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Haydee E P Bazan - One of the best experts on this subject based on the ideXlab platform.
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the pedf neuroprotective domain plus dha induces corneal nerve regeneration after Experimental Surgery
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Soledad M Cortina, Azucena H Kakazu, Haydee E P BazanAbstract:The cornea is densely innervated, and several studies have shown that the health of corneal nerves is vital to maintain homeostasis of the ocular surface and tissue clarity.1–4 Many diseases that affect the cornea can compromise corneal innervation, leading to a decrease in tear production and blink reflex as well as impaired epithelial wound healing.4–8 As a result, neurotrophic keratitis and corneal opacification may ensue. It is estimated that 1.57 million people suffer from corneal blindness worldwide.9 In turn, some of surgical interventions such as refractive Surgery and corneal transplantation sever corneal nerves, and studies have shown that corneal sensation can take years to recover, and in some cases it is permanently reduced.10,11 Unfortunately, there are few therapeutic interventions available today that can successfully promote the recovery of corneal sensation. Acknowledging our current limitations, the National Eye Institute (NEI) has identified the need for development of therapeutic agents that can stimulate corneal nerve regeneration as one of the highest priorities in vision research.12 Several molecules have been studied that may have a positive effect on corneal nerve regeneration, including nerve growth factor (NGF), VEGF, semaphorins, neurotrophins 3 and 4 (NT-3; NT-4), growth associated protein-43 (GAP-43), and others, all with variable success.13–17 Neuropeptides, such as substance P (SP) and insulin-like growth factor-1 (IGF-1), have been used to treat delayed wound healing due to corneal nerve damage when traditional treatments have failed.18 Pigment epithelial-derived factor (PEDF) is a glucoprotein discovered in the culture media of retinal pigment epithelial (RPE) cells and is widely expressed in different tissues, including the cornea.19,20 Pigment epithelial-derived factor has broad neurotrophic, neuroprotective, and antiangiogenic activity.21 Work in our laboratory has previously shown that treatment with PEDF in association with the ω-3 fatty acid, docosahexaenoic acid (DHA), after lamellar keratectomy increases regeneration of rabbit corneal nerves.22 We have also shown that corneal sensation returns to normal levels in treated animals only 8 weeks after surgical injury.23 The mechanisms of the neuroregenerative action of PEDF and DHA is not completely understood, but our studies suggest that it involves the synthesis of neuroprotectin D1 (NPD1), a docosanoid synthetized from DHA with strong anti-inflammatory and neuroprotective activity.24–26 Pigment epithelial-derived factor is a 50-kDa protein, and synthetic peptides derived from the sequence of human PEDF, which maintain part of its bioactivity, have been tried in models of choroid and corneal neovascularization, and in diabetic retinopathy.27–29 A 44-amino-acid fragment of PEDF, corresponding to positions Val78-Thr121 of the 418 amino acids of PEDF, has neuroprotective activity and has been shown to stimulate survival and differentiation of spinal motor neurons.30 However, the adjacent 34-amino-acid peptide, corresponding to positions Asp44–Asn77, has been shown to be antiangiogenic.31 Some therapeutic advantages of using small peptides include better tissue penetration, a narrower spectrum of action with reduced side effects, and ease of synthesis in reproducibly large-scale quantities, while a possible disadvantage could be faster biodegradation and lower efficacy of the drug. These are all important considerations in the development of therapeutic agents. In this study we compare the effect of the synthetic 44-mer PEDF and 34-mer PEDF peptides and the whole PEDF molecule in association with DHA on the regeneration of corneal nerves.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:PURPOSE To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy. METHODS An 8-mm stromal dissection was performed in the left eye of each rabbit. The rabbits were treated with NPD1, pigment epithelial-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) or vehicle for 6 weeks, and corneas were obtained at 8 weeks. After fixation, corneal wholemounts were stained with mouse monoclonal anti-βIII-tubulin antibody and double stained with chicken anti-calcitonin gene-related peptide (CGRP) antibody. Corneal sensitivity and tear secretion were measured using the Cochet-Bonnet esthesiometer and the Schirmer's test, respectively. Additional rabbits were treated with NPD1, PEDF+DHA, or vehicle, and corneal sections were stained with a rat monoclonal anti-neutrophil antibody. Cultures of trigeminal ganglia from 5-day-old mice were treated with NPD1, PEDF+DHA, lipoxin A4 (LXA4), 12- or 15-hydroxyeicosatetraenoic acid (12[S] or 15[S]-HETE), and nerve growth factor (NGF) as positive control. RESULTS NPD1 increased subepithelial corneal nerve area three times compared with vehicle-treated rabbits. The effect was similar to PEDF+DHA-treated animals. There was recovery of CGRP-positive neurons and an increase in corneal sensitivity and tear secretion in NPD1-treated animals. NPD1 decreased neutrophil infiltration after 2 and 4 days of treatment. In the in vitro cultures, NPD1 and PEDF+DHA induced a 3-fold increase in neurite outgrowth compared with cultures without supplementation. Treatments with LXA4, 12(S)-, and 15(S)- HETE did not stimulate neurite outgrowth. CONCLUSIONS NPD1 has anti-inflammatory and nerve regenerative properties. This study demonstrates that NPD1 may offer an effective treatment for neurotrophic corneas.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:Purpose. To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy.
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recovery of corneal sensitivity calcitonin gene related peptide positive nerves and increased wound healing induced by pigment epithelial derived factor plus docosahexaenoic acid after Experimental Surgery
Archives of Ophthalmology, 2012Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Objective To assess function of regenerated corneal nerves in correlation with epithelial wound healing after Experimental nerve damage in rabbits treated with pigment epithelial–derived factor (PEDF) plus docosahexaenoic acid (DHA). Methods An 8-mm stromal dissection was performed in the right eyes of adult New Zealand rabbits. Treatment with PEDF+DHA was for 6 weeks. Corneal sensation was measured weekly by Cochet-Bonnet esthesiometer. After 8 weeks, immunofluorescence with βIII-tubulin, calcitonin gene-related peptide, and substance P antibodies was performed to quantify nerves. Also, rabbits were treated with PEDF+DHA for 4 weeks after lamellar keratectomy, followed by 8-mm epithelial debridement and epithelial defect assessment. One week after Surgery, corneas were stained with anti-Ki67 antibody to assess cell proliferation. Results Eight weeks after Surgery, calcitonin gene-related peptide–positive nerve fibers in the PEDF+DHA group were similar to normal rabbit corneas but were decreased in the vehicle. Substance P was localized in the subepithelial plexus but appeared in epithelial cells after nerve injury regardless of treatment. Five weeks after Surgery, an increase in corneal sensitivity occurred in the PEDF+DHA group and reached normal values by 8 weeks. Pigment epithelial–derived factor plus DHA increased epithelial wound healing after lamellar keratectomy. One week after epithelial injury, Ki67-positive cells increased in the limbal area. Conclusion Pigment epithelial–derived factor plus DHA promotes regeneration of calcitonin gene-related peptide–positive corneal nerves, accelerating wound healing and return of corneal sensitivity. Clinical Relevance Pigment epithelial–derived factor plus DHA represents a new approach to regenerate nerves and a potential treatment for prevention of severe dry eye after Surgery or diseases of the ocular surface.
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neuroprotectin d1 synthesis and corneal nerve regeneration after Experimental Surgery and treatment with pedf plus dha
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Purpose. This study was conducted to define whether pigment epithelial–derived growth factor (PEDF), together with docosahexaenoic acid (DHA), enhances the synthesis of neuroprotectin D1 (NPD1) and the regeneration of corneal nerves damaged after Surgery.
Nicolas G Bazan - One of the best experts on this subject based on the ideXlab platform.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:PURPOSE To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy. METHODS An 8-mm stromal dissection was performed in the left eye of each rabbit. The rabbits were treated with NPD1, pigment epithelial-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) or vehicle for 6 weeks, and corneas were obtained at 8 weeks. After fixation, corneal wholemounts were stained with mouse monoclonal anti-βIII-tubulin antibody and double stained with chicken anti-calcitonin gene-related peptide (CGRP) antibody. Corneal sensitivity and tear secretion were measured using the Cochet-Bonnet esthesiometer and the Schirmer's test, respectively. Additional rabbits were treated with NPD1, PEDF+DHA, or vehicle, and corneal sections were stained with a rat monoclonal anti-neutrophil antibody. Cultures of trigeminal ganglia from 5-day-old mice were treated with NPD1, PEDF+DHA, lipoxin A4 (LXA4), 12- or 15-hydroxyeicosatetraenoic acid (12[S] or 15[S]-HETE), and nerve growth factor (NGF) as positive control. RESULTS NPD1 increased subepithelial corneal nerve area three times compared with vehicle-treated rabbits. The effect was similar to PEDF+DHA-treated animals. There was recovery of CGRP-positive neurons and an increase in corneal sensitivity and tear secretion in NPD1-treated animals. NPD1 decreased neutrophil infiltration after 2 and 4 days of treatment. In the in vitro cultures, NPD1 and PEDF+DHA induced a 3-fold increase in neurite outgrowth compared with cultures without supplementation. Treatments with LXA4, 12(S)-, and 15(S)- HETE did not stimulate neurite outgrowth. CONCLUSIONS NPD1 has anti-inflammatory and nerve regenerative properties. This study demonstrates that NPD1 may offer an effective treatment for neurotrophic corneas.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:Purpose. To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy.
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recovery of corneal sensitivity calcitonin gene related peptide positive nerves and increased wound healing induced by pigment epithelial derived factor plus docosahexaenoic acid after Experimental Surgery
Archives of Ophthalmology, 2012Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Objective To assess function of regenerated corneal nerves in correlation with epithelial wound healing after Experimental nerve damage in rabbits treated with pigment epithelial–derived factor (PEDF) plus docosahexaenoic acid (DHA). Methods An 8-mm stromal dissection was performed in the right eyes of adult New Zealand rabbits. Treatment with PEDF+DHA was for 6 weeks. Corneal sensation was measured weekly by Cochet-Bonnet esthesiometer. After 8 weeks, immunofluorescence with βIII-tubulin, calcitonin gene-related peptide, and substance P antibodies was performed to quantify nerves. Also, rabbits were treated with PEDF+DHA for 4 weeks after lamellar keratectomy, followed by 8-mm epithelial debridement and epithelial defect assessment. One week after Surgery, corneas were stained with anti-Ki67 antibody to assess cell proliferation. Results Eight weeks after Surgery, calcitonin gene-related peptide–positive nerve fibers in the PEDF+DHA group were similar to normal rabbit corneas but were decreased in the vehicle. Substance P was localized in the subepithelial plexus but appeared in epithelial cells after nerve injury regardless of treatment. Five weeks after Surgery, an increase in corneal sensitivity occurred in the PEDF+DHA group and reached normal values by 8 weeks. Pigment epithelial–derived factor plus DHA increased epithelial wound healing after lamellar keratectomy. One week after epithelial injury, Ki67-positive cells increased in the limbal area. Conclusion Pigment epithelial–derived factor plus DHA promotes regeneration of calcitonin gene-related peptide–positive corneal nerves, accelerating wound healing and return of corneal sensitivity. Clinical Relevance Pigment epithelial–derived factor plus DHA represents a new approach to regenerate nerves and a potential treatment for prevention of severe dry eye after Surgery or diseases of the ocular surface.
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neuroprotectin d1 synthesis and corneal nerve regeneration after Experimental Surgery and treatment with pedf plus dha
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Purpose. This study was conducted to define whether pigment epithelial–derived growth factor (PEDF), together with docosahexaenoic acid (DHA), enhances the synthesis of neuroprotectin D1 (NPD1) and the regeneration of corneal nerves damaged after Surgery.
Soledad M Cortina - One of the best experts on this subject based on the ideXlab platform.
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the pedf neuroprotective domain plus dha induces corneal nerve regeneration after Experimental Surgery
Investigative Ophthalmology & Visual Science, 2015Co-Authors: Soledad M Cortina, Azucena H Kakazu, Haydee E P BazanAbstract:The cornea is densely innervated, and several studies have shown that the health of corneal nerves is vital to maintain homeostasis of the ocular surface and tissue clarity.1–4 Many diseases that affect the cornea can compromise corneal innervation, leading to a decrease in tear production and blink reflex as well as impaired epithelial wound healing.4–8 As a result, neurotrophic keratitis and corneal opacification may ensue. It is estimated that 1.57 million people suffer from corneal blindness worldwide.9 In turn, some of surgical interventions such as refractive Surgery and corneal transplantation sever corneal nerves, and studies have shown that corneal sensation can take years to recover, and in some cases it is permanently reduced.10,11 Unfortunately, there are few therapeutic interventions available today that can successfully promote the recovery of corneal sensation. Acknowledging our current limitations, the National Eye Institute (NEI) has identified the need for development of therapeutic agents that can stimulate corneal nerve regeneration as one of the highest priorities in vision research.12 Several molecules have been studied that may have a positive effect on corneal nerve regeneration, including nerve growth factor (NGF), VEGF, semaphorins, neurotrophins 3 and 4 (NT-3; NT-4), growth associated protein-43 (GAP-43), and others, all with variable success.13–17 Neuropeptides, such as substance P (SP) and insulin-like growth factor-1 (IGF-1), have been used to treat delayed wound healing due to corneal nerve damage when traditional treatments have failed.18 Pigment epithelial-derived factor (PEDF) is a glucoprotein discovered in the culture media of retinal pigment epithelial (RPE) cells and is widely expressed in different tissues, including the cornea.19,20 Pigment epithelial-derived factor has broad neurotrophic, neuroprotective, and antiangiogenic activity.21 Work in our laboratory has previously shown that treatment with PEDF in association with the ω-3 fatty acid, docosahexaenoic acid (DHA), after lamellar keratectomy increases regeneration of rabbit corneal nerves.22 We have also shown that corneal sensation returns to normal levels in treated animals only 8 weeks after surgical injury.23 The mechanisms of the neuroregenerative action of PEDF and DHA is not completely understood, but our studies suggest that it involves the synthesis of neuroprotectin D1 (NPD1), a docosanoid synthetized from DHA with strong anti-inflammatory and neuroprotective activity.24–26 Pigment epithelial-derived factor is a 50-kDa protein, and synthetic peptides derived from the sequence of human PEDF, which maintain part of its bioactivity, have been tried in models of choroid and corneal neovascularization, and in diabetic retinopathy.27–29 A 44-amino-acid fragment of PEDF, corresponding to positions Val78-Thr121 of the 418 amino acids of PEDF, has neuroprotective activity and has been shown to stimulate survival and differentiation of spinal motor neurons.30 However, the adjacent 34-amino-acid peptide, corresponding to positions Asp44–Asn77, has been shown to be antiangiogenic.31 Some therapeutic advantages of using small peptides include better tissue penetration, a narrower spectrum of action with reduced side effects, and ease of synthesis in reproducibly large-scale quantities, while a possible disadvantage could be faster biodegradation and lower efficacy of the drug. These are all important considerations in the development of therapeutic agents. In this study we compare the effect of the synthetic 44-mer PEDF and 34-mer PEDF peptides and the whole PEDF molecule in association with DHA on the regeneration of corneal nerves.
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recovery of corneal sensitivity calcitonin gene related peptide positive nerves and increased wound healing induced by pigment epithelial derived factor plus docosahexaenoic acid after Experimental Surgery
Archives of Ophthalmology, 2012Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Objective To assess function of regenerated corneal nerves in correlation with epithelial wound healing after Experimental nerve damage in rabbits treated with pigment epithelial–derived factor (PEDF) plus docosahexaenoic acid (DHA). Methods An 8-mm stromal dissection was performed in the right eyes of adult New Zealand rabbits. Treatment with PEDF+DHA was for 6 weeks. Corneal sensation was measured weekly by Cochet-Bonnet esthesiometer. After 8 weeks, immunofluorescence with βIII-tubulin, calcitonin gene-related peptide, and substance P antibodies was performed to quantify nerves. Also, rabbits were treated with PEDF+DHA for 4 weeks after lamellar keratectomy, followed by 8-mm epithelial debridement and epithelial defect assessment. One week after Surgery, corneas were stained with anti-Ki67 antibody to assess cell proliferation. Results Eight weeks after Surgery, calcitonin gene-related peptide–positive nerve fibers in the PEDF+DHA group were similar to normal rabbit corneas but were decreased in the vehicle. Substance P was localized in the subepithelial plexus but appeared in epithelial cells after nerve injury regardless of treatment. Five weeks after Surgery, an increase in corneal sensitivity occurred in the PEDF+DHA group and reached normal values by 8 weeks. Pigment epithelial–derived factor plus DHA increased epithelial wound healing after lamellar keratectomy. One week after epithelial injury, Ki67-positive cells increased in the limbal area. Conclusion Pigment epithelial–derived factor plus DHA promotes regeneration of calcitonin gene-related peptide–positive corneal nerves, accelerating wound healing and return of corneal sensitivity. Clinical Relevance Pigment epithelial–derived factor plus DHA represents a new approach to regenerate nerves and a potential treatment for prevention of severe dry eye after Surgery or diseases of the ocular surface.
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neuroprotectin d1 synthesis and corneal nerve regeneration after Experimental Surgery and treatment with pedf plus dha
Investigative Ophthalmology & Visual Science, 2010Co-Authors: Soledad M Cortina, Nicolas G Bazan, Haydee E P BazanAbstract:Purpose. This study was conducted to define whether pigment epithelial–derived growth factor (PEDF), together with docosahexaenoic acid (DHA), enhances the synthesis of neuroprotectin D1 (NPD1) and the regeneration of corneal nerves damaged after Surgery.
Maria S Cortina - One of the best experts on this subject based on the ideXlab platform.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:PURPOSE To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy. METHODS An 8-mm stromal dissection was performed in the left eye of each rabbit. The rabbits were treated with NPD1, pigment epithelial-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) or vehicle for 6 weeks, and corneas were obtained at 8 weeks. After fixation, corneal wholemounts were stained with mouse monoclonal anti-βIII-tubulin antibody and double stained with chicken anti-calcitonin gene-related peptide (CGRP) antibody. Corneal sensitivity and tear secretion were measured using the Cochet-Bonnet esthesiometer and the Schirmer's test, respectively. Additional rabbits were treated with NPD1, PEDF+DHA, or vehicle, and corneal sections were stained with a rat monoclonal anti-neutrophil antibody. Cultures of trigeminal ganglia from 5-day-old mice were treated with NPD1, PEDF+DHA, lipoxin A4 (LXA4), 12- or 15-hydroxyeicosatetraenoic acid (12[S] or 15[S]-HETE), and nerve growth factor (NGF) as positive control. RESULTS NPD1 increased subepithelial corneal nerve area three times compared with vehicle-treated rabbits. The effect was similar to PEDF+DHA-treated animals. There was recovery of CGRP-positive neurons and an increase in corneal sensitivity and tear secretion in NPD1-treated animals. NPD1 decreased neutrophil infiltration after 2 and 4 days of treatment. In the in vitro cultures, NPD1 and PEDF+DHA induced a 3-fold increase in neurite outgrowth compared with cultures without supplementation. Treatments with LXA4, 12(S)-, and 15(S)- HETE did not stimulate neurite outgrowth. CONCLUSIONS NPD1 has anti-inflammatory and nerve regenerative properties. This study demonstrates that NPD1 may offer an effective treatment for neurotrophic corneas.
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neuroprotectin d1 restores corneal nerve integrity and function after damage from Experimental Surgery
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Maria S Cortina, Nicolas G Bazan, Tiffany C Russ, Haydee E P BazanAbstract:Purpose. To investigate if topical treatment of neuroprotectin D1 (NPD1) increases regeneration of functional nerves after lamellar keratectomy.
Lars Heijl - One of the best experts on this subject based on the ideXlab platform.
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periodontal regeneration with enamel matrix derivative in one human Experimental defect a case report
Journal of Clinical Periodontology, 1997Co-Authors: Lars HeijlAbstract:: The purpose of the present study was to histologically assess the effect of enamel matrix derivative on periodontal regeneration in one human Experimental defect. Experimental Surgery was performed in a healthy male volunteer to create a buccal dehiscence defect in a mandibular incisor. Following bone removal and conditioning of the exposed root surface, enamel matrix derivative was applied onto the root surface. The flaps were then replaced and sutured. Clinical healing was uneventful. After 4 months, the Experimental tooth together with the surrounding soft and hard tissues were removed surgically for histological evaluation. The microscopic examination revealed formation of a new acellular extrinsic fibre cementum, which was firmly attached to the underlying dentin. A new periodontal ligament with inserting and functionally-oriented collagen fibres and an associated alveolar bone was also present. The new cementum covered 73% of the original defect. Regain of bone was 65% of the presurgical bone height. It was concluded that adjunctive use of enamel matrix derivative could provide a regenerative technology with a potential for true periodontal regeneration.
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periodontal regeneration with enamel matrix derivative in one human Experimental defect a case report
Journal of Clinical Periodontology, 1997Co-Authors: Lars HeijlAbstract:: The purpose of the present study was to histologically assess the effect of enamel matrix derivative on periodontal regeneration in one human Experimental defect. Experimental Surgery was performed in a healthy male volunteer to create a buccal dehiscence defect in a mandibular incisor. Following bone removal and conditioning of the exposed root surface, enamel matrix derivative was applied onto the root surface. The flaps were then replaced and sutured. Clinical healing was uneventful. After 4 months, the Experimental tooth together with the surrounding soft and hard tissues were removed surgically for histological evaluation. The microscopic examination revealed formation of a new acellular extrinsic fibre cementum, which was firmly attached to the underlying dentin. A new periodontal ligament with inserting and functionally-oriented collagen fibres and an associated alveolar bone was also present. The new cementum covered 73% of the original defect. Regain of bone was 65% of the presurgical bone height. It was concluded that adjunctive use of enamel matrix derivative could provide a regenerative technology with a potential for true periodontal regeneration.
