Courtney E. Morgan

Shape‐Dependent Targeting of Injured Blood Vessels by Peptide Amphiphile Supramolecular Nanostructures

Targeting of vascular intervention by systemically delivered supramolecular nanofibers after balloon angioplasty is described. Tracking of self-assembling peptide amphiphiles using fluorescence shows selective binding to the site of vascular intervention. Cylindrical nanostructures are observed to target the site of arterial injury, while spherical nanostructures with an equivalent diameter display no binding.

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage

Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.

Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury

AIMS Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. RESULTS Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. INNOVATION This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. CONCLUSION We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases.

Development and Validation of 4 Different Rat Models of Uncontrolled Hemorrhage

IMPORTANCE Hemorrhage is the leading cause of death in military trauma and second leading cause of death in civilian trauma. Although many well-established animal models of hemorrhage exist in the trauma and anticoagulant literature, few focus on directly quantitating blood loss. OBJECTIVE To establish and validate a reproducible rodent model of uncontrolled hemorrhage to serve as the foundation for developing therapies for noncompressible torso trauma. DESIGN, SETTINGS, AND SUBJECTS We developed and evaluated 4 different hemorrhage models using male Sprague-Dawley rats (6 rats/model), aged 10 to 14 weeks and weighing 330 to 460 g, at the Department of Surgery, Northwestern University. INTERVENTIONS We used tail-cut (4 cm), liver punch biopsy (12 mm), liver laceration (3.0 × 1.5 cm), and spleen transection models. All animals underwent invasive hemodynamic monitoring. MAIN OUTCOMES AND MEASURES Blood loss, expressed as a percentage of total blood volume (TBV), mean arterial pressure, and heart rate, which were recorded at 2- to 5-minute intervals. RESULTS The tail-cut model resulted in a mean (SD) TBV loss of 15.4% (6.0%) with hemodynamics consistent with class I hemorrhagic shock. The liver punch biopsy model resulted in a mean (SD) TBV loss of 16.7% (3.3%) with hemodynamics consistent with class I hemorrhagic shock. The liver laceration model resulted in a mean (SD) TBV loss of 19.8% (3.0%) with hemodynamics consistent with class II hemorrhagic shock. The spleen transection model resulted in the greatest blood loss (P < .01), with a mean (SD) TBV loss of 27.9% (3.4%) and hemodynamics consistent with class II hemorrhagic shock. The liver laceration and punch biopsy models resulted in most of the blood loss within the first 2 minutes, whereas the spleen transection and tail-cut models resulted in a steady loss during 10 minutes. The liver laceration and spleen transection models resulted in the greatest degree of hemodynamic instability (mean [SD] arterial pressure decreases of 25 [1] and 41 [11] mm Hg, respectively). One-hour survival was 100% in all 4 models. CONCLUSIONS AND RELEVANCE We established and validated the reproducibility of 4 different rat models of uncontrolled hemorrhage. These models provide a foundation to design novel nonsurgical therapies to control hemorrhage, and the different degrees of hemorrhagic shock produced from these models allow for flexibility in experimental design.

High-Risk Anatomic Variables and Plaque Characteristics in Carotid Artery Stenting

Objectives: To determine anatomic and plaque-related risk factors for patients undergoing carotid artery stenting. Methods: A retrospective review of patients from a prospectively maintained database undergoing carotid artery stenting at our institution between 2001 and 2010 was performed. Preoperative imaging studies (ie, ultrasound, computed tomography angiography, magnetic resonance angiography, and angiograms) were reviewed for specific anatomic criteria and plaque characteristics. Primary outcomes included 30-day stroke or transient ischemic attack (TIA). Secondary outcomes included 30-day death and myocardial infarction (MI). Statistical significance was assumed for P = .05. Results: Imaging was reviewed for 381 carotid arteries in 375 patients. There were 14 (3.7%) perioperative neurologic events, which included 8 TIA and 6 strokes. Thirty-day mortality and MI were 0.5% and 0.75%, respectively. Degree of internal carotid artery stenosis was associated with primary outcomes (P = .03), and the presence of arch calcification trended toward an increase in primary outcomes (P = .07). However, arch type, ostial involvement, tandem lesions, and plaque calcification did not correlate with primary outcomes. Differences were noted between the sexes, with females having more common carotid artery tortuosity than males (34% vs 27%, P = .04). Females also had a trend toward more plaque calcification and more severe arch calcification than males. These differences did not translate to differences in perioperative neurologic events. Conclusion: Our data suggest that degree of internal carotid artery stenosis and aortic arch calcification may be associated with increased perioperative neurologic risk during carotid stenting, but arch type is not.

Targeted Nanotherapies for the Treatment of Surgical Diseases.

Objective:To describe the components of targeted nanotherapeutics and to review their applications in the treatment of surgical diseases. Background:Targeted nanotherapeutic is a novel strategy for treating a variety of diseases and is an emerging technology that offers advantages over current treatment strategies. The nanoscale size, combined with the ability to surface functionalize the delivery vehicle to enable targeting and incorporate a therapeutic payload, provides a new and innovative therapeutic platform to treat surgical diseases that has yet to be fully realized in the surgical arena. Methods:A comprehensive literature review of nanotherapeutics, targeting strategies, and their utility in treating surgical diseases is performed. Results:Targeted nanotherapeutics have demonstrated safety and biocompatibility in treating surgical diseases. The ability to surface functionalize the nanoparticles affords a unique tailorability that enables targeting specificity and therapeutic payload delivery to treat a variety of surgical diseases. Moreover, the small size and targeting capabilities allow access to biological compartments, such as the blood–brain barrier, that have previously been difficult to treat. Conclusions:Targeted nanotherapeutics represent a novel therapeutic platform and have great potential to impact the treatment of surgical diseases.

Ten-year review of isolated spontaneous mesenteric arterial dissections

Objective: Isolated spontaneous dissection of the superior mesenteric artery (SMA) and celiac artery (CA) remains a rare condition; however, it has been increasingly noted incidentally on diagnostic imaging. The purpose of this study was to examine the natural history and outcomes of patients presenting with isolated spontaneous mesenteric artery dissection (SMAD). We hypothesized that most SMADs can be treated nonoperatively. Methods: This was a single‐center retrospective review of patients presenting with the diagnosis of SMAD between 2006 and 2016. Data analysis included demographics, clinical data, radiologic review, treatment, and outcomes. Results: A total of 77 patients were found to have CA dissection, SMA dissection, or both in the absence of aortic dissection diagnosed on computed tomography or magnetic resonance imaging. The average age was 56 years (range, 26–86 years), 80% were male, and 10 patients (13%) had underlying connective tissue disorders. The majority, 64%, presented with symptoms including abdominal pain, back pain, and chest pain; the remaining 36% were asymptomatic. Combined SMA and CA dissection was found in 14 (18%) patients; 33 (43%) presented with isolated CA dissection, and 30 (39%) presented with isolated SMA dissection. Only four patients required intervention. Mesenteric bypass was performed in two patients, and SMA endarterectomy with patch angioplasty was performed in one patient for signs of bowel ischemia. No patient required bowel resection. The two bypasses were anastomosed to a branch of the SMA, and complete lumen restoration was seen on long‐term imaging follow‐up. One patient underwent stent grafting of the CA and hepatic artery for aneurysmal degeneration 1 month after diagnosis. The remaining 73 patients were managed nonoperatively; 40 (52%) were treated with a short course of anticoagulation, 23 (30%) were treated with antiplatelet therapy, and 10 (13%) were treated with observation alone. No other late interventions or recurrences were noted during a mean follow‐up of 21 months. Conclusions: Whereas isolated SMAD poses a risk of visceral ischemia, most patients presenting with this diagnosis can be treated nonoperatively with a short course of antiplatelet or anticoagulant therapy. Only a small number of patients require surgical revascularization for bowel ischemia.

Novel large animal model of xanthoma formation.

0923-1811/ ã 2015 Japanese Society for Investigative Dermatology. Published by Elsev presentation, underlying etiology, and histological features. Initial treatment for xanthomas relies on treating the underlying dyslipidemia. Surgical excision or local destruction may be appropriate for lesions that do not respond to lipid-lowering therapy and impair function or are disfiguring [1]. To better understand the underlying pathogenesis of xanthomas and develop new medical therapeutic approaches, a reproducible animal model of xanthoma formation is needed. Currently, the exact mechanism of formation is unknown, but xanthomas are believed to result from low density lipoprotein infiltration of the dermis and subsequent phagocytosis by resident macrophages, which then become foam cells. Xanthomas have been reported to occur in mice, rats, and rabbits with hyperlipidemia [2–4], but major differences between their skin and human skin in terms of structure, mechanism of healing, and immune

Femoral Vein Blood Flow During a Total Hip Arthroplasty Using a Modified Heuter Approach

Several modifications to traditional surgical approaches for total hip arthroplasty (THA) have been introduced in an attempt to improve upon minimally invasive approaches and enhance short-term recovery. However, minimally invasive approaches are not without risk, including that of postoperative venous thromboembolism (VTE). There has been no published literature evaluating the femoral vein during an anterior approach. We aimed to study femoral vein blood flow using duplex ultrasonography during THA performed through a modified Heuter approach. Peek flow and vessel cross-sectional area were affected by limb position as well as acetabular and femoral retractor placement. No VTE was observed, but there was observed femoral vein compression, which may represent a risk of postoperative VTE similar to that seen in standard surgical approaches for THA.