A mathematical framework for nerve regeneration in implantable conduits

Matching the performance of autografts with engineered scaffolds remains a challenge in peripheral nerve repair. A combination of 3D biomimetic architecture interspersed with 2D surfaces has been hypothesized to be an ideal environment for neurite regeneration. However, the problem of how best to arrange material within a conduit is an open one. Optimizing material parameters such as density, cross-sectional geometry and spatial distribution would require an extensive programme of experimental testing. By contrast, developing a modelling framework that is capable of testing key parameters may accelerate the design process, and reduce the dependency on animal testing

Mathematical modelling with Bayesian inference to quantitatively characterize therapeutic cell behaviour in nerve tissue engineering

Cellular engineered neural tissues have significant potential to improve peripheral nerve repair strategies. Traditional approaches depend on quantifying tissue behaviours using experiments in isolation, presenting a challenge for an overarching framework for tissue design. By comparison, mathematical cell–solute models benchmarked against experimental data enable computational experiments to be performed to test the role of biological/biophysical mechanisms, as well as to explore the impact of different design scenarios and thus accelerate the development of new treatment strategies. Such models generally consist of a set of continuous, coupled, partial differential equations relying on a number of parameters and functional forms. They necessitate dedicated in vitro experiments to be informed, which are seldom available and often involve small datasets with limited spatio-temporal resolution, generating uncertainties. We address this issue and propose a pipeline based on Bayesian inference enabling the derivation of experimentally informed cell–solute models describing therapeutic cell behaviour in nerve tissue engineering. We apply our pipeline to three relevant cell types and obtain models that can readily be used to simulate nerve repair scenarios and quantitatively compare therapeutic cells. Beyond parameter estimation, the proposed pipeline enables model selection as well as experiment utility quantification, aimed at improving both model formulation and experimental design

Local Administration of Minocycline Improves Nerve Regeneration in Two Rat Nerve Injury Models

Peripheral nerve injuries are quite common and often require a surgical intervention. However, even after surgery, patients do not often regain satisfactory sensory and motor functions. This, in turn, results in a heavy socioeconomic burden. To some extent, neurons can regenerate from the proximal nerve stump and try to reconnect to the distal stump. However, this regenerating capacity is limited, and depending on the type and size of peripheral nerve injury, this process may not lead to a positive outcome. To date, no pharmacological approach has been used to improve nerve regeneration following repair surgery. We elected to investigate the effects of local delivery of minocycline on nerve regeneration. This molecule has been studied in the central nervous system and was shown to improve the outcome in many disease models. In this study, we first tested the effects of minocycline on SCL 4.1/F7 Schwann cells in vitro and on sciatic nerve explants. We specifically focused on the Schwann cell repair phenotype, as these cells play a central role in orchestrating nerve regeneration. Finally, we delivered minocycline locally in two different rat models of nerve injury, a sciatic nerve transection and a sciatic nerve autograft, demonstrating the capacity of local minocycline treatment to improve nerve regeneration

Simultaneous optogenetic manipulation and calcium imaging in freely moving C. elegans

A fundamental goal of systems neuroscience is to probe the dynamics of neural activity that drive behavior. Here we present an instrument to simultaneously manipulate neural activity via Channelrhodopsin, monitor neural response via GCaMP3, and observe behavior in freely moving C. elegans. We use the instrument to directly observe the relation between sensory stimuli, interneuron activity and locomotion in the mechanosensory circuit

Spinal cord stimulation for predominant low back pain in failed back surgery syndrome: study protocol for an international multicenter randomized controlled trial (PROMISE study)

Background: Although results of case series support the use of spinal cord stimulation in failed back surgery syndrome patients with predominant low back pain, no confirmatory randomized controlled trial has been undertaken in this patient group to date. PROMISE is a multicenter, prospective, randomized, open-label, parallel-group study designed to compare the clinical effectiveness of spinal cord stimulation plus optimal medical management with optimal medical management alone in patients with failed back surgery syndrome and predominant low back pain. Method/Design: Patients will be recruited in approximately 30 centers across Canada, Europe, and the United States. Eligible patients with low back pain exceeding leg pain and an average Numeric Pain Rating Scale score >= 5 for low back pain will be randomized 1:1 to spinal cord stimulation plus optimal medical management or to optimal medical management alone. The investigators will tailor individual optimal medical management treatment plans to their patients. Excluded from study treatments are intrathecal drug delivery, peripheral nerve stimulation, back surgery related to the original back pain complaint, and experimental therapies. Patients randomized to the spinal cord stimulation group will undergo trial stimulation, and if they achieve adequate low back pain relief a neurostimulation system using the Specify (R) 5-6-5 multi-column lead (Medtronic Inc., Minneapolis, MN, USA) will be implanted to capture low back pain preferentially in these patients. Outcome assessment will occur at baseline (pre-randomization) and at 1, 3, 6, 9, 12, 18, and 24 months post randomization. After the 6-month visit, patients can change treatment to that received by the other randomized group. The primary outcome is the proportion of patients with >= 50% reduction in low back pain at the 6-month visit. Additional outcomes include changes in low back and leg pain, functional disability, health-related quality of life, return to work, healthcare utilization including medication usage, and patient satisfaction. Data on adverse events will be collected. The primary analysis will follow the intention-to-treat principle. Healthcare use data will be used to assess costs and long-term cost-effectiveness. Discussion: Recruitment began in January 2013 and will continue until 2016

The homotopy theory of dg-categories and derived Morita theory

The main purpose of this work is the study of the homotopy theory of dg-categories up to quasi-equivalences. Our main result provides a natural description of the mapping spaces between two dg-categories $C$ and $D$ in terms of the nerve of a certain category of $(C,D)$-bimodules. We also prove that the homotopy category $Ho(dg-Cat)$ is cartesian closed (i.e. possesses internal Hom's relative to the tensor product). We use these two results in order to prove a derived version of Morita theory, describing the morphisms between dg-categories of modules over two dg-categories $C$ and $D$ as the dg-category of $(C,D)$-bi-modules. Finally, we give three applications of our results. The first one expresses Hochschild cohomology as endomorphisms of the identity functor, as well as higher homotopy groups of the \emph{classifying space of dg-categories} (i.e. the nerve of the category of dg-categories and quasi-equivalences between them). The second application is the existence of a good theory of localization for dg-categories, defined in terms of a natural universal property. Our last application states that the dg-category of (continuous) morphisms between the dg-categories of quasi-coherent (resp. perfect) complexes on two schemes (resp. smooth and proper schemes) is quasi-equivalent to the dg-category of quasi-coherent complexes (resp. perfect) on their product.Comment: 50 pages. Few mistakes corrected, and some references added. Thm. 8.15 is new. Minor corrections. Final version, to appear in Inventione