Neuropathic Pain After Dental Implant Surgery: Literature Review and Proposed Algorithm for Medicosurgical Treatment.

The objective of this study is to establish an algorithm for the medicosurgical treatment of dental implant-induced neuropathic pain. The methodology was based on the good practice guidelines from the French National Authority for Health: the data were searched on the Medline database. A working group has drawn up a first draft of professional recommendations corresponding to a set of qualitative summaries. Consecutive drafts were amended by the members of an interdisciplinary reading committee. A total of 91 publications were screened, of which 26 were selected to establish the recommendations: 1 randomized clinical trial, 3 controlled cohort studies, 13 case series, and 9 case reports. In the event of the occurrence of post-implant neuropathic pain, a thorough radiological assessment by at least a panoramic radiograph (orthopantomogram) or especially a cone-beam computerized tomography scan is recommended to ensure that the tip of the implant is placed more than 4 mm from the anterior loop of the mental nerve for an anterior implant and 2 mm from the inferior alveolar nerve for a posterior implant. Very early administration of high-dose steroids, possibly associated with partial unscrewing or full removal of the implant preferably within the first 36-48 hours after placement, is recommended. A combined pharmacological therapy (anticonvulsants, antidepressants) could minimize the risk of pain chronicization. If a nerve lesion occurs in the context of dental implant surgery, treatment should be initiated within the first 36-48 hours after implant placement, including partial or full removal of the implant and early pharmacological treatment.

Preconditioning of surgical pedicle flaps with DNA plasmid expressing hypoxia-inducible factor-1α (HIF-1α) promotes tissue viability.

Ischemic necrosis of surgical flaps after reconstruction is a major clinical problem. Hypoxia-inducible factor-1α (HIF-1α) is considered the master regulator of the adaptive response to hypoxia. Among its many properties, it regulates the expression of genes encoding angiogenic growth factors, which have a short half-life in vivo. To achieve a continuous application of the therapeutic, we utilized DNA plasmid delivery. Transcription of the DNA plasmid confirmed by qRT-PCR showed significantly increased mRNA for HIF-1α in the transfected tissue compared to saline control tissue. Rats were preconditioned by injecting with either HIF-1α DNA plasmid or saline intradermally in the designated flap region on each flank. Seven days after preconditioning, each rat had two isolated pedicle flaps raised with a sterile silicone sheet implanted between the skin flap and muscle layer. The flaps preconditioned with HIF-1α DNA plasmid had significantly less necrotic area. Angiogenesis measured by CD31 staining showed a significant increase in the number of vessels per high powered field in the HIF-1α group (p < 0.05). Our findings offer a potential therapeutic strategy for significantly promoting the viability of surgical pedicle flaps by ischemic preconditioning with HIF-1α DNA plasmid.

Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma.

OBJECTIVE: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. BACKGROUND: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. METHODS: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. RESULTS: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. CONCLUSION: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Strengthening the skin with topical delivery of keratinocyte growth factor-1 using a novel DNA plasmid.

Fragile skin, susceptible to decubitus ulcers and incidental trauma, is a problem particularly for the elderly and for those with spinal cord injury. Here, we present a simple approach to strengthen the skin by the topical delivery of keratinocyte growth factor-1 (KGF-1) DNA. In initial feasibility studies with the novel minimalized, antibiotic-free DNA expression vector, NTC8385-VA1, the reporter genes luciferase and enhanced green fluorescent protein were delivered. Transfection was documented when luciferase expression significantly increased after transfection. Microscopic imaging of enhanced green fluorescent protein-transfected skin showed green fluorescence in hair follicles, hair shafts, and dermal and superficial epithelial cells. With KGF-1 transfection, KGF-1 mRNA level and protein production were documented with quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Epithelial thickness of the transfected skin in the KGF group was significantly increased compared with the control vector group (26 ± 2 versus 16 ± 4 µm) at 48 hours (P = 0.045). Dermal thickness tended to be increased in the KGF group (255 ± 36 versus 162 ± 16 µm) at 120 hours (P = 0.057). Biomechanical assessment showed that the KGF-1-treated skin was significantly stronger than control vector-transfected skin. These findings indicate that topically delivered KGF-1 DNA plasmid can increase epithelial thickness and strength, demonstrating the potential of this approach to restore compromised skin.

Do proton pump inhibitors protect against cancer progression in GERD?

Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.

Hypoxia and hypoxia-inducible factor in the burn wound.

The importance of hypoxia-inducible factor (HIF) in promoting angiogenesis and vasculogenesis during wound healing has been demonstrated. It is widely accepted that HIF activity can be promoted by many factors, including hypoxia in the wound or cytokines from inflammatory cells infiltrating the wound. However, there has not been a systematic exploration of the relationship between HIF activity and hypoxia in the burn wound. The location of the hypoxic tissue has not been clearly delineated. The time course of the appearance of hypoxia and the increased activity of HIF and appearance of HIF's downstream transcription products has not been described. The aim of this study was to utilize pimonidazole, a specific tissue hypoxia marker, to characterize the spatial and temporal course of hypoxia in a murine burn model and correlate this with the appearance of HIF-1α and its important angiogenic and vasculogenic transcription products vascular endothelial growth factor and SDF-1. Hypoxia was found in the healing margin of burn wounds beginning at 48 hours after burn and peaking at day 3 after burn. On sequential sections of the same tissue block, positive staining of HIF-1α, SDF-1, and vascular endothelial growth factor all occurred at the leading margin of the healing area and peaked at day 3, as did hypoxia. Immunohistochemical analysis was used to explore the characteristics of the hypoxic region of the wound. The localization of hypoxia was found to be related to cell growth and migration, but not to proliferation or inflammatory infiltration.

Rabeprazole impedes the development of reflux-induced esophageal cancer in a surgical rat model.

BACKGROUND: The role of proton pump inhibitors in Barrett's metaplasia and esophageal adenocarcinoma has been an area of controversy. AIMS: We evaluated the effectiveness of the proton pump inhibitor rabeprazole as a chemoprevention agent in a surgical rat reflux model of esophageal cancer. METHODS: The rat reflux model was created by performing a jejuno-esophagostomy on Sprague-Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. Rabeprazole sodium (Eisai, Tokyo, Japan) was dissolved in 0.9% physiological saline to a desired concentration of 1.5% (W/V). Beginning 4 weeks post-surgery, all animals were administered either 0.2 ml per 100 g body weight injections of rabeprazole or equivalent injections of saline 3 days per week into the subcutaneous tissue of the back. Forty animals were killed 40 weeks after surgery and their esophagi were examined. Of these, 23 were included in the control group, while the remaining 17 were subjected to rabeprazole. RESULTS: While 74% (17/23) of the controls developed esophageal cancer, animals administered rabeprazole had an incidence of cancer of 29% (5/17) (p < 0.05, Fisher's exact test). Barrett's metaplasia was found on 100% (23/23) of the rats in the placebo group, but there was a protective effect in the rabeprazole group with 65% (11/17) of the rats displaying signs of Barrett's metaplasia (p < 0.05, Fisher's exact test). All of the rats developed proliferative hyperplasia. CONCLUSIONS: Rabeprazole protected against the development of esophageal cancer in a clinically relevant surgical reflux model. Rabeprazole warrants further investigation for potential clinical use as a chemoprevention agent.

Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding.

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that controls vascular responses to hypoxia and ischemia. In this study, mice that were heterozygous (HET) for a null allele at the locus encoding the HIF-1alpha subunit (HET mice) and their wild-type (WT) littermates were subjected to a thermal injury involving 10% of the body surface area. HIF-1alpha protein levels were increased in burn wounds of WT but not of HET mice on day 2. The serum levels of stromal-derived factor 1alpha, which binds to CXCR4, were increased on day 2 in WT but not in HET mice. Circulating angiogenic cells were also increased on day 2 in WT but not in HET mice and included CXCR4(+)Sca1(+) cells. Laser Doppler perfusion imaging demonstrated increased blood flow in burn wounds of WT but not HET mice on day 7. Immunohistochemistry on day 7 revealed a reduced number of CD31(+) vessels at the healing margin of burn wounds in HET as compared with WT mice. Vessel maturation was also impaired in wounds of HET mice as determined by the number of alpha-smooth muscle actin-positive vessels on day 21. The remaining wound area on day 14 was significantly increased in HET mice compared with WT littermates. The percentage of healed wounds on day 14 was significantly decreased in HET mice. These data delineate a signaling pathway by which HIF-1 promotes angiogenesis during burn wound healing.

Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells.

Wound healing is impaired in elderly patients with diabetes mellitus. We hypothesized that age-dependent impairment of cutaneous wound healing in db/db diabetic mice: (a) would correlate with reduced expression of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) as well as its downstream target genes; and (b) could be overcome by HIF-1alpha replacement therapy. Wound closure, angiogenesis, and mRNA expression in excisional skin wounds were analyzed and circulating angiogenic cells (CACs) were quantified in db/db mice that were untreated or received electroporation-facilitated HIF-1alpha gene therapy. HIF-1alpha mRNA levels in wound tissue were significantly reduced in older (4-6 months) as compared to younger (1.5-2 months) db/db mice. Expression of mRNAs encoding the angiogenic cytokines vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), ANGPT2, platelet-derived growth factor B (PDGF-B), and placental growth factor (PLGF) was also impaired in wounds of older db/db mice. Intradermal injection of plasmid gWIZ-CA5, which encodes a constitutively active form of HIF-1alpha, followed by electroporation, induced increased levels of HIF-1alpha mRNA at the injection site on day 3 and increased levels of VEGF, PLGF, PDGF-B, and ANGPT2 mRNA on day 7. CACs in peripheral blood increased 10-fold in mice treated with gWIZ-CA5. Wound closure was significantly accelerated in db/db mice treated with gWIZ-CA5 as compared to mice treated with empty vector. Thus, HIF-1alpha gene therapy corrects the age-dependent impairment of HIF-1alpha expression, angiogenic cytokine expression, and CACs that contribute to the age-dependent impairment of wound healing in db/db mice.

Vaccine impedes the development of reflux-induced esophageal cancer in a surgical rat model: efficacy of the vaccine in a Pre-Barrett's esophagus setting.

BACKGROUND & AIMS: We developed a granulocyte-macrophage-colony-stimulating factor (GM-CSF) tumor vaccine for esophageal cancer. We evaluated the effectiveness of the vaccine as a prevention option in a surgical reflux rat model of esophageal cancer. METHODS: A surgical model involving a jejuno-esophagostomy was used to create Barrett's esophagus and esophageal cancer in rats. No carcinogen exposure was utilized. Cell lines derived from these tumors were stably passaged in vitro. GM-CSF-secreting tumor cells were generated using stable transfection. All rats underwent a total gastrectomy, followed by a jejuno-esophagostomy. The surgery promoted the reflux of duodenal contents into the esophagus. All animals were administered either a GM-CSF secreting whole cell vaccine or a phosphate-buffered saline (PBS) placebo injection 4, 6, 14, and 16 weeks post-surgery. RESULTS: While 15 of 16 animals in the non-vaccinated placebo group developed esophageal cancer, 94% (15 of 16), animals in the vaccine group had an incidence of cancer of 25% (4 of 16) (p<0.05). Barrett's esophagus was seen in 100% (16 of 16) of the controls and 83% (13 of 16) of the vaccinated animals. CONCLUSIONS: A GM-CSF-secreting whole cell tumor vaccine impeded esophageal tumor growth, but not the development of Barrett's esophagus, in a clinically relevant surgical reflux model.

KGF-1 for wound healing in animal models.

Keratinocyte growth factor-1 (KGF-1) is a member of the fibroblast growth factor (FGF) family FGF7 and is expressed in normal and wounded skin. KGF-1 is massively produced in the early stages of the wound healing process as well as during the later remodeling process (1, 2). We have studied the effects of the electroporation of a KGF-1 plasmid into excisional wounds of different rodent models mimicking diseases known to impair the normal wound healing process. We have used a genetically diabetic mouse model and a septic rat model in our experiments, and we have shown improvement of the healing rate (92% of the wounds are healed at day 12 vs. 40% of the control), the quality of epithelialization (histological score of 3.3 vs. 1.5), and the density of new blood vessels (85% more new blood vessels in the superficial layers than that of the control) (3, 4). Considering these results, we believe we can further explore the treatment modalities for using the electroporation-assisted transfection of DNA plasmid expression vectors of growth factors to enhance cutaneous wound healing.

Efficacy of Chitosan-Based Dressing for Control of Bleeding in Excisional Wounds.

Introduction: Excessive bleeding is a complication of wound debridement in patients receiving anticoagulation treatment. Chitosan is a linear, positively charged polysaccharide that has potential as a hemostatic topical dressing. This study examined the hemostatic efficacy of the chitosan based Opticell dressing (Medline Industries, Chicago, Ill) in heparinized rats with excisional wounds mimicking debridement. Methods: Three paired 12-mm excisional wounds were created on the dorsum of 600-g Sprague-Dawley rats 2 hours after intraperitoneal injection of heparin 800 IU/kg. Opticell or gauze dressings were applied with 3 seconds of gentle pressure. Results:Total Bleeding: The dressings were left in place until cessation of bleeding. Ten minutes was enough time for complete bleeding cessation in both groups. Gauze and Opticell were weighed before and after bleeding cessation, with the difference representing blood loss. Total blood loss was 627 ± 47 mg/10 min with the standard gauze, but 247 ± 47 mg/10 min with Opticell (P = .002 Mann-Whitney). N = 6 wounds per group. Rate of Bleeding: Gauze and Opticell dressings were removed and instantly replaced with 3 seconds of gentle pressure every minute until bleeding cessation. The removed dressings were weighed before and after application. There was less bleeding in the Opticell group at minutes 1, 2, and 3. Gauze: 183 ± 40, 140 ± 30, and 109 ± 15 mg/min vs Opticell: 91 ± 17, 54 ± 8, and 57 ± 11 mg/min). Analysis of variance, Tukey's test, P < .05. N = 12 wounds per group. Conclusion: Topical application of Opticell dressing with chitosan has hemostatic effects that could be a useful tool to control bleeding associated with wound debridement.

Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds.

Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers losartan and valsartan and the angiotensin-converting enzyme inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. The application of 1% valsartan gel compared with other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. One percent of valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated mothers against decapentaplegic homologs 2 and 3 and common mothers against decapentaplegic homolog 4, alpha-smooth muscle actin, CD31, phospho-vascular endothelial growth factor receptor 2, and p42/44 mitogen-activated protein kinase. Knockout of the angiotensin subtype 2 receptors abolished the beneficial effects of angiotensin type 1 receptor blockers, suggesting a role for angiotensin subtype 2 receptors in chronic wound healing.

Raising Awareness Among Healthcare Providers about Epidermolysis Bullosa and Advancing Toward a Cure.

Objective: Epidermolysis bullosa (EB) is an orphan disease that affects about half a million people worldwide, but may not be familiar to all clinicians. The authors' goal was to present a short description of this condition and current research in the form of a narrative review. Methods: The authors reviewed the literature on epidermolysis bullosa in order to describe the condition and current genetic research. Results: There are at least 31 subtypes of EB, including junctional EB, dystrophic EB, and Kindler syndrome. Genetic research is crucial in finding strategies to manage and possibly cure EB, which is often undiagnosed or misdiagnosed. EB may present in newborns and may persist over the course of a lifetime. Serious complications can occur with EB, including chronic blisters, wounds, ulcers, pruritus, clubbing of hands and feet, and amputations. Pain is frequently reported. About 80 percent of patients with recessive dystrophic EB will succumb to squamous cell carcinoma by age 55. Promising directions for future research include genome editing, gene therapy, and cell-based therapies. Conclusion: Our growing understanding of genetics and cell therapies may lead to promising therapeutic advances to treat this challenging condition.

Cellular GFP Toxicity and Immunogenicity: Potential Confounders in in Vivo Cell Tracking Experiments.

Green Fluorescent protein (GFP), used as a cellular tag, provides researchers with a valuable method of measuring gene expression and cell tracking. However, there is evidence to suggest that the immunogenicity and cytotoxicity of GFP potentially confounds the interpretation of in vivo experimental data. Studies have shown that GFP expression can deteriorate over time as GFP tagged cells are prone to death. Therefore, the cells that were originally marked with GFP do not survive and cannot be accurately traced over time. This review will present current evidence for the immunogenicity and cytotoxicity of GFP in in vivo studies by characterizing these responses.

Knockout of Angiotensin AT2 receptors accelerates healing but impairs quality.

Wounds are among the most common, painful, debilitating and costly conditions in older adults. Disruption of the angiotensin type 1 receptors (AT1R), has been associated with impaired wound healing, suggesting a critical role for AT1R in this repair process. Biological functions of angiotensin type 2 receptors (AT2R) are less studied. We investigated effects of genetically disrupting AT2R on rate and quality of wound healing. Our results suggest that AT2R effects on rate of wound closure depends on the phase of wound healing. We observed delayed healing during early phase of wound healing (inflammation). An accelerated healing rate was seen during later stages (proliferation and remodeling). By day 12, fifty percent of AT2R(-/-) mice had complete wound closure as compared to none in either C57/BL6 or AT1R(-/-) mice. There was a significant increase in AT1R, TGFß1 and TGFß2 expression during the proliferative and remodeling phases in AT2R(-/-) mice. Despite the accelerated closure rate, AT2R(-/-) mice had more fragile healed skin. Our results suggest that in the absence of AT2R, wound healing rate is accelerated, but yielded worse skin quality. Elucidating the contribution of both of the angiotensin receptors may help fine tune future intervention aimed at wound repair in older individuals.

Callus stimulation in distraction osteogenesis.

Distraction osteogenesis has been described as in vivo tissue engineering. The ability to stimulate this process for the repair of bony defects or lengthening of congenitally shortened facial structures is likely to significantly impact the field of craniofacial surgery. The purpose of this study was to determine whether mechanical stimulation of the distracted rabbit mandible would accelerate the maturation of the bony callus when applied during the early consolidation period. Twenty adult New Zealand White rabbits underwent unilateral mandibular osteotomy. A uni-directional internal distractor device (Synthes, Paoli, Pa.) was positioned along a plane perpendicular to the line of osteotomy. After a 7-day latency period, distraction was commenced at a rate of 1.0 mm/day for 12 days in all animals. In a control group of 10 rabbits, a consolidation period of 8 weeks was observed before they were killed. In the experimental group of 10 rabbits, daily alternate compression and distraction of 1 mm (sequential compression and distraction) was performed for 3 weeks followed by a 5-week period of rigid fixation. Each animal received a dose of a fluorescent label at three different time points during the study: at the end of the distraction period, 3 weeks after the completion of the distraction phase, and 3 days before it was killed. All animals were killed 8 weeks after the completion of the distraction phase. Undecalcified histologic analysis and 3-point bending tests to failure were performed on the extracted mandibles. The results of the experimental and control groups were compared. Four animals in the control group and three animals in the experimental group were excluded from the study because of screw loosening resulting in distractor dislodgment or because of infection. On histologic analysis, cortical thickness at the center of the callus was found to be significantly greater in the experimental group compared with the control group when normalized to the contralateral hemimandible (83 percent versus 49 percent, respectively; p < 0.007). The ratio of cortical to cancellous bone in the distracted callus was uniformly found to be greater in the experimental specimens. The mineral apposition rate was calculated by using fluorescence microscopy and found to be significantly greater in the experimental group both during the period of sequential compression and distraction (3.2 microm/day versus 2.1 microm/day, p = 0.02) and after the period of sequential compression and distraction (1.4 microm/day versus 1.1 microm/day, p = 0.006). Mechanical testing revealed no significant differences in bending strength or stiffness between experimental or control groups (p = 0.54 and 0.47, respectively). This study has demonstrated that daily alternating compression and distraction of 1 mm amplitude during the early consolidation period has a stimulatory impact on callus formation with respect to osteoblastic activity, remodeling, and maturation of bone. Optimal timing and amplitude of sequential movement, long-term biomechanical differences, and molecular pathways have yet to be elucidated.

Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells.

AIMS: Hypoxia-inducible factor 1 (HIF-1) is a heterodimer composed of HIF-1α and HIF-1ß subunits. HIF-1 is known to promote tissue vascularization by activating the transcription of genes encoding angiogenic factors, which bind to receptors on endothelial cells (ECs) and bone marrow-derived angiogenic cells (BMDACs). In this study, we analysed whether HIF-1 activity in the responding ECs and BMDACs is also required for cutaneous vascularization during burn wound healing. METHODS AND RESULTS: We generated mice with floxed alleles at the Hif1a or Arnt locus encoding HIF-1α and HIF-1ß, respectively. Expression of Cre recombinase was driven by the Tie2 gene promoter, which is expressed in ECs and bone marrow cells. Tie2Cre(+) and Tie2Cre(-) mice were subjected to burn wounds of reproducible diameter and depth. Deficiency of HIF-1α or HIF-1ß in Tie2-lineage cells resulted in delayed wound closure, reduced vascularization, decreased cutaneous blood flow, impaired BMDAC mobilization, and decreased BMDAC homing to burn wounds. CONCLUSION: HIF-1 activity in Tie2-lineage cells is required for the mobilization and homing of BMDACs to cutaneous burn wounds and for the vascularization of burn wound tissue.

Aging impairs the mobilization and homing of bone marrow-derived angiogenic cells to burn wounds.

Impaired wound healing in the elderly represents a major clinical problem. Delineating the cellular and molecular mechanisms by which aging impairs wound healing may lead to the development of improved treatment strategies for elderly patients with non-healing wounds. Neovascularization is an essential step in wound healing, and bone marrow-derived angiogenic cells (BMDACs) play an important role in vascularization. Using a mouse full-thickness burn wound model, we demonstrate that perfusion and vascularization of burn wounds were impaired by aging and were associated with dramatically reduced mobilization of BMDACs bearing the cell surface molecules CXCR4 and Sca1. Expression of stromal-derived factor 1 (SDF-1), the cytokine ligand for CXCR4, was significantly decreased in peripheral blood and burn wounds of old mice. Expression of hypoxia-inducible factor (HIF)-1α was detected in burn wounds from young (2-month-old), but not old (2-year-old), mice. When BMDACs from young donor mice were injected intravenously, homing to burn wound tissue was impaired in old recipient mice, whereas the age of the BMDAC donor mice had no effect on homing. Our results indicate that aging impairs burn wound vascularization by impairing the mobilization of BMDACs and their homing to burn wound tissue as a result of impaired HIF-1 induction and SDF-1 signaling.

Biomechanical properties of skin in massive weight loss patients.

BACKGROUND: The aim of this study is to assess skin strength in MWL patients relative to control cosmetic abdominoplasty patients biophysically, biochemically, and histologically. Growing success of weight loss programs has brought about an increase in the MWL population. Skin quality is thought to be impaired by MWL, but there are no compelling studies that have fully addressed the structural mechanisms involved. METHODS: Skin from the medial and lateral abdomen was harvested fresh from patients undergoing cosmetic abdominoplasty (n = 6) or abdominal panniculectomy for MWL (n = 35), and burst strength was tested in the horizontal and vertical directions. Collagen content was measured, and histological studies were performed to assess epidermal and dermal thickness, vascularity as well as the morphology and density of the collagen fibers. RESULTS: In all groups, skin stretched horizontally was stronger than skin stretched vertically (p < 0.001). The skin of MWL patients was stronger medially compared to the skin of cosmetic patients. (p = 0.047) Newly formed collagen was diminished in MWL than that in the control group, but the results were not statistically significant. Epidermal thickness was significantly higher medially in MWL (p = 0.049). Elastin fibers were decreased in the MWL group, while dermal vascularity was higher in the MWL group. CONCLUSIONS: The skin of MWL patients demonstrated stronger mechanical parameters than that of cosmetic patients in the medial part of the abdomen; however, the decrease in elastic fibers associated with a decrease in newly formed collagen seemingly provides a contradiction. Skin changes with MWL merits further study to understand it more completely.