Shear stress injury induces morphological and structural changes in cultured chick forebrain neurons

Poster presented at Biomedical Technology Showcase 2006, Philadelphia, PA. Retrieved 18 Aug 2006 from http://www.biomed.drexel.edu/new04/Content/Biomed_Tech_Showcase/Poster_Presentations/Barbee_2.pdf.We applied fluid shear stress injury (FSSI) to cultured chick forebrain neurons to determine if this type of injury mimics the structural and morphological changes in central nervous system neurons following traumatic brain injury (TBI). Our results demonstrate that axonal beading, which is the hallmark of TBI, is increased following FSSI, suggesting that our in vitro model system mimics TBI-like changes observed in vivo. Beads appeared at distinct locations along the axon where microtubule (MT) mass is decreased, supporting the hypothesis that beading is related with impaired axonal transport conducted over MTs. We suggest that focal changes in axolemmal permeability following trauma is responsible for focal peaks of intracellular calcium, which, in turn, depolymerize MTs locally. We are currently investigating if focal peaks of calcium exist and if axolemmal permeability changes occur in response to FSSI

A model of NO/O2 transport in capillary-perfused tissue containing an arteriole and venule pair

Biomedical Engineering, 35(4): pp. 517-529.The goal of this study was to investigate the complex co-transport of nitric oxide (NO) and oxygen (O2) in a paired arteriole-venule, surrounded by capillary-perfused tissue using a computer model. Blood flow was assumed to be steady in the arteriolar and venular lumens and to obey Darcy’s law in the tissue. NO consumption rate was assumed to be constant in the core of the arteriolar and venular lumen and to decrease linearly to the endothelium. Average NO consumption rate by capillary blood in a unit tissue volume was assumed proportional to the blood flux across the volume. Our results predict that: 1) the capillary bed, which connects the arteriole and venule, facilitates the release of O2 from the vessel pair to the surrounding tissue; 2) decreasing the distance between arteriole and venule can result in a higher NO concentration in the venular wall than in the arteriolar wall; 3) in the absence of capillaries in the surrounding tissue, diffusion of NO from venule to arteriole contributes little to NO concentration in the arteriolar wall; and 4) when capillaries are added to the simulation, a significant increase of NO in the arteriolar wall is observed

Validation of high gradient magnetic field based drug delivery to magnetizable implants under flow

IEEE Transactions on Biomedical Engineering, 55(2): pp. 643-649.The drug-eluting stent’s increasingly frequent occurrence late stage thrombosis have created a need for new strategies for intervention in coronary artery disease. This paper demonstrates further development of our minimally invasive, targeted drug delivery system that uses induced magnetism to administer repeatable and patient specific dosages of therapeutic agents to specific sites in the human body. Our first aim is the use of magnetizable stents for the prevention and treatment of coronary restenosis; however, future applications include the targeting of tumors, vascular defects, and other localized pathologies. Future doses can be administered to the same site by intravenous injection. This implant-based drug delivery system functions by placement of a weakly magnetizable stent or implant at precise locations in the cardiovascular system, followed by the delivery of magnetically susceptible drug carriers. The stents are capable of applying high local magnetic field gradients within the body, while only exposing the body to a modest external field. The local gradients created within the blood vessel create the forces needed to attract and hold drug-containing magnetic nanoparticles at the implant site. Once these particles are captured, they are capable of delivering therapeutic agents such as antineoplastics, radioactivity, or biological cells

Improving the efficacy of cellular therapy by magnetic cell targeting

Poster presented at Biomedical Technology Showcase 2006, Philadelphia, PA. Retrieved 18 Aug 2006 from http://www.biomed.drexel.edu/new04/Content/Biomed_Tech_Showcase/Poster_Presentations/Barbee.pdf.The hot topic of stem cell research has raised hopes for new treatments for a breadth of ailments. As the expectations continue to mount, most related engineering research has been focused around new tools for isolation and propagation of cell lines, with inadequate attention to effective delivery strategies. Invasive or systemic injections come with increased risk and poor efficiency, often wasting a vast majority of the total cellular dosage. We present a method for magnetic targeting of cells in the body with the use of a two-source method of magnetic drug delivery proposed previously in the literature

Cellular response of vascular smooth muscle to mechanical stimuli

Cultured vascular smooth muscle cells (VSM) were mechanically deformed by applying an equibiaxial strain to the compliant substrate to which they were adhered. The state of strain in the cells was determined from measurements of the displacements of fluorescent microspheres attached to the cell surface. The magnitude and orientation of principal strains were found to vary spatially and temporally. Uniaxially elongated cells experienced significant strains only in the longitudinal direction. Results indicate that these cells form strong adhesions only at the ends of their lamellipodal processes. A mathematical model for the mechanics of cell deformation was developed to investigate the influences of contractile force generation, viscoelasticity, and regionally varying mechanical properties and geometry on the time-dependence and regional variation of cell strain and the rate dependence of lamellipod detachment. The physiologic an pathophysiologic responses of vascular smooth muscle cells to trauma were investigated by applying strain impulses to cells in culture. Elevation of intracellular calcium and cell contraction were produced by applied strains of 10-30% at strain rates of 10-30 s\sp{-1}. Various degrees of cell injury manifested by localized cell swelling (blebs) were also produced. Blebs appeared within 10 seconds of the impulse. In a mild injury, the blebs were spontaneously reabsorbed within one minute. Severe injury led to uncontrolled cell swelling associated with the accumulation of intracellular calcium. These experiments represent the first cell-culture model for mechanically-induced vasospasm and cellular injury

Membrane Integrity as a Therapeutic Target in Neural Cell Injury

ABSTRACT The importance of cell membrane integrity for normal cell function and indeed survival is well established, yet the role of membrane disruption in cellular pathology is seldom considered except as a prelude to, or indication of, cell death. However, evidence from diverse fields strongly implicates membrane disruption as a key precipitating event in the pathological responses to various stimuli. Dynamic mechanical loading of neural cells produces an acute disruption of the plasma membrane as indicated by a rapid and transient release of LDH from the cytoplasm of injured cells. In this report, we show that this cellular level injury is not immediately fatal, but rather gives rise to a cascade of signaling events that lead to cell death in the long term. In our model, over 50% of the cells were dead at 24 hours post injury, the majority of which were apoptotic as assessed by the TUNEL assay using flow cytometry. Though many of the signaling pathways involved in this response to injury have been studied, the link between the initial membrane damage and the subsequent signaling is poorly understood. We report for the first time that treating injured neurons with an agent that promotes resealing of membrane pores can rescue the cells from both necrotic cell death and apoptosis at 24 hours post injury. Treatment with the nonionic surfactant, poloxamer 188 (P188), at 15 minutes post injury restored cell viability at 24 hours to control values. The role of the pro-apoptosis MAP kinase, p38, in cell death following injury was investigated using Western blot analysis. Activation of p38 was increased over 2-fold at 15 minutes post injury. P188 treatment at 10 minutes inhibited p38 activation. However, treatment with a specific inhibitor of p38 activation produced only a partial reduction in apoptosis and had no effect on necrotic cell death. These data suggest multiple signaling pathways are involved in the long term response of neurons to mechanical injury. Furthermore, the putative mechanism of action of P188 to promote membrane resealing suggests that the acute membrane damage due to trauma is a critical precipitating event lying upstream of the many signaling cascades that contribute to the subsequent pathology. INTRODUCTION Traumatic Brain Injury (TBI) is one of the leading causes of death and disability in the U.S. Each year more than 2 million individuals are affected by TBI The loss of cell membrane integrity due to trauma and plasma membrane modifications including membrane blebbing and altered permeability, have recently been found to be the major contributors to the development of neuronal damage subsequent to traumatic injury by leading to ionic imbalances and activation of several cellular pathway

Nanostructured porous silicon scaffolds and augmented surface coatings for enhanced biocompatibility of multichannel microelectrodes

Poster presented at Biomedical Technology Showcase 2006, Philadelphia, PA. Retrieved 18 Aug 2006 from http://www.biomed.drexel.edu/new04/Content/Biomed_Tech_Showcase/Poster_Presentations/Moxon_3.pdf.Many different types of microelectrodes have been developed for use as a direct Brain-Machine Interface (BMI) to chronically record. Unfortunately, the recordings from these microelectrode devices are not consistent and often last for only a few weeks. The loss of these recordings is most likely due to damage to surrounding tissue that results in the formation of non-conductive glial-scar. In conjunction with developing nanostructured electrode surfaces to mimic the extracellular environment, we have also begun to study the effects of novel surface coatings. Preliminary data show that Poloxamer has a positive effect on neuronal survival and is successful in decreasing the proliferation of glial cells