From micro- to nanostructured implantable device for local anesthetic delivery

Local anesthetics block the transmission of painful stimuli to the brain by acting on ion channels of nociceptor fibers, and find application in the management of acute and chronic pain. Despite the key role they play in modern medicine, their cardio and neurotoxicity (together with their short half-life) stress the need for developing implantable devices for tailored local drug release, with the aim of counterbalancing their side effects and prolonging their pharmacological activity. This review discusses the evolution of the physical forms of local anesthetic delivery systems during the past decades. Depending on the use of different biocompatible materials (degradable polyesters, thermosensitive hydrogels, and liposomes and hydrogels from natural polymers) and manufacturing processes, these systems can be classified as films or micro- or nanostructured devices. We analyze and summarize the production techniques according to this classification, focusing on their relative advantages and disadvantages. The most relevant trend reported in this work highlights the effort of moving from microstructured to nanostructured systems, with the aim of reaching a scale comparable to the biological environment. Improved intracellular penetration compared to microstructured systems, indeed, provides specific drug absorption into the targeted tissue and can lead to an enhancement of its bioavailability and retention time. Nanostructured systems are realized by the modification of existing manufacturing processes (interfacial deposition and nanoprecipitation for degradable polyester particles and high- or low-temperature homogenization for liposomes) or development of novel strategies (electrospun matrices and nanogels). The high surface-to-volume ratio that characterizes nanostructured devices often leads to a burst drug release. This drawback needs to be addressed to fully exploit the advantage of the interaction between the target tissues and the drug: possible strategies could involve specific binding between the drug and the material chosen for the device, and a multiscale approach to reach a tailored, prolonged drug release

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

Bioengineering the Pancreas: Cell-on-Scaffold Technology

Nowadays, type I diabetes mellitus is a pathology afflicting millions of people globally with a dramatic assessment in the next future. Current treatments including exogenous insulin, pancreas transplantation and islets transplantation, are not free from important lifelong side effects. In the last decade, tissue engineering and regenerative medicine have shown encouraging results about the possibility to produce a functional bioengineered pancreas. Among many technologies, decellularization offers the opportunity to produce an organ-specific acellular matrix that could subsequently repopulate with endocrine cellular population. Herein, we aim to review the state-of-art and this technology highlighting the diabetes burden for the healthcare system and the major achievements toward the manufacturing of a bioengineered pancreas obtained by cell-on-scaffold technology

FPGA-based Low-Latency Audio Coprocessor for Networked Music Performance

Networked Music Performance (NMP) applications are acknowledged to be a particularly challenging field due to their stringent latency requirements and their demand for high audio quality. Most solutions developed in the last decades tried to overcome these obstacles by leveraging software approaches, that can introduce excessive time delays as a consequence of the general-purpose nature of the architectures on which they are implemented. Alternatively, a dedicated audio processor can be employed to minimize the mouth-to-ear latency.This paper presents the ongoing development of an hardware system that exploits an Application-Specific Instruction set Processor (ASIP) implemented on a Field-Programmable Gate Array (FPGA) to accelerate audio sample management. Specifically, a Transport Triggered Architecture (TTA) is being investigated as a processor design that aligns well with the required application domains. Preliminary empirical results indicate that the proposed solution has the potential to achieve extremely low latency, compatible with NMP requirements. Further optimizations and enhancements are actively being pursued to address the yet open challenges posed by NMP applications

Chapter Magnetic Resonance-Guided Focused Ultrasound in the Treatment of Colorectal Cancer Liver Metastases

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