2480
CrossRef35
Teruo Nishida, Tai-ichiro Chikama, Naoyuki Morishige, Ryoji Yanai, Naoyuki Yamada, Jun Saito. (2007) Persistent Epithelial Defects Due to Neurotrophic Keratopathy Treated with a Substance P-Derived Peptide and Insulin-Like Growth Factor 1. Japanese Journal of Ophthalmology 51:6, 442-447
CrossRef36
Seow Hoon Saw, Karen Wang, Thomas Yong, Seeram Ramakrishna. 2007. Polymeric Nanofibers in Tissue Engineering. .
CrossRef37
Kyung-Chul Yoon, In-Cheon You, Seong-Kyu Im, Tae-Sun Jeong, Yeoung-Geol Park, Jin Choi. (2007) Application of Umbilical Cord Serum Eyedrops for the Treatment of Neurotrophic Keratitis. Ophthalmology 114:9, 1637-1642.e2
CrossRef38
Thomas Fuchsluger, Emre Tuerkeli, Henrike Westekemper, Joachim Esser, Klaus-Peter Steuhl, Daniel Meller. (2007) Rate of epithelialisation and re-operations in corneal ulcers treated with amniotic membrane transplantation combined with botulinum toxin-induced ptosis. Graefe's Archive for Clinical and Experimental Ophthalmology 245:7, 955-964
CrossRef39
Kuniko Hori, Chie Sotozono, Junji Hamuro, Kenta Yamasaki, Yu Kimura, Makoto Ozeki, Yasuhiko Tabata, Shigeru Kinoshita. (2007) Controlled-release of epidermal growth factor from cationized gelatin hydrogel enhances corneal epithelial wound healing. Journal of Controlled Release 118:2, 169-176
CrossRef40
N. Tirelli, F. Cellesi. 2007. Combined tissue engineering and drug delivery. , 129-152.
CrossRef41
K. Ramaesh, J. Stokes, E. Henry, G.N. Dutton, B. Dhillon. (2007) Congenital Corneal Anesthesia. Survey of Ophthalmology 52:1, 50-60
CrossRef42
Alessandro Lambiase, Lucia Pagani, Veronica Di Fausto, Valentina Sposato, Marco Coassin, Stefano Bonini, Luigi Aloe. (2007) Nerve growth factor eye drop administrated on the ocular surface of rodents affects the nucleus basalis and septum: Biochemical and structural evidence. Brain Research 1127, 45-51
CrossRef43
Alessandra Micera, Alessandro Lambiase, Ilaria Puxeddu, Luigi Aloe, Barbara Stampachiacchiere, Francesca Levi-Schaffer, Sergio Bonini, Stefano Bonini. (2006) Nerve growth factor effect on human primary fibroblastic-keratocytes: Possible mechanism during corneal healing. Experimental Eye Research 83:4, 747-757
CrossRef44
A Lockwood, M Hope-Ross, P Chell. (2006) Neurotrophic keratopathy and diabetes mellitus. Eye 20:7, 837-839
CrossRef45
Mei Hong Tan, John Bryars, Jonathan Moore. (2006) Use of Nerve Growth Factor to Treat Congenital Neurotrophic Corneal Ulceration. Cornea 25:3, 352-355
CrossRef46
Marco Coassin, Alessandro Lambiase, Alessandra Micera, Paola Tirassa, Luigi Aloe, Stefano Bonini. (2006) Nerve growth factor modulates in vitro the expression and release of TGF-β1 by amniotic membrane. Graefe's Archive for Clinical and Experimental Ophthalmology 244:4, 485-491
CrossRef47
M. Cellini, E. Bendo, G.O. Bravetti, E.C. Campos. (2006) The Use of Nerve Growth Factor in Surgical Wound Healing of the Cornea. Ophthalmic Research 38:4, 177-181
CrossRef48
David Carlsson, May Griffith, Shigeto Shimmura, Fengfu Li, Heather Sheardown, Chris Lohmann. 2005. Tissue Engineering of the Cornea. , 413-423.
CrossRef49
Sudarshan Khokhar, Tanie Natung, Parul Sony, Namrata Sharma, Nutan Agarwal, Rasik B Vajpayee. (2005) Amniotic Membrane Transplantation in Refractory Neurotrophic Corneal Ulcers. Cornea 24:6, 654-660
CrossRef50
Heung-Myong Woo, Ellison Bentley, Sean F. Campbell, Carl F. Marfurt, Christopher J. Murphy. (2005) Nerve growth factor and corneal wound healing in dogs. Experimental Eye Research 80:5, 633-642
CrossRef51
A. Micera, I. Puxeddu, A. Lambiase, A. Antonelli, S. Bonini, S. Bonini, L. Aloe, J. Pe'er, F. Levi-Schaffer. (2005) The pro-fibrogenic effect of nerve growth factor on conjunctival fibroblasts is mediated by transforming growth factor-beta. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 35:5, 650-656
CrossRef52
Marco Coassin, Alessandro Lambiase, Nicola Costa, Alessandra Gregorio, Roberto Sgrulletta, Marta Sacchetti, Luigi Aloe, Stefano Bonini. (2005) Efficacy of topical nerve growth factor treatment in dogs affected by dry eye. Graefe's Archive for Clinical and Experimental Ophthalmology 243:2, 151-155
CrossRef53
C. Cursiefen, B. Seitz, F. E. Kruse. (2005) Neurotrophe Keratopathie. Der Ophthalmologe 102:1, 7-14
CrossRef54
Koray Topgül, Oğuz Uzun, A Ziya Anadol, Ali Gök. (2005) Surgical Management of Enoxaparin- and/or Warfarin-induced Massive Retroperitoneal Bleeding: Report of a Case and Review of the Literature. Southern Medical Journal 98:1, 104-106
CrossRef55
B. Seitz, M. Gr
terich, C. Cursiefen, F. E. Kruse. (2005) Konservative und chirurgische Therapie der neurotrophen Keratopathie. Der Ophthalmologe 102:1, 15-26
CrossRef56
Alessandra Micera, Alessandro Lambiase, Luigi Aloe, Sergio Bonini, Francesca Levi-Schaffer, Stefano Bonini. (2004) Nerve growth factor involvement in the visual system: implications in allergic and neurodegenerative diseases. Cytokine & Growth Factor Reviews 15:6, 411-417
CrossRef57
Bettina Klenkler, Heather Sheardown. (2004) Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology. Experimental Eye Research 79:5, 677-688
CrossRef58
Rainer Amann, Rufina Schuligoi. (2004) Beta adrenergic inhibition of capsaicin-induced, NK1 receptor-mediated nerve growth factor biosynthesis in rat skin. Pain 112:1-2, 76-82
CrossRef59
Nelly Frossard, Véronique Freund, Charles Advenier. (2004) Nerve growth factor and its receptors in asthma and inflammation. European Journal of Pharmacology 500:1-3, 453-465
CrossRef60
Carsten Heinz, Anja Eckstein, Klaus-Peter Steuhl, Daniel Meller. (2004) Amniotic Membrane Transplantation for Reconstruction of Corneal Ulcer in Graves Ophthalmopathy. Cornea 23:5, 524-526
CrossRef61
Luigi Aloe. (2004) Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends in Cell Biology 14:7, 395-399
CrossRef62
M. Labetoulle. (2004) Actualités thérapeutiques de l’herpès cornéen. Journal Français d'Ophtalmologie 27:5, 547-557
CrossRef63
Akane Tanaka, Utako Wakita, Naotomo Kambe, Tadashi Iwasaki, Hiroshi Matsuda. (2004) An autocrine function of nerve growth factor for cell cycle regulation of vascular endothelial cells. Biochemical and Biophysical Research Communications 313:4, 1009-1014
CrossRef64
Martin Grueterich, Edgar M. Espana, Scheffer C.G. Tseng. (2003) Ex vivo expansion of limbal epithelial stem cells: amniotic membrane serving as a stem cell niche. Survey of Ophthalmology 48:6, 631-646
CrossRef65
Alessandra Micera, Ilaria Puxeddu, Luigi Aloe, Francesca Levi-Schaffer. (2003) New insights on the involvement of Nerve Growth Factor in allergic inflammation and fibrosis. Cytokine & Growth Factor Reviews 14:5, 369-374
CrossRef66
David J. Carlsson, Fengfu Li, Shigeto Shimmura, May Griffith. (2003) Bioengineered corneas: how close are we?. Current Opinion in Ophthalmology 14:4, 192-197
CrossRef67
S. Bonini. (2003) Do neurotrophins play a role in allergic diseases and asthma?. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 33:5, 543-545
CrossRef68
Elizabeth A. Davis, Claes H. Dohlman. (2002) Neurotrophic Keratitis. International Ophthalmology Clinics 41:1, 1-11
CrossRef69
L Aloe, E Alleva, M Fiore. (2002) Stress and nerve growth factor. Pharmacology Biochemistry and Behavior 73:1, 159-166
CrossRef70
S. Bonini, A. Lambiase, F. Properzi, M. Bresciani, G. Sacerdoti, S. Bonini, L. Aloe. (2002) Nerve growth factor and asthma. Allergy 57:s72, 13-15
CrossRef71
Grażyna Niewiadomska, Sebastian Komorowski, Marta Baksalerska-Pazera. (2002) Amelioration of cholinergic neurons dysfunction in aged rats depends on the continuous supply of NGF. Neurobiology of Aging 23:4, 601-613
CrossRef72
Abraham Solomon, Daniel Meller, Pinnita Prabhasawat, Thomas John, Edgar M Espana, Klaus-Peter Steuhl, Scheffer C.G Tseng. (2002) Amniotic membrane grafts for nontraumatic corneal perforations, descemetoceles, and deep ulcers. Ophthalmology 109:4, 694-703
CrossRef73
George N. Chaldakov, Ivan S. Stankulov, Marco Fiore, Peter I. Ghenev, Luigi Aloe. (2001) Nerve growth factor levels and mast cell distribution in human coronary atherosclerosis. Atherosclerosis 159:1, 57-66
CrossRef74
Jae-Soon Kim, Jae-Chan Kim, Tae-Won Hahn, Woo-Chan Park. (2001) Amniotic Membrane Transplantation in Infectious Corneal Ulcer. Cornea 20:7, 720-726
CrossRef75
Anthony L Mescher. 2001. Regeneration: Nerve-dependent and Nerve-independent. .
CrossRef76
L. Aloe, M. Fiore, D. Santucci, T. Amendola, A. Antonelli, N. Francia, G. Corazzi, E. Alleva. (2001) Effect of hypergravity on the mouse basal expression of NGF and BDNF in the retina, visual cortex and geniculate nucleus: correlative aspects with NPY immunoreactivity. Neuroscience Letters 302:1, 29-32
CrossRef77
Stuart C. Apfel. (2001) Neurotrophic Factor Therapy – Prospects and Problems. Clinical Chemistry and Laboratory Medicine 39:4, 351-355
CrossRef78
Brett Ueeck, Bach Le, Shawn Goodman, Larry Rich, Michael Wheatley. (2001) Corneal Ulcers in Patients with Apert Syndrome. Journal of Craniofacial Surgery 12:2, 134-135
CrossRef79
L. Aloe. (2001) Nerve Growth Factor and Neuroimmune Responses: Basic and Clinical Observations. Archives Of Physiology And Biochemistry 109:4, 354-356
CrossRef80
L Aloe. (2000) Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by Cisplatin: behavioral, structural and biochemical analysis. Autonomic Neuroscience 86:1-2, 84-93
CrossRef81
Perry Rosenthal, Janis M Cotter, Jules Baum. (2000) Treatment of persistent corneal epithelial defect with extended wear of a fluid-ventilated gas-permeable scleral contact lens. American Journal of Ophthalmology 130:1, 33-41
CrossRef82
Masakazu Yamada, Masaro Ogata, Masataka Kawai, Yukihiko Mashima. (2000) Decreased substance P concentrations in tears from patients with corneal hypesthesia. American Journal of Ophthalmology 129:5, 671-672
CrossRef83
H.Uri Saragovi, Kalle Gehring. (2000) Development of pharmacological agents for targeting neurotrophins and their receptors. Trends in Pharmacological Sciences 21:3, 93-98
CrossRef84
Stuart J. Forbes, Mike Themis, Malcolm R. Alison, Ildiko Sarosi, Charles Coutelle, Humphrey J.F. Hodgson. (2000) Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein. Gastroenterology 118:3, 591-598
CrossRef85
Alessandro Lambiase, Paolo Rama, Luigi Aloe, Stefano Bonini. (1999) Management of neurotrophic keratopathy. Current Opinion in Opthalmology 10:4, 270-276
CrossRef86
Roberto Bernabei, Francesco Landi, Stefano Bonini, Graziano Onder, Alessandro Lambiase, Roberto Pola, Luigi Aloe. (1999) Effect of topical application of nerve-growth factor on pressure ulcers. The Lancet 354:9175, 307
CrossRef87
Luigi Aloe. (1999) Rita Levi-Montalcini: A brief biographic view of past and present studies on nerve growth factor. Microscopy Research and Technique 45:4-5, 207-209
CrossRef88
Tai-ichiro Chikama, Masatsugu Nakamura, Teruo Nishida. (1999) Up-Regulation of Integrin α5 by a C-Terminus Four-Amino-Acid Sequence of Substance P (Phenylalanine-Glycine-Leucine-Methionine-Amide) Synergistically with Insulin-like Growth Factor-1 in SV-40 Transformed Human Corneal Epithelial Cells. Biochemical and Biophysical Research Communications 255:3, 692-697
CrossRef89
Smith, Ronald E., Sadun, Alfredo A., . (1998) Clearing the Cornea with Nerve Growth Factor. New England Journal of Medicine 338:17, 1222-1223
Full Text
