Local Administration of Interleukin-1 Receptor Antagonist Improves Diabetic Wound Healing.

Impaired healing of the skin is a notable cause of patient morbidity and mortality. In diabetic individuals, dysregulated inflammation contributes to delayed wound healing. Specific immunomodulatory agents may have a role in the treatment of diabetic wounds. One of these molecules is interleukin-1 receptor antagonist (Anakinra; Amgen Corp.). Although interleukin-1 receptor antagonist (Anakinra; Amgen Corp.) is approved by the Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis and neonatal-onset multisystem inflammatory disease, little is known about the local use this drug in cutaneous wound healing. Therefore, the aim of this study is to determine the effect of locally administered interleukin-1 receptor antagonist on delayed wound healing, specifically, in a diabetic mouse model. Two 6-mm full-thickness wounds were created on the dorsa of diabetic (db/db) mice and stented. One-hour postwounding, wound margins were subcutaneously injected with either (1) low-dose interleukin-1 receptor antagonist in a gelatin-transglutaminase gel vehicle or (2) the gel vehicle only. Wounds were imaged on days 0, 7, 14, and 21 postwounding, and wound area was determined. Wound biopsies were collected on day 21 and immunohistochemically stained for neutrophil and macrophage infiltration. Wounds treated with interleukin-1 receptor antagonist had significantly smaller wound area than nontreated wounds on day 7 and day 14 postwounding. Treated wounds also showed significantly less neutrophil and macrophage infiltration. These findings support the hypothesis that interleukin-1 receptor antagonist may have an important role in cutaneous wound healing, possibly by promoting successful resolution of acute inflammation and hence accelerating wound closure. Thereby, administration of IL-1Ra may be useful in the treatment of nonhealing wounds.

Prevention of Postsurgical Lymphedema by 9-cis Retinoic Acid.

OBJECTIVE: To determine the effect of 9-cis retinoic acid (9-cis RA) on postsurgical lymphedema. BACKGROUND: 9-cis RA promotes lymphangiogenesis in vitro and in vivo and has promise as a therapeutic agent to limit the development of postsurgical lymphedema. METHODS: Lymphedema was induced in the right hind limb after a single fraction of 20 Gy radiation, popliteal lymphadenectomy, and lymphatic vessel ablation. Postoperatively, mice were randomly divided in to 2 groups that received daily intraperitoneal injections of either (1) an oil-based vehicle solution (control) or (2) 0.08 mg/kg of 9-cis RA dissolved in a vehicle solution. Outcome measures included paw thickness, lymphatic drainage, and lymphatic vessel density as measured by podoplanin immunohistochemistry and whole mount skin analysis. RESULTS: Using our combined injury protocol, postsurgical lymphedema was observed 89% of the time. 9-cis RA-treated animals had less early postsurgical edema and significantly less paw lymphedema compared with vehicle-treated animals at all time-points (P < 0.001). 9-cis RA-treated animals had significantly faster lymphatic drainage as measured by indocyanine green clearance and increased lymphatic vessel density as measured by podoplanin immunohistochemistry (P < 0.001) and whole mount skin analysis (P < 0.05). CONCLUSIONS: We have developed a highly reproducible model of secondary lymphedema and have demonstrated that 9-cis RA significantly prevents postsurgical lymphedema. Treatment with 9-cis RA is associated with increased lymphatic clearance and lymphangiogenesis. Because 9-cis RA (alitretinoin) is already approved for clinical use by the US Food and Drug Administration for other conditions, it has the potential to be repurposed as a preventative agent for postsurgical lymphedema in humans.

Comparison of Postoperative Outcomes of Laparoscopic vs Open Inguinal Hernia Repair.

Importance: Advocates of laparoscopic surgery argue that all inguinal hernias, including initial and unilateral ones, should be repaired laparoscopically. Prior work suggests outcomes of open repair are improved by using local rather than general anesthesia, but no prior studies have compared laparoscopic surgery with open repair under local anesthesia. Objective: To evaluate postoperative outcomes of open inguinal hernia repair under general or local anesthesia compared with laparoscopic repair. Design, Setting, and Participants: This retrospective cohort study identified 107 073 patients in the Veterans Affairs Surgical Quality Improvement Program database who underwent unilateral initial inguinal hernia repair from 1998 to 2019. Data were analyzed from October 2021 to March 2022. Exposures: Patients were divided into 3 groups for comparison: (1) open repair with local anesthesia (n = 22 333), (2) open repair with general anesthesia (n = 75 104), and (3) laparoscopic repair with general anesthesia (n = 9636). Main Outcomes and Measures: Operative time and postoperative morbidity were compared using quantile regression and inverse probability propensity weighting. A 2-stage least-squares regression and probabilistic sensitivity analysis was used to quantify and address bias from unmeasured confounding in this observational study. Results: Of 107 073 included patients, 106 529 (99.5%) were men, and the median (IQR) age was 63 (55-71) years. Compared with open repair with general anesthesia, laparoscopic repair was associated with a nonsignificant 0.15% (95% CI, -0.39 to 0.09; P = .22) reduction in postoperative complications. There was no significant difference in complications between laparoscopic surgery and open repair with local anesthesia (-0.05%; 95% CI, -0.34 to 0.28; P = .70). Operative time was similar for the laparoscopic and open general anesthesia groups (4.31 minutes; 95% CI, 0.45-8.57; P = .048), but operative times were significantly longer for laparoscopic compared with open repair under local anesthesia (10.42 minutes; 95% CI, 5.80-15.05; P < .001). Sensitivity analysis and 2-stage least-squares regression demonstrated that these findings were robust to bias from unmeasured confounding. Conclusions and Relevance: In this study, laparoscopic and open repair with local anesthesia were reasonable options for patients with initial unilateral inguinal hernias, and the decision should be made considering both patient and surgeon factors.

Hemostatic and pharmacologic resuscitation: results of a long-term survival study in a swine polytrauma model.

BACKGROUND: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, and spray-dried plasma (SDP) improve early survival after lethal hemorrhage and polytrauma, but their effect on long-term survival and organ function remains untested. METHODS: Yorkshire swine (n=27; 6-8/group) underwent a protocol simulating different phases of trauma care: (1) prehospital-rib fracture, soft-tissue injury, hemorrhage (50% blood volume), 30 minutes of shock, and infusion of 0.9% saline (3× shed blood); (2) early hospital/treatment-grade IV liver (partial amputation of the median lobe) and grade V splenic (transection of spleen into three pieces) injuries to simulate rupture of contained hematomas, followed by 30 minutes of uncontrolled hemorrhage. Animals were treated with (a) Hextend (6% hetastarch), (b) fresh whole blood (FWB), (c) SDP, and (d) VPA (300 mg/kg) plus Hextend. VPA was given during the prehospital phase, and the volumes of Hextend, FWB and SDP (reconstituted in water) matched shed blood; (3) repair/resuscitation-liver injury was controlled by suture control of the transected edge, and splenic injury was treated by partial splenectomy; 1 hour after repair of injuries, surviving animals were fully resuscitated with packed red blood cells; and (4) monitoring-survival was monitored for 7 days (primary endpoint), and blood samples were drawn serially to measure organ function. RESULTS: Only 25% of the Hextend-treated animals survived. Addition of VPA improved survival to only 50% (p=0.28), whereas treatment with SDP and FWB increased survival significantly to 83% and 100%, respectively (p<0.05). Surviving animals showed no long-term organ dysfunction, postoperative hemorrhage, and delayed complications. CONCLUSIONS: In a clinically relevant lethal polytrauma model, administration of SDP significantly improves survival without any long-term organ dysfunction or complications.

Porcine Mesothelium-Wrapped Diced Cartilage Grafts for Nasal Reconstruction.

BACKGROUND: Fascia-wrapped diced cartilage grafts have become a useful tool in modern rhinoplasty surgery. Unfortunately, fascial harvest is associated with donor site morbidity; therefore, a nonautologous alternative to fascia would be ideal. Decellularized porcine mesothelium (PM), Meso BioMatrix™, is an acellular scaffold that could potentially fill this need. To determine if PM could serve as an acceptable alternative, we histologically compared diced cartilage grafts wrapped in fascia versus PM. METHODS: Human rib cartilage and temporoparietal fascia were obtained under an IRB-approved protocol. Cartilage was diced into 0.5 mm pieces and implanted in subcutaneous pockets in nude rats. Implanted materials included cartilage alone, cartilage wrapped in fascia, cartilage wrapped in PM, fascia alone, or PM alone. Specimens were harvested at 8 weeks and stained with hematoxylin and eosin, Masson's trichrome, Safranin-O, and Verhoeff's stain to assess cartilage viability, architecture, and regenerative potential. RESULTS: Unwrapped diced cartilage showed the highest cartilage viability, but was associated with loss of contour and dispersion of the cartilage pieces. Meso BioMatrix-wrapped grafts maintained contour and cartilage pieces had not dispersed; however, there was a significantly lower number of nucleated lacunae and a greater amount of basophilia than both fascia-wrapped cartilage and unwrapped cartilage. There was no significant difference in cartilage resorption between fascia-wrapped cartilage and Meso BioMatrix-wrapped cartilage or in the proteoglycan or collagen content between all groups. CONCLUSION: Off-the-shelf decellularized PM was associated with lower cartilage viability than unprocessed fascial allograft. No cartilage piece dispersion, fibrosis, resorption, or a foreign body reaction to Meso BioMatrix was observed. PM, although not equivalent to autologous tissue, may be utilized to achieve acceptable clinical results and be a viable alternative that limits donor side morbidity. This experimental study supports further clinical investigation of this material in rhinoplasty procedures.

Human Acellular Dermis as Spacer for Small-Joint Arthroplasty: Analysis of Revascularization in a Rabbit Trapeziectomy Model.

BACKGROUND: Carpometacarpal joint osteoarthritis affects 8 to 12 percent of the general population. Surgical management provides symptomatic relief for 78 percent of patients who fail conservative therapy, but little consensus exists regarding which surgical procedure provides superior patient outcomes. Recent human trials substituted exogenous acellular dermal matrices in the bone space, but there are no quantitative histologic data on the outcome of acellular dermal matrices in this environment. The authors aimed to quantify the revascularization and recellularization of acellular dermal matrices in the joint space using a rabbit model. METHODS: Bilateral lunate carpal bones were surgically removed in New Zealand rabbits. Acellular dermal matrix and autologous tissue were implanted in place of the lunate of the right and left wrists, respectively. Acellular dermal matrix was also implanted subcutaneously as a nonjoint control. Histologic and immunofluorescence analysis was performed after collection at 0, 6, and 12 weeks. RESULTS: Quantitative analysis of anti-α-smooth muscle actin and CD31 immunofluorescence revealed a sequential and comparable increase of vascular lumens in joint space and subcutaneous acellular dermal matrices. In contrast, autologous tissue implanted in the joint space did not have a similar increase in α-smooth muscle actin-positive or CD31-positive lumens. Semiquantitative analysis revealed increased cellularity in both autologous and acellular dermal matrix wrist implants at each time point, whereas average cellularity of subcutaneous acellular dermal matrix peaked at 6 weeks and regressed by 12 weeks. Trichrome and Sirius red staining revealed abundant collagen at all time points. CONCLUSION: The trapeziectomy joint space supports both cellular and vascular ingrowth into human acellular dermal matrix.

Topical Fibronectin Improves Wound Healing of Irradiated Skin.

Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, we utilized a reverse phase protein array (RPPA) to identify significant changes in paired samples of normal and irradiated human skin. Of the 210 proteins studied, fibronectin was the most significantly and consistently downregulated in radiation-damaged skin. Using a murine model, we confirmed that radiation leads to decreased fibronectin expression in the skin as well as delayed wound healing. Topically applied fibronectin was found to significantly improve wound healing in irradiated skin and was associated with decreased inflammatory infiltrate and increased angiogenesis. Fibronectin treatment may be a useful adjunctive modality in the treatment of non-healing radiation wounds.

Efficient Assessment of Developmental, Surgical and Pathological Lymphangiogenesis Using a Lymphatic Reporter Mouse and Its Embryonic Stem Cells.

Several lymphatic reporter mouse lines have recently been developed to significantly improve imaging of lymphatic vessels. Nonetheless, the usage of direct visualization of lymphatic vessels has not been fully explored and documented. Here, we characterized a new Prox1-tdTomato transgenic lymphatic reporter mouse line, and demonstrated how this animal tool enables the researchers to efficiently assess developmental, surgical and pathological lymphangiogenesis by direct visualization of lymphatic vessels. Moreover, we have derived embryonic stem cells from this reporter line, and successfully differentiated them into lymphatic vessels in vivo. In conclusion, these experimental tools and techniques will help advance lymphatic research.

The interplay between hemostasis and malignancy: the oral cancer paradigm.

Accumulating evidence has revealed the role of various components of the coagulatory system in different stages of carcinogenesis including precancerous and initial stages, tumor growth, angiogenesis, stroma generation, and metastasis of malignant cells. This comprehensive review discusses major points of evidence, in addition to recent findings on specific factors associated with the paradigm of oral squamous cell carcinoma. During carcinogenesis, angiogenesis is favored by local conditions of hypoxia, cell-to-cell interactions, and by expression of paracrine growth factors and inflammatory cytokines. In the oral region specifically, genetic association studies have revealed that constitutively high gene expression of certain inflammatory cytokines plays a major role in carcinogenesis. Tissue factor (TF) has a physiological role in hemostasis, but it also constitutes a notable procoagulant in many types of cancer, since it appears to be constitutively expressed by tumor cells. Furthermore, its pathway regulates mechanisms which involve plasmin and matrix metallo-proteinases, both of which seem to be critical in oral carcinogenesis. Thrombin has a central role in hemostasis but it may also promote angiogenesis through pathways independently of fibrin generation. Thrombomodulin may act through attenuation of the tumor-promoting properties of thrombin, but it also may function as a cell-to-cell adhesion molecule, independently of its anticoagulant action. The activation of fibrinogen by thrombin and its cleavage to fibrin monomers result in the rapid formation of fibrin matrix. Furthermore, it is well documented that fibrinogen and cross-linked fibrin reside inside the tumor stroma, facilitating its remodeling, angiogenesis, tumor growth and metastasis. In conclusion, the hemostatic system contributes to the development of the malignant phenotype acting on many different levels.

Predictors of bleeding from stable pelvic fractures.

HYPOTHESIS: Stable pelvic fractures (SPFs) that do not need operative fixation are only infrequently associated with significant bleeding (SigBleed). Our hypothesis is that simple indicators, easily detectable at the bedside, can alert the clinician about the likelihood of bleeding and the need for closer monitoring or early intervention in patients with SPFs. DESIGN: Retrospective review of medical records. SETTING: Academic level 1 trauma center. PATIENTS: The medical records of patients with SPFs admitted to our academic level 1 trauma center from January 1, 2002, to June 30, 2007, were reviewed. Stable pelvic fractures were defined as fractures not requiring external or internal fixation. SigBleed was defined as the need for blood transfusion and/or intervention for bleeding control within the first 24 hours after admission. The patients were divided into group A, which included patients without SigBleed; group B, which included patients with SigBleed of a nonpelvic cause; and group C, which included patients with SigBleed caused by the SPF. The 3 groups were compared by univariate and multivariate analysis. MAIN OUTCOME MEASURE: Significant bleeding from SPFs. RESULTS: Of 391 patients with SPFs, 280 (72%) were in group A, 90 (23%) were in group B, and 21 (5%) were in group C. Compared with group A patients, those in group C were older and had a lower hematocrit and systolic blood pressure on admission. They also had longer hospital stays and a higher mortality. The following independent predictors of SigBleed from SPF were identified: hematocrit of 30% or lower (odds ratio [OR], 43.93; 95% confidence interval [CI], 9.78-197.32; P < .001); presence of pelvic hematoma on computed tomographic scan (OR, 39.37; 95% CI, 4.58-338.41; P < .001); and systolic blood pressure of 90 mm Hg or lower (OR, 18.352; 95% CI, 1.98-169.87; P = .01). When all independent predictors were present, 100% of the patients had SigBleed; when all were absent, no one had SigBleed. CONCLUSIONS: The incidence of SigBleed due to SPFs is low (5% in this study) and independently predicted by an admission hematocrit of 30% or lower, the presence of a pelvic hematoma on computed tomographic scan, and systolic blood pressure of 90 mm Hg or lower.

Successful selective nonoperative management of abdominal gunshot wounds despite low penetrating trauma volumes.

OBJECTIVE: To determine whether selective nonoperative management of abdominal gunshot wounds (AGSW) is safe in trauma centers with a low volume of penetrating trauma. DESIGN: Retrospective study. SETTING: Academic level 1 trauma center with approximately 10% penetrating trauma. PATIENTS: All patients with anterior and posterior AGSW (January 1, 1999, through December 31, 2009), excluding tangential injuries, transfers, and deaths in the emergency department. Patients with hemodynamic instability or peritonitis received an urgent laparotomy. The remaining patients had selective nonoperative management. A delayed laparotomy was offered for worsening symptoms or worrisome computed tomography findings. MAIN OUTCOME MEASURES: Hospital stay, complications, and mortality. RESULTS: Of 125 AGSW patients, 38 (30%) were initially managed by selective nonoperative management (25 of 99 anterior and 13 of 26 posterior AGSW patients). Seven selective nonoperative management patients received delayed laparotomy as late as 11 hours after admission. At the end, 30 of the 125 patients (24%) were successfully managed without an operation (20 of 99 anterior and 10 of 26 posterior AGSW patients). There were no predictors of delayed laparotomy and no complications or mortality attributed to it. Ten patients (8%) had a nontherapeutic laparotomy, and 3 of them developed complications. CONCLUSIONS: Selective nonoperative management of AGSW is feasible and safe in trauma centers with low penetrating trauma volumes. Nearly 1 in 4 AGSW patients does not need a laparotomy, and nontherapeutic laparotomies are associated with complications. The volume of AGSW per se should not be an excuse for routine laparotomies. These data become particularly important because penetrating trauma volumes are decreasing around the country.