Scaffold Translation: Barriers Between Concept and Clinic

Translation of scaffold-based bone tissue engineering (BTE) therapies to clinical use remains, bluntly, a failure. This dearth of translated tissue engineering therapies (including scaffolds) remains despite 25 years of research, research funding totaling hundreds of millions of dollars, over 12,000 papers on BTE and over 2000 papers on BTE scaffolds alone in the past 10 years (PubMed search). Enabling scaffold translation requires first an understanding of the challenges, and second, addressing the complete range of these challenges. There are the obvious technical challenges of designing, manufacturing, and functionalizing scaffolds to fill the Form, Fixation, Function, and Formation needs of bone defect repair. However, these technical solutions should be targeted to specific clinical indications (e.g., mandibular defects, spine fusion, long bone defects, etc.). Further, technical solutions should also address business challenges, including the need to obtain regulatory approval, meet specific market needs, and obtain private investment to develop products, again for specific clinical indications. Finally, these business and technical challenges present a much different model than the typical research paradigm, presenting the field with philosophical challenges in terms of publishing and funding priorities that should be addressed as well. In this article, we review in detail the technical, business, and philosophical barriers of translating scaffolds from Concept to Clinic. We argue that envisioning and engineering scaffolds as modular systems with a sliding scale of complexity offers the best path to addressing these translational challenges.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90495/1/ten-2Eteb-2E2011-2E0251.pd

Genome Sequence of the Versatile Fish Pathogen Edwardsiella tarda Provides Insights into its Adaptation to Broad Host Ranges and Intracellular Niches

BACKGROUND:Edwardsiella tarda is the etiologic agent of edwardsiellosis, a devastating fish disease prevailing in worldwide aquaculture industries. Here we describe the complete genome of E. tarda, EIB202, a highly virulent and multi-drug resistant isolate in China. METHODOLOGY/PRINCIPAL FINDINGS:E. tarda EIB202 possesses a single chromosome of 3,760,463 base pairs containing 3,486 predicted protein coding sequences, 8 ribosomal rRNA operons, and 95 tRNA genes, and a 43,703 bp conjugative plasmid harboring multi-drug resistant determinants and encoding type IV A secretion system components. We identified a full spectrum of genetic properties related to its genome plasticity such as repeated sequences, insertion sequences, phage-like proteins, integrases, recombinases and genomic islands. In addition, analysis also indicated that a substantial proportion of the E. tarda genome might be devoted to the growth and survival under diverse conditions including intracellular niches, with a large number of aerobic or anaerobic respiration-associated proteins, signal transduction proteins as well as proteins involved in various stress adaptations. A pool of genes for secretion systems, pili formation, nonfimbrial adhesions, invasions and hemagglutinins, chondroitinases, hemolysins, iron scavenging systems as well as the incomplete flagellar biogenesis might feature its surface structures and pathogenesis in a fish body. CONCLUSION/SIGNIFICANCE:Genomic analysis of the bacterium offered insights into the phylogeny, metabolism, drug-resistance, stress adaptation, and virulence characteristics of this versatile pathogen, which constitutes an important first step in understanding the pathogenesis of E. tarda to facilitate construction of a practical effective vaccine used for combating fish edwardsiellosis

Distributed control of motor circuits for backward walking in Drosophila

How do descending inputs from the brain control leg motor circuits to change how an animal walks? Conceptually, descending neurons are thought to function either as command-type neurons, in which a single type of descending neuron exerts a high-level control to elicit a coordinated change in motor output, or through a population coding mechanism, whereby a group of neurons, each with local effects, act in combination to elicit a global motor response. The Drosophila Moonwalker Descending Neurons (MDNs), which alter leg motor circuit dynamics so that the fly walks backwards, exemplify the command-type mechanism. Here, we identify several dozen MDN target neurons within the leg motor circuits, and show that two of them mediate distinct and highly-specific changes in leg muscle activity during backward walking: LBL40 neurons provide the hindleg power stroke during stance phase; LUL130 neurons lift the legs at the end of stance to initiate swing. Through these two effector neurons, MDN directly controls both the stance and swing phases of the backward stepping cycle. These findings suggest that command-type descending neurons can also operate through the distributed control of local motor circuits. Drosophila Moonwalker Descending Neurons (MDNs) alter leg motor circuit dynamics so that the fly walks backwards. The authors identify two MDN effector neurons that directly control the stance and swing phases of the backward stepping cycle, indicating distributed control of local motor circuits via command-type descending neurons