Martin Humphrey - Academia.edu (original) (raw)
Papers by Martin Humphrey
Cells, 2024
The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical res... more The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical resection, or prosthetic placement, is a complex process often necessitating the use of bone graft materials. Autogenous bone from the patient is generally the gold standard in terms of outcomes but also has disadvantages, which have resulted in extensive research in the field of tissue engineering to develop better and more convenient alternatives. In the dental field, several initiatives have demonstrated that the dentin material derived from extracted teeth produces excellent results in terms of repairing bone defects and supporting dental implants. Dentin is acellular and thus, in contrast to autogenous bone, cannot provide osteoblasts or other cellular elements to the grafted region, but it does contain growth and differentiation factors, and has other properties that make it an impressive material for bone repair. In this review, the beneficial properties of dentin and the ways it interacts with the host bone are described in the context of bone graft materials. Autogenous tooth material has limitations, particularly in terms of the need for tooth extraction and the limited amount available, which currently restrict its use to particular dental procedures. The development of a xenograft dentin-derived material, which retains the properties of autogenous dentin, is described. Such a material could potentially enable the use of dentin-derived material more widely, particularly in orthopedic indications where its properties may be advantageous.
Neuroscience Letters, 1985
Clinical Oral Investigations
Objectives Assessment of the clinical performance of a porcine dentin-derived particulate bone gr... more Objectives Assessment of the clinical performance of a porcine dentin-derived particulate bone graft material for bone regeneration after tooth extraction with implant placement at 4 months, in comparison to a commercially available porcine bone-derived graft. Material and methods This study was a randomized, parallel-group, semi-double-blinded clinical trial evaluating the clinical safety, tolerability, and performance of Ivory Dentin Graft™ in comparison with a commercial bone-derived material in alveolar ridge preservation following tooth extraction (registered at ClinicalTrials.gov, May 12th, 2017, Identifier NCT03150472). Extraction sites were grafted with test or comparator material and a titanium implant placed at 4 months after taking a graft site biopsy. Primary endpoints were the extent of new bone growth and bone-graft integration at 4 months. Results The dentin graft material had statistically significantly more new bone formation (60.75% vs 42.81%, p = 0.0084, N = 20 vs...
,"\ and IanJ. Constable* Purpose. The aim of this study was to identify whether abnormal... more ,"\ and IanJ. Constable* Purpose. The aim of this study was to identify whether abnormalities in the synthesis of basic fibroblast growth factor (bFGF) or its receptor (bFGF-R) were responsible for the photoreceptor dystrophy in Royal College of Surgeons (RCS) rats. Methods. The polymerase chain reaction was used to detect the expression of bFGF and bFGF-R messenger RNA in the retinal pigment epithelial (RPE) cells and the neural retina of RCS dystrophic rats and in PVG/C and RCS-rrf)> + control animals. Results. In the RPE, it was found that there was no significant difference in the expression of bFGF and bFGF-R between RCS rats and the controls at the ages of 21 days and 3 mo. In the neural retina, the level of bFGF expression was lower in the 21-day-old RCS rats compared with the control group, but bFGF-R expression was as strong as in the PVG/C and RCS-rd)> + animals. However, in 3-mo-old RCS rat neural retina, the bFGF and bFGF-R expression was found to be significantly lower than in the control animals. Conclusions. Although the mutant gene in RCS rats is expressed in the RPE cells, these results suggest that there is no significant defect in bFGF or bFGF-R expression in the RPE cells of RCS rats, which would be an initiating factor in the development of photoreceptor degeneration in these animals. The lowered bFGF levels in the neural retina at early stages (postnatal day 21) may explain the prolongation of photoreceptor survival when exogenous bFGF is injected. Invest Ophthalmol Vis Sci. 1993; 34:1845-1852 JLJegeneration of photoreceptors leads to permanent blindness because, in common with other central nervous system neuronal cells, they cannot be replaced by cell division in adults. The Royal College of Surgeons (RCS) mutant strain of rats with inherited retinal dys- trophy has been used widely as a model to study photoreceptor degeneration. 1 Although this particular type of defect is not common in humans, the procedures that prolong photoreceptor survival in this condition may be more widely applicable. The cellular nature of the genetic abnormality in RCS rats is known, but the underlying molecular defect has not yet been identified. In the RCS rat, the retinal pigment epithelium (RPE) does not phagocytose shed outer segments, 2 thus resulting in accumulation of membranous debris in the subretinal space and subsequent death of the rod photoreceptors. Transplantation of RPE cells from normal rats results in long-term (5 mo after treatment) rescue of photore-
Neuroscience Research, 1986
Blood, 2013
Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its... more Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its in vitro and in vivo characterization are described. First published hepcidin inhibitor that entered clinical trials for the treatment of anemia due to functional iron deficiency.
Experimental Eye Research, 1997
The expression of GFAP and bFGF after retinal photocoagulation injury in the rat was assessed by ... more The expression of GFAP and bFGF after retinal photocoagulation injury in the rat was assessed by immunocytochemistry and reverse transcriptase PCR. Beta-actin mRNA expression was unaltered after injury and was therefore a good control for the quality of the RNA samples and the PCR reaction. GFAP mRNA increased from undetectable levels in normal retina to relatively high levels at 24 and 48 hr after injury, returning to barely detectable levels at 3 and 7 days. Müller cell GFAP immunoreactivity was elevated by 24 hr, stronger by 48 hr and persisted for 30-45 days. Thus, the expression of GFAP immunoreactivity after photocoagulation was due to new protein synthesis but the mRNA, and therefore the stimulus, was only present for a few days. This indicates that the GFAP protein in Müller cells has a long lifetime similar to that of astrocytes despite different gene control elements. bFGF is a possible stimulus for Müller GFAP expression because Müller cells have bFGF receptors. bFGF mRNA...
Development, Mar 1, 1988
The tectal pathways of regenerating goldfish optic axons are abnormal but not random. The relativ... more The tectal pathways of regenerating goldfish optic axons are abnormal but not random. The relative proportion of temporal axons is highest in rostral tectum (65 %) drops in midtectum (31 %) and is very low in caudal tectum (4 %). By contrast, nasal axons proceed into caudal tectum and are therefore relatively evenly distributed throughout the tectum. In this study, we have tested whether temporal axons are confined to rostral tectum by the presence of nasal axons in caudal tectum or whether they have a preference for rostral tectum regardless of other axons. We similarly tested whether nasal axons would grow preferentially into caudal tectum in the absence of temporal axons. At the time of optic nerve section either the nasal or temporal half retina was removed. Either 35 or 70 days after nerve section, the regenerating optic axons were labelled with HRP and both their pathways and distribution determined in DAB-reacted tectal wholemounts. In the absence of nasal axons, the relative density of temporal axons in rostral, mid and caudal tectum was 70 %, 28 % and 2 %, respectively. The corresponding values for nasal axons, in the absence of temporal axons, were 30 %, 40 % and 30 %, respectively. Thus, the overall distribution of nasal and temporal axons in the half retinal regenerates was similar to that of whole retinal regenerates, demonstrating that the retinotopic preferences of the axons were not dependent upon interaxonal interactions. Thus, nasal and temporal axons obviously discriminate between rostral and caudal tectum despite pathway disorganization and the absence of axons from the opposite hemiretina. This is consistent with axonal growth being under the influence of positional markers in tectum.
Investigative Ophthalmology Visual Science, 1993
Investigative Ophthalmology Visual Science, Apr 1, 1993
C41. EMERGING PHARMACOLOGY FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: MECHANISMS AND OUTCOMES, 2010
NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12... more NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.
J Comp Neurol, 1993
A wide variety of retinal pathology is associated with an increase in Müller glial cell expressio... more A wide variety of retinal pathology is associated with an increase in Müller glial cell expression of glial fibrillary acidic protein (GFAP). In this study the time course and spatial spread of the Müller cell GFAP response following argon laser photocoagulation lesions was examined in wholemounted rabbit retina.At 24 hours single focal lesions were surrounded by GFAP positive Müller cell end feet which declined in density with distance but extended as far as 2–3 mm from the lesion. The Müller cell reaction reached a maximal spread of 4–5 mm at 14 to 21 days and had started to contract by 30 days, leaving a core of GFAP positive processes immediately around the lesion site at 60 days. This zone of spread was much larger than the area of disrupted pigment epithelium. Isodensity plots did not reveal any correlation with the trajectory of retinal ganglion cell axons. The spread of reaction was more confined for lesions within the visual streak than in the dorsal or ventral retinal periphery.Multiple lesions within a focal region of retina resulted in a greater density of GFAP reactive end feet with a corresponding greater spread. However, when five to ten lesions were made in a horizontal row, the Müller cells over the entire retina became GFAP immunoreactive. This pan-retinal reaction took several days to spread, peaked at 7–14 days, and contracted back to the primary lesion sites by 2 months.This spread of Müller cell reactivity may be triggered by the diffusion of substances released by injury or it may be due to direct cellular communication. The extensive indirect effect on Müller cells of laser irradiation might be an important component of the clinical effect of laser photocoagulation and indicates a long distance communication mechanism between retinal glia which is poorly understood. This study also shows the importance of the time at which the Müller cell response is assessed. © 1993 Wiley-Liss, Inc.
Current Eye Research, May 1, 1993
In the RCS rat there is a progressive degeneration of the photoreceptors which starts at two to t... more In the RCS rat there is a progressive degeneration of the photoreceptors which starts at two to three weeks after birth. We have demonstrated that there is prolonged survival of photoreceptors on the flanks of argon laser lesions made at post-natal day 23, just as degeneration begins. The cells in the outer nuclear layer retained a relatively normal appearance on the flanks of the lesions for the first two weeks and there was a very low percentage of pyknotic cells. By one month some cell loss occurred but much less than in non-irradiated regions where very few cells remained. At two months after lesion there were still elevated numbers on the flanks but only 2-3 rows of cells remained. The prolonged survival correlated with disruption to the pigment epithelial layer, increased migration of phagocytic cells into the outer segment/debris layer and a reduction in thickness of the debris layer at late stages. The mechanisms of this effect are unknown however laser lesions provide a well controlled and reproducible situation in which to study these mechanisms.
Degenerative Diseases of the Retina, 1995
Retinal Degeneration, 1993
Cells, 2024
The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical res... more The optimal repair of rigid mineralized tissues, such as bone, in cases of fracture, surgical resection, or prosthetic placement, is a complex process often necessitating the use of bone graft materials. Autogenous bone from the patient is generally the gold standard in terms of outcomes but also has disadvantages, which have resulted in extensive research in the field of tissue engineering to develop better and more convenient alternatives. In the dental field, several initiatives have demonstrated that the dentin material derived from extracted teeth produces excellent results in terms of repairing bone defects and supporting dental implants. Dentin is acellular and thus, in contrast to autogenous bone, cannot provide osteoblasts or other cellular elements to the grafted region, but it does contain growth and differentiation factors, and has other properties that make it an impressive material for bone repair. In this review, the beneficial properties of dentin and the ways it interacts with the host bone are described in the context of bone graft materials. Autogenous tooth material has limitations, particularly in terms of the need for tooth extraction and the limited amount available, which currently restrict its use to particular dental procedures. The development of a xenograft dentin-derived material, which retains the properties of autogenous dentin, is described. Such a material could potentially enable the use of dentin-derived material more widely, particularly in orthopedic indications where its properties may be advantageous.
Neuroscience Letters, 1985
Clinical Oral Investigations
Objectives Assessment of the clinical performance of a porcine dentin-derived particulate bone gr... more Objectives Assessment of the clinical performance of a porcine dentin-derived particulate bone graft material for bone regeneration after tooth extraction with implant placement at 4 months, in comparison to a commercially available porcine bone-derived graft. Material and methods This study was a randomized, parallel-group, semi-double-blinded clinical trial evaluating the clinical safety, tolerability, and performance of Ivory Dentin Graft™ in comparison with a commercial bone-derived material in alveolar ridge preservation following tooth extraction (registered at ClinicalTrials.gov, May 12th, 2017, Identifier NCT03150472). Extraction sites were grafted with test or comparator material and a titanium implant placed at 4 months after taking a graft site biopsy. Primary endpoints were the extent of new bone growth and bone-graft integration at 4 months. Results The dentin graft material had statistically significantly more new bone formation (60.75% vs 42.81%, p = 0.0084, N = 20 vs...
,"\ and IanJ. Constable* Purpose. The aim of this study was to identify whether abnormal... more ,"\ and IanJ. Constable* Purpose. The aim of this study was to identify whether abnormalities in the synthesis of basic fibroblast growth factor (bFGF) or its receptor (bFGF-R) were responsible for the photoreceptor dystrophy in Royal College of Surgeons (RCS) rats. Methods. The polymerase chain reaction was used to detect the expression of bFGF and bFGF-R messenger RNA in the retinal pigment epithelial (RPE) cells and the neural retina of RCS dystrophic rats and in PVG/C and RCS-rrf)> + control animals. Results. In the RPE, it was found that there was no significant difference in the expression of bFGF and bFGF-R between RCS rats and the controls at the ages of 21 days and 3 mo. In the neural retina, the level of bFGF expression was lower in the 21-day-old RCS rats compared with the control group, but bFGF-R expression was as strong as in the PVG/C and RCS-rd)> + animals. However, in 3-mo-old RCS rat neural retina, the bFGF and bFGF-R expression was found to be significantly lower than in the control animals. Conclusions. Although the mutant gene in RCS rats is expressed in the RPE cells, these results suggest that there is no significant defect in bFGF or bFGF-R expression in the RPE cells of RCS rats, which would be an initiating factor in the development of photoreceptor degeneration in these animals. The lowered bFGF levels in the neural retina at early stages (postnatal day 21) may explain the prolongation of photoreceptor survival when exogenous bFGF is injected. Invest Ophthalmol Vis Sci. 1993; 34:1845-1852 JLJegeneration of photoreceptors leads to permanent blindness because, in common with other central nervous system neuronal cells, they cannot be replaced by cell division in adults. The Royal College of Surgeons (RCS) mutant strain of rats with inherited retinal dys- trophy has been used widely as a model to study photoreceptor degeneration. 1 Although this particular type of defect is not common in humans, the procedures that prolong photoreceptor survival in this condition may be more widely applicable. The cellular nature of the genetic abnormality in RCS rats is known, but the underlying molecular defect has not yet been identified. In the RCS rat, the retinal pigment epithelium (RPE) does not phagocytose shed outer segments, 2 thus resulting in accumulation of membranous debris in the subretinal space and subsequent death of the rod photoreceptors. Transplantation of RPE cells from normal rats results in long-term (5 mo after treatment) rescue of photore-
Neuroscience Research, 1986
Blood, 2013
Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its... more Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its in vitro and in vivo characterization are described. First published hepcidin inhibitor that entered clinical trials for the treatment of anemia due to functional iron deficiency.
Experimental Eye Research, 1997
The expression of GFAP and bFGF after retinal photocoagulation injury in the rat was assessed by ... more The expression of GFAP and bFGF after retinal photocoagulation injury in the rat was assessed by immunocytochemistry and reverse transcriptase PCR. Beta-actin mRNA expression was unaltered after injury and was therefore a good control for the quality of the RNA samples and the PCR reaction. GFAP mRNA increased from undetectable levels in normal retina to relatively high levels at 24 and 48 hr after injury, returning to barely detectable levels at 3 and 7 days. Müller cell GFAP immunoreactivity was elevated by 24 hr, stronger by 48 hr and persisted for 30-45 days. Thus, the expression of GFAP immunoreactivity after photocoagulation was due to new protein synthesis but the mRNA, and therefore the stimulus, was only present for a few days. This indicates that the GFAP protein in Müller cells has a long lifetime similar to that of astrocytes despite different gene control elements. bFGF is a possible stimulus for Müller GFAP expression because Müller cells have bFGF receptors. bFGF mRNA...
Development, Mar 1, 1988
The tectal pathways of regenerating goldfish optic axons are abnormal but not random. The relativ... more The tectal pathways of regenerating goldfish optic axons are abnormal but not random. The relative proportion of temporal axons is highest in rostral tectum (65 %) drops in midtectum (31 %) and is very low in caudal tectum (4 %). By contrast, nasal axons proceed into caudal tectum and are therefore relatively evenly distributed throughout the tectum. In this study, we have tested whether temporal axons are confined to rostral tectum by the presence of nasal axons in caudal tectum or whether they have a preference for rostral tectum regardless of other axons. We similarly tested whether nasal axons would grow preferentially into caudal tectum in the absence of temporal axons. At the time of optic nerve section either the nasal or temporal half retina was removed. Either 35 or 70 days after nerve section, the regenerating optic axons were labelled with HRP and both their pathways and distribution determined in DAB-reacted tectal wholemounts. In the absence of nasal axons, the relative density of temporal axons in rostral, mid and caudal tectum was 70 %, 28 % and 2 %, respectively. The corresponding values for nasal axons, in the absence of temporal axons, were 30 %, 40 % and 30 %, respectively. Thus, the overall distribution of nasal and temporal axons in the half retinal regenerates was similar to that of whole retinal regenerates, demonstrating that the retinotopic preferences of the axons were not dependent upon interaxonal interactions. Thus, nasal and temporal axons obviously discriminate between rostral and caudal tectum despite pathway disorganization and the absence of axons from the opposite hemiretina. This is consistent with axonal growth being under the influence of positional markers in tectum.
Investigative Ophthalmology Visual Science, 1993
Investigative Ophthalmology Visual Science, Apr 1, 1993
C41. EMERGING PHARMACOLOGY FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: MECHANISMS AND OUTCOMES, 2010
NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12... more NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.
J Comp Neurol, 1993
A wide variety of retinal pathology is associated with an increase in Müller glial cell expressio... more A wide variety of retinal pathology is associated with an increase in Müller glial cell expression of glial fibrillary acidic protein (GFAP). In this study the time course and spatial spread of the Müller cell GFAP response following argon laser photocoagulation lesions was examined in wholemounted rabbit retina.At 24 hours single focal lesions were surrounded by GFAP positive Müller cell end feet which declined in density with distance but extended as far as 2–3 mm from the lesion. The Müller cell reaction reached a maximal spread of 4–5 mm at 14 to 21 days and had started to contract by 30 days, leaving a core of GFAP positive processes immediately around the lesion site at 60 days. This zone of spread was much larger than the area of disrupted pigment epithelium. Isodensity plots did not reveal any correlation with the trajectory of retinal ganglion cell axons. The spread of reaction was more confined for lesions within the visual streak than in the dorsal or ventral retinal periphery.Multiple lesions within a focal region of retina resulted in a greater density of GFAP reactive end feet with a corresponding greater spread. However, when five to ten lesions were made in a horizontal row, the Müller cells over the entire retina became GFAP immunoreactive. This pan-retinal reaction took several days to spread, peaked at 7–14 days, and contracted back to the primary lesion sites by 2 months.This spread of Müller cell reactivity may be triggered by the diffusion of substances released by injury or it may be due to direct cellular communication. The extensive indirect effect on Müller cells of laser irradiation might be an important component of the clinical effect of laser photocoagulation and indicates a long distance communication mechanism between retinal glia which is poorly understood. This study also shows the importance of the time at which the Müller cell response is assessed. © 1993 Wiley-Liss, Inc.
Current Eye Research, May 1, 1993
In the RCS rat there is a progressive degeneration of the photoreceptors which starts at two to t... more In the RCS rat there is a progressive degeneration of the photoreceptors which starts at two to three weeks after birth. We have demonstrated that there is prolonged survival of photoreceptors on the flanks of argon laser lesions made at post-natal day 23, just as degeneration begins. The cells in the outer nuclear layer retained a relatively normal appearance on the flanks of the lesions for the first two weeks and there was a very low percentage of pyknotic cells. By one month some cell loss occurred but much less than in non-irradiated regions where very few cells remained. At two months after lesion there were still elevated numbers on the flanks but only 2-3 rows of cells remained. The prolonged survival correlated with disruption to the pigment epithelial layer, increased migration of phagocytic cells into the outer segment/debris layer and a reduction in thickness of the debris layer at late stages. The mechanisms of this effect are unknown however laser lesions provide a well controlled and reproducible situation in which to study these mechanisms.
Degenerative Diseases of the Retina, 1995
Retinal Degeneration, 1993