Lavinia Anzai

Restoration of Nrf2 Signaling Normalizes the Regenerative Niche

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)–based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia–associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.

Optimizing venous outflow in reconstruction of Gustilo IIIB lower extremity traumas with soft tissue free flap coverage: Are two veins better than one?

The dependent nature of the lower extremity predisposes to venous congestion, especially following significant trauma. The benefit of a second venous anastomosis, however, remains unclear in lower extremity trauma free flap reconstruction. This study investigated the effect of an additional venous anastomosis on flap outcomes in lower extremity trauma reconstruction.

Abstract QS10: Comparing Reconstructive Outcomes in Patients with Gustillo Type IIIB Fractures and Concomitant Arterial Injuries

PURPOSE: Despite advances in microsurgery, higher complication rates have persisted among lower extremity free tissue transfers. Historically, the Gustillo Classification has been utilized as a proxy for injury severity, but recent studies have shown that the rate of complications, notably flap failure, directly increase as arterial runoff decreases. When injured arteries are identified in patients requiring lower extremity free tissue transfer, a wide array of treatment options are possible: end-to-end or end-to-side anastomosis can be performed on either the injured vessel in question or on uninjured adjacent vessels. This study aims to compare the outcomes of these different treatment methods based on the number of injured vessels identified.

Proximal versus Distal Recipient Vessels in Lower Extremity Reconstruction: A Retrospective Series and Systematic Review

Background Recipient vessels proximal to the zone of injury have traditionally been preferred for lower extremity reconstruction. However, more recent data have shown mixed outcomes when performing anastomoses distal to the zone of injury. We investigated the impact of recipient vessel location on free flap outcomes. Methods Retrospective review (1979‐2016); 312 soft tissue free flaps for open tibia fractures met inclusion criteria. Flap characteristics and perioperative outcomes were examined. Systematic review identified articles evaluating anastomosis location and flap outcomes; pooled data analysis was performed. Results More anastomoses were performed proximal to the zone of injury (80.7%) than distal (19.3%). Distal anastomoses were not associated with increased take back rates (19.6%) compared with proximal (23.8%) anastomoses (p = 0.356). Regression analysis comparing proximal and distal anastomoses found no difference in partial flap failures (7.4% vs 11.9%; p = 0.978) or total flap failures (9.3% vs 9.3%; p = 0.815) when controlling for the presence of arterial injury, flap type, and time from injury to coverage. Systematic review yielded 11 articles with 1,245 proximal and 127 distal anastomoses for comparison. Pooled analysis (p = 0.58) and weighted comparative analysis (p = 0.39) found no difference in flap failure rates between proximal and distal groups. Conclusion Our results are congruent with the current lower extremity literature and demonstrate no difference in perioperative complication rates between anastomoses performed proximal or distal to the zone of injury. These findings suggest that anastomotic location choice should be based primarily on recipient vessel quality/flow and ease of access/exposure rather than orientation relative to the zone of injury.

Comparison of Hand-Sewn versus Coupled Venous Anastomoses in Traumatic Lower Extremity Reconstruction

Background Microvascular reconstruction of the lower extremity has the highest reported complication and flap failure rates of any anatomical region. Despite widespread adoption of the mechanical anastomotic venous coupler and encouraging results in other anatomical regions, there are limited reports examining its use in the lower extremity. This study compares outcomes between coupled and hand‐sewn venous anastomoses in traumatic lower extremity reconstruction. Methods Retrospective review of our institutional flap registry from 1979 to 2016 identified soft tissue free flaps performed for the reconstruction of Gustilo type IIIB/IIIC open tibial fractures. Patient demographics, flap characteristics, use of a venous anastomotic coupler, and perioperative outcomes were examined. Analysis was performed using chi‐square and Students t ‐tests. Results A total of 361 patients received a microvascular free flap for coverage of a Gustilo type IIIB or IIIC tibial fracture following traumatic injury. After excluding cases that lacked adequate information on coupler use, 358 free flaps were included in the study. There were 72 (20%) free flaps performed using a venous coupler and 286 (80%) performed with hand‐sewn venous anastomoses. There were comparable rates of major complications (22.2 vs. 26.1%; p = 0.522), total flap failure (6.5%, vs. 10.2%; p = 0.362), and partial flap failure (9.7 vs. 12.2%; p = 0.579) between venous coupler and hand‐sewn anastomoses, respectively. Furthermore, use of the venous coupler was not associated with increased rates of operative take backs (22.8 vs. 23.0%; p = 0.974). However, reconstructions performed using a venous coupler were significantly more likely to have a second venous anastomosis performed (37.5 vs. 21.3%; p = 0.004). Conclusion Complication and flap failure rates were similar between reconstructions performed with a venous coupler and those performed with hand‐sewn venous anastomoses. These findings suggest that use of the venous anastomotic coupler is safe and effective in lower extremity reconstruction, with comparable outcomes to conventional sutured anastomoses.

Abstract 108: 35 Years of Lower Extremity Take-Backs

Sarday, M ay 6, 2017 moyamoya disease (6). Flaps included flow through radial forearm fasciocutaneous flaps (2), a flow through radial forearm fascial flap (1) and flow through pedicled temporoparietal fascial flaps (4). The superficial temporal vessels (6) and facial vessels (1) were used as the recipient site pedicle. Flow through reperfusion was established into the middle cerebral artery (5) and anterior communicating artery (2). There were no intraoperative complications. All flaps survived and there were no donor site complications. Postoperative imaging demonstrated graft patency in 6/7 patients. In one case of flow through TPF flap, the direct graft failed, but the indirect flap remained vascularized.

Abstract 106: Optimizing Venous Outflow in Lower Extremity Free Flaps

PURPOSE: A lack of recipient vessels for microsurgical extremity reconstructions may result from peripheral vascular disease, trauma, or oncologic resections and can be managed by vascular reconstructions with arteriovenous (AV) loops, which serve as recipient vessels for free flap anastomoses. In small and large animal models AV loops promote angiogenesis, presumably through elevated shear stress on the vascular endothelium. It has been postulated that vascularized free flaps are able to induce angiogenesis in ischemic lower extremities of patients with peripheral vascular disease, however, the molecular basis of this “nutrient flap” concept has never been examined in a clinical setting. In this study we analyzed miRNA and gene expression profiles in AV loops from patients with combined vascular and soft-tissue reconstructions in order to investigate whether enhanced blood flow in an AV loop leads to an upregulation of proangiogenic miRNAs and genes in humans.