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ABSTRACT: Sub-lethal temperature elevations in the tumour incurred during laser cancer therapy can induce heat shock protein (HSP) expression leading to enhanced tumour survival and recurrence. Nanoshells utilised in combination with laser therapy can potentially enable selective heat deposition, greater thermal injury, and diminished HSP expression in the tumour. The study objective was to measure the distribution of temperature and HSP expression in prostate tumours in response to laser therapy alone or with nanoshells to determine if these combinatorial therapies can minimise HSP expression.
PC3 cells were inoculated in the backs of CB17-Prkd c SCID/J mice and treated with external laser irradiation (wavelength of 810 nm, irradiance of 5 W/cm(2), spot size of 5 mm, and heating duration of 3 min) alone or in combination with gold nanoshells (diameter of 55 nm and outer gold shell thickness of 10 nm) introduced into the tumour 24 h prior to laser treatment. Magnetic resonance temperature imaging was used to measure the distribution of temperature elevation in the tumours during laser treatment. Tumours were sectioned 16 h following laser treatment, stained for Hsp27 and Hsp70, imaged with a confocal microscope, and HSP expression levels were quantified as a function of depth in the tumours.
Maximum temperature elevations at the tumour surface were 28°C for laser treatment only and 50°C for laser heating in combination with gold nanoshells. Laser therapy alone caused significant induction of HSP expression in the first few millimeters of the tumour depth, whereas decreasing HSP expression occurred with greater tumour depth. Tumours treated with laser and nanoshells experienced substantial temperatures (73-78°C) at the tumour surface and temperatures greater than 53°C in the first few millimeters which eliminated HSP expression.
Inclusion of nanoshells in laser therapy can provide a mechanism for enhancing heat deposition capable of eliminating HSP expression within a larger tumour region compared to laser heating alone.
International Journal of Hyperthermia 01/2011; 27(8):791-801. · 1.92 Impact Factor
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ABSTRACT: Hyperthermia can induce heat shock protein (HSP) expression in tumours, which will cause enhanced tumour viability and increased resistance to additional thermal, chemotherapy, and radiation treatments. The study objective was to determine the relationship of hyperthermia protocols with HSP expression kinetics and cell death and develop corresponding computational predictive models of normal and cancerous prostate cell response.
HSP expression kinetics and cell viability were measured in PC3 prostate cancer and RWPE-1 normal prostate cells subjected to hyperthermia protocols of 44° to 60°C for 1 to 30 min. Hsp27, Hsp60, and Hsp70 expression kinetics were determined by western blotting and visualised with immunofluorescence and confocal microscopy. Based on measured HSP expression data, a mathematical model was developed for predicting thermally induced HSP expression. Cell viability was measured with propidium iodide staining and flow cytometry to quantify the injury parameters necessary for predicting cell death following hyperthermia.
Significant Hsp27 and Hsp70 levels were induced in both cell types with maximum HSP expression occurring at 16 h post-heating, and diminishing substantially after 72 h. PC3 cells were slightly more sensitive to thermal stress than RWPE-1 cells. Arrhenius analysis of injury data suggested a transition between injury mechanisms at 54°C. HSP expression and injury models were effective at predicting cellular response to hyperthermia.
Measurement of thermally induced HSP expression kinetics and cell viability associated with hyperthermia enabled development of thermal dosimetry guidelines and predictive models for HSP expression and cell injury as a function of thermal stress to investigate and design more effective hyperthermia therapies.
International Journal of Hyperthermia 01/2010; 26(8):748-64. · 1.92 Impact Factor
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ABSTRACT: The healing effect of therapeutic hyperthermia induced by widely available heat wrap products is understood to be based on concomitant temperature dependent vasodilation and increase in mass transport. We hypothesize that an additional mechanism of healing associated with increased heat shock protein (HSP) expression is also a contributing factor. HSP expression is controlled by the level and duration of heating and can have a potent effect on healing. We have developed a combined thermal stress and HSP expression model for bioheat transport into the tissues of the back produced by a therapeutic heat wrap. The model predicts temperature distribution in the deep tissues of the back by a modified version of the Pennes (1948, "Analysis of Tissue and Arterial Blood Temperatures in the Resting Human Forearm," J. Appl. Physiol., 1(2), pp. 93-122) bioheat equation. The model also predicts HSP70/actin concentrations based on existing empirical expression data from our laboratory as a function of heating time and temperature. Thermal boundary conditions were input for a typical heat wrap worn for its functional duration of 8 h or more. Temperatures in the paraspinal muscles of the back increase by a minimum of 1 degrees C after 1 h of heating and persist for at least 2 h. HSP70/actin expression is increased 1.7-fold above the control. The model demonstrates that elevated HSP expression may provide an important contribution to the healing process in injured tissue when a therapeutic heat wrap is worn.
Journal of Biomechanical Engineering 08/2009; 131(7):074510. · 1.90 Impact Factor
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ABSTRACT: Induced hypothermia is an acknowledged useful therapy for treating conditions that lead to cell and tissue damage caused by ischemia, including traumatic brain injury, stroke, and cardiac arrest. An accumulating body of clinical evidence, together with several decades of research, has documented that the efficacy of hypothermia is dependent on achieving a reduced temperature in the target tissue before or soon following the ischemia-precipitating event. The temperature must be lowered to within a rather small range of values to effect therapeutic benefit without introducing collateral problems. Rewarming must be much slower than cooling. Many different methods and devices have been used for cooling, with mixed results. There are existing opportunities for bioengineers to improve our understanding of the mechanisms of hypothermia and to develop more effective methods of cooling the brain following trauma.
Annual review of biomedical engineering 05/2009; 11:135-62. · 11.24 Impact Factor
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ABSTRACT: Hot beverages such as tea, hot chocolate, and coffee are frequently served at temperatures between 160 degrees F (71.1 degrees C) and 185 degrees F (85 degrees C). Brief exposures to liquids in this temperature range can cause significant scald burns. However, hot beverages must be served at a temperature that is high enough to provide a satisfactory sensation to the consumer. This paper presents an analysis to quantify hot beverage temperatures that balance limiting the potential scald burn hazard and maintaining an acceptable perception of adequate product warmth. A figure of merit that can be optimized is defined that quantifies and combines both the above effects as a function of the beverage temperature. An established mathematical model for simulating burns as a function of applied surface temperature and time of exposure is used to quantify the extent of thermal injury. Recent data from the literature defines the consumer preferred drinking temperature of coffee. A metric accommodates the thermal effects of both scald hazard and product taste to identify an optimal recommended serving temperature. The burn model shows the standard exponential dependence of injury level on temperature. The preferred drinking temperature of coffee is specified in the literature as 140+/-15 degrees F (60+/-8.3 degrees C) for a population of 300 subjects. A linear (with respect to temperature) figure of merit merged the two effects to identify an optimal drinking temperature of approximately 136 degrees F (57.8 degrees C). The analysis points to a reduction in the presently recommended serving temperature of coffee to achieve the combined result of reducing the scald burn hazard and improving customer satisfaction.
Burns 09/2008; 34(5):648-54. · 1.96 Impact Factor
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ABSTRACT: The direct correlation between levels of heat shock protein expression and efficiency of its tissue protection function motivates this study of how thermal doses can be used for an optimal stress protocol design. Heat shock protein 70 (HSP70) expression kinetics were visualized continuously in cultured bovine aortic endothelial cells (BAECs) on a microscope heating stage using green fluorescent protein (GFP) as a reporter. BAECs were transfected with a DNA vector, HSP(p)-HSP70-GFP which expresses an HSP70-GFP fusion protein under control of the HSP70 promoter. Expression levels were validated by western blot analysis. Transfected cells were heated on a controlled temperature microscope stage at 42 degrees C for a defined period, then shifted to 37 degrees C for varied post-heating times. The expression of HSP70-GFP and its sub-cellular localization were visualized via fluorescence microscopy. The progressive expression kinetics were measured by quantitative analysis of serial fluorescence images captured during heating protocols from 1 to 2 h and post-heating times from 0 to 20 h. The results show two sequential peaks in HSP70 expression at approximately 3 and 12 h post-heat shock. A progressive translocation of HSP70 from the cytoplasm to the nucleus was observed from 6 to 16 h. We conclude that we have successfully combined molecular cloning and optical imaging to study HSP70 expression kinetics. The kinetic profile for HSP70-GFP fusion protein is consistent with the endogenous HSP70. Furthermore, information on dynamic intracellular translocation of HSP70 was extracted from the same experimental data.
Biotechnology and Bioengineering 02/2008; 99(1):146-54. · 3.95 Impact Factor
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ABSTRACT: Hyperthermia can induce heat shock protein (HSP) expression in tumor regions where non-lethal temperature elevation occurs, enhancing cell viability and resistance to chemotherapy and radiation treatments typically employed in conjunction with thermal therapy. However, HSP expression control has not been incorporated into current thermal therapy design. Treatment planning models based on achieving the desired post-therapy HSP expression and injury distribution in the tumor and healthy surrounding tissue can enable design of more effective thermal therapies that maximize tumor destruction and minimize healthy tissue injury.
An optimization algorithm for prostate cancer laser therapy design was integrated into a previously developed treatment planning model, permitting prediction and optimization of the spatial and temporal temperature, HSP expression, and injury distributions in the prostate. This optimization method is based on dosimetry guidelines developed from measured HSP expression kinetics and injury data for normal and cancerous prostate cells and tumors exposed to hyperthermia.
The optimization model determines laser parameters (wavelength, power, pulse duration, fiber position, and number of fibers) necessary to satisfy prescribed HSP expression and injury distributions in tumor and healthy tissue. Optimization based on achieving desired injury and HSP expression distributions within the tumor and normal tissue permits more effective tumor destruction and diminished injury to healthy tissue compared to temperature driven optimization strategies.
Utilization of the treatment planning optimization model can permit more effective tumor destruction by mitigating tumor recurrence and resistance to chemotherapy and radiation arising from HSP expression and insufficient injury.
Lasers in Surgery and Medicine 11/2007; 39(9):731-46. · 2.75 Impact Factor
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ABSTRACT: This paper presents the results of a study comparing student learning in an inquiry-based and a traditional course in biotransport. Collaborating learning scientists and biomedical engineers designed and implemented an inquiry-based method of instruction that followed learning principles presented in the National Research Council report "How People Learn" (HPL). In this study, the intervention group was taught a core biomedical engineering course in biotransport following the HPL method. The control group was taught by traditional didactic lecture methods. A primary objective of the study was to identify instructional methods that facilitate the early development of adaptive expertise (AE). AE requires a combination of two types of engineering skills: subject knowledge and the ability to think innovatively in new contexts. Therefore, student learning in biotransport was measured in two dimensions: A pre and posttest measured knowledge acquisition in the domain and development of innovative problem-solving abilities. HPL and traditional students' test scores were compared. Results show that HPL and traditional students made equivalent knowledge gains, but that HPL students demonstrated significantly greater improvement in innovative thinking abilities. We discuss these results in terms of their implications for improving undergraduate engineering education.
Annals of Biomedical Engineering 09/2007; 35(8):1312-23. · 2.37 Impact Factor
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Chandrajit L. Bajaj,
J. Tinsley Oden, Kenneth R. Diller,
James C. Browne,
J. Hazle,
Ivo Babuska,
Jon Bass,
L. Bidaut,
Leszek F. Demkowicz,
Andrew Elliott,
Yusheng Feng,
David Fuentes,
Boseob Kwon,
Serge Prudhomme,
R. Jason Stafford,
Yongjie Zhang
Computational Science - ICCS 2007, 7th International Conference Beijing, China, May 27-30, 2007, Proceedings, Part I; 01/2007
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Chandrajit L. Bajaj,
J. Tinsley Oden, Kenneth R. Diller,
James C. Browne,
J. Hazle,
Ivo Babuska,
J. Bass,
L. Bidaut,
Leszek F. Demkowicz,
A. Elliott,
Yusheng Feng,
David Fuentes
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ABSTRACT: Hyperthermia based cancer treatments are used to increase the susceptibility of cancerous tissue to subsequent radiation or chemotherapy treatments, and in the case in which a tumor exists as a well-defined region, higher intensity heat sources may be used to ab- late the tissue. Utilizing the guidance of real-time treatment data while applying a laser heat source has the potential to provide unprecedented control over the outcome of the treatment process (6,12). The goals of this work are to provide a working snapshot of the current system architec- ture developed to provide a real-time finite element solution of the prob- lems of calibration, optimal heat source control, and goal-oriented error estimation applied the equations of bioheat transfer and demonstrate that current finite element technology, parallel computer architecture, peer-to-peer data transfer infrastructure, and thermal imaging modali- ties are capable of inducing a precise computer controlled temperature field within the biological domain.
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ABSTRACT: This chapter describes a model for continuous development of adaptive expertise, including growth along the dimensions of innovation and knowledge, examined in the context of a biotransport course in biomedical engineering. Students improved on both knowledge and innovation, moving along a continuum toward adaptive expertise.
New Directions for Teaching and Learning 11/2006; 2006(108):35 - 47.
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Kenneth R Diller
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ABSTRACT: In all organisms there is an elevated synthesis of a select family of "stress proteins" in response to a broad array of environmentally driven stress vectors including elevated or depressed temperature, changes in pH, treatment with many classes of chemicals, ischemia, desiccation, and UV irradiation. The presence of stress proteins, often termed heat shock proteins (HSPs), has been recognized for more than four decades, and there is an extensive literature that addresses the structure and properties of HSPs, their function in normal and injured cells and tissues, and the molecular mechanisms of HSP expression in response to stress. Owing to this substantial aggregate of research, there is a growing appreciation of the potential for manipulating the magnitude and timing of elevated HSP expression to achieve targeted therapeutic objectives. The successful realization of this potential requires an understanding of the kinetics of the HSP expression process in response to sublethal stress regimens along with the ability to model the governing events in the process to design practical protocols that could be applied in therapeutic settings. Significant progress has been made in recent years in defining and developing capabilities in these two areas.
Annual Review of Biomedical Engineering 02/2006; 8:403-24. · 12.21 Impact Factor
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ABSTRACT: Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. Initiating insults, such as elevated or depressed temperature, diminished oxygen, and pressure, increase HSP expression and can protect cells against subsequent, otherwise lethal, insults. Although HSPs are very beneficial to the normal cell, cancer cells can also use HSPs in response to stresses associated with various therapies (hyperthermia, chemotherapy, radiation), mitigating injury incurred by these treatments. Hyperthermia is a common treatment option for prostate cancer. HSPs can be induced in regions of the tumor where temperatures are insufficient to cause lethal thermal necrosis. Elevated HSP expression can enhance tumor cell viability and impart increased resistance to subsequent chemotherapy and radiation treatments, thereby promoting tumor recurrence. An understanding of the structure, function, and thermally stimulated HSP kinetics and cell injury for prostate cancer cells is essential to designing effective hyperthermia protocols. Measured thermally induced cellular HSP expression and injury data can be employed to develop a treatment planning model for optimization of the tissue response to therapy based on accurate prediction of the HSP expression and cell damage distribution.
Annals of the New York Academy of Sciences 01/2006; 1066:222-42. · 3.15 Impact Factor
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J. Tinsley Oden, Kenneth R. Diller,
Chandrajit L. Bajaj,
James C. Browne,
J. Hazle,
Ivo Babuska,
Jon Bass,
Leszek F. Demkowicz,
Yusheng Feng,
David Fuentes,
Serge Prudhomme,
Marissa Nichole Rylander,
R. Jason Stafford,
Yongjie Zhang
Computational Science - ICCS 2006, 6th International Conference, Reading, UK, May 28-31, 2006, Proceedings, Part III; 01/2006
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ABSTRACT: This paper investigates gender differences (n=54) in adaptive performance and beliefs in a nontraditional "How People Learn" (HPL) challenge based biotransport course at a large public university. The HPL challenge framework is similar to problem-based or inquiry-based learning, but with a significant emphasis on knowledge taxonomy and formative feedback. The course consisted of a series of 10 challenges. Performance was measured on three dimensions (knowledge, innovation, and adaptive expertise) at three different time points over the course of the semester. The results showed that all students significantly improved on all three performance dimensions over time. Student adaptive beliefs were measured using a Likert scale self-reporting survey. There were significant gender differences in performance, but no gender differences in beliefs. Females had lower initial performance, but showed more improvement. By the end of the course, males and females performed similarly on all three measures. These results suggest that HPL curriculum/instruction can help mediate the gender gap in SMET education.
01/2006;
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ABSTRACT: Thermal preconditioning protocols for cardiac cells were identified which produce elevated HSP70 levels while maintaining high cell viability. Bovine aortic endothelial cells were heated with a water bath at temperatures ranging from 44 to 50 degrees C for periods of 1-30 min. Thermal stimulation protocols were determined which induce HSP70 expression levels ranging from 2.3 to 3.6 times the control while maintaining cell viabilities greater than 90%. An Arrhenius injury model fit to the cell damage data yielded values of A = 1.4 X 10(66) s(-1) and Ea = 4.1 X 10(5) J/mol. Knowledge of the injury parameters and HSP70 kinetics will enhance dosimetry guideline development for thermal stimulation of heat shock proteins expression in cardiac tissue.
Journal of Biomechanical Engineering 11/2005; 127(5):751-7. · 1.90 Impact Factor
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ABSTRACT: A workshop was convened at Bethesda, Maryland on May 5 and 6, 2004 under the sponsorship of the NSF and NIH with the objectives of identifying emerging intellectual opportunities and applications in biotransport sciences and of guiding future research in the field. Approximately 50 leading researchers in the fields of fluid, heat, and mass biotransport were presented forward-looking perspectives and discussed how to synthesize broad cross-disciplinary areas: this defined guidelines for a roadmap document. Applications were presented in the context of disease analysis and diagnosis, therapy and prevention, and for physiologic and engineered living systems. The roadmap prioritizes specific research thrusts that reflect projected impacts on intellectuals, medical, and biological advances. Several overarching themes emerged. Most central is the expanded integration of fundamental transport sciences into the understanding of living systems and the great potential of patient specific modeling in designing a broad array of medical procedures.
Annals of Biomedical Engineering 10/2005; 33(9):1136-41. · 2.37 Impact Factor
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ABSTRACT: This paper considers an approach to teaching ethics in bioengineering based on the How People Learn (HPL) framework. Curricula based on this framework have been effective in mathematics and science instruction from the kindergarten to the college levels. This framework is well suited to teaching bioengineering ethics because it helps learners develop "adaptive expertise". Adaptive expertise refers to the ability to use knowledge and experience in a domain to learn in unanticipated situations. It differs from routine expertise, which requires using knowledge appropriately to solve routine problems. Adaptive expertise is an important educational objective for bioengineers because the regulations and knowledge base in the discipline are likely to change significantly over the course of their careers. This study compares the performance of undergraduate bioengineering students who learned about ethics for stem cell research using the HPL method of instruction to the performance of students who learned following a standard lecture sequence. Both groups learned the factual material equally well, but the HPL group was more prepared to act adaptively when presented with a novel situation.
Science and Engineering Ethics 05/2005; 11(2):257-76. · 0.74 Impact Factor
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Kenneth R Diller
Journal of Biomechanical Engineering 03/2005; 127(1):67-84. · 1.90 Impact Factor
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ABSTRACT: We describe a method for en face phase-contrast imaging of cells with a fiber-based differential phase-contrast optical coherence microscopy system. Recorded en face images are quantitative phase-contrast maps of cells due to spatial variation of the refractive index and (or) thickness of various cellular components. Quantitative phase-contrast images of human epithelial cheek cells obtained with the fiber-based differential phase-contrast optical coherence microscopy system are presented.
Optics Letters 08/2004; 29(13):1509-11. · 3.40 Impact Factor
