Perivascular application of NO-releasing self-assembling nanofiber gels is an effective and simple therapy to prevent neointimal hyperplasia after arterial injury. Our study demonstrates that the PROLI/NO nanofiber gel most effectively prevented neointimal hyperplasia and resulted in less inflammation than the DPTA/NO nanofiber gel. This therapy has great clinical potential to prevent neointimal hyperplasia after open vascular interventions in patients.

Since its discovery, nitric oxide (NO) has emerged as a biologically important molecule and was even named Molecule of the Year by Science magazine in 1992. Specific to our interests, NO has been implicated in the regulation of vascular pathology. This review begins with a summary of the molecular biology of NO, from its discovery to the mechanisms of endogenous production. Next, we turn our attention to describing the arterial injury response of neointimal hyperplasia, and we review the role of NO in the pathophysiology of neointimal hyperplasia. Finally, we review the literature regarding NO-based therapies. This includes the development of inhalational-based NO therapies, systemically administered L-arginine and NO donors, NO synthase gene therapy, locally applied NO donors, and NO-releasing prosthetic materials. By reviewing the current literature, we emphasize the tremendous clinical potential that NO-based therapies can have on the development of neointimal hyperplasia.

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.

Prosthetic devices that come into contact with blood ultimately fail secondary to thrombus formation. This limits the utility of a variety of materials used to surgically treat cardiovascular disease, including vascular grafts and stents, as well as sensors and catheters placed within the circulatory system. Moreover, systemic anticoagulation that is used to prevent malfunction of these devices has potential for serious complications. It is known that nitric oxide (NO) produced via the endothelium imparts thromboresistant properties to native blood vessels. Thus, if NO were delivered locally to the site of the prosthetic material, it has the potential to halt thrombus formation while limiting life-threatening side effects. This review serves to examine the variety of NO-releasing materials that have been created with the two different classes of NO donors, the diazeniumdiolates and S-nitrosothiols, and the clinical applications of these prosthetics for potential future use.