Magnetically Actuated Protease Sensors for in Vivo Tumor Profiling

Targeted cancer therapies require a precise determination of the underlying biological processes driving tumorigenesis within the complex tumor microenvironment. Therefore, new diagnostic tools that capture the molecular activity at the disease site in vivo are needed to better understand tumor behavior and ultimately maximize therapeutic responses. Matrix metalloproteinases (MMPs) drive multiple aspects of tumorigenesis, and their activity can be monitored using engineered peptide substrates as protease-specific probes. To identify tumor specific activity profiles, local sampling of the tumor microenvironment is necessary, such as through remote control of probes, which are only activated at the tumor site. Alternating magnetic fields (AMFs) provide an attractive option to remotely apply local triggering signals because they penetrate deep into the body and are not likely to interfere with biological processes due to the weak magnetic properties of tissue. Here, we report the design and evaluation of a protease-activity nanosensor that can be remotely activated at the site of disease via an AMF at 515 kHz and 15 kA/m. Our nanosensor was composed of thermosensitive liposomes containing functionalized protease substrates that were unveiled at the target site by remotely triggered heat dissipation of coencapsulated magnetic nanoparticles (MNPs). This nanosensor was combined with a unique detection assay to quantify the amount of cleaved substrates in the urine. We applied this spatiotemporally controlled system to determine tumor protease activity in vivo and identified differences in substrate cleavage profiles between two mouse models of human colorectal cancer.National Cancer Institute (U.S.) (Grant P30-CA14051)National Institute of Environmental Health Sciences (Grant P30-ES002109)United States. Defense Advanced Research Projects Agency (Award HR0011-15-C-0155

Magnetic manipulation of superparamagnetic colloids in droplet-based optical devices

Magnetically assembled superparamagnetic colloids have been exploited as fluid mixers, swimmers and delivery systems in several microscale applications. The encapsulation of such colloids in droplets may open new opportunities to build magnetically controlled displays and optical components. Here, we study the assembly of superparamagnetic colloids inside droplets under rotating magnetic fields and exploit this phenomenon to create functional optical devices. Colloids are encapsulated in monodisperse droplets produced by microfluidics and magnetically assembled into dynamic two-dimensional clusters. Using an optical microscope equipped with a magnetic control setup, we investigate the effect of the magnetic field strength and rotational frequency on the size, stability and dynamics of 2D colloidal clusters inside droplets. Our results show that cluster size and stability depend on the magnetic forces acting on the structure under the externally imposed field. By rotating the cluster in specific orientations, we illustrate how magnetic fields can be used to control the effective refractive index and the transmission of light through the colloid-laden droplets, thus demonstrating the potential of the encapsulated colloids in optical applications

The local soft tissue status and the prediction of local complications following fractures of the ankle region

INTRODUCTION Well-known risk factors (RF) for soft tissue complications following surgical treatment of fracture of the ankle region include diabetes, smoking, and the local soft tissue status. A weighted analysis might provide a risk profile that guides the surgical treatment strategy. The aim of this meta-analysis was to provide a risk profile for soft tissue complications following closed fractures of the ankle region. METHODS This review provides a meta-analysis of studies that investigate potential risk factors for complications in fractures of the ankle region. INCLUSION CRITERIA Original articles that were published between 2000 and 2020 in English or German language that calculated odds ratios (OR) of RF for soft tissue complications. Further, this study only includes articles that investigated fractures of the ankle region including pilon fracture, calcaneal fractures, and fractures of the malleoli. This study excluded articles that provide exploratory analyses, narrative reviews, and case reports. RF were stratified as patient specific systemic RF (PSS), patient specific local RF (PSL), and non-patient specific RF (NPS). PSS RF includes comorbidities, American society of anaesthesiology (ASA), requirement of medication, additional injuries, and smoking or substance abuse. PSL RF includes soft tissue status, wounds, and associated complications. NPS RF includes duration of surgery, staged procedure, or time to definitive surgery. Random effect (RE) models were utilized to summarize the effect measure (OR) for each group or specific RF. RESULTS Out of 1352 unique articles, 34 were included for quantitative analyses. Out of 370 complications, the most commonly assessed RF were comorbidities (34.6%). Local soft tissue status accounted for 7.5% of all complications. The overall rate for complication was 10.9% (standard deviation, SD 8.7%). PSS RF had an OR of 1.04 (95%CI 1.01 to 1.06, p = 0.006), PSL an OR of 1.79 (95% 1.28 to 2.49, p = 0.0006), and NPS RF an OR of 1.01 (95%CI 0.97 to 1.05, p = 0.595). Additional injuries did not predict complications (OR 1.23, 95%CI 0.44 to 3.45, p = 0.516). The most predictive RF were open fracture (OR 3.47, 95%CI 1.64 to 7.34, p < 0.001), followed by local tissue damage (OR 3.05, 95%CI 1.23 to 40.92, p = 0.04), and diabetes (OR 2.3, 95%CI 1.1 to 4.79, p = 0.26). CONCLUSION Among all RFs for regional soft tissue complications, the most predictive is the local soft tissue status, while additional injuries or NPS RF were less predictive. The soft tissue damage can be quantified and outweighs the cofactors described in previous publications. The soft tissue status appears to have a more important role in the decision making of the treatment strategy when compared with comorbidities such as diabetes

A pulsatile flow system to engineer aneurysm and atherosclerosis mimetic extracellular matrix

Alterations of blood flow patterns strongly correlate with arterial wall diseases such as atherosclerosis and aneurysm. Here, a simple, pumpless, close-loop, easy-to-replicate, and miniaturized flow device is introduced to concurrently expose 3D engineered vascular smooth muscle tissues to high-velocity pulsatile flow versus low-velocity disturbed flow conditions. Two flow regimes are distinguished, one that promotes elastin and impairs collagen I assembly, while the other impairs elastin and promotes collagen assembly. This latter extracellular matrix (ECM) composition shares characteristics with aneurysmal or atherosclerotic tissue phenotypes, thus recapitulating crucial hallmarks of flow-induced tissue morphogenesis in vessel walls. It is shown that the mRNA levels of ECM of collagens and elastin are not affected by the differential flow conditions. Instead, the differential gene expression of matrix metalloproteinase (MMP) and their inhibitors (TIMPs) is flow-dependent, and thus drives the alterations in ECM composition. In further support, treatment with doxycycline, an MMP inhibitor and a clinically used drug to treat vascular diseases, halts the effect of low-velocity flow on the ECM remodeling. This illustrates how the platform can be exploited for drug efficacy studies by providing crucial mechanistic insights into how different therapeutic interventions may affect tissue growth and ECM assembly

Conductometric Sensors for Monitoring Degradation of Automotive Engine Oil†

Conductometric sensors have been fabricated by applying imprinted polymers as receptors for monitoring engine oil quality. Titania and silica layers are synthesized via the sol-gel technique and used as recognition materials for acidic components present in used lubricating oil. Thin-film gold electrodes forming an interdigitated structure are used as transducers to measure the conductance of polymer coatings. Optimization of layer composition is carried out by varying the precursors, e.g., dimethylaminopropyltrimethoxysilane (DMAPTMS), and aminopropyl-triethoxysilane (APTES). Characterization of these sensitive materials is performed by testing against oil oxidation products, e.g., carbonic acids. The results depict that imprinted aminopropyltriethoxysilane (APTES) polymer is a promising candidate for detecting the age of used lubricating oil. In the next strategy, polyurethane-nanotubes composite as sensitive material is synthesized, producing appreciable differentiation pattern between fresh and used oils at elevated temperature with enhanced sensitivity

Synthetic and living micropropellers for convection-enhanced nanoparticle transport

Nanoparticles (NPs) have emerged as an advantageous drug delivery platform for the treatment of various ailments including cancer and cardiovascular and inflammatory diseases. However, their efficacy in shuttling materials to diseased tissue is hampered by a number of physiological barriers. One hurdle is transport out of the blood vessels, compounded by difficulties in subsequent penetration into the target tissue. Here, we report the use of two distinct micropropellers powered by rotating magnetic fields to increase diffusion-limited NP transport by enhancing local fluid convection. In the first approach, we used a single synthetic magnetic microrobot called an artificial bacterial flagellum (ABF), and in the second approach, we used swarms of magnetotactic bacteria (MTB) to create a directable “living ferrofluid” by exploiting ferrohydrodynamics. Both approaches enhance NP transport in a microfluidic model of blood extravasation and tissue penetration that consists of microchannels bordered by a collagen matrix.ISSN:2375-254

Renal clearable catalytic gold nanoclusters for in vivo disease monitoring

Ultra-small gold nanoclusters (AuNCs) have emerged as agile probes for in vivo imaging, as they exhibit exceptional tumour accumulation and efficient renal clearance properties. However, their intrinsic catalytic activity, which can enable increased detection sensitivity, has yet to be explored for in vivo sensing. By exploiting the peroxidase-mimicking activity of AuNCs and the precise nanometer size filtration of the kidney, we designed multifunctional protease nanosensors that respond to disease microenvironments to produce a direct colorimetric urinary readout of disease state in less than 1 h. We monitored the catalytic activity of AuNCs in collected urine of a mouse model of colorectal cancer where tumour-bearing mice showed a 13-fold increase in colorimetric signal compared to healthy mice. Nanosensors were eliminated completely through hepatic and renal excretion within 4 weeks after injection with no evidence of toxicity. We envision that this modular approach will enable rapid detection of a diverse range of diseases by exploiting their specific enzymatic signatures

Electrochemistry: A basic and powerful tool for micro- and nanomotor fabrication and characterization

Electrochemistry, although an ancient field of knowledge, has become of paramount importance in the synthesis of materials at the nanoscale, with great interest not only for fundamental research but also for practical applications. One of the promising fields in which electrochemistry meets nanoscience and nanotechnology is micro/nanoscale motors. Micro/nano motors, which are devices able to perform complex tasks at the nanoscale, are commonly multifunctional nanostructures of different materials - metals, polymers, oxides- and shapes -spheres, wires, helices- with the ability to be propelled in fluids. Here, we first introduce the topic of micro/nanomotors and make a concise review of the field up to day. We have analyzed the field from different points of view (e.g. materials science and nanotechnology, physics, chemistry, engineering, biology or environmental science) to have a broader view of how the different disciplines have contributed to such exciting and impactful topic. After that, we focus our attention on describing what electrochemical technology is and how it can be successfully used to fabricate and characterize micro/nanostructures composed of different materials and showing complex shapes. Finally, we will review the micro and nanomotors fabricated using electrochemical techniques with applications in biomedicine and environmental remediation, the two main applications investigated so far in this field. Thus, different strategies have thus been shown capable of producing core-shell nanomaterials combining the properties of different materials, multisegmented nanostructures made of, for example, alternating metal and polymer segments to confer them with flexibility or helicoidal systems to favor propulsion. Moreover, further functionalization and interaction with other materials to form hybrid and more complex objects is also shown

Nanotechnology intervention of the microbiome for cancer therapy

The microbiome is emerging as a key player and driver of cancer. Traditional modalities to manipulate the microbiome (for example, antibiotics, probiotics and microbiota transplants) have been shown to improve efficacy of cancer therapies in some cases, but issues such as collateral damage to the commensal microbiota and consistency of these approaches motivates efforts towards developing new technologies specifically designed for the microbiome–cancer interface. Considering the success of nanotechnology in transforming cancer diagnostics and treatment, nanotechnologies capable of manipulating interactions that occur across microscopic and molecular length scales in the microbiome and the tumour microenvironment have the potential to provide innovative strategies for cancer treatment. As such, opportunities at the intersection of nanotechnology, the microbiome and cancer are massive. In this Review, we highlight key opportunistic areas for applying nanotechnologies towards manipulating the microbiome for the treatment of cancer, give an overview of seminal work and discuss future challenges and our perspective on this emerging area