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Introduction: KNP-301 is a bi-specific fragment crystallizable region (Fc) fusion protein, which inhibits both C3b and vascular endothelial growth factor (VEGF) simultaneously for patients with late-stage age-related macular degeneration (AMD). The present study evaluated in vitro potency, in vivo efficacy, intravitreal pharmacokinetics (IVT PK), and injectability of KNP-301. Methods: C3b and VEGF binding of KNP-301 were assessed by surface plasmon resonance (SPR) and enzyme-linked immunosorbent assay (ELISA), and cellular bioassays. A laser-induced choroidal neovascularization (CNV) model and a sodium iodate-induced nonexudative AMD model were used to test the in vivo efficacy of mouse surrogate of KNP-301. Utilizing fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) scans, the reduction in disease lesions were analyzed in a CNV mouse model. In the nonexudative AMD mouse model, outer nuclear layer (ONL) was assessed by immunofluorescence staining. Lastly, intravitreal pharmacokinetic study was conducted with New Zealand white rabbits via IVT administration of KNP-301 and injectability of KNP-301 was examined by a viscosity test at high concentrations. Results: KNP-301 bound C3b selectively, which resulted in a blockade of the alternative pathway, not the classical pathway. KNP-301 also acted as a VEGF trap, impeding VEGF-mediate signaling. Our dual-blockade strategy was effective in both neovascular and nonexudative AMD models. Moreover, KNP-301 had an advantage of potentially less frequent dosing due to the long half-life in the intravitreal chamber. Our viscosity assessment confirmed that KNP-301 meets the criteria of the IVT injection. Conclusions: Unlike current therapies, KNP-301 is expected to cover patients with late-stage AMD of both neovascular and nonexudative AMD, and its long-term PK profile at the intravitreal chamber would allow convenience in the dosing interval of patients. [ABSTRACT FROM AUTHOR]

The effect of recombinant human bone morphogenetic protein-2 mediated wingless-related integration site beta-catenin pathway on bone defect repair and angiogenesis of rabbit radius was explored. 18 New Zealand rabbits were divided into 3 groups, control group (group A), low dose recombinant human bone morphogenetic protein-2 group (group B), and high dose recombinant human bone morphogenetic protein-2 group (group C). The bone mineral density of each group was compared. Rabbit bone marrow mesenchymal stem cell line cells were resuscitated and the proliferation ability, protein expression, messenger ribonucleic acid expression and cell migration ability of the three groups were detected by cell counting kit-8, Western blot, quantitative polymerase chain reaction and Transwell methods. The radial bone mineral density of rabbits in the group B was higher than that in group A at 4 w and 8 w, while in group C was higher than that group B. The cell proliferation and migration activity in the group B increased than group A, while those in the group C were raised than the group B. The protein levels of angiopoietin-1 and vascular endothelial growth factor in group B increased than those in the group A and these levels in group C raised comparatively than in group B. The relative expression of wingless-related integration site beta and catenin in group B reduced than group A, while this expression in group C was lower than group B. Recombinant human bone morphogenetic protein-2 can promote the repair of radial bone defect and angiogenesis by mediating wingless-related integration betacatenin pathway in rabbits. [ABSTRACT FROM AUTHOR]

Background: To explore the safety of Neodymium:Yttrium-aluminum-garnet (Nd:YAG) laser vitreolysis based on the histological examination of the retina and the alteration of vitreous cytokines in the rabbits. Methods: Nine male New Zealand rabbits underwent Nd:YAG laser vitreolysis of 10 mJ x 500 pulses in the left eyes, while the right eyes were used as controls. Intraocular pressure, color fundus photography, and ultrasound B scan were measured before, as well as 1 day, 4 weeks, and 12 weeks after Nd:YAG laser vitreolysis. Three rabbits were euthanized 1 day, 4 weeks, and 12 weeks after treatment, respectively. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin-eosin (H&E) staining were used to look for pathological changes in the retina. An enzyme-linked immunosorbent assay (ELISA) was utilized to detect the expression of vascular endothelial growth factor (VEGF) and some inflammatory cytokines, including interferon inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1) and interlenkin 6 (IL-6) in the vitreous humor. The ascorbic acid (AsA) and total reactive antioxidant potential (TRAP) in the vitreous humor were also measured. Results: Following Nd:YAG laser vitreolysis, the levels of VEGF, IP-10, MCP-1, IL6, AsA, and TRAP in the vitreous humor did not change substantially (P > 0.05). There were no detectable pathological changes in the retinal tissues, and no apoptotic signal was found. Conclusions: Rabbits tolerate Nd:YAG laser vitreolysis without observable impact on retinal tissue or the microenvironment of the vitreous. [ABSTRACT FROM AUTHOR]

BACKGROUND: A large number of studies have confirmed that exosomes can promote osteogenesis and vascularization. However, simple exosome therapy has problems such as poor targeting, and the content of loaded molecules cannot reach the therapeutic concentration. OBJECTIVE: To load exosomes into injectable gluconolactone-sodium alginate β-tricalcium phosphate-polyethylene glycol hydrogel, and observe the effect of the hydrogel on peri-implant bone defect in vivo and in vitro. METHODS: Exosomes were extracted from bone marrow mesenchymal stem cells and wrapped in injectable gluconolactone-sodium alginate β-tricalcium phosphate-polyethylene glycol hydrogel. (1) In vitro experiment: The hydrogel loaded with exosomes and the hydrogel without exosomes were cocultured with endothelial progenitor cells, and exosomes uptake experiment, tubule formation experiment, cell proliferation, migration ability, and angiogenic gene detection were carried out. (2) In vivo experiment: Twelve male New Zealand white rabbits were used to prepare two standard implant cavities and corresponding bone defects in the long axis of one femur. A hydrogel loaded with exosomes was implanted in the bone defect after an implant was implanted in a cavity at the proximal end of the implant (experimental group), and an unloaded exosome hydrogel was implanted in the bone defect after an implant was implanted in a cavity at the distal end of the implant (control group). At 3, 6 and 9 weeks after operation, bone defects with implants were removed and stained with hematoxylin-eosin staining and Masson staining. Simultaneously, osteogenic and angiogenic genes were detected at 9 weeks after operation. RESULTS AND CONCLUSION: (1) In vitro experiment: Exosomes could enter endothelial progenitor cells. The proliferation, migration, angiogenesis and gene (CD31, vascular endothelial growth factor and basic fibroblast growth factor) expression of endothelial progenitor cells in the hydrogel-loaded group were higher than those in the hydrogel-unloaded group (P < 0.05). (2) In vivo experiment: Hematoxylin-eosin staining and Masson staining showed that at 3 weeks after operation, only a small amount of new bone was found in the two groups, and the material was partially degraded. At 6 weeks after operation, the amount of new bone in the two groups increased, and a large amount of new bone was found in the experimental group, with obvious calcium deposition. At 9 weeks after operation, compared with the control group, a large number of bone trabeculae thicker than mature were found in the experimental group, calcium salt deposition was more obvious, and a large number of osteoblasts were found around the bone trabeculae. The protein expressions of CD31, vascular endothelial growth factor, basic fibroblast growth factor, bone morphogenetic protein 2, type I collagen and osteocalcin in the experimental group were higher than those in the control group at 9 weeks after operation (P < 0.05). (3) The exosome-loaded gluconolactone-sodium alginate β-tricalcium phosphate-polyethylene glycol hydrogel could promote the proliferation, migration and angiogenic differentiation of endothelial progenitor cells and promote the repair and regeneration of bone defects around implants. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of bevacizumab in 3 different application methods, subconjunctival injection (SCI), hyaluronic acid retardant (HAR), and eye drop (ED), on attenuating scar formation in the filtering bleb. Methods: Trabeculectomy (TRAB) was performed on New Zealand rabbits. TRAB rabbits were intervened with bevacizumab SCI, HAR, ED, or mitomycin C, respectively. Intraocular pressure (IOP) of 1, 7, 14, and 28 days after TRAB was recorded, and the bleb survival rate was analyzed. Bleb height, area, and vascularization were evaluated using anterior segment optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) at 7, 14 and 28 days after surgery. A histopathology examination of the bleb tissue was performed. The expression levels of vascular endothelial growth factor (VEGF)-A, interleukin (IL)-1α, tumor necrosis factor-alpha (TNF-α), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA) were measured by Western blot. Results: Bevacizumab significantly reduced postoperative IOP and increased the survival of the filtering bleb, especially in the ED group. Less vascularization was shown in the SCI, HAR, and ED groups. Histopathological results showed the fewest levels of scarring and fibrosis in the ED group. The local VEGF-A, IL-1α, and TNF-α expression levels after bevacizumab ED were decreased, combined with suppression of TGF-β1 and α-SMA. Conclusions: Postoperative use of bevacizumab EDs was an effective application method for improving surgical outcomes after TRAB in rabbits. It might be effective in preventing scarring of the filtering bleb by antivascularization and anti-inflammation. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the most prevalent type of retinal vasculopathy and the most widespread cause of preventable blindness in adults. Excessive increases in reactive oxygen species (ROS) and vascular endothelial growth factor are major initiators and drivers of DR progression, respectively. However, current DR treatment options remain limited, particularly for early DR. Nanotechnology‐mediated antioxidant strategies are gaining increasing popularity to treat ocular diseases. Quercetin has excellent ROS scavenging efficiency but poor stability and low bioavailability in physiological environments. In this study, ultrasmall Fe‐Quer nanozymes (NZs) formed by coupling quercetin with low‐toxic iron ions are reported that can mimic the activities of three important antioxidant enzymes, superoxide dismutase, catalase, and peroxidase, thereby exhibiting excellent water dispersion and efficient ROS scavenging ability. In vitro and in vivo assays validate the effects of Fe‐Quer NZs against inflammation, oxidative stress damage, microvascular leakage, and angiogenesis, particularly their vascular protective effect in early DR. Transcriptomic analysis further reveals a potential multitarget‐specific therapeutic mechanism of Fe‐Quer NZs against DR. These observations open avenues for Fe‐Quer NZs, composed of molecules of a natural product and metal ions with artificial NZ activity, as microvascular protective agents for DR and other ROS‐related diseases. [ABSTRACT FROM AUTHOR]

Background: Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Questions/purposes: Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Methods: Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits' ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Results: Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). Conclusion: Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. Clinical Relevance: If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled. [ABSTRACT FROM AUTHOR]

Background: Age‐related macular degeneration (AMD) is a major cause of irreversible central vision loss. The main reason for lost vision due to AMD is choroidal neovascularization (CNV). In the clinic, current treatments for CNV include photodynamic therapy, laser photocoagulation, and anti‐vascular endothelial growth factor (VEGF) therapy. Purpose: This study evaluates a novel treatment technique combining synchronized nanosecond laser pulses and ultrasound bursts, namely photo‐mediated ultrasound therapy (PUT) as a potential treatment method for CNV, for its efficacy and safety in the treatment of CNV via the experiments in a clinically‐relevant rabbit model in vivo. Methods: CNV was created by subretinal injection of Matrigel and vascular endothelial growth factor (M&V) in 10 New Zealand white rabbits. Six rabbits were used in the PUT group. In the control groups, two rabbits were treated by laser‐only, and two rabbits were treated by ultrasound‐only. The treatment efficacy was evaluated through fundus photography and fluorescein angiography (FA) longitudinally for up to 4 weeks. Rabbits were sacrificed for histopathology 3 months after treatment to examine the safety of PUT. Results: The fluorescein leakage on FA was quantified to longitudinally evaluate treatment outcome. Compared with baseline, the relative intensity index was reduced by 26.57% ± 8.66% at 3 days after treatment, 27.24% ± 6.21% at 1 week after treatment, 27.79% ± 2.61% at 2 weeks after treatment, and 32.12% ± 3.23% at 4 weeks after treatment, all with a statistically significant difference of p < 0.01. The comparison between the relative intensity indexes from the two control groups (laser‐only treatment and ultrasound‐only treatment) did not show any statistically significant difference at all time points. Safety evaluation at 3 months with histopathology demonstrated that the PUT did not result in morphologic changes to the neurosensory retina. Conclusions: This study introduces PUT for the first time for the treatment of CNV. The results demonstrated good efficacy and safety of PUT to treat CNV in a clinically‐relevant rabbit model. With a single session of treatment, PUT can safely reduce the leakage of CNV for at least 1 month after treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recently, numerous basic and clinical data have shown the superiority of platelet-rich fibrin in the regeneration and repair of soft and hard tissues, while there are few relevant reports in the field of microvascular anastomosis. OBJECTIVE: To evaluate the efficacy of platelet-rich fibrin applied to the femoral artery after microvascular anastomosis surgery in a rabbit model. METHODS: Thirty-six adult New Zealand white rabbits of either sex were randomly divided into experimental group and control group (n=18 per group) after establishing femoral artery transection-reanastomosis models. In the experimental group, autologous ear venous blood were extracted and centrifuged to prepare platelet-rich fibrin gel, and the prepared gel was immediately applied to the anastomotic site of the femoral artery. The control group was given the same volume of normal saline. Incision infection, healing, and adhesion were evaluated at 3, 7, 14 days after surgery. Vascular structure of the femoral artery at the anastomotic site was observed using hematoxylin-eosin staining. Immunohistochemistry detection was performed to analyze the expression levels of vascular endothelial growth factor, platelet-derived growth factor, and transforming growth factor β1. RESULTS AND CONCLUSION: The overall number of incision infections in the experimental group was lower than that in the control group animals (P < 0.05), and the number of incision infections showed no significant changes in each group (P > 0.05). The overall incision healing level in the experimental group was better than that in the control group (P < 0.05), and the incision healing showed no significant changes in the experimental group (P > 0.05) but changed significantly in the control group at different time points (P < 0.05). The degree of femoral artery adhesion in the operation area was generally lighter in the experimental group than the control group (P < 0.05). The degree of adhesion had insignificant changes in the experimental group at different time points (P > 0.05) but gradually increased in the control group after operation (P < 0.05). The results of hematoxylin-eosin staining showed better repair of vascular endothelial cells and inner elastic lamina in the experimental group than the control group. Compared with the control group, the reconstruction of the intima was more complete in the experimental group, with less necrosis, proliferation, and migration of vascular smooth muscle cells in the media and traumatic hyperplasia of the extima. The overall healing condition of the vascular wall was better in the experimental group than the control group. Immunohistochemical results revealed that the expression levels of vascular endothelial growth factor, platelet-derived growth factor, and transforming growth factor β1 in the experimental group were higher than those in the control group (P < 0.05). To conclude, platelet-rich fibrin can promote the growth of vascular endothelial cells, contribute to the in situ reconstruction of various layers of vascular tissue, reduce postoperative complications, such as infection and adhesion, in the surgical area, and shorten the repair and healing time after vascular injury. This novel treatment method is expected to improve the therapeutic effect of arterial anastomosis in microsurgery. [ABSTRACT FROM AUTHOR]

Treatment of large segmental bone defects has been a challenging and long process for both physicians and patients. At present, the induced membrane technique is one of the reconstruction techniques commonly utilized in treating large segmental bone defects. It consists of a two-step procedure. In the first one, after bone debridement, the defect is filled with bone cement. The aim at this stage is to support and protect the defective area with cement. A membrane is formed around the area where cement was inserted 4-6 weeks after the first surgical stage. This membrane secretes vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), as shown in the earliest studies. In the second step, the bone cement is removed, and the defect is filled with cancellous bone autograft. In the first stage, antibiotics can be added to the applied bone cement, depending on the infection. Still, the histological and micromolecular effects of the added antibiotic on the membrane are unknown.This study investigates the molecular and histological effects of antibiotics addition into bone cement on the induced membrane.In this study, conducted on 27 male New Zealand rabbits, the 2 cm long defects of a bone were created in the rabbit femurs. Three groups were formed by placing antibiotic-free, gentamicin, and vancomycin-containing cement in the defect area.These groups were followed for six weeks, and the membrane formed at the end of 6 weeks was examined histologically. As a result of this study, it found that the membrane quality markers (Von Willebrand factor (vwf), Interleukin 6-8 (IL), Transforming growth factor beta (TGF-β), Vascular endothelial growth factor (VEGF) were significantly higher in the antibiotic-free bone cement group. Our study has shown that antibiotics added to the cement have negative effects on the membrane. Based on the results we obtained, it would be a better choice to use antibiotic-free cement in aseptic nonunions. However, more data is needed to understand the effects of these changes on the cement on the membrane. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this investigation was to assess vertical bone augmentation using deproteinized bovine bone mineral (DBBM) infused or not with recombinant human bone morphogenetic protein (rhBMP-2) in rabbit tibiae. Materials and Methods: A total of 18 female rabbits (New Zealand) received two blocks of DBBM in each tibia. The DBBM blocks were randomly assigned into four experimental groups: DBBM (only the bone graft); DBBM associated with absorbable collagen sponge (ACS); DBBM plus rhBMP-2 (1.5 mg/mL); and DBBM infused with rhBMP-2 (1.5 mg/mL) in an ACS carrier. Animals were sacrificed after 12 weeks, and the tibiae containing the DBBM blocks were dissected and analyzed radiographically (microcomputed tomography [micro-CT]), histologically, and immunohistochemically. Results: Micro-CT analysis showed a considerable increase in bone volume (BV) and BV/tissue volume in the rhBMP-2/ACS group compared with all the others. Trabeculae thickness also increased in the rhBMP-2/ACS group compared with the DBBM/ACS group. Trabecular number, separation, and bone mineral density were not different among groups. Histomorphometric evaluation showed increased newly formed bone in the rhBMP-2/ACS group compared with the DBBM and DBBM/ACS groups. The amount of residual bone graft was statistically higher in the rhBMP-2 groups compared with the DBBM/ACS group. Immunohistochemical analysis showed that the vascular endothelial growth factor (VEGF) expression was more intense in the rhBMP-2/ACS group compared with the DBBM/ACS group. The immunopositivity for type 1 collagen tended to be higher in the two groups with rhBMP-2. Conclusion: Collectively, the results of this study suggest that the addition of rhBMP-2 in an ACS carrier placed on top of the DBBM graft enhanced bone formation in this animal model. [ABSTRACT FROM AUTHOR]

BACKGROUND: As one of the effective angiogenic factors, basic fibroblast growth factor can not only increase the blood perfusion of ischemic tissues and accelerate the regeneration of tissue microvessels, but also improve the formation of blood vessels in muscle tissues and increase the blood perfusion of muscles. OBJECTIVE: Basic fibroblast growth factor was incorporated into poly(lactic acid)/collagen scaffold to repair rabbit urethral defects and to improve the ability of tissue engineered scaffolds to induce urethral regeneration. METHODS: The electrospun poly(lactic acid)/collagen urethral scaffold and the electrospun poly(lactic acid)/collagen scaffold loaded with basic fibroblast growth factor were prepared and named as control scaffold and experimental scaffold, respectively. The in vitro release properties of the scaffolds were tested. The third passage of rabbit adipose derived mesenchymal stem cells was seeded on the two scaffolds for 7 days. CCK-8 assay, cell adhesion test, and cell livedead staining were performed respectively. Twenty-four adult male New Zealand white rabbits were used to establish a 5 cm long urethral defect model and randomly divided into two groups (n=12). The control scaffold + adipose derived mesenchymal stem cell complex and the experimental scaffold + adipose derived mesenchymal stem cell complex were implanted, respectively. At 12 and 24 weeks after operation, retrograde urethrography and histology were performed. RESULTS AND CONCLUSION: (1) In vitro sustained release experiment: Basic fibroblast growth factor was released at an average rate of 2.5 ng/d in the first 6 days, 1.52 ng/d from the seventh to fourteenth days, and 1.12 ng/d thereafter. The release rate gradually decreased after 21 days. (2) In vitro cell experiments showed that the cell proliferation rate on the experimental scaffold was faster than that on the control scaffold (P < 0.05). Adipose-derived mesenchymal stem cells could adhere to the surfaces of the two scaffolds, grow well and protrude pseudopodia, among which the cells on the experimental scaffold proliferated rapidly. The survival rate of the cells on the experimental scaffolds was higher than that of the control scaffold (P < 0.05). (3) In vivo experimental results: At 24 weeks postoperatively, urethral angiography exhibited that there was no urethral stricture in the experimental scaffold group, and mild urethral stricture was seen in the control scaffold group. Histological observation demonstrated that at 24 weeks after operation, there was a thick and complete epithelial layer in the experimental scaffold group, with a large number of muscle fiber bundles and blood vessels. In the control scaffold group, there was a thin epithelial layer, with a small number of muscle fiber bundles and blood vessels. (4) The results confirm that electrospun poly(lactic acid)/collagen scaffold loaded with basic fibroblast growth factor for repairing rabbit urethral defects could promote local angiogenesis, improve local urethral microenvironment and promote urethral regeneration. [ABSTRACT FROM AUTHOR]

BACKGROUND: Early studies have confirmed that multi-scale hydroxyapatite/chitosan microtubules are excellent in osteogenesis. Angiogenesis is critical in the process of osteogenesis. It is significant to explore the role of tube structure with multi-scale microtubules in its vascularization and related mechanisms. OBJECTIVE: To explore the effect of multi-scale hydroxyapatite/chitosan microtubule structure on rabbit bone defect repair and vascularization. METHODS: Multi-scale hydroxyapatite/chitosan microtubule structure and hydroxyapatite/chitosan monomer structure were constructed and co-cultured with bone marrow mesenchymal stem cells for 21 days. The adsorption ability of the material to cells and the cell state were observed under the electron microscope. Bone defect models were made on the radius of 48 adult New Zealand white rabbits. Rabbits in the experimental group (n=24) were implanted with multi-scale hydroxyapatite/chitosan microtubule structure material. Rabbits in the control group (n=24) were implanted with hydroxyapatite/chitosan monomer structure material. Emission computed tomography, X-ray, histomorphological examination, and immunohistochemistry for CD31 and vascular endothelial growth factor protein detection were performed at 4, 8, and 12 weeks after surgery. The animal experiment was approved by the Ethics Committee of Jiangxi Provincial People’s Hospital. RESULTS AND CONCLUSION: (1) Under the electron microscope, the multi-scale hydroxyapatite/chitosan microtubule structure materials were interlinked and had a good spatial structure. The number of bone marrow mesenchymal stem cells on the multi-scale hydroxyapatite/chitosan microtubule structure material was more than that on the hydroxyapatite/chitosan monomer structure material. (2) Emission computed tomography exhibited that the blood pool image was higher in the experimental group than that in the control group at various time points after surgery (P < 0.05). (3) X-ray films showed that the formation of multi-scale microtubules was more obvious in the experimental group than that in the control group. (4) Hematoxylin-eosin staining demonstrated that at 12 weeks after surgery, the appearance of osteoblasts and angiogenesis was obvious in the experimental group; only a few regenerated blood vessels and osteoblast attachment were found at the fractured end in the control group. Immunohistochemistry for CD31 exhibited that the microvessel density of the experimental group was higher than that of the control group at each time point (P < 0.05). (5) Western blot assay results displayed that the expression of vascular endothelial growth factor protein in the experimental group was higher than that in the control group at each time point (P < 0.05). (6) The results showed that the multi-scale hydroxyapatite/chitosan microtubule structure had better osteogenesis and vascularization ability than its monomer structure. [ABSTRACT FROM AUTHOR]

Bone grafts a commonly used therapeutic technique for the reconstruction and facilitation of bone regeneration due to fractures. BHA–GEL (bovine hydroxyapatite–gelatin) pellet implants have been shown to be able accelerate the process of bone repair by looking at the percentage of new bone, and the contact between the composite and bone. Based on these results, a study was conducted by placing BHA–GEL (9:1) pellet implants in rabbit femoral bone defects, accompanied by 500 mg oral supplement of BHA or calcium lactate to determine the effectiveness of addition supplements. The research model used was a burr hole defect model with a diameter of 4.2 mm in the cortical part of the rabbit femur. On the 7th, 14th and 28th days after treatment, a total of 48 New Zealand rabbits were divided into four groups, namely defect (control), implant, implant + oral BHA, and implant + oral calcium lactate. Animal tests were terminated and evaluated based on X-ray radiology results, Hematoxylin-Eosin staining, vascular endothelial growth Factor (VEGF), osteocalcin, and enzyme-linked immunosorbent assay (ELISA) for bone alkaline phosphatase (BALP) and calcium levels. From this research can be concluded that Oral BHA supplementation with BHA–GEL pellet implants showed faster healing of bone defects compared to oral calcium lactate with BHA–GEL pellet implants. [ABSTRACT FROM AUTHOR]

Objective To observe and investigate the therapeutic effect of scorpion ointment on early hypertrophic scar in rabbit ear model. Methods From October 2019 to October 2020, 8 New Zealand white rabbits were randomly divided into control group and treatment group, 4 rabbits in each group. The rabbit ear hypertrophic scar model was established. The scorpion ointment was used in the treatment group and the PBS was used in the control group. At 7 and 28 days after treatment, the tissues of each group were taken for HE staining, Masson's trichrome staining and immunohistochemistry. Results At 28 days after rabbit ear model established, the wounds of rabbit ears in each group were completely healed and hypertrophic scar was formed. Significant hyperplasia of scars was found in the control group. In the treatment group, the scar volume was gradually decreased, and the texture and color were improved. The results of HE staining and Masson's trichrome staining showed that the degree of tissue fibrosis was significantly reduced after treatment with scorpion ointment (P<0.05). Compared with the control group, the immunohistochemistry results showed that the expression of CD31 and vascular endothelial growth factor (VEGF) in the treatment group at 7 and 28 days were significantly decreased (P<0.05). Conclusion Scorpion ointment can treat hypertrophic scar by reducing the degree of fibrosis and down regulating the expression of CD31 and VEGF. [ABSTRACT FROM AUTHOR]

Understanding the does reproductive hemodynamic changes during the estrous cycle is crucial for improving reproductive competence and fertility potential in this species. The objective of this study is to investigate the hemodynamic variations in ovarian (OA) and uterine (UA) arteries, histological and morphometric changes in ovarian and uterine tissues throughout the follicular (FP) and luteal (LP) phases in rabbits and determine estrogen (ER), progesterone (PR) receptors, and vascular endothelial growth factor (VEGF) distributions using immunohistochemistry. Fourteen adults pluriparous New Zealand rabbits were divided into rabbits at the FP (Day − 1; n = 7) and those at the LP (Day 9; n = 7). Animals were subjected to Doppler, hormonal (estrogen [E2], progesterone [P4], insulin-like growth factor [ILGF], and VEGF), histological, and immunohistochemical analyses. In LP, OA Doppler indices were significantly increased, whereas peak systolic velocity (PSV) was decreased compared with that in FP. UA Doppler indices were significantly decreased in the LP, whereas PSV was increased (P < 0.05). E2 levels were increased in the FP, whereas P4 levels were increased in the LP. The morphometric analysis of uterine tissues during the LP revealed an increase in the mean uterine endometrium length, endometrial connective tissue area percentage (%), endometrial glands number, myometrial area (%) and thickness. Furthermore, ovarian follicles and corpus luteum (CL) displayed strong positive immunoreactivity for ER, PR, and VEGF-A during both phases. The ovarian sections displayed a substantial (P < 0.05) increase in the area % of VEGF-A in the ovarian follicles during FP while in the CL during LP. Conversely, area percentage of VEGF-A immunoreactivity in the uterine luminal and glandular epithelia during the FP and LP revealed no differences. However, the number of VEGF-A–stained blood capillaries revealed an increase during LP than FP. In conclusion, this study demonstrated for the first time the changes in both ovarian and uterine arteries during two different phases of the rabbit cycle in relation to the histo-morphometric analysis and distribution of ER, PR, and VEGF-A, which regulate uterine functions that play a role in reproduction. [ABSTRACT FROM AUTHOR]

Now it is possible to combine the different biomaterial properties of graphene and 3 D printing scaffolds produced by tissue engineering for cartilage repair. In the study graphene-containing (1, 3, 5, 10 wt%), porous and oriented poly-ε-caprolactone-based scaffolds were prepared by robocasting method to use in the regeneration of large osteochondral defects. The scaffolds were implanted into the full-thickness osteochondral defect in a rabbit model to evaluate the regeneration of the defect in vivo. For this purpose, twenty female New Zealand white rabbits were used and they were euthanized at 4 and 8 weeks of implantation. The reparative osteochondral tissues were harvested from rabbit distal femurs and then processed for gross appearance assessment, radiographic imaging, histopathological, histochemical and immunohistochemical examinations. Results revealed that graphene-containing graft materials caused significant amelioration at the defect areas. Graphene-containing graft materials improved the fibrous, chondroid and osseous tissue regeneration compared to the control group. The expressions of bone morphogenetic protein-2 (BMP-2), collagen-1 (col-1), vascular endothelial growth factor (VEGF) and alkaline phosphatase (ALP) expressions were more prominent in graphene-containing PCL implanted groups (p <.001). Picrosirrius red method was used for to evaluate connective and muscle tissues. Results also revealed that the ameliorative effect of graphene increased by the elevation in concentration. The most prominent healing was observed in 10 wt% graphene-containing PCL based composite scaffold implanted group. This study results showed that graphene-containing PCL scaffolds enhanced the healing significantly in large osteochondral defect areas compared to the control groups. [ABSTRACT FROM AUTHOR]

To investigate the effect of platelet-rich fibrin (PRF) on post-operative wound healing following strabismus surgery in a rabbit model. Nine New Zealand white rabbits were involved in the study. One of these nine rabbits was kept in control without having any operation. Both eyes of eight rabbits underwent superior rectus muscle (SRM) resection. After resection of SRM, PRF was applied to SRM of the right eyes. In the left eye, SRM was not wrapped with PRF and served as a control. The rabbits were sacrificed and enucleated 6 weeks after the surgery. Inflammation and vascular proliferation were assessed by staining with haematoxylin-eosin. Scar and fibrosis were examined by the Masson trichrome staining. Immunohistochemical staining was performed for a vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA). There was no significant difference in terms of inflammation (p = 0.535), vascularization (p = 0.602), and fibrosis (p = 0.745) between the eyes. Immunohistochemical staining for VEGF demonstrated no significant difference (p = 0.745). However, significant staining for α-SMA was detected in PRF-treated eyes compared with control eyes (p = 0.037). Consistent with the hypothesis that PRF facilitates wound healing as a biocatalyst, there was only a significant difference for α-SMA related to myofibroblast activity which is important for wound remodelling. Future comprehensive studies are needed to extend these results. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies have shown that Miao medicine fumigation therapy has a definite effect on the treatment of osteoarthritis; however, its mechanism is unclear. Because excessive angiogenesis in synovial tissue and subchondral bone tissue is an important cause of the occurrence and development of osteoarthritis, vascular endothelial growth factor is an important pro-angiogenesis factor in the body, and the stromal cell-derived factor 1/CXCR4 signaling pathway is closely related to the overexpression of vascular endothelial growth factor. OBJECTIVE: To explore the role of stromal cell-derived factor 1/CXCR4 signaling pathway in the osteoarthritic occurrence and development and the therapeutic mechanism of Miao medicine fumigation on knee osteoarthritis. METHODS: Fifty healthy New Zealand white rabbit were randomized into normal, model, positive control (voltaren ointment for external use), early intervention, and Miao medicine fumigation groups. The knee osteoarthritis model was established in the latter four groups by injecting sodium iodoacetate into the knee joint cavity of rabbits. Hematoxylin-eosin staining was used to observe the pathological changes of synovium and cartilage. Immunohistochemical method was used to detect the levels of interleukin-1β and tumor necrosis factor-α in synovial tissue. ELISA method was used to detect the level of stromal cell-derived factor 1 in synovial fluid and the level of vascular endothelial growth factor in serum. Real-time fluorescence quantitative PCR was used to detect vascular endothelial growth factor mRNA expression in articular cartilage tissue. Western blot assay was used to detect the expression of type II collagen and aggrecan protein in cartilage tissue. RESULTS AND CONCLUSION: Compared with the model group, Miao medicine fumigation treatment significantly inhibited the inflammation in synovium and cartilage tissue and reduced its pathological changes. Compared with the model group, the integral absorbance values of interleukin-1β and tumor necrosis factor-α in synovium and the levels of vascular endothelial growth factor in serum and stromal cell-derived factor in joint fluid were significantly reduced in the Miao medicine fumigation group (P < 0.05). Compared with the model group, the serum vascular endothelial growth factor mRNA was reduced in the Miao medicine fumigation group, while type II collagen and aggrecan expressions were increased (P < 0.05). The above experimental results indicated no significant differences among Miao medicine fumigation group, positive control group and early intervention group (P > 0.05). To conclude, the Miao medicine fumigation therapy maybe by reducing the binding of stromal cell-derived factor 1 to its receptor CXCR4 inhibits the expression of interleukin-1β, tumor necrosis factor-α, and vascular endothelial growth factor, delays the destruction of extracellular matrix, and plays a therapeutic role. [ABSTRACT FROM AUTHOR]

The inhibitory effect of conbercept on corneal neovascularization (CNV) after penetrating keratoplasty (PKP) and its effect on postoperative wound healing and corneal strength recovery was investigated. New Zealand white rabbits were randomly divided into 3 groups, two experimental arms A and B and one control arm C. Topical conbercept and subconjunctival injection were carried out respectively after PKP. Slit lamp microscope was used to observe the growth of CNV. The expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and vimentin (Vim) were determined via real-time quantitative polymerase chain reaction (RT-qPCR). The placenta growth factor and vimentin, determination of corneal biomechanical machine strength changed. To measure the maximal strength of the corneal, uniaxial tensile test was carried out on the electroforce 3220-AT biomechanics machine. Two weeks after PKP, CNV appeared, inflammatory cell infiltration and new blood vessel formation were observed in the corneal stroma and superficial stroma layer. Compared with the control arm, the expression levels of VEGF and PlGF in the experimental arms were significantly decreased after using conbercept (P < 0.05), and the expression levels reached the maximum at the 4th week and then decreased gradually. The expression level of Vimentin and corneal intensity increased gradually over time. Conbercept effectively inhibited the formation of CNV after PKP in rabbits, and did not affect postoperative wound healing, nor did it affect postoperative corneal strength recovery. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) is a cytotoxic, vesicating, chemical warfare agent, first used in 1917; corneas are particularly vulnerable to SM exposure. They may develop inflammation, ulceration, neovascularization (NV), impaired vision, and partial/complete blindness depending upon the concentration of SM, exposure duration, and bio-physiological conditions of the eyes. Comprehensive in vivo studies have established ocular structural alterations, opacity, NV, and inflammation upon short durations (<4 min) of SM exposure. In this study, detailed analyses of histopathological alterations in corneal structure, keratocytes, inflammatory cells, blood vessels, and expressions of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and cytokines were performed in New Zealand white rabbits, in a time-dependent manner till 28 days, post longer durations (5 and 7 min) of ocular SM exposure to establish quantifiable endpoints of injury and healing. Results indicated that SM exposure led to duration-dependent increases in corneal thickness, opacity, ulceration, epithelial-stromal separation, and epithelial degradation. Significant increases in NV, keratocyte death, blood vessels, and inflammatory markers (COX-2, MMP-9, VEGF, and interleukin-8) were also observed for both exposure durations compared to the controls. Collectively, these findings would benefit in temporal delineation of mechanisms underlying SM-induced corneal toxicity and provide models for testing therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Corneal alkali burn is one of the most severe ophthalmic emergencies that requires prompt treatment. Recently, the attention of researchers has been attracted to the use of exosomes as a novel non-cell therapy for treatment of corneal alkali burn. Aim: to evaluate the possible role of mesenchymal stem cells (MSCs)-derived exosomes on healing of experimentally induced corneal alkali burn in rabbits by histological and immunohisto-chemical techniques. Materials and Methods: Forty-five adult male New Zealand white rabbits were divided into three groups: group I (control group); group II in which corneal alkali burn was left for spontaneous healing, and group III (exosomes treated group): in which rabbits received a sub-conjunctival injection of 100 ig MSCs-exosomes after one hour from corneal alkali burn induction. Injection of exosomes was repeated every other day. All groups were further subdivided into two subgroups; subgroup A and B, where corneal specimens were collected after 7 days and 14 days, respectively. Characterization of exosomes was done using transmission electron microscope. Gross examination of the cornea was done at days 0, 1, 4,7,10 and 14. At the end of experiment, corneal specimens were collected and subjected to hematoxylin and eosin, Massons trichrome, periodic acid Schiff, transforming growth factor-beta and vascular endothelial growth factor immunohistochemical techniques. Histo-morphometric study and statistical analysis were also done. Results: Administration of MSCs-derived exosomes in group III improved healing of corneal alkali burn by inhibiting angiogenesis and inflammation, enhancing corneal reepithelization, and providing better organization of newly formed stromal collagen fibers. Conclusion: Sub-conjunctival injection of MSCs-derived exosomes could be effective in the healing of corneal alkali burn in adult rabbits. [ABSTRACT FROM AUTHOR]

We studied a rabbit model of rheumatoid arthritis (RA) to examine the time course of changes in synovial neovascularization based on quantitative power Doppler ultrasound and contrast-enhanced ultrasound (CEUS). Twenty-five male New Zealand rabbits were in the ovalbumin-induced arthritis (OIA) group, and 5 were in the control group. Both rear knee joints of all rabbits were examined using conventional US and CEUS over 16 weeks. The knee synoviums of OIA rabbits were sampled by US-guided biopsy, and expression of CD31 and vascular endothelial growth factor (VEGF) was determined by immunohistochemistry. The correlation of joint damage based on multimodal US with microvessel density (CD31 positivity) and VEGF expression at different times was analyzed. OIA rabbits had increased synovial expression of CD31 and VEGF from weeks 6 to 12 (p < 0.01). During the early stage of CEUS enhancement, "dot enhancement" was more common at weeks 6 and 8, and "stripe enhancement" was more common at weeks 12 and 16 (p < 0.05). There were significant positive correlations of synovial CD31 and VEGF expression with power Doppler image grade, CEUS grade and peak intensity (p < 0.05 for all). Thus, OIA rabbits mimicked early-stage RA at 6 to 8 weeks, middle-stage RA at 8 to 12 weeks and late-stage RA at 12 to 16 weeks. Power Doppler image grade, CEUS grade and peak intensity, especially when combined with CD31 expression data, accurately characterized the extent of synovial vascularization in a rabbit model of RA. Increased vascularity based on CEUS may have value for the early diagnosis of RA. [ABSTRACT FROM AUTHOR]

Background: PRO-169 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that inhibits vascular endothelial growth factor-A (VEGF-A) developed for intravitreal use. The current study demonstrates the intraocular pharmacokinetics (PK) of PRO-169 and its safety using New Zealand white (NZW) rabbits. Methods: Intraocular concentration was evaluated in thirty-six rabbits at 1h, 1, 2, 5, 14 and 30 days after a single bilateral injection of PRO-169 or BEV (1.25 mg/0.05 mL). In a secondary experiment, safety was evaluated after three consecutive unilateral injections at 30-day intervals in twenty-four rabbits (PRO-169: 1.25 mg/0.05 mL or ranibizumab [RZB]: 0.5 mg/0.05 mL), by liver-associated enzymes (LAE), ophthalmological examination and adverse event (AE) incidence. Primary endpoints were vitreous maximum concentration (Cmax), time to attain maximum concentration (tmax), area under curve (AUC0-t), half-life (t1/2) and LAE. Secondary endpoints included aqueous humor (AH) and plasma pharmacokinetics, clinical examination and AEs. Results: The Cmax in the vitreous was 593.75 ± 45.63 (PRO-169) vs 644.79 ± 62.65 μg/mL (BEV) (p= 0.136). Tmax was 0.53 ± 0.82 vs 0.85 ± 0.73 days (p= 0.330). The AUC0-t was 3837.72 ± 465.91 vs 4247.31 ± 93.99 days*μg/mL (p= 0.052) and the half-life was 4.99 ± 0.89 vs 5.18 ± 0.88 days (p= 0.711). LAEs were normal in 92% of NZW rabbits; no differences between groups were observed (p> 0.05). The AH and plasma PKs were also similar. Finally, clinical examinations found no alterations. AEs were observed in 25% of PRO-169 rabbits, without differences vs RZB (p=0.399). Conclusion: PRO-169 can be efficiently diffused and distributed in ocular compartments, showing vitreous pharmacokinetics analogous to BEV. The safety experiment did not find evidence of clinical alterations from a repeated injection of PRO-169. These results provide scientific justification supporting that PRO-169 should be evaluated in future clinical trials to confirm its safety and efficacy. [ABSTRACT FROM AUTHOR]

Background. Vascular adventitia contains progenitor cells and is shown to participate in vascular remolding. Progenitor cells are recruited into the venous thrombi in mice to promote neovascularization. We hypothesized that the adventitial progenitor cells of human great saphenous vein (HGSV-AdPC) enhance the resolution of venous thrombosis via neovascularization. Methods. Human great saphenous vein (HGSV) was harvested from the patients with great saphenous vein varicose and sectioned for immunohistochemistry, or minced for progenitor cell primary culture, or placed in sodium dodecyl sulfate solution for decellularization. Human venous thrombi were collected from patients with great saphenous vein varicose and superficial thrombophlebitis. Infrarenal abdominal aorta of New Zealand white rabbits was replaced with interposing decellularized vessel, and the patency of the grafts was confirmed by ultrasonic examination. Animal venous thrombi in the left infrarenal vena cava of mice were produced with Prolene suture ligation and ophthalmic force clipping of this portion. After HGSVs were digested by collagenase, the CD34+CD117+ HGSV-AdPC were isolated on FACS system, labelled with CM-Dil, and transplanted into the adventitia of infrarenal vena cava of nude mice. The percentage of thrombus organization area to the thrombus area was calculated as the organization rate. The thrombus cell, endothelial cells, and macrophages in the thrombi were counted in sections. Cell smears and frozen sections of human saphenous veins and venous thrombi were labeled with Sca1, CD34, CD117, Flk1, CD31, and F4/80 antibodies. The CD34+CD117+ HGSV-AdPC were cultured in endothelial growth medium with vascular endothelial growth factor (VEGF) to induce endothelial cell differentiation and analyzed with real time-PCR, Western blotting, and tube formation assays. Results. Immunohistochemical staining showed that the CD34+CD117+ cells were located within the adventitia of HGSVs, and many CD34+ and CD117+ cells have emerged in the human venous thrombi. The number of progenitor cells within the marginal area of 7 days mice thrombi was shown to be Sca1+ ≈21%, CD34+ ≈12%, CD117+ ≈9%, and Flk1+ ≈5%. Many CD34+adventitial progenitor cells have migrated into the decellularized vessels. FACS showed that the number of CD34+CD117+ HGSV-AdPC in primary cultured cells as 1.2 ± 0.07 %. After CD34+CD117+HGSV-AdPC were transplanted into the adventitia of nude mice vena cava with venous thrombi, the organization rate, nucleate cell count, endothelial cells, and macrophage cells of thrombi were shown to be significantly increased. The transplanted CD34+CD117+ HGSV-AdPC at the adventitia have crossed the vein wall, entered the venous thrombi, and differentiated into endothelial cells. The CD34+CD117+ HGSV-AdPC in the culture medium in the presence of VEGF-promoted gene and protein expression of endothelial cell markers in vitro and induced tube formation. Conclusions. HGSV-AdPC could cross the vein wall and migrate from the adventitia into the venous thrombi. Increased HGSV-AdPC in the adventitia has enhanced the resolution of venous thrombi via differentiating into endothelial cells of neovascularization. [ABSTRACT FROM AUTHOR]

Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100–300 μm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo, sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography–tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer. [ABSTRACT FROM AUTHOR]

Background: Distraction osteogenesis has been broadly used to treat various structural bone deformities and defects. However, prolonged healing time remains a major problem. Various approaches including the use of low-intensity pulsed ultrasound, parathyroid hormone, and bone morphogenetic proteins (BMPs) have been studied to shorten the treatment period with limited success. Our previous studies of rats have reported that the transcutaneous application of CO2 accelerates fracture repair and bone-defect healing in rats by promoting angiogenesis, blood flow, and endochondral ossification. This therapy may also accelerate bone generation during distraction osteogenesis, but, to our knowledge, no study investigating CO2 therapy on distraction osteogenesis has been reported.Questions/purposes: We aimed to investigate the effect of transcutaneous CO2 during distraction osteogenesis in rabbits, which are the most suitable animal as a distraction osteogenesis model for a lengthener in terms of limb size. We asked: Does transcutaneous CO2 during distraction osteogenesis alter (1) radiographic bone density in the distraction gap during healing; (2) callus parameters, including callus bone mineral content, volumetric bone mineral density, and bone volume fraction; (3) the newly formed bone area, cartilage area, and angiogenesis, as well as the expression of interleukin-6 (IL-6), BMP-2, BMP-7, hypoxia-inducible factor (HIF) -1α, and vascular endothelial growth factor (VEGF); and (4) three-point bend biomechanical strength, stiffness, and energy?Methods: Forty 24-week-old female New Zealand white rabbits were used according to a research protocol approved by our institutional ethical committee. A distraction osteogenesis rabbit tibia model was created as previously described. Briefly, an external lengthener was applied to the right tibia, and a transverse osteotomy was performed at the mid-shaft. The osteotomy stumps were connected by adjusting the fixator to make no gap. After a 7-day latency phase, distraction was continued at 1 mm per day for 10 days. Beginning the day after the osteotomy, a 20-minute transcutaneous application of CO2 on the operated leg using a CO2 absorption-enhancing hydrogel was performed five times per week in the CO2 group (n = 20). Sham treatment with air was administered in the control group (n = 20). Animals were euthanized immediately after the distraction period (n = 10), 2 weeks (n = 10), and 4 weeks (n = 20) after completion of distraction. We performed bone density quantification on the plain radiographs to evaluate consolidation in the distraction gap with image analyzing software. Callus parameters were measured with micro-CT to assess callus microstructure. The newly formed bone area and cartilage area were measured histologically with safranin O/fast green staining to assess the progress of ossification. We also performed immunohistochemical staining of endothelial cells with fluorescein-labeled isolectin B4 and examined capillary density to evaluate angiogenesis. Gene expressions in newly generated callus were analyzed by real-time polymerase chain reaction. Biomechanical strength, stiffness, and energy were determined from a three-point bend test to assess the mechanical strength of the callus.Results: Radiographs showed higher pixel values in the distracted area in the CO2 group than the control group at Week 4 of the consolidation phase (0.98 ± 0.11 [95% confidence interval 0.89 to 1.06] versus 1.19 ± 0.23 [95% CI 1.05 to 1.34]; p = 0.013). Micro-CT demonstrated that bone volume fraction in the CO2 group was higher than that in the control group at Week 4 (5.56 ± 3.21 % [95% CI 4.32 to 6.12 %] versus 11.90 ± 3.33 % [95% CI 9.63 to 14.25 %]; p = 0.035). There were no differences in any other parameters (that is, callus bone mineral content at Weeks 2 and 4; volumetric bone mineral density at Weeks 2 and 4; bone volume fraction at Week 2). At Week 2, rabbits in the CO2 group had a larger cartilage area compared with those in the control group (2.09 ± 1.34 mm [95% CI 1.26 to 2.92 mm] versus 5.10 ± 3.91 mm [95% CI 2.68 to 7.52 mm]; p = 0.011). More newly formed bone was observed in the CO2 group than the control group at Week 4 (68.31 ± 16.32 mm [95% CI 58.19 to 78.44 mm] versus 96.26 ± 19.37 mm [95% CI 84.25 to 108.26 mm]; p < 0.001). There were no differences in any other parameters (cartilage area at Weeks 0 and 4; newly formed bone area at Weeks 0 and 2). Immunohistochemical isolectin B4 staining showed greater capillary densities in rabbits in the CO2 group than the control group in the distraction area at Week 0 and surrounding tissue at Weeks 0 and 2 (distraction area at Week 0, 286.54 ± 61.55 /mm [95% CI 232.58 to 340.49] versus 410.24 ± 55.29 /mm [95% CI 361.78 to 458.71]; p < 0.001; surrounding tissue at Week 0 395.09 ± 68.16/mm [95% CI 335.34 to 454.83] versus 589.75 ± 174.42/mm [95% CI 436.86 to 742.64]; p = 0.003; at Week 2 271.22 ± 169.42 /mm [95% CI 122.71 to 419.73] versus 508.46 ± 49.06/mm [95% CI 465.45 to 551.47]; p < 0.001 respectively). There was no difference in the distraction area at Week 2. The expressions of BMP -2 at Week 2, HIF1-α at Week 2 and VEGF at Week 0 and 2 were greater in the CO2 group than in the control group (BMP -2 at Week 2 3.84 ± 0.83 fold [95% CI 3.11 to 4.58] versus 7.32 ± 1.63 fold [95% CI 5.88 to 8.75]; p < 0.001; HIF1-α at Week 2, 10.49 ± 2.93 fold [95% CI 7.91 to 13.06] versus 20.74 ± 11.01 fold [95% CI 11.09 to 30.40]; p < 0.001; VEGF at Week 0 4.80 ± 1.56 fold [95% CI 3.43 to 6.18] versus 11.36 ± 4.82 fold [95% CI 7.13 to 15.59]; p < 0.001; at Week 2 31.52 ± 8.26 fold [95% CI 24.27 to 38.76] versus 51.05 ± 15.52 fold [95% CI 37.44 to 64.66]; p = 0.034, respectively). There were no differences in any other parameters (BMP-2 at Week 0 and 4; BMP -7 at Weeks 0, 2 and 4; HIF-1α at Weeks 0 and 4; IL-6 at Weeks 0, 2 and 4; VEGF at Week 4). In the biomechanical assessment, ultimate stress and failure energy were greater in the CO2 group than in the control group at Week 4 (ultimate stress 259.96 ± 74.33 N [95% CI 167.66 to 352.25] versus 422.45 ± 99.32 N [95% CI 299.13 to 545.77]; p < 0.001, failure energy 311.32 ± 99.01 Nmm [95% CI 188.37 to 434.25] versus 954.97 ± 484.39 Nmm [95% CI 353.51 to 1556.42]; p = 0.003, respectively). There was no difference in stiffness (216.77 ± 143.39 N/mm [95% CI 38.73 to 394.81] versus 223.68 ± 122.17 N/mm [95% CI 71.99 to 375.37]; p = 0.92).Conclusion: Transcutaneous application of CO2 accelerated bone generation in a distraction osteogenesis model of rabbit tibias. As demonstrated in previous studies, CO2 treatment might affect bone regeneration in distraction osteogenesis by promoting angiogenesis, blood flow, and endochondral ossification.Clinical Relevance: The use of the transcutaneous application of CO2 may open new possibilities for shortening healing time in patients with distraction osteogenesis. However, a deeper insight into the mechanism of CO2 in the local tissue is required before it can be used in future clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of the vascular endothelial growth factor inhibitor conbercept (KH902) on corneal neovascularization and wound healing following penetrating keratoplasty in rabbits. Methods: Conbercept was administered to New Zealand white rabbits through topical and subconjunctival routes. Corneal neovascularization and wound healing were examined by slit-lamp photography and histological analyses. The expressions of vascular endothelial growth factor inhibitor, α-smooth muscle actin, and keratocan in the corneal grafts were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Results: The anterior segment photographs demonstrated that corneal neovascularization started in the 2nd week. In the 4th week, histologically, the superficial corneal stroma layer showed disordered arrangement, and there were large numbers of dense inflammatory cells and blood vessels in the stroma layer. Vascular endothelial growth factor in the experimental groups was significantly decreased at all time points compared with the control group (both P = 0.001). Expression of α-smooth muscle actin in corneal grafts demonstrated an increase in time even it was lower in experimental groups, but the difference was not statistically significant (P equaled to 0.507 and 0.723, respectively). There were no significant differences with the expression of keratocan in all groups except that it significantly declined at the 4th week as to the second week in all groups and P values were 0.022, 0.020 and 0.014 in control (C), topical (E1), and subconjunctival (E2) group, respectively. Conclusion: The study found that conbercept inhibited the formation of corneal neovascularization without affecting keratocan-mediated corneal wound healing and there were no significant differences between topical administration of different doses of conbercept on the rabbit corneal neovascularization after penetrating keratoplasty in this study. [ABSTRACT FROM AUTHOR]

In this study bevacizumab was labeled with 99mTc using p-SCN-Bzl-TCMC as a chelator for non invasive imaging of VEGF receptor in ovarian tumor Sprague Dawley rat and New Zealand rabbit models. High radiochemical purity and stability were observed using 0.4 mL of conjugated TCMC-bevacizumab. In vitro binding studies showed higher uptake of labeled conjugated bevacizumab with high metastatic SKOV-3 ipl cells as compared to poor metastatic SKOV-3. Biodistribution in rat model confirmed higher accumulation of labeled conjugated bevacizumab in the site infected with SKOV-3 ipl cells as compared to SKOV-3. Images of ovarian tumor rabbit model validated its specificity and efficacy as a promising ovarian tumor imaging agent. [ABSTRACT FROM AUTHOR]

Vasospasm after subarachnoid hemorrhage (SAH) plays a vital role in the development of delayed cerebral ischemia. Anti- vascular endothelial growth factor (VEGF) antibodies, like bevacizumab (BEV), may attenuate VEGF-stimulated angiogenesis, reduced vascular cell proliferation, and improve vasospasm after SAH. Thirty-two adult male New Zealand white rabbits were randomly divided into 4 groups of 8 rabbits in each group: group 1 (control); group 2 (SAH); group 3 (SAH + vehicle); and group 4 (SAH + BEV). BEV (5 mg/kg, intraperitoneally) was administered 5 minutes after the intracisternal blood injection and continued for 72 hours once per day in the same dose for group 4. Animals were sacrificed 72 hours after SAH. Basilar artery cross-sectional areas, arterial wall thicknesses, and hippocampal degeneration scores were evaluated in all groups. VEGF is associated with the narrowing of the basilar artery. Treatment with BEV statistically significantly increased the cross-sectional area of the basilar artery when compared with the SAH and the vehicle groups. Basilar artery wall thicknesses in the BEV group was statistically significant smaller than in the SAH and vehicle groups. The hippocampal degeneration scores for the BEV and control groups were similar and significantly lower than those for the SAH and vehicle groups. Cellular proliferation and subsequent vessel wall thickening is a reason to delay cerebral ischemia and deterioration of the neurocognitive function. Intraperitoneal administration of BEV was found to attenuate cerebral vasospasm and prevent delayed cerebral ischemia and improve neurocognitive function after SAH in rabbits. [ABSTRACT FROM AUTHOR]

Background. Angiogenesis is a prerequisite step to achieve the success of bone regeneration by tissue engineering technology. Previous studies have shown the role of cerebrospinal fluid pulsation (CSFP) stress in the reconstruction of tissue-engineered laminae. In this study, we investigated the role of CSFP stress in the angiogenesis of tissue-engineered laminae. Methods. For the in vitro study, a CSFP bioreactor was used to investigate the impact of CSFP stress on the osteogenic mesenchymal stem cells (MSCs). For the in vivo study, forty-eight New Zealand rabbits were randomly divided into the CSFP group and the Non-CSFP group. Tissue-engineered laminae (TEL) was made by hydroxyapatite-collagen I scaffold and osteogenic MSCs and then implanted into the lamina defect in the two groups. The angiogenic and osteogenic abilities of newborn laminae were examined with histological staining, qRT-PCR, and radiological analysis. Results. The in vitro study showed that CSFP stress could promote the vascular endothelial growth factor A (VEGF-A) expression levels of osteogenic MSCs. In the animal study, the expression levels of angiogenic markers in the CSFP group were higher than those in the Non-CSFP group; moreover, in the CSFP group, their expression levels on the dura mater surface, which are closer to the CSFP stress stimulation, were also higher than those on the paraspinal muscle surface. The expression levels of osteogenic markers in the CSFP group were also higher than those in the Non-CSFP group. Conclusion. CSFP stress could promote the angiogenic ability of osteogenic MSCs and thus promote the angiogenesis of tissue-engineered laminae. The pretreatment of osteogenic MSC with a CSFP bioreactor may have important implications for vertebral lamina reconstruction with a tissue engineering technique. [ABSTRACT FROM AUTHOR]

Background. Although Botulinum Toxin Type A (BTXA) has been applied to scar prevention and treatment, the mechanisms still require further exploration. Objective. To investigate the effects of BTXA on microvessels in the hypertrophic scar models on rabbit ears. Methods. Eight big-eared New Zealand rabbits (males or females) were selected to establish scar models. One ear of each rabbit (4 models in each ear) was selected randomly to be injected with BTXA immediately after modeling and included in the treated group, while the opposite ear was untreated and included in the control group. The growth of scars in each group was observed and recorded, and 4 rabbits were sacrificed on days 30 and 45 after modeling. Then, scar height was measured by hematoxylin-eosin (HE) staining, vascular endothelial growth factor (VEGF) expression was detected by immunohistochemical (IHC) testing, and microvessel density (MVD) was calculated based on CD34 (human hematopoietic progenitor cell antigen). Results. The wounds in each group were well healed and free from infection or necrosis. On days 30 and 45, the scar height, MVD value, and VEGF expression in the treated group were lower than those in the control group (P < 0.05). For the treated group, the above indicators on day 45 were lower than on day 30 (P > 0.05). Besides, there was a positive correlation between the MVD value and the VEGF expression in the treated group (P < 0.05). Conclusion. The injection of BTXA immediately after modeling inhibits VEGF expression and reduces angiogenesis, thereby inhibiting hypertrophic scar formation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Studies have shown that platelet-rich plasma has a strong role in promoting chondrocyte repair and proliferation. OBJECTIVE: To investigate the efficacy of platelet-rich plasma in chondrocyte repair and synovial inflammation inhibition in osteoarthritis. METHODS: The blood samples were extracted from the central artery of the ear in 40 New Zealand white rabbits and platelet-rich plasma was prepared by the method of Hokugo. The platelet, platelet-derived growth factor, transfonning growth factor-~, vascular endothelial growth factor in the peripheral blood and platelet-rich plasma were detected simultaneously. Animal models were made by resection of anterior cruciate ligament and divided into experimental group and control group. In the experimental group, 0.3 ml of platelet-rich plasma was injected once a week for 1 O weeks; in the control group, 0.3 ml of sterile saline was injected once a week for 10 weeks. Gross observation and histological observation of knee joints were perfonned: articular cartilage type 11 collagen and matrix metalloproteinase 13 levels were measured: and Mankin score of the cartilage tissue was perfonned at 2, 4, 6, 8, and 1 O weeks after injection. The study protocol was approved by the Animal Experiment Ethics Committee of Chongqing Medical University. RESULTS AND CONCLUSION: (1) The concentrations of platelet, platelet-derived growth factor, transforming growth factor-β. vascular endothelial growth factor in platelet-rich plasma were 5.5, 4.8, 7.7, and 6.2 times those of the peripheral blood, respectively. And there were significant differences between the platelet-rich plasma and peripheral blood (P < 0.05). (2) From the 6th week, the Mankin score of the experimental group was significantly lower than that of the control group (P < 0.05). (3) The expression of type II collagen protein in the experimental group was significantly higher than that in the control group at the 4th, 6th, 8th and 10th weeks after injection (P < 0.05). The expression of matrix metalloproteinase-13 was significantly lower than that in the control group at the 2nd, 4th, 6th, 8th and 10th week (P < 0.05). All these findings indicate that intra-articular injection of platelet-rich plasma can inhibit the development of osteoarthritis by alleviating synovial inflammation and delaying or blocking the damage of chondrocytes. [ABSTRACT FROM AUTHOR]

Background: The integration of the tendon graft within the bone tunnel is one of the decisive success factors of the Anterior Cruciate Ligament (ACL) reconstruction. In ACL reconstruction that uses tendons as graft, the healing process that occurs in the bone tunnel is healing with fibrotic tissue.Aim: This study aims to determine the role of bone marrow mesenchymal stem cells and vascular endothelial growth factor intraarticularly in improving the biomechanical strength.Methods: This study uses experimental research design by using animal as a testing tool. The animals used in this study are male New Zealand white rabbits (Oryctolagus cuniculus), with the weight ranging of 2000 grams up to 3000 grams.Results: From the experiment, all samples from both treatment and control groups were all evaluated and no post-operative complication was found. At the evaluation time of 3 weeks, the difference between the mean of maximum strain rate between the treatment group and the control group was not statistically significant (p >0.05). At the evaluation time of 6 weeks, it was found that the difference in mean value of the maximum strain load force between the treatment groups versus the group was statistically significant.Conclusions: From this study, it can be concluded that intraarticular BM-MSC and VEGF administration can increase the ultimate tension strength of postoperative graft tendon rosary ACL reconstruction. [ABSTRACT FROM AUTHOR]

Background: Aloe vera was used to enhance defense mechanisms, and it has a variety of components that affected on periodontal healing and other oral condition .It was used also around dental implants to control inflammation from bacteria contamination. Vascular endothelial growth factor(VEGF) is of particular interest because of its ability to induce neovascularization (angiogenesis), VEGF also acts to recruit and activate osteoclasts as well as stimulate osteoblast chemotaxis, differentiation, and matrix mineralization. Aim of study: The objective of this research was to illustrate the biological actions of topical application of aloe vera and growth factor VEGF on implant tissue contact surface which is involved in osseointegration . Materials and Method: Commercially pure Titanium(cpTi) implants with aloe vera /and VEGF,were placed in the tibia of (24) New Zealand white rabbits, Mechanical test (torque removal test) was performed as an indicator for the presence of osseointegration and bone implant contact (BIC)measurement as a test for the property of bone-implant interface. Histological investigation was performed on all the implants of both control and experimental groups at (1,2, and 6weeks) healing intervals. Results: Findings illustrated that removal torque mean and BIC values in experimental implant showed high value in comparison to control. Histological results show an early bone deposition and early maturation in combination group . Conclusions: Bone formation &maturation was accelerated by adding biological materials and using a combination of Aloe Vera and VEGF is a powerful tool for enhancement of osseointegration. [ABSTRACT FROM AUTHOR]

Resident/endogenous mesenchymal stromal cells function to promote the normal development, growth, and repair of tissues. Following premature birth, the effects of routine neonatal care (e.g. oxygen support and mechanical ventilation) on the biological properties of lung endogenous mesenchymal stromal cells is (L-MSCs) is poorly understood. New Zealand white preterm rabbits were randomized into the following groups: (i) sacrificed at birth (Fetal), (ii) spontaneously breathing with 50% O2 for 4 hours (SB), or (iii) mechanical ventilation with 50% O2 for 4h (MV). At time of necropsy, L-MSCs were isolated, characterized, and compared. L-MSCs isolated from the MV group had decreased differentiation capacity, ability to form stem cell colonies, and expressed less vascular endothelial growth factor mRNA. Compared to Fetal L-MSCs, 98 and 458 genes were differentially expressed in the L-MSCs derived from the SB and MV groups, respectively. Gene ontology analysis revealed these genes were involved in key regulatory processes including cell cycle, cell division, and angiogenesis. Furthermore, the L-MSCs from the SB and MV groups had smaller mitochondria, nuclear changes, and distended endoplasmic reticula. Short-term hyperoxia/mechanical ventilation after birth alters the biological properties of L-MSCs and stimulates genomic changes that may impact their reparative potential. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the effect of Hypericum perforatum (HP) oil on wound-healing process in rabbit palatal mucosa. Materials and Methods: Thirty-six New Zealand albino rabbits were randomly allocated to following groups; (1) HP oil (test, n = 18) and (2) olive oil (control, n = 18). Palatinal excisional wounds were created and the oils were topically applied (0.1 ml, 30 s, twice a day). Gingival biopsies were excised, and analyzed for re-epithelialization (RE) and granulation tissue maturation (GTM) on days 3, 7, and 14 after surgery. Levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) were assessed using the immunohistochemical method. Apoptotic cells (ACs) were evaluated using TUNEL staining. Enzyme-linked immunosorbent assay was used to assess tissue catalase (CAT) and malondialdehyde (MDA) levels. Results: RE and GTM were completed earlier in the HP oil group than in the control group. The number of positively stained cells/vessels was higher in olive oil than in the test group on day 3 for FGF-2 and on days 3 and 7 for VEGF (p < 0.05). In contrast, on day 14, a higher number of vessels was observed in the HP oil group than in the control group. HP oil treatment reduced the number of ACs compared to olive oil (p < 0.05), but the difference during the healing period did not reach significance. Tissue CAT and MDA levels between groups were not different, and also the results were the same when the levels were analyzed by the evaluated time periods (p > 0.05). Conclusions: The results of this study demonstrated that topical HP oil treatment did not provide an additional benefit to its base, olive oil, in the early phase of secondary wound healing. [ABSTRACT FROM AUTHOR]

Statins may precipitate the onset of type 2 diabetes (T2D) in high-risk patients. In contrast, only the subset of individuals with insulin resistance and/or diabetes receives cardiovascular benefits with fibrates. In this context, previous observations from our laboratory suggested that atorvastatin induced an increase in visceral adipose tissue (VAT), whereas fenofibrate had the opposite effects in rabbits. Therefore, we determined the mass, morphology, and vascularization of VAT in New Zealand white rabbits (n = 6/group) that received 0.33 or 2.6 mg/kg/d of atorvastatin or fenofibrate, respectively, during 2 months. As expected, the cholesterol from the atorvastatin group was lower after treatment, while triglycerides decreased in the fenofibrate group. The mass of VAT from the fenofibrate group was 46% lower compared to the controls, meanwhile atorvastatin was associated with a larger diameter of adipocytes (+65%) than that of the control and fenofibrate groups. Fibroblast growth factor 2 (FGF2) gene expression was lower in the fenofibrate group than in the control group (-54%). By contrast, vascular endothelial growth factor A (VEGF-A) gene expression in fenofibrate-treated rabbits was 110% higher than in the control group. In agreement with the gene expression, the marker of angiogenesis platelet endothelial cell adhesion molecule 1 was slightly but significantly higher (+10%) in rabbits treated with fenofibrate than in controls, as determined by immunohistochemistry. These results suggest that fenofibrate is associated with a favorable remodeling of VAT, that is, reduced mass and increased vascularization in normolipemic rabbits; in contrast, atorvastatin induced a nonfavorable remodeling of VAT. These results may be related to the cardiovascular benefits of fenofibrate and the increased risk of T2D in high-risk patients induced by atorvastatin. [ABSTRACT FROM AUTHOR]

Introduction: There is growing evidence for a preventative effect of resistance training on cognitive decline through physiological mechanisms; yet, the effect of resistance training on resting growth factors and homocysteine levels is incompletely understood. This study aimed to investigate the effect of intense resistance training, for 12 weeks, on changes in peripheral growth factors and homocysteine in late middle-aged adults. Methods: 45 healthy adults were enrolled into the single-site parallel groups' randomized-controlled trial conducted at the Department of Exercise Science, Strength and Conditioning Laboratory, Murdoch University. Participants were allocated to the following conditions: (1) high-load resistance training (n = 14), or (2) moderate-load resistance training (n = 15) twice per week for 12 weeks; or (3) non-exercising control group (n = 16). Data were collected from September 2016 to December 2017. Fasted blood samples were collected at baseline and within 7 days of trial completion for the analysis of resting serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1, vascular endothelial growth factor, and plasma homocysteine levels. Results: No differences in baseline to post-intervention change in serum growth factors or plasma homocysteine levels were observed between groups. A medium effect was calculated for BDNF change within the high-load condition alone (+ 12.9%, g = 0.54). Conclusions: High-load or moderate-load resistance training twice per week for 12 weeks has no effect on peripheral growth factors or homocysteine in healthy late middle-aged adults. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12616000690459. [ABSTRACT FROM AUTHOR]

Objectives: T o assess the effects of anti-vascular endothelial growth factor (VEGF) drugs on retinal pigment epithelium cell culture. Materials and Methods: Aflibercept (0.5 mg/mL), bevacizumab (0.3125 mg/mL), and ranibizumab (0.125 mg/mL) were applied to retinal pigment epithelium cell cultures isolated from the enucleated eyes of New Zealand white rabbits. Viability, apoptosis, proliferation, and senescence of the cells were evaluated in control and drug-treated cultures at the end of 72 hours. Results: Cells treated with aflibercept showed increased viability and decreased apoptosis compared to the control culture and both the bevacizumab- and ranibizumab-treated groups (p<0.05). Statistically increased apoptosis and decreased viability were found in the bevacizumab and ranibizumab-treated groups compared with the control group (p<0.05). There were no statistically significant differences in cell proliferation and senescence between the groups (p>0.05). Conclusion: Anti-VEGF drugs did not affect senescence or proliferation of retinal pigment epithelium cells. Aflibercept was found to decrease apoptosis and increase cell viability, while ranibizumab and bevacizumab increased apoptosis and reduced cell viability in retinal pigment epithelium culture. [ABSTRACT FROM AUTHOR]

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Healing is delayed in limb wounds relative to body wounds of horses, partly because of sustained inflammation and inefficient angiogenesis. In laboratory animals, proteins derived from orf virus modulate these processes and enhance healing. We aimed to compare immune cell trafficking and the inflammatory, vascular, and epidermal responses in body and limb wounds of horses and then to investigate the impact of orf virus interleukin-10 and vascular endothelial growth factor-E on these processes. Standardized excisional wounds were created on the body and forelimb of horses and their progression monitored macroscopically until healed. Tissue samples were harvested to measure the expression of genes regulating inflammation and repair (quantitative polymerase chain reaction) and to observe epithelialization (histology), innate immune cell infiltration, and angiogenesis (immunofluorescence). Delayed healing of limb wounds was characterized by intensified and extended pro-inflammatory signaling and exacerbated innate immune response, concomitant with the absence of anti-inflammatory eIL-10. Blood vessels were initially more permeable and then matured belatedly, concomitant with retarded production of angiogenic factors. Epithelial coverage was achieved belatedly in limb wounds. Viral proteins were administered to wounds of one body and one limb site/horse at days 1-3, while wounds at matching sites served as controls. Treatment dampened pro-inflammatory gene expression and the innate immune response in all wounds. It also improved angiogenic gene expression, but primarily in body wounds, where it altered blood vessel density and myofibroblast persistence. Moreover, the viral proteins increased epithelialization of all wounds. The short-term viral protein therapy did not, however, improve the healing rate of wounds in either location, likely due to suboptimal dosing. In conclusion, we have further detailed the processes contributing to protracted healing in limb wounds of horses and shown that short-term administration of viral proteins exerts several promising though transient effects that, if optimized, may positively influence healing. [ABSTRACT FROM AUTHOR]

Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-stabilizing agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in Matrigel™ was also inhibited in a dose-dependent manner with an IC of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16-18 h incubations for both stabilizing agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop. [ABSTRACT FROM AUTHOR]

To study the relationship between vascular endothelial growth factor (VEGF) and formation and repair of engineering bone, second-generation bone marrow stromal cells (BMSCs) of New Zealand white rabbits that were separated in vitro were transfected with VEGF 165 gene vectors by adenovirus to detect gene expressions. Transfected BMSCs and β-tricalcium phosphate material were complexed and implanted at the femoral injury sites of the study group (n = 12), and the control group (n = 12) were implanted with engineering bones that were not transfected with VEGF. Femoral recoveries of the two groups were observed on the 15th, 30th, 45th and 60th days, and their vascularization and ossification statuses were observed by immunohistochemical methods. The BMSCs transfected with VEGF highly expressed VEGF genes and excreted VEGF. The two groups both experienced increased vascularization and bone volume after implantation (t = 7.92, P<0.05), and the increases of the study group were significantly higher than those of the control group (t = 6.92, P<0.05). VEGF is clinically applicable because it can accelerate the formation and repair of engineering bone by promoting vascularization and ossification. [ABSTRACT FROM AUTHOR]

Abstract: Parapoxvirus of red deer in New Zealand (PVNZ), a species of the Parapoxvirus genus, causes scabby lesions on the skin and the velvet of red deer. The three other species of the genus have each been shown to encode homologs of vascular endothelial growth factor (VEGF). We report here that PVNZ strain RD86 also encodes a VEGF and that the predicted PVNZ protein shows only 37–54% amino acid identity to VEGFs encoded by the other species of the genus. Despite this extensive sequence divergence, assays of purified PVNZ VEGF (PVNZRD86VEGF) demonstrated that it shares the unique VEGF receptor (VEGFR) binding profile of the other parapoxvirus VEGFs, in that it binds VEGFR-2 and induces VEGFR-2-mediated proliferation of Ba/F3-derived cells, but does not bind VEGFR-1 or VEGFR-3. In contrast to some other viral VEGFs, it does not bind neuropilin-1. Our results indicate that PVNZRD86VEGF is a biologically active member of the VEGF family and is likely to contribute to the proliferative and highly vascularized nature of PVNZ lesions. Our data also reveal that all members of the genus encode a VEGF and that an extraordinary degree of inter-species sequence variation is a general feature of the parapoxvirus VEGFs. [Copyright &y& Elsevier]

Cinchonine is practically insoluble in water, slightly soluble in chloroform and alcohol, so that penetration of cinchonine passes through the transfollicular into the dermal papillae is low. Thus, it requires a delivery system that can reduce the hydrophobicity and increase the penetration of cinchonine into the dermal papillae. Niosomes is a vesicle system that able to reduce hydrophobicity and increase cinchonine penetration into the dermal papillae. The aim of this study was formulation and activity test of cinchonine niosomes as hair growth stimulants. Cinchonine niosomes was made by using thin layer hydration method. Formulation of cinchonine niosomes was Span 60 100 µmol, cinchonine 0,03% w/v and cholesterol 15% from the total number of surfactants. The stability test of cinchonine niosomes was stored at room temperature and 40oC, humidity level of 75% for 28 days with 7-day observation interval. The in vivo test included the irritation test using male rabbits of New Zealand strain with observation interval 1, 24, 48 and 72 hours, and the activity test of the hair growth stimulant using male guinea pig of Hartley strain for 14 days with 2-day observation interval. The result of the stability test showed that the cinchonine niosomes had good stability was seen from the vesicle size parameter of 200 - 350 nm, vesicle polydispersity index 0,250 - 0,450 and the entrapment efficiency of cinchonine 83 - 85%. The result of irritation test showed that cinchonine was non-irritant with erythema and edema index of 0. The result of activity test showed that cinchonine had activity as hair growth stimulant was seen from the hair length of test area was 17-43% lengthier than the control area (p<0.05) and the number of hairs was 22- 30% more than the control area. Cinchonine stimulates hair growth by telangiectasis through the mechanism of angiogenesis and vasodilation of blood. Cinchonine stimulates the production of Vascular Endothelial Growth Factor (VEGF) cytokines produced by endothelial cells that play a role in the vasodilation process and stimulates new blood formation, thereby increasing the supply of nutrients and oxygen needed for hair growth and regeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: Postfracture treatment with nonsteroidal anti-inflammatory drugs might result in delayed healing. This study was aimed to evaluate and compare the effects of flunixin meglumine (FM) and ketoprofen on bone fracture healing in rabbits. A simple unilateral diaphyseal fracture was made and followed by fixation by K-wire. Healing was evaluated with radiography, histopathology, and immunohistochemistry. Interestingly, the results revealed that FM enhanced bone fracture healing combined with the activation of early collagen deposition, marked angiogenesis, and enhanced vascular endothelial growth factor. However, ketoprofen delayed bone fracture healing. These findings provide novel baseline information about the potential beneficial effects of FM on bone fracture healing cases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used postoperative analgesics, antipyretics, and anti-inflammatories, and they help prevent blood clotting. However, most NSAIDs delay bone healing. This study was aimed to investigate bone healing in a rabbit animal model by assessing the ability of flunixin meglumine (FM) and ketoprofen to induce fracture healing by examining histology, radiological changes, and vascular endothelial growth factor (VEGF) immunostaining during bone healing. For this purpose, 24 New Zealand rabbits were assigned to three groups: the control group, the FM group, and the ketoprofen group. Our results revealed that there were no intraoperative complications, and all surviving rabbits achieved full-weight bearing. Significant periosteal reaction and callus formation were confirmed at 2 postoperative weeks. Interestingly, FM enhanced callus formation, bone union, and remodeling in the FM group compared to the control and ketoprofen groups. FM enhanced bone healing through early collagen deposition and marked angiogenesis process activation by increasing the expression of VEGF. Our findings demonstrated, for the first time, the potential imperative action of FM in the bone healing process rather than other NSAIDs in animals. [ABSTRACT FROM AUTHOR]

Prosthetic mesh infection is a devastating complication of abdominal hernia repair which impairs natural healing in the implant area, leading to increased rates of patient morbidity, mortality, and prolonged hospitalization. This preclinical study was designed to assess the effects on abdominal wall tissue repair of coating meshes with a chlorhexidine or rifampicin-carboxymethylcellulose biopolymer gel in a Staphylococcus aureus (S. aureus) infection model. Partial abdominal wall defects were created in New Zealand white rabbits (n = 20). Four study groups were established according to whether the meshes were coated or not with each of the antibacterial gels. Three groups were inoculated with S. aureus and finally repaired with lightweight polypropylene mesh. Fourteen days after surgery, implanted meshes were recovered for analysis of the gene and protein expression of collagens, macrophage phenotypes, and mRNA expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Compared to uncoated meshes, those coated with either biopolymer gel showed higher collagen 1/3 messenger RNA and collagen I protein expression, relatively increased VEGF mRNA expression, a significantly reduced macrophage response, and lower relative amounts of MMPs mRNAs. Our findings suggest that following mesh implant these coatings may help improving abdominal wall tissue repair in the presence of infection. [ABSTRACT FROM AUTHOR]

The study aimed to evaluate the intraocular pharmacokinetics and efficacy of aflibercept after subconjunctival injection in animal models for treating choroidal neovascularization (CNV) associated with Age-Related Macular Degeneration (AMD). New Zealand albino rabbits received aflibercept (2000 μg/50 μl) in one eye, and the other eye was used as control. At 7, 14, 21 and 28 days, the animals were sacrificed to dissect the ocular tissues, and serum was collected at 1hr, 3 h, 1, 7, 14, 21 and 28 days. The concentration of aflibercept in various ocular tissues and serum were measured using the immunoassay technique. The concentration maximum (C max) at the Retinal Pigment Epithelium (RPE)-choroid complex and retina in treated eyes was 261.55 and 33.83 ng/gm, respectively. The area under the curve (AUC 0-last) for RPE-Choroid and retina were 2094.02 and 290.33 days. ng/gm respectively. The time maximum (T max) for the ocular tissues was reached on day 7. In the vitreous humour, a lower level of aflibercept was retrieved. The C max (1766.84 ng/mL) in the serum was reached on day 1, followed by a decline in the concentration till the end of the study period. In treated eyes, the levels of aflibercept in most of the ocular tissues were maintained for at least 21 days above the invitro IC 50 concentration. The results of the efficacy study show that subconjunctival aflibercept could reach the therapeutic target to inhibit CNV. The subconjunctival aflibercept could be a less invasive route for treating CNV with AMD. • A delivery system that could release aflibercept in the subconjunctival space for a longer period, as well to protect it from the conjunctival clearance to avoid increased systemic exposure would be highly beneficial. • The subconjunctival aflibercept could be a less invasive route for treating chorioretinal diseases. [ABSTRACT FROM AUTHOR]