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The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary \'reflex\' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjects was designed to compare the effects of repeated administration in different conditions (arms). Tests with a motorized treadmill, a harness for body weight support, a transdermal spinal cord stimulator and/or an exoskeleton were proposed because: 1) these devices are unlikely to alter safety but, 2) they are reasonably expected to increase spinal locomotor neuron activation, reflex walking induction, and musculoskeletal/cardiovascular benefits. This approach would normally allow the phase III study to demonstrate clearly, with fewer subjects and at lower costs, long-term benefits on health of SpinalonTM used in optimized conditions and settings. This innovative strategy in drug development may contribute to further describe the mechanisms of action as well as optimized conditions of use for patients. Adapted to the development of other products, such an approach may enable greater safety, efficacy, clinical utility and compliance to be sought for next-generation CNS drugs.

The use of case-based reasoning in teaching professional ethics has come of age. The fields of medicine, engineering, and business all have incorporated ethics case studies into leading textbooks and journal articles, as well as undergraduate and graduate professional ethics courses. The most recent guidelines from the National Institutes of Health recognize case studies and face-to-face discussion as best practices to be included in training programs for the Responsible Conduct of Research. While there is a general consensus that case studies play a central role in the teaching of professional ethics, there is still much to be learned regarding how professionals learn ethics using case-based reasoning. Cases take many forms, and there are a variety of ways to write them and use them in teaching. This paper reports the results of a study designed to investigate one of the issues in teaching case-based ethics: the role of one\'s professional knowledge in learning methods of moral reasoning. Using a novel assessment instrument, we compared case studies written and analyzed by three groups of students whom we classified as: (1) Experts in a research domain in bioengineering. (2) Novices in a research domain in bioengineering. (3) The non-research group--students using an engineering domain in which they were interested but had no in-depth knowledge. This study demonstrates that a student\'s level of understanding of a professional knowledge domain plays a significant role in learning moral reasoning skills.

Assessment in ethics education faces a challenge. From the perspectives of teachers, students, and third-party evaluators like the Accreditation Board for Engineering and Technology and the National Institutes of Health, assessment of student performance is essential. Because of the complexity of ethical case analysis, however, it is difficult to formulate assessment criteria, and to recognize when students fulfill them. Improvement in students\' moral reasoning skills can serve as the focus of assessment. In previous work, Rosa Lynn Pinkus and Claire Gloeckner developed a novel instrument for assessing moral reasoning skills in bioengineering ethics. In this paper, we compare that approach to existing assessment techniques, and evaluate its validity and reliability. We find that it is sensitive to knowledge gain and that independent coders agree on how to apply it.

A focused theme in systems biology is to uncover design principles of biological networks, that is, how specific network structures yield specific systems properties. For this purpose, we have previously developed a reverse engineering procedure to identify network topologies with high likelihood in generating desired systems properties. Our method searches the continuous parameter space of an assembly of network topologies, without enumerating individual network topologies separately as traditionally done in other reverse engineering procedures. Here we tested this CPSS (continuous parameter space search) method on a previously studied problem: the resettable bistability of an Rb-E2F gene network in regulating the quiescence-to-proliferation transition of mammalian cells. From a simplified Rb-E2F gene network, we identified network topologies responsible for generating resettable bistability. The CPSS-identified topologies are consistent with those reported in the previous study based on individual topology search (ITS), demonstrating the effectiveness of the CPSS approach. Since the CPSS and ITS searches are based on different mathematical formulations and different algorithms, the consistency of the results also helps cross-validate both approaches. A unique advantage of the CPSS approach lies in its applicability to biological networks with large numbers of nodes. To aid the application of the CPSS approach to the study of other biological systems, we have developed a computer package that is available in Information S1.

Infectious disease control faces significant challenges including: how to therapeutically target the highest-risk populations, circumvent behavioral barriers, and overcome pathogen persistence and resistance mechanisms. We review a recently proposed solution to overcome these challenges: antivirals that transmit by \'piggybacking\' on viral replication. These proposed antivirals, termed \'therapeutic interfering particles\' (TIPs), are engineered molecular parasites of viruses that are designed to steal replication resources from the wild type virus. Depriving viruses of crucial replication machinery, TIPs would reduce viral loads. As obligate parasites, TIPs would transmit via the same risk factors and transmission routes as wild type viruses, automatically reaching high-risk populations, and thereby substantially limiting viral transmission even in resource-poor settings. Design issues and ethical/safety considerations of this proposed intervention are discussed.

LEGO bricks are commercially available interlocking pieces of plastic that are conventionally used as toys. We describe their use to build engineered environments for cm-scale biological systems, in particular plant roots. Specifically, we take advantage of the unique modularity of these building blocks to create inexpensive, transparent, reconfigurable, and highly scalable environments for plant growth in which structural obstacles and chemical gradients can be precisely engineered to mimic soil.

Batch anaerobic digestion was employed to investigate the efficient start-up strategies for the liquefied food waste, and sequencing batch digestion was also performed to determine maximum influent organic loading rate (OLR) for efficient and stable operation. The results indicated that the start-up could be well improved using appropriate wastewater organic load and food-to-microorganism ratios (F/M). When digestion was initialized at low chemical oxygen demand (COD) concentration of 20.0 gCOD L(-1), the start-up would go well using lower F/M ratio of 0.5-0.7. The OLR 7.0 gCOD L(-1) day(-1) was recommended for operating the ASBR digestion, in which the COD conversion of 96.7 ± 0.53% and biomethane yield of 3.5 ± 0.2 L gCOD(-1) were achieved, respectively. The instability would occur when OLR was higher than 7.0 gCOD L(-1) day(-1), and this instability was not recoverable. Lipid was suggested to be removed before anaerobic digestion. The anaerobic digestion process in engineering project ran well, and good performance was achieved when the start-up and operational strategies from laboratory study were applied. For case application, stable digestion performance was achieved in a digester (850 m(3) volume) with biogas production of 1.0-3.8 m(3) m(-3) day(-1).

An ultra scale-down primary recovery sequence was established for a platform E. coli Fab production process. It was used to evaluate the process robustness of various bioengineered strains. Centrifugal discharge in the initial dewatering stage was determined to be the major cause of cell breakage. The ability of cells to resist breakage was dependant on a combination of factors including host strain, vector, and fermentation strategy. Periplasmic extraction studies were conducted in shake flasks and it was demonstrated that key performance parameters such as Fab titre and nucleic acid concentrations were mimicked. The shake flask system also captured particle aggregation effects seen in a large scale stirred vessel, reproducing the fine particle size distribution that impacts the final centrifugal clarification stage. The use of scale-down primary recovery process sequences can be used to screen a larger number of engineered strains. This can lead to closer integration with and better feedback between strain development, fermentation development, and primary recovery studies.