Medical prototyping using two photon polymerization

Two-photon polymerization (2PP) is an innovative technology that in recent years showed a tremendous potential for three-dimensional structuring of photopolymers at the submicron scale. It is based on the nonlinear absorption of ultrashort laser pulses in transparent photosensitive materials. 2PP has been so far exploited in various fields, including photonics, microfluidics, regenerative medicine and MEMS prototyping. The versatility of this technology relies also on the photomaterials; indeed, polymers are easy to process, low cost and they allow the tailoring of their chemical and mechanical properties. 2PP nanotechnology is here exploited to produce micro and nanostructures that can be easily customized both in the geometry and in polymer functionalization. In particular, atomic force microscopy tips are fabricated on top of commercial cantilevers to demonstrate the technology feasibility and customizability. Moreover nanoporous membranes that can be fabricated by 2PP as a single custom product or as a mould for mass production through replica moulding are realized to evaluate the scalability of the fabrication process.

Femtosecond laser pulses are capable of producing very high light intensities at moderate pulse energies. We study the laser light absorption at flux densities of 1017 W/cm2 and higher during the plasma formation and the plasma heating process. In the first stage multiphoton and collisional ionization dominate. Modification of the inverse bremsstrahlung absorption occur owing to ionization dephasing. In the second stage beam energy conversion is mainly by collisional absorption at normal incidence, and by resonance absorption at oblique illumination. Simultaneously strong electron heat conduction provides for plasma formation and heating in deeper layers of the solid not accessible to the laser light. The penetration depth of the laser beam is modified by the anomalous skin effect. The electron-ion collision frequency at the high laser intensities under consideration is determined by the oscillation energy of the electrons rather than by their thermal motion. Although it reaches high values (1014-1016 S-1), all kinds of solid targets become strongly reflecting (>60%) owing to the formation of electron densities largely exceeding those of solid-state plasmas. Effects modifying the degree of absorption are briefly discussed.

The nonlinear absorption of ultrashort laser pulses with intensities of 0.17–1.7 TW/cm2 at an intrinsic two-photon absorption wavelength of 4673 nm in type IIb diamond has been studied experimentally. It has been shown that the main absorption mechanism in the studied sample is two-photon absorption with a coefficient of β2 = (72 ± 7) cm/TW. Transmission microspectroscopy, visible photoluminescence, and infrared Fourier-transform microspectroscopy have demonstrated the possibility of laser-induced transformation of nitrogen impurity centers in synthetic type Ib diamond at higher radiation intensities.

The theory on the magnetic field energy absorption by metal nanoparticles of a nonspherical shape irradiated with ultrashort laser pulses of different duration is developed. The effect of both the particle surface and the particle shape on the absorbed energy is studied. For the particles having an oblate or prolate spheroidal shape, the dependence of this energy on the orientation of the magnetic field upon a particle, the degree of its deviation from a spherical shape, a pulse duration, and the carrier frequency of the laser ray are found. A significant increase in the absorption is established when an electron mean free path coincides with the size of the particle. The Drude and kinetic approaches are used and the results are compared with each other.

Wirelessly enabling Medical Devices such as Vital Signs Monitors, Ventilators and Infusion Pumps allows central data collection. This paper discusses how data from these types of devices can be integrated into hospital systems using wireless sensor networking technology. By integrating devices you are protecting investment and opening up the possibility of networking with similar devices. In this context we present how Zigbee meets our requirements for bandwidth, power, security and mobility. We have examined the data throughputs for various medical devices, the requirement of data frequency, security of patient data and the logistics of moving patients while connected to devices. The paper describes a new tested architecture that allows this data to be seamlessly integrated into a User Interface or Healthcare Information System (HIS). The design supports the dynamic addition of new medical devices to the system that were previously unsupported by the system. To achieve this, the hardware design is kept generic and the software interface for different types of medical devices is well defined. These devices can also share the wireless resources with other types of sensors being developed in conjunction on this project such as wireless ECG (Electrocardiogram) and Pulse-Oximetry sensors.

Femtosecond laser microprocessing is a direct, maskless fabrication technique that has attracted much attention in the past 10 years due to its unprecedented versatility in the 3D patterning of transparent materials. Two common modalities of femtosecond laser microfabrication include buried optical waveguide writing and surface laser ablation, which have been applied to a wide range of transparent substrates including glasses, polymers and crystals. In two photon polymerization, a third modality of femtosecond laser fabrication, focused femtosecond laser pulses drive photopolymerization in photoresists, enabling the writing of complex 3D structures with submicrometer resolution. In this paper, we discuss several microdevices realized by these diverse modalities of femtosecond laser microfabrication, for applications in microfluidics, sensing and quantum information.

The absorption of 250-fs KrF laser pulses incident on solid targets of aluminum and gold has been measured as a function of polarization and angle of incidence for the intensity range of ${10}^{14}$--2.5\ifmmode\times\else\texttimes\fi{}${10}^{15}$ W ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}2}$. Maximum absorption of over 60% occurs for p-polarized radiation at angles of incidence in the range of 48\ifmmode^\circ\else\textdegree\fi{}--57\ifmmode^\circ\else\textdegree\fi{}. The measured results are in agreement with absorption on a steep density gradient.

Mathematical expressions for the shape and amplitude of a photoacoustic signal generated due to the multiphoton absorption of Gaussian laser pulses are derived. It was found that the sensitivity of a photoacoustic spectrometer increases in proportion to n 3/4 when changing from one-photon linear absorption to nonlinear multiphoton absorption, where n is the nonlinearity exponent. Calibration of the photoacoustic spectrometer used in the measurements of multiphoton absorption cross sections is discussed.

The absorption of subpicosecond uv laser pulses has been measured at intensities above 10(17) W/cm(2). High levels of absorption were observed, up to 55% for s polarization and 65% for p polarization. The behavior with angle of incidence and polarization can be interpreted as due to a combination of resonance and collisional absorption, taking place in a plasma with a scale length of the order of a fraction of the laser wavelength.

Novel magnetic stimulation methodology for low-current implantable medical devices

Microfluidic devices combined with Raman Spectroscopy have great promise for in-situ and online detection of reaction processes with only a small volume of liquid required. This advanced method allows for flexible manipulation of fluids, micro/nano-particles, and biological samples1. Lab-on-a-chip applications are often used for chemical analysis, but Raman microscopy has also been used to monitor reactions within microreactors. The combination of the controlled mass transport in microfluidics with detection of soluble intermediate and product species by Raman offers the possibility of mechanistic kinetic studies of electrocatalytic reactions. We here show the feasibility of this method for studying electrocatalysis of oxidation of alcohols.Two types of microfluidic flow devices were fabricated, which used glass slides and printed circuit boards (PCBs) as substrates, respectively. For glass-slide-based microfluidic devices, Raman spectra were used to monitor methanol oxidation catalyzed by a Pt mesh electrode, and calibration with known solutions enabled quantification of methanol and formate concentrations. A comparative study of catalytic oxidations of glycerol, ethanol, ethylene glycol and 1-propanol using electrodeposited Ni on carbon paper showed that under strong alkaline conditions, glycerol and ethylene glycol principally gave formate and carbonate products, while ethanol and 1-propanol did not give formate. Acetate was found to be the major oxidation product of ethanol, with only a small amount of carbonate. For PCB-based microfluidic substrates, electroplated Ni on Cu pads gave planar working electrodes, which were used to catalyze the oxidation of glycerol. On-board PdH reference electrodes were incorporated2.1. A.F. Chrimes, K. Khoshmanesh, P.R. Stoddart, A. Mitchell, K. Kalantar-zadeh, Microfluidics and Raman microscopy: current applications and future challenges, Chem. Soc. Rev., 42, 5880 (2013).2. E.V. Fanavoll, D.A. Harrington, S. Sunde, G. Singh and F. Seland, A Microfluidic Electrochemical Cell with Integrated PdH Reference Electrode for High Current Experiments, Electrochim. Acta., 225 , 69 (2017).Acknowledgement: This research was conducted as part of the Engineered Nickel Catalysts for Electrochemical Clean Energy project administered from Queen’s University and supported by Grant No. RGPNM 477963-2015 under the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Frontiers Program. Figure 1

Medical devices are manifold and one of the most innovative fields of technology. As technologies advance, former limits cease to exist and complex devices become reality. Medical devices represent a very dynamic field with high economic relevance. The manufacturer of a medical device is obliged to minimize product-related risks as well as to demonstrate compliance with the so-called "essential requirements" regarding safety and performance before placing the device on the market. Any critical incident in relation to the application of a medical device has to be reported to the competent authority for risk assessment, which in Germany is either the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI) depending on the type of device. In this article, the German regulatory framework for medical devices and the resulting tasks for BfArM are described as well as the topics of its recently installed research and development group on prospective risk identification and application safety for medical devices. Results of failure mode and root cause analyses of incident data are presented as well as further data on cases with the result "root-cause analysis not possible". Finally an outlook is given on future challenges regarding risk assessment for medical devices.

A theoretical and experimental investigation was made of the thermal generation of sound by the absorption of laser pulses whose duration was short compared with the transit time of sound across the absorption region. An approximate theoretical model was used in calculations of the acoustic field in the near and far zones of a bulk antenna formed by the absorption zone. Experiments were carried out using a YAG laser emitting pulses of 30 nsec duration and 0.06 J energy. The experimental results were in good agreement with the theory.

Research on microfluidic devices for biological analysis has progressed sufficiently to be developed into point-of-care diagnostics products. The goal of this thesis is to improve multiple aspects of capillary-driven microfluidic devices. In particular, the objective is to provide devices with a fast time to result, that are simple to use (one-step), that can be portable, that accept a variety of samples, that operate reliably, that provide a range of detection signals, that are mass manufacturable at lost cost, and that are able to detect medically relevant biological molecules. First, we survey the evolution of microfluidic research into portable medical diagnostic devices. By looking at several gaps and opportunities in current medical diagnostics, we provide an overview of research topics that have the potential to shape the next generation of point-of-care diagnostics. Specifically we explain technologies in the order of sample interacting with different components of a device. We investigate the materials, surface treatments, sample processing, microfluidic elements (such as valves, pumps and mixers), receptors and analytes and the integration of these components into a device that might conceivably leave the laboratory for the hands of consumers. The knowledge of what is important in a point-of-care diagnostics device was used to develop a proof of concept. One of the main challenges is to make microfluidics easy to use by incorporating reagents and microfluidic elements. We integrated a number of functional elements on a chip such as a sample collector, delay valves, flow resistors, a deposition zone for detection antibodies (dAbs), a reaction chamber sealed with a polydimethylsiloxane (PDMS) substrate, and a capillary pump and vents. We further incorporated capture antibodies (cAbs), detection antibodies (dAbs) and analyte molecules for making one-step immunoassays. The integrated microfluidic chip requires only the addition of sample to trigger a sequence of events controlled by capillary forces to detect C-reactive protein (CRP), a general inflammation and cardiac marker, at a concentration of 1 ng mL-1 within 14 min using only 5 µL of human serum. The proof-of-concept is extended to easily modify several assay parameters such as the flow rates and the volumes of samples for tests, and the type of reagents and receptors for analytes. The multiparametric microfluidic chip is capable of analyzing 20 µL of human serum in 6 parallel flow paths in a range of flow rates with filling times from 10 minutes to 72 minutes. The asymmetric release of dAbs in a stream of human serum is compensated by a Dean flow mixer. Sample is equally split into 6 reaction chambers connected to flow resistances that vary flow rates, and the kinetics of capture of analyte-dAb complexes. The increased incubation time leads to a fourfold increase in detection signal in the reaction chamber with the longer incubation time. Furthermore, integrating reagents and controlling their release is essential for simple and accurate point-of-care diagnostic devices. We developed reagent integrators (RIs) to release small amounts of dried reagents (ng quantities and less) into microliters of sample. Typical RIs are composed of an inlet splitting into a central reagent channel, with a high hydraulic resistance, and two diluter channels. Reagents spotted in the central channel reconstitute in sample during filling and merge at the end of the RI with a dilution factor corresponding to the relative hydraulic resistance of the channels forming the RI. RIs are simple to integrate in lateral flow assays and provide a great degree of control over reagent integration and dissolution. Finally, the one-step capillary-driven microfluidic chips have the ability to not only detect a variety of proteins, but also to detect nucleic acids for molecular diagnostics. These devices, especially if manufactured in low cost plastic and used with portable fluorescence readers, have the potential to identify a wide variety of health conditions and to enable truly decentralized medical diagnostics.

Moderate-risk medical devices constitute 99% of those that have been regulated by the U.S. Food and Drug Administration (FDA) since it gained authority to regulate medical technology nearly five decades ago. This article presents an analysis of the interaction between the 510(k) process —the historically dominant path to market for most medical devices— and the De Novo pathway, a more recent alternative that targets more novel devices, including those involving new technologies, diagnostics, hardware, and software. The De Novo pathway holds significant potential for innovators seeking to define new categories of medical devices, as it represents a less burdensome approach than would have otherwise been needed historically. Moreover, it supports the FDA in its effort to modernize the long-established 510(k) pathway by promoting the availability of up-to-date device “predicates” upon which subsequent device applications can be based, reflecting positive spillovers that are likely to encourage manufacturers to adopt current state-of-the-art technologies and modern standards of safety and effectiveness. We analyze the of characteristics all the De Novo classification requests to date, including the submission type, trends, FDA review times, and device types. After characterizing how the De Novo process has been used over time, we discuss its unique challenges and opportunities with respect to medical device software and AI-enabled devices, including considerations for intellectual property, innovation, and competition economics.