ECMO Biocompatibility: Surface Coatings, Anticoagulation, and Coagulation Monitoring

The interaction between the patient and the ECMO (extracorporeal membrane oxygenation) circuit initiates a significant coagulation and inflammatory response due to the large surface area of foreign material contained within the circuit. This response can be blunted with the appropriate mix of biocompatible materials and anticoagulation therapy. The use of anticoagulants, in turn, requires appropriate laboratory testing to determine whether the patient is appropriately anticoagulated. Physicians must balance the risks of bleeding with the risks of thrombosis; the proper interpretation of these tests is often shrouded in mystery. It is the purpose of this chapter to help demystify the coagulation system, anticoagulants, biocompatible surfaces, and coagulation testing so that ECMO practitioners can make informed decisions about their patients and to spur coordinated efforts for future research to improve our understanding of these complex processes

Paracorporeal Lung Devices: Thinking Outside the Box

Extracorporeal Membrane Oxygenation (ECMO) is a resource intensive, life-preserving support system that has seen ever-expanding clinical indications as technology and collective experience has matured. Clinicians caring for patients who develop pulmonary failure secondary to cardiac failure can find themselves in unique situations where traditional ECMO may not be the ideal clinical solution. Existing paracorporeal ventricular assist device (VAD) technology or unique patient physiologies offer the opportunity for thinking “outside the box.” Hybrid ECMO approaches include splicing oxygenators into paracorporeal VAD systems and alternative cannulation strategies to provide a staged approach to transition a patient from ECMO to a VAD. Alternative technologies include the adaptation of ECMO and extracorporeal CO2 removal systems for specific physiologies and pediatric aged patients. This chapter will focus on: (1) hybrid and alternative approaches to extracorporeal support for pulmonary failure, (2) patient selection and, (3) technical considerations of these therapies. By examining the successes and challenges of the relatively select patients treated with these approaches, we hope to spur appropriate research and development to expand the clinical armamentarium of extracorporeal technology

In Vivo assessment of a tissue-engineered vascular graft combining a biodegradable elastomeric scaffold and muscle-derived stem cells in a rat model

Limited autologous vascular graft availability and poor patency rates of synthetic grafts for bypass or replacement of small-diameter arteries remain a concern in the surgical community. These limitations could potentially be improved by a tissue engineering approach. We report here our progress in the development and in vivo testing of a stem-cell-based tissue-engineered vascular graft for arterial applications. Poly(ester urethane)urea scaffolds (length=10mm; inner diameter=1.2mm) were created by thermally induced phase separation (TIPS). Compound scaffolds were generated by reinforcing TIPS scaffolds with an outer electrospun layer of the same biomaterial (ES-TIPS). Both TIPS and ES-TIPS scaffolds were bulk-seeded with 10×106 allogeneic, LacZ-transfected, muscle-derived stem cells (MDSCs), and then placed in spinner flask culture for 48h. Constructs were implanted as interposition grafts in the abdominal aorta of rats for 8 weeks. Angiograms and histological assessment were performed at the time of explant. Cell-seeded constructs showed a higher patency rate than the unseeded controls: 65% (ES-TIPS) and 53% (TIPS) versus 10% (acellular TIPS). TIPS scaffolds had a 50% mechanical failure rate with aneurysmal formation, whereas no dilation was observed in the hybrid scaffolds. A smooth-muscle-like layer of cells was observed near the luminal surface of the constructs that stained positive for smooth muscle α-actin and calponin. LacZ+ cells were shown to be engrafted in the remodeled construct. A confluent layer of von Willebrand Factor-positive cells was observed in the lumen of MDSC-seeded constructs, whereas acellular controls showed platelet and fibrin deposition. This is the first evidence that MDSCs improve patency and contribute to the remodeling of a tissue-engineered vascular graft for arterial applications. © 2010 Mary Ann Liebert, Inc

In vivo PEG modification of vascular surfaces for targeted delivery

ObjectiveThrombosis and restenosis remain problematic for many intravascular procedures. Previously, it has been demonstrated that modifying an injured vascular surface with a protein-reactive polymer could block undesirable platelet deposition. As an added benefit, it would be advantageous if one could target therapeutics to the injured site. This study investigates a site-specific delivery system to target microspheres to vascular surfaces modified with a reactive polyethylene glycol tagged with biotin.MethodsRabbit femoral arteries were injured with a 2F embolectomy catheter. Modification of the vascular surface was achieved using a channeled balloon catheter or small-diameter tube. Microspheres were injected intravenously through catheterization of the ear vein. Polymer modification on the injured surface and delivery of microspheres was quantified using epifluorescence microscopy at 0, 24, 48, and 72 hours.ResultsPolymer modification of the vascular surface could be achieved using a channeled drug delivery catheter or small-diameter tube with similar results. Maximum polymer coverage occurred at 0 hours and decreased to 85% maximal at 24 hours, 72% at 48 hours, and 67% at 72 hours. The initial number of microspheres per mm2 binding to modified, injured arteries was 304 versus 141 for the unmodified, damaged control (P < .01). At subsequent times, the number of adherent microspheres to modified, injured arteries decreased by 50%, 70%, and 84% at 24, 48, and 72 hours, respectively; while nonspecific binding to unmodified, injured arteries quickly decreased by 93%. Initial microsphere binding to modified, healthy arteries was 153 microspheres/mm2 as opposed to 26 microspheres/mm2 for the unmodified, healthy controls (P < .01).ConclusionsChemical modification of injured vessels following intravascular procedures can be readily accomplished in vivo to create a substrate for targeted delivery systems. As a proof of concept, targeted microspheres preferentially adhered to polymer-modified surfaces as opposed to injured, unmodified, or healthy vascular surfaces.Clinical RelevanceClinical outcomes of intravascular procedures are often complicated by thrombosis and restenosis due to vascular injury. These results demonstrate the feasibility of providing site-specific recognition signals for delivery of agents to healthy and damaged vascular tissue, which could prove valuable in a variety of clinical settings where the localization of therapeutics is desirable. In particular, the delivery of antimitotic or antithrombotic particulate pharmaceuticals or carriers to arterial lumens following angioplasty or endarterectomy, or chemotherapeutic agents to tumor vasculature might be feasible

Limiting Dietary Sugar Improves Pediatric Sinonasal Symptoms And Reduces Inflammation

Excessive sugar consumption is associated with many chronic inflammatory diseases in adults. The effects of excessive sugar consumption in children have not been determined. In this study, we hypothesized that sinonasal symptoms and proinflammatory cytokine levels would be related and could be altered through reduction in sugar-sweetened beverage (SSB) consumption. To test this, we conducted a pilot study involving behavior modification and a 2-week follow-up. Seventeen children participants were recruited, and eleven completed the study. The experimental group presented with chronic nasal congestion or rhinorrhea defined by daily symptoms without acute illness for at least 3 months. The control group presented for non-nasal problems. Both groups received counseling to decrease SSB consumption. The Sinus and Nasal Quality of Life (SN-5) Survey was administered, and a blood sample was obtained by venipuncture at baseline and 2 weeks after counseling. Participants kept a 2-week food diary to document sugar intake. Serum lipid profile and inflammatory cytokines were measured. The experimental group reduced daily sugar intake, 46% versus 11% in the control. Baseline SN-5 scores were significantly worse in the experimental group and normalized to controls after intervention. Inflammatory cytokine levels were not different at baseline, but the experimental group significantly reduced in proinflammatory markers and increased the levels of anti-inflammatory markers after intervention. Our pilot data demonstrate higher sugar consumption may be associated with increased inflammatory stress and sinonasal symptoms. Reducing SSB and controlling inflammation in early childhood may have future health benefits

Biocompatibility Assessment of the CentriMag-Novalung Adult ECMO Circuit in a Model of Acute Pulmonary Hypertension

Extracorporeal membrane oxygenation (ECMO) is rarely used in patients with severe pulmonary hypertension (PH) as a bridge to lung transplantation. In this study, we assess the blood biocompatibility of the integrated CentriMag-Novalung ECMO system (venoarterial) in an acute model of PH. Severe PH (≥2/3 systemic) was induced in eight sheep through progressive ligation of the main pulmonary artery. System performance, platelet activation, thromboelastography (TEG) parameters, fibrinogen, plasma-free hemoglobin, and total plasma protein were measured at initiation, 3, and 6 hr of support in the ECMO (N = 4) and sham (N = 4) groups. A stable ECMO flow (2.2 ± 0.1 L/min), low transmembrane pressure gradient, and steady blood O2 and CO2 levels were maintained. Platelet activation was low (&lt;4%) in both the groups, whereas platelet responsiveness to agonist (platelet activating factor) was reduced in the sham group when compared with the ECMO group. There were no differences in the TEG parameters, fibrinogen concentration, plasma-free hemoglobin (&lt;10 mg/dl), and plasma total protein between the two groups. The findings of low levels of platelet activation and plfHb suggest adequate blood biocompatibility of the integrated CentriMag-Novalung circuit use for short-term support in a model of PH

PediaFlow™ Maglev Ventricular Assist Device: A Prescriptive Design Approach.

This report describes a multi-disciplinary program to develop a pediatric blood pump, motivated by the critical need to treat infants and young children with congenital and acquired heart diseases. The unique challenges of this patient population require a device with exceptional biocompatibility, miniaturized for implantation up to 6 months. This program implemented a collaborative, prescriptive design process, whereby mathematical models of the governing physics were coupled with numerical optimization to achieve a favorable compromise among several competing design objectives. Computational simulations of fluid dynamics, electromagnetics, and rotordynamics were performed in two stages: first using reduced-order formulations to permit rapid optimization of the key design parameters; followed by rigorous CFD and FEA simulations for calibration, validation, and detailed optimization. Over 20 design configurations were initially considered, leading to three pump topologies, judged on the basis of a multi-component analysis including criteria for anatomic fit, performance, biocompatibility, reliability, and manufacturability. This led to fabrication of a mixed-flow magnetically levitated pump, the PF3, having a displaced volume of 16.6 cc, approximating the size of a AA battery and producing a flow capacity of 0.3-1.5 L/min. Initial in vivo evaluation demonstrated excellent hemocompatibility after 72 days of implantation in an ovine. In summary, combination of prescriptive and heuristic design principles have proven effective in developing a miniature magnetically levitated blood pump with excellent performance and biocompatibility, suitable for integration into chronic circulatory support system for infants and young children; aiming for a clinical trial within 3 years.</p