Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model superior?

Murine models have provided valuable insights into the pathogenesis of both diabetes and chronic wounds. However, only a few published reports to date have investigated wound healing differences among the differing diabetic mouse models. The goal of the present study was to further define the wound healing deficiency phenotypes of streptozotocin-induced (STZ-induced), Akita, and db/db diabetic mice in comparison with a promising new polygenic strain of Type 2 diabetes (NONcNZO10) by using three specific wound models that targeted different critical processes in the pathogenesis of chronic wounds. Incisional, excisional, and ischemia/reperfusion wound models were established on mice of each strain. Wound healing parameters including tensile strength, epithelial gap, and wound necrosis were evaluated. In contrast to the other diabetic mice, the NONcNZO10 strain was found to have significant wound healing impairments in all wound healing models. Not only do the NONcNZO10 mice appear to better model human Type 2 diabetes, these provocative findings suggest that the mice may show more clinically relevant wound healing deficiencies than previous diabetic mouse models.

Antisense inhibition of connective tissue growth factor (CTGF/CCN2) mRNA limits hypertrophic scarring without affecting wound healing in vivo.

Augmented expression of connective tissue growth factor (CTGF/CCN2) is observed in healing wounds and in a variety of fibrotic disorders. It appears to enhance many of the effects of transforming growth factor-beta and has been shown to have independent fibrogenic functions. Despite these observations, its importance to dermal wound healing and the transition from wound to scar remains poorly defined. In this study, we use established rabbit models to evaluate the roles of CTGF in dermal wound healing and hypertrophic scarring. We show that CTGF mRNA demonstrates persistent up-regulation in hypertrophic scars. Treatment of wounds with antisense oligonucleotides to CTGF has no measurable effect on early wound closure. However, antisense therapy significantly limits subsequent hypertrophic scarring. Inhibition of CTGF is associated with a marked reduction in the number of myofibroblasts in scars and decreased transcription of TIMP-1 and types I and III collagen. These findings confirm CTGF to be a key mediator of hypertrophic scarring in this model. Its effect on myofibroblasts in this setting suggests a mechanism whereby it plays this role. Its limited participation in early healing implies that it may be a useful and specific target for modulating hypertrophic scarring following injury.

Decreased postoperative pain, narcotic, and antiemetic use after breast reduction using a local anesthetic pain pump.

The purpose of this study was to conduct a prospective trial evaluating the efficacy of a local anesthetic pain pump in breast reduction surgery. Ninety-eight women undergoing bilateral breast reduction were enrolled. Thirty-seven patients received a pain pump containing 0.25% bupivicaine, and 61 patients received no pain pump. Parameters measured included subjective pain, episodes of postoperative nausea and vomiting (PONV), and the amount of narcotics and antiemetics used. Patients receiving a pain pump reported significantly lower pain scores on the day of surgery, as well as on the first and second postoperative days when compared with patients who did not (P < 0.01). The amount of intravenous and oral narcotics used paralleled the reduction in pain (P < 0.01), and there were fewer episodes of PONV and antiemetics used in the patients receiving a pain pump (P < 0.01). A postoperative local anesthetic pain pump can reduce pain, narcotic use, and PONV in women undergoing breast reduction.

Temporal expression of the transforming growth factor-Beta pathway in the rabbit ear model of wound healing and scarring.

BACKGROUND: Despite numerous studies that have investigated the cellular and molecular mechanisms underlying scar formation, this process still remains poorly understood. The importance of transforming growth factor-beta (TGF-beta) in these processes has been well recognized, and this study sought to define the temporal expression of the key members in this pathway in a well-established, clinically relevant, rabbit ear model of hypertrophic scarring. STUDY DESIGN: Seven-millimeter (hypertrophic) and 5-mm (nonhypertrophic) punch wounds were made on the ears of 12 rabbits. Wounds were harvested at days 0, 7, 15, 28, and 40. RESULTS: There were no appreciable histologic differences between the 5- and 7-mm wounds at days 7 and 15. At day 28, however, the 7-mm scars were considerably more hypertrophic compared with the 5-mm control scars (p<0.001). The mRNA levels of TGF-beta1 and collagen Ialpha2 were notably higher in the hypertrophic 7-mm scars at day 28 than in the nonhypertrophic 5-mm scars (p<0.03). Although not pronounced, levels of TGF-beta2 were higher in the hypertrophic scars. There were no other statistically significant differences between the 7- and 5-mm scars. CONCLUSIONS: Elevated levels of TGF-beta1, and possibly TGF-beta2, are associated with hypertrophic scar formation.

The outcome of abdominoplasty performed under conscious sedation: six-year experience in 153 consecutive cases.

The use of conscious sedation is rapidly gaining acceptance and popularity in plastic surgery. At the present time, many procedures are performed using intravenous sedation and local anesthesia. The purpose of this article was to examine the safety and outcome of full abdominoplasties performed under conscious sedation at the authors' institution. Over a 6-year period from 1997 to 2002, 266 abdominoplasties were performed by the two senior authors. One hundred thirteen of these (42 percent) were performed under a general or regional anesthetic because a concurrent procedure was performed that precluded the use of conscious sedation (64 hysterectomies, 18 hernia repairs, six urogynecologic procedures, 10 breast reductions, and one laparoscopic cholecystectomy) or because of patient and surgeon preference (14 cases). One hundred fifty-three abdominoplasties (58 percent) were performed under conscious sedation using intravenous midazolam and fentanyl along with a local anesthetic. No patients had an unplanned conversion to deep sedation or general anesthesia. Eighty percent of these cases were performed with a concurrent procedure (80 liposuctions, 19 breast augmentations, 20 mastopexies, three capsulotomies, and 13 varied facial aesthetic procedures). In addition, 12 patients had concurrent hernia repairs (five ventral and seven umbilical) under conscious sedation. Mean follow-up was 10 months (range, 1 to 56 months). There were no intraoperative complications and no major postoperative complications. The minor complication rate was 11.1 percent (10 seromas requiring needle aspiration in the office, three superficial wound infections, two cases of marginal skin necrosis, one stitch abscess, and one pseudobursa requiring reexcision). Seven revisions were performed for suboptimal scars (5 percent). The results of this study demonstrate that abdominoplasties can be performed under conscious sedation in a safe and cost-effective manner for almost all patients. This type of procedure is well tolerated, has a low complication rate, and has high patient satisfaction. Increasing experience and small modifications in local anesthesia and surgical technique have strengthened the authors' conviction that conscious sedation is the preferred method of anesthesia for most patients undergoing abdominoplasty.

Surgical management of large and giant congenital pigmented nevi of the lower extremity.

BACKGROUND: The surgical treatment of large and giant congenital pigmented nevi of the lower extremity is a challenging endeavor with limited reconstructive options. METHODS: Fifty large (>10 cm) and giant (>20 cm) congenital pigmented nevi of the lower extremity treated by the senior author (B.S.B.) over a 25-year period were reviewed. All of these nevi were too large for serial excision or direct closure. RESULTS: A reconstructive algorithm based on the extent and location (thigh, knee, popliteal fossa, leg, and foot) of the nevus is proposed. The approach to each anatomical region is described in detail, along with nuances of tissue expansion in the extremities. CONCLUSIONS: Treating large and giant congenital pigmented nevi of the lower extremity requires careful planning and often multiple stages. An evolution of the authors' approach to these lesions has led to improved outcomes. Contour and the limiting of scar contracture around the joints are of paramount importance.

A local anesthetic pump reduces postoperative pain and narcotic and antiemetic use in breast reconstruction surgery: a randomized controlled trial.

BACKGROUND: The purpose of this study was to conduct a double-blind, randomized, prospective trial evaluating the efficacy of a local anesthetic pain pump in reducing postoperative pain, narcotic use, and the incidence of postoperative nausea and vomiting in breast reduction surgery. METHODS: Thirty-one patients undergoing bilateral breast reduction using a single technique (inferior pedicle, Wise pattern with supplemental liposuction) were enrolled. The patients were randomized to receive either 0.25% bupivacaine (n = 16) or 0.9% saline (n = 15) delivered over a period of 48 to 55 hours. All patients were monitored postoperatively and completed a written survey and telephone interview. Parameters measured over a period of 48 hours included subjective pain, episodes of postoperative nausea and vomiting, and the amount of narcotics and antiemetics used. RESULTS: There were no statistically significant differences between the two groups regarding patient age, body mass index, weight of the breast reduction, complication rate, and standardized subjective pain perception. Patients randomized to bupivacaine reported significantly lower pain scores on the day of surgery and on the first and second postoperative days when compared with patients receiving placebo (p < 0.01). The amount of intravenous and oral narcotics used paralleled the reduction in pain (p < 0.01), and there were fewer episodes of postoperative nausea and vomiting and antiemetics used in the patients randomized to the bupivacaine group (p < 0.01). CONCLUSION: The results of this study support the efficacy of a postoperative local anesthetic pain pump in reducing pain, narcotic use, and postoperative nausea and vomiting in women undergoing breast reduction.

Treatment of chronic digital ischemia with direct microsurgical revascularization.

The authors present their technique for treating digital ischemia using a radial-to-digital artery bypass graft performed in a bloodless field under tourniquet with the use of a microscope. The outcomes in 6 patients were resolution of fingertip ulcers, avoidance of more proximal amputations, and elimination of ischemic pain.

Reduced up-regulation of cytoprotective genes in rat cutaneous tissue during the second cycle of ischemia-reperfusion.

Chronic wounds are major health problems that affect millions of people in the United States every year. Management of these wounds costs billions of dollars annually in the United States. Despite their clinical importance, the molecular mechanisms underlying these clinical conditions remain elusive. Repetitive ischemia-reperfusion (I-R) may play a pivotal role in chronic wound formation. The development of therapies for these wounds is hindered by the lack of animal models that allow identification of the molecular mechanisms underlying chronic wound formation. In the first study of its kind, we adapted our rat pressure sore model by imposing two cycles of ischemia (2 hours) and two cycles of reperfusion (24 hours), and we examined gene expression to better understand the molecular events that occur at the very early stages of cutaneous I-R injury with a goal of devising preventing strategies. We successfully tested our hypothesis and demonstrated that while cytoprotective genes, such as heat shock protein 70, heat shock protein 90, hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and heme oxygenase-1, were initially up-regulated during the first cycle of I-R, their up-regulation was subsequently reduced or completely abolished during the second cycle of I-R. These findings raise the possibility that reduced up-regulation of these cytoprotective genes may be causally linked to cutaneous I-R injury.