Nikolay V. Vasilyev

Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling but Not Infarct Size After Myocardial Infarction

Background— Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common &agr;-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. Methods and Results— In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% (P<0.001) less LV dilation and a 52.2% (P<0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. Conclusions— The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.

GPU Based Real-time Instrument Tracking with Three Dimensional Ultrasound

Real-time 3D ultrasound can enable new image-guided surgical procedures, but high data rates prohibit the use of traditional tracking techniques. We present a new method based on the modified Radon transform that identifies the axis of instrument shafts as bright patterns in planar projections. Instrument rotation and tip location are then determined using fiducial markers. These techniques are amenable to rapid execution on the current generation of personal computer graphics processor units (GPU). Our GPU implementation detected a surgical instrument in 31 ms, sufficient for real-time tracking at the 26 volumes per second rate of the ultrasound machine. A water tank experiment found instrument tip position errors of less than 0.2 mm, and an in vivo study tracked an instrument inside a beating porcine heart. The tracking results showed good correspondence to the actual movements of the instrument.

A bioinspired soft actuated material.

A class of soft actuated materials that can achieve lifelike motion is presented. By embedding pneumatic actuators in a soft material inspired by a biological muscle fibril architecture, and developing a simple finite element simulation of the same, tunable biomimetic motion can be achieved with fully soft structures, exemplified here by an active left ventricle simulator.

A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects

A light-activated, biodegradable adhesive seals cardiovascular defects in the presence of blood flow and could be useful during minimally invasive surgery. Light-Activated Adhesive Seals Tissues An easy way to repair vessels or attach devices to tissues would be welcomed by surgeons. An adhesive, for instance, can reconnect tissue and interface prosthetics, but currently available materials have limitations such as low strength, high toxicity, and most do not function well in wet environments. In response, Lang and colleagues developed a new biomaterial glue that is biocompatible, biodegradable, and easily manipulated. This material, called poly(glycerol sebacate acrylate) (PGSA), when combined with a photoinitiator, creates a solution that the authors called HLAA: hydrophobic light-activated adhesive. The HLAA is a thick gel that can be slathered on a tissue and then cross-linked within seconds by ultraviolet light, which is a unique feature that avoids stitches. The resulting bond is water-tight yet flexible and stays intact in the face of high pressure and flowing blood. The authors first tested their material in rats, showing that the HLAA could be used to attach a polymer patch to the heart and that the HLAA alone could seal up defects in the heart wall, performing as well as sutures. Lang et al. then moved into pigs, whose hearts beat at similar rates to humans (by contrast, rats have much higher heart rates). Lang et al. showed that the light-activated adhesive could attach a patch to the interventricular septum of a pig’s beating heart and that this patch remained in place even under higher than normal heart rates (induced by adrenaline). Additionally, the HLAA alone was able to immediately close up defects in the pig carotid artery without any bleeding complications. The light-responsive adhesive performed well in several different in vivo scenarios, suggesting its broad applicability in the clinic, at least for cardiovascular surgeries and defects. As an added bonus, components of PGSA—namely, glycerol and sebacic acid—exist in the body and are readily metabolized. It is expected that this material could be translated soon to use in people. Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.

Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart

Cell delivery to the infarcted heart has emerged as a promising therapy, but is limited by very low acute retention and engraftment of cells. The objective of this study was to compare a panel of biomaterials to evaluate if acute retention can be improved with a biomaterial carrier. Cells were quantified post-implantation in a rat myocardial infarct model in five groups (n = 7-8); saline injection (current clinical standard), two injectable hydrogels (alginate, chitosan/β-glycerophosphate (chitosan/ß-GP)) and two epicardial patches (alginate, collagen). Human mesenchymal stem cells (hMSCs) were delivered to the infarct border zone with each biomaterial. At 24 h, retained cells were quantified by fluorescence. All biomaterials produced superior fluorescence to saline control, with approximately 8- and 14-fold increases with alginate and chitosan/β-GP injectables, and 47 and 59-fold increases achieved with collagen and alginate patches, respectively. Immunohistochemical analysis qualitatively confirmed these findings. All four biomaterials retained 50-60% of cells that were present immediately following transplantation, compared to 10% for the saline control. In conclusion, all four biomaterials were demonstrated to more efficiently deliver and retain cells when compared to a saline control. Biomaterial-based delivery approaches show promise for future development of efficient in vivo delivery techniques.

Vascular Endothelial Growth Factor Prevents Apoptosis and Preserves Contractile Function in Hypertrophied Infant Heart

Background— Cardiac hypertrophy is an adaptive response to increased workload that, if unrelieved, leads to heart failure. It has been reported that cardiomyocyte apoptosis contributes to failure, and that vascular endothelial growth factor (VEGF) treatment of hypertrophied myocardium increases capillary density and improves myocardial perfusion. In this study we hypothesized that VEGF treatment reduces cardiomyocyte apoptosis and thereby preserves myocardial contractile function. Methods and Results— Newborn rabbits underwent aortic banding. At 4 and 6 weeks of age, hypertrophied animals were treated with intrapericardial administration of recombinant VEGF protein. Three groups of animals were investigated: age-matched controls (C), untreated hypertrophied (H), and VEGF-treated hypertrophied hearts (T). Cardiomyocyte apoptosis was determined by TUNEL staining and PARP cleavage (immunoblotting of nuclear extracts) and cardiac function by transthoracic echocardiography. Death attributable to severe heart failure occurred in 14 of 43 untreated and 2 of 29 VEGF-treated animals (P<0.01). TUNEL-positive cardiomyocyte nuclei (n/1000 nuclei) were significantly increased in untreated hearts at 5 weeks (H: 10±1.8 versus T: 3±0.7) and at 7 weeks (H: 13±3.6 versus T: 5±1.5; P<0.05). Increased apoptosis in untreated hypertrophy was also confirmed by the presence of PARP cleavage (H: 74±7 versus T: 41±4 arbitrary densitometry units; P<0.05). VEGF treatment preserved left ventricular mass, prevented dilation (T: 1.01±0.06 versus H: 0.77±0.07; P<0.05), and preserved contractility indices compared with untreated hearts. Conclusions— Lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery in hypertrophying myocardium. VEGF treatment reduces myocardial apoptosis and prolongs survival in a model of severe progressive left ventricular hypertrophy. Promoting capillary growth with VEGF reduces apoptosis, preserves myocardial contractile function, and delays the onset of failure in pressure-loaded infant myocardium.

Force tracking with feed-forward motion estimation for beating heart surgery

The manipulation of fast-moving, delicate tissues in beating heart procedures presents a considerable challenge to the surgeon. A robotic force tracking system can assist the surgeon by applying precise contact forces to the beating heart during surgical manipulation. Standard force control approaches cannot safely attain the required bandwidth for this application due to vibratory modes within the robot structure. These vibrations are a limitation even for single degree-of-freedom systems that drive long surgical instruments. These bandwidth limitations can be overcome by the incorporation of feed-forward motion terms in the control law. For intracardiac procedures, the required motion estimates can be derived from 3-D ultrasound imaging. Dynamic analysis shows that a force controller with feed-forward motion terms can provide safe and accurate force tracking for contact with structures within the beating heart. In vivo validation confirms that this approach confers a 50% reduction in force fluctuations when compared with a standard force controller and a 75% reduction in fluctuations when compared with manual attempts to maintain the same force.

Imaging Artifacts of Medical Instruments in Ultrasound-Guided Interventions

Real‐time 3‐dimensional (3D) ultrasound imaging has the potential to become a dominant imaging technique for minimally invasive surgery. One barrier to its widespread use is that surgical instruments generate imaging artifacts, which can obfuscate their location, orientation, and geometry and obscure nearby tissue. The purpose of this study was to identify and describe the types of artifacts which could be produced by metallic instruments during interventions guided by 3D ultrasound imaging.

Tough adhesives for diverse wet surfaces

Sticky even when wet Tissue adhesives are used as an alternative to stitches or staples and can be less damaging to the healthy tissues. But they can suffer from low biocompatibility and poor matching of the mechanical properties with the tissues. Li et al. combined an adhesive surface with a flexible matrix to develop an adhesive that has the right level of stick but moves with the surrounding tissues. The adhesive is effective in the presence of blood and thus might work during wound repair. Science, this issue p. 378 Tough adhesives stick to wet surfaces and show compatibility with blood exposure and dynamic movements. Adhesion to wet and dynamic surfaces, including biological tissues, is important in many fields but has proven to be extremely challenging. Existing adhesives are cytotoxic, adhere weakly to tissues, or cannot be used in wet environments. We report a bioinspired design for adhesives consisting of two layers: an adhesive surface and a dissipative matrix. The former adheres to the substrate by electrostatic interactions, covalent bonds, and physical interpenetration. The latter amplifies energy dissipation through hysteresis. The two layers synergistically lead to higher adhesion energies on wet surfaces as compared with those of existing adhesives. Adhesion occurs within minutes, independent of blood exposure and compatible with in vivo dynamic movements. This family of adhesives may be useful in many areas of application, including tissue adhesives, wound dressings, and tissue repair.

Mitral Annulus Segmentation From 3D Ultrasound Using Graph Cuts

The shape of the mitral valve annulus is used in diagnostic and modeling applications, yet methods to accurately and reproducibly delineate the annulus are limited. This paper presents a mitral annulus segmentation algorithm designed for closed mitral valves which locates the annulus in three-dimensional ultrasound using only a single user-specified point near the center of the valve. The algorithm first constructs a surface at the location of the thin leaflets, and then locates the annulus by finding where the thin leaflet tissue meets the thicker heart wall. The algorithm iterates until convergence metrics are satisfied, resulting in an operator-independent mitral annulus segmentation. The accuracy of the algorithm was assessed from both a diagnostic and surgical standpoint by comparing the algorithms results to delineations made by a group of experts on clinical ultrasound images of the mitral valve, and to delineations made by an expert with a surgical view of the mitral annulus on excised porcine hearts using an electromagnetically tracked pointer. In the former study, the algorithm was statistically indistinguishable from the best performing expert (p = 0.85 ) and had an average RMS difference of 1.81±0.78 mm to the expert average. In the latter, the average RMS difference between the algorithms annulus and the electromagnetically tracked points across six hearts was 1.19±0.17 mm .