Byeong Han Lee

Lapabot: A compact telesurgical robot system for minimally invasive surgery: Part II. Telesurgery evaluation

Abstract As described in Part I, the Lapabot was developed considering telesurgery from the initial design stage. The robot configuration is based on the master-slave structure in which the operator can be separated spatially from the patient. The distributed control architecture communicating through high-speed network enables remote control of surgical robot manipulators. In this work, we added network communication modules using user datagram protocol/internet protocol for implementation of the telesurgical system. For a stable network environment, a dedicated research network was adopted. To characterize the network environment, a data packet sender and a repeater whose packet length and packet structure are similar to those of the real data packet were developed. The developed system was evaluated through in-vitro and in-vivo experiments. With the developed system, we have successfully performed remote control of the Lapabot. The roundtrip time delay for the control signal ranged from 1.4 to 4.1 ms. The total time delay for the operator including image signal acquisition and transmission delays was under 333 ms. It did not impede surgical procedures. Initial evaluation results demonstrate the feasibility of the developed telesurgical system.

DJ-1 is involved in epigenetic control of sphingosine-1-phosphate receptor expression in vascular neointima formation

DJ-1 and sphingosine-1-phosphate (S1P) receptors (S1PRs) are implicated in the control of physiology and pathophysiology of cardiovascular systems such as blood pressure, atherosclerosis, and restenosis. Here, we investigated whether DJ-1 with antioxidant function participates in the regulation of S1PR1 and S1PR2 expression in vascular smooth muscle cells (VSMCs) and whether this response is related to vascular neointima formation. In vitro studies used cellular migration assay, western blot, reverse transcriptase and real-time PCR analysis, and immunocytochemistry. In vivo studies were performed using the carotid artery ligation model together with immunohistochemistry in DJ-1 knockout (DJKO) and corresponding wild-type (DJWT) mice. S1P stimulated migration of VSMCs from DJKO and DJWT mice. VSMC migration was suppressed by S1PR1 inhibitor but was elevated by S1PR2 inhibitor. Compared with DJWT mice, S1PR1 expression was higher in VSMCs and neointimal plaque from DJKO mice, but S1PR2 expression was lower. Overexpression of DJ-1 in DJKO VSMCs reduced S1PR1 expression and elevated S1PR2 expression. Compared with DJWT mice, histone deacetylase-1 recruitment and histone H3 acetylation at the S1PR1 promoter region were lower and higher, respectively, but this pattern was reversed at the S1PR2 promoter region in DJKO VSMCs. S1PR expressions and epigenetic changes at S1PR promoter regions in DJWT VSMCs treated with H2O2 showed similar patterns to those in DJKO VSMCs. Our findings suggest that DJ-1 may be involved in the regulation of S1PR1 and S1PR2 expression via H2O2-mediated histone modification in VSMCs. Consequently, this modification may affect S1P-induced VSMC migration and be related to vascular neointima formation.

Increased HoxB4 Inhibits Apoptotic Cell Death in Pro-B Cells

HoxB4, a homeodomain-containing transcription factor, is involved in the expansion of hematopoietic stem cells and progenitor cells in vivo and in vitro, and plays a key role in regulating the balance between hematopoietic stem cell renewal and cell differentiation. However, the biological activity of HoxB4 in other cells has not been reported. In this study, we investigated the effect of overexpressed HoxB4 on cell survival under various conditions that induce death, using the Ba/F3 cell line. Analysis of phenotypical characteristics showed that HoxB4 overexpression in Ba/F3 cells reduced cell size, death, and proliferation rate. Moreover, the progression from early to late apoptotic stages was inhibited in Ba/F3 cells subjected to HoxB4 overexpression under removal of interleukin-3-mediated signal, leading to the induction of cell cycle arrest at the G2/M phase and attenuated cell death by Fas protein stimulation in vitro. Furthermore, apoptotic cell death induced by doxorubicin-treated G2/M phase cell-cycle arrest also decreased with HoxB4 overexpression in Ba/F3 cells. From these data, we suggest that HoxB4 may play an important role in the regulation of pro-B cell survival under various apoptotic death environments.

In vitro evaluation of hydraulic characteristics of prototype implantable intrathecal infusion pump.

The use of the intrathecal infusion pump for therapeutic treatment and pain management is increasing. For example, one such application is the pain treatment of cancer patients suffering from severe chronic pain, where all other treatment methods have failed. This method is gaining popularity because of its high cure effect with low dosage. In this study, we developed a prototype implantable intrathecal infusion pump and evaluated its mechanical and hydraulic characteristics in vitro to determine how its performance varied under different environmental conditions. The data are reported as means (standard deviations). In the experiments, the prototype pump could control the micro-scale infusion amount, and its performance was affected by ambient temperature and pressure conditions. In a temperature change test, at a constant pressure of 1.0 atm, the minimal amounts of a bolus were 4.44 (1.07), 5.06 (1.17), and 5.54 (0.90) uL for the temperature of 27.5, 36.5, and 42°C, respectively. In a pressure change test, at a constant temperature of 36.5°C, the minimal amounts of a bolus were 5.06 (1.17), 5.94 (0.67), and 6.13 (0.39) uL for pressures of 1.0, 0.9 and 0.8 atm, respectively. These experimental results demonstrate the possibility of using the prototype pump as an implantable micro-volumetric infusion device. However, this prototype pump will have to undergo further design enhancement before being clinically feasible for such an application.

Angiotensin II facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of APE/Ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1

ABSTRACT Angiotensin II (Ang II) is implicated in the development of cardiovascular disorders including hypertension and atherosclerosis. However, the role of Ang II in the interaction between apurinic/apyrimidinic endonuclease/redox factor‐1 (APE/Ref‐1) and sphingosine‐1‐phosphate (S1P) signals in relation to vascular disorders remains to be clarified. This study aimed to determine whether APE/Ref‐1 plays a role in epigenetic regulation of the S1P receptor (S1PR) in response to Ang II in vascular smooth muscle cell (VSMC) migration and vascular neointima formation. Ang II augmented the expression of S1PR1 in aortic smooth muscle cells of Sprague Dawley rats (RASMCs), which was attenuated by Ang II receptor (AT) 1 inhibitors, antioxidants, and APE/Ref‐1 knockdown with small interference RNA. Ang II stimulation produced H2O2, and exogenous H2O2 elevated S1PR1 expression in RASMCs. Moreover, Ang II caused translocation of cytoplasmic APE/Ref‐1 into the nucleus in RASMCs. H3 histone acetylation and APE/Ref‐1 binding at the S1PR1 promoter were increased in RASMCs treated with Ang II. In addition, Ang II induced migration in RASMCs, which was suppressed by AT1 and S1PR1 inhibitors. The expression of S1PR1, and colocalization of APE/Ref‐1 and acetylated histone H3 in vascular neointima, were greater in Ang II‐infused rats compared with a control group. These findings demonstrate that Ang II stimulates the epigenetic regulation of S1PR1 expression via H2O2‐mediated APE/Ref‐1 translocation, which may consequently be involved in Ang II‐induced VSMC migration and vascular neointima formation. Therefore, APE/Ref‐1‐mediated overexpression of S1PR1 may be implicated in the vascular dysfunction evoked by Ang II. HIGHLIGHTSAng II increased S1PR1 expression and H2O2 generation in VSMCs.H2O2 elevated S1PR1 expression in VSMCs.Ang II epigenetically enhanced S1PR1 expression via APE/Ref‐1 translocation by H2O2.These events may be linked to Ang II‐increased VSMC migration and vascular neointima. Abbreviations: DCF‐DA: 6‐carboxy‐2′,7′‐dichlorofluoroscein diacetate; Ang II: angiotensin II; AT: Ang II receptor; APE/Ref‐1: apurinic/apyrimidinic endonuclease/redox factor‐1; ChIP: chromatin immunoprecipitation; DABd: iaminobenzidine; H&E: hematoxylin and eosin; HDAC: histone deacetylase; HAT: histone acetyltransferase; MAPK: mitogen‐activated protein kinase; PDGF: platelet‐derived growth factor; RASMCs: rat aortic smooth muscle cells; ROS: reactive oxygen species; S1PR: S1P receptor; siRNA: small interfering RNA; SDS: sodium dodecyl sulfate; S1P: sphingosine‐1‐phosphate; SD: Sprague Dawley; SBP: systolic blood pressure; VEGF: vascular endothelial growth factor; VSMC: vascular smooth muscle cell.

Nootropic nanocomplex with enhanced blood-brain barrier permeability for treatment of traumatic brain injury-associated neurodegeneration

ABSTRACT Traumatic brain injury (TBI) is an intracranial injury which can induce immediate neuroinflammation and long‐term neurological deficits. Methylene blue (MB) as a nootropic has a great potential to treat neurodegeneration after TBI because of its anti‐inflmmatory and neuroprotective functions. However, its limited accumulation to the brain across the blood‐brain barrier (BBB) remains a major hurdle to be overcome. In this paper, we present a polymer surfactant‐encapsulated nanocomplex of MB as a delivery system with high BBB permeability for efficacious treatment of TBI‐induced neurodegeneration. MB was formulated via electrostatically/hydrophobically directed assembly with fatty acid and Pluronic surfactant (F‐127 or F‐68) to construct nanocomplexes of two different colloidal sizes (<10 nm and ˜108 nm in hydrodynamic diameter for NanoMB‐127 and NanoMB‐68, respectively). Compared to uncomplexed free MB, formulation into the ultrasmall nanocomplex (NanoMB‐127) significantly enhanced the uptake of MB by blood‐brain vascular endothelial bEnd3 cells in vitro, and indeed improved its BBB penetration upon systemic administration to normal mice in vivo. However, large‐size NanoMB‐68 showed negligible BBB crossing despite the efficient bEnd3 cell internalization in vitro, probably due to the unfavorable pharmacokinetic profile associated with its large particle size. By virtue of the efficient BBB penetration and cellular uptake, ultrasmall NanoMB‐127 was shown to distinctively reduce the expression level of an inflammatory cytokine with no notable toxicity in vitro and also considerably prevent the neurodegeneration after TBI in mice at much lower doses than free MB. Overall, the Pluronic‐supported nanocomplexation method allows efficient brain delivery of MB, offering a novel way of enhancing the efficacy of neurotherapeutics to treat brain diseases. Graphical abstract Figure. No caption available.