Acellular Injectable Biomaterials for Treating Cardiovascular Disease

In the last decade, the field of tissue engineering has emerged as a potential therapeutic strategy for the regeneration and/or repair of various tissues afflicted by cardiovascular disease, such as myocardial infarction (MI) or peripheral artery disease (PAD). Among the different tissue engineering strategies, injectable hydrogels have been extensively studied and show encouraging results in both small and large animal models. An injectable hydrogel provides a favorable microenvironment for endogenous regeneration or repair, and depending on the material's design can be used either alone or as a carrier to deliver therapeutic molecules or stem cells. The type of injectable biomaterial is key for a successful hydrogel-based treatment, and in this chapter, we will focus on acellular injectable biomaterial approaches for both MI and PAD

Extracellular Matrix Hydrogel Promotes Tissue Remodeling, Arteriogenesis, and Perfusion in a Rat Hindlimb Ischemia Model.

ObjectiveThis study aimed to examine acellular extracellular matrix based hydrogels as potential therapies for treating peripheral artery disease (PAD). We tested the efficacy of using a tissue specific injectable hydrogel, derived from decellularized porcine skeletal muscle (SKM), compared to a new human umbilical cord derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of its young tissue source age.BackgroundThe prevalence of PAD is increasing and can lead to critical limb ischemia (CLI) with potential limb amputation. Currently there are no therapies for PAD that effectively treat all of the underlying pathologies, including reduced tissue perfusion and muscle atrophy.MethodsIn a rodent hindlimb ischemia model both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis (LASCA) to 35 days post-injection. Histology and immunohistochemistry were used to assess neovascularization and muscle health. Whole transcriptome analysis was further conducted on SKM injected animals on 3 and 10 days post-injection.ResultsSignificant improvements in hindlimb tissue perfusion and perfusion kinetics were observed with both biomaterials. End point histology indicated this was a result of arteriogenesis, rather than angiogenesis, and that the materials were biocompatible. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue specific, SKM hydrogel more closely matched healthy tissue morphology. Short term histology also indicated arteriogenesis rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development.ConclusionThese results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment

Specialization and integration of brain responses to object recognition and location detection

Visual information is processed in the brain primarily through two distinct pathways, the dorsal and the ventral visual streams. The present functional magnetic resonance imaging study investigated the specialization and integration of dorsal and ventral streams using tasks of object recognition and location detection. The study included 22 healthy adult volunteers who viewed stimuli consisting of grayscale photographs of common household objects presented in blocked design. Participants were asked to either recognize an object or to locate its position. While the location detection task elicited greater activation in the dorsal visual stream, recognizing objects showed greater activation in the middle occipital gyri, left inferior temporal gyrus, and in the left inferior frontal gyrus. The integration between dorsal and ventral brain areas was stronger during location detection than during object recognition. In addition, a principal components analysis found preliminary evidence for a group of regions, such as frontal and parietal cortex, working together in this task. Overall, the results of this study indicate the existence of specialized modules for object recognition and location detection, and possible interactions between areas beyond the visual cortex that may play a role in such tasks

The complex relationship between pediatric cardiac surgical case volumes and mortality rates in a national clinical database

ObjectiveWe sought to determine the association between pediatric cardiac surgical volume and mortality using sophisticated case-mix adjustment and a national clinical database.MethodsPatients 18 years of age or less who had a cardiac operation between 2002 and 2006 were identified in the Society of Thoracic Surgeons Congenital Heart Surgery Database (32,413 patients from 48 programs). Programs were grouped by yearly pediatric cardiac surgical volume (small, <150; medium, 150–249; large, 250–349; and very large, ≥350 cases per year). Logistic regression was used to adjust mortality rates for volume, surgical case mix (Aristotle Basic Complexity and Risk Adjustment for Congenital Heart Surgery, Version 1 categories), patient risk factors, and year of operation.ResultsWith adjustment for patient-level risk factors and surgical case mix, there was an inverse relationship between overall surgical volume as a continuous variable and mortality (P = .002). When the data were displayed graphically, there appeared to be an inflection point between 200 and 300 cases per year. When volume was analyzed as a categorical variable, the relationship was most apparent for difficult operations (Aristotle technical difficulty component score, >3.0), for which mortality decreased from 14.8% (60/406) at small programs to 8.4% (157/1858) at very large programs (P = .02). The same was true for the subgroup of patients who underwent Norwood procedures (36.5% [23/63] vs 16.9% [81/479], P < .0001). After risk adjustment, all groups performed similarly for low-difficulty operations. Conversely, for difficult procedures, small programs performed significantly worse. For Norwood procedures, very large programs outperformed all other groups.ConclusionThere was an inverse association between pediatric cardiac surgical volume and mortality that became increasingly important as case complexity increased. Although volume was not associated with mortality for low-complexity cases, lower-volume programs underperformed larger programs as case complexity increased

How does aging influence object-location and name-location binding during a visual short-term memory task?

Objective: Age-related impairments in human visual short-term memory (VSTM) may reflect a reduced ability to retain bound object representations, viz., object form, name, spatial, and temporal location (so called ‘memory sources’). Our objective is to examine how healthy aging affects VSTM in a battery of memory recognition tasks in which sequentially presented objects, locations, and names (as auditory stimuli) were learned, with one component cued at test. Methods: Thirty-six young healthy adults (18-30 years) and 36 normally aging older adults (>60 years with no underlying health and vision issues) completed five VSTM tasks: 1. Object recognition for two or four objects; 2. Spatial location recognition for two or four objects; 3. Bound object-location recognition for two or four objects; 4. Object recognition with location priming for two or four objects; 5. Bound name (auditory)-location (cross-modal) recognition for four objects. Results: Significantly lower performance for older adults was found in spatial location recognition [task 2, p=0.03, 2 (memory loads) × 2 (age groups) ANOVA], bound object-location recognition [task 3, p˂0.001, 2 (memory loads) × 2 (age groups) ANOVA], object recognition with location priming [task 4, p=0.02, 2 (memory loads) × 2 (age groups) ANOVA], and bound name-location recognition [task 5, p=0.001, independent samples t-test] tasks. A significant age group-task interaction was found (p =0.02) Conclusion: Performance for all tests except test 1 was impaired in older adults. Lower performance for older adults was most significant in VSTM tasks requiring object-location (visual only) or name-location (auditory and visual) binding. The findings are compatible with the ‘memory source’ model, demonstrating that age-related binding performance is influenced by spatial coding and location priming deficits

Contributions from cognitive neuroscience to understanding functional mechanisms of visual search.

We argue that cognitive neuroscience can contribute not only information about the neural localization of processes underlying visual search, but also information about the functional nature of these processes. First we present an overview of recent work on whether search for form - colour conjunctions is constrained by processes involved in binding across the two dimensions. Patients with parietal lesions show a selective problem with form - colour conjunctive search relative to a more difficult search task not requiring cross-dimensional binding. This is consistent with an additional process - cross-dimensional binding - being involved in the conjunctive search task. We then review evidence from preview search using electrophysiological, brain imaging, and neuropsychological techniques suggesting preview benefits in search are not simply due to onset capture. Taken together the results highlight the value of using converging evidence from behavioural studies of normal observers and studies using neuroscientific methods. © 2006 Psychology Press Ltd

Measuring the response to visually presented faces in the human lateral prefrontal cortex

Neuroimaging studies identify multiple face-selective areas in the human brain. In the current study, we compared the functional response of the face area in the lateral prefrontal cortex to that of other face-selective areas. In Experiment 1, participants (n = 32) were scanned viewing videos containing faces, bodies, scenes, objects, and scrambled objects. We identified a face-selective area in the right inferior frontal gyrus (rIFG). In Experiment 2, participants (n = 24) viewed the same videos or static images. Results showed that the rIFG, right posterior superior temporal sulcus (rpSTS), and right occipital face area (rOFA) exhibited a greater response to moving than static faces. In Experiment 3, participants (n = 18) viewed face videos in the contralateral and ipsilateral visual fields. Results showed that the rIFG and rpSTS showed no visual field bias, while the rOFA and right fusiform face area (rFFA) showed a contralateral bias. These experiments suggest two conclusions; firstly, in all three experiments, the face area in the IFG was not as reliably identified as face areas in the occipitotemporal cortex. Secondly, the similarity of the response profiles in the IFG and pSTS suggests the areas may perform similar cognitive functions, a conclusion consistent with prior neuroanatomical and functional connectivity evidence

Effects of mixed versus blocked design on stimulus evaluation: combining underaddative effects.

(from the journal abstract) According to the asynchronous discrete coding model of Miller, two manipulations should display underadditive effects on reaction time if they slow down noncontingent stages associated with the processing of two separable dimensions of a stimulus. Underadditive effects are also predicted by a dual route model when a task variable is factorially varied with design type (mixed vs blocked). Interpretations of both underadditive effects and their combination were evaluated. Intact and degraded stimuli were presented to 18 young adults either in a single block (mixed) or in separate blocks (blocked). Spatial stimulus-response (S-R) compatibility was manipulated in all conditions. Stimulus degradation and S-R compatibility interacted underadditively, but only in blocked presentations. Both interpretations of underadditive effects were supported. Eye-movement registrations provided additional support for the alternative routes model