Regelverket för medicintekniska produkter är omfattande och medicintekniska företag lägger idag stora resurser på att säkerställa att deras produkter uppfyller de lagar och krav som finns. Detta arbete beskriver författarnas bidrag till CE-märkningsprocessen på det nystartade företaget LARA Diagnostics första produkt, en handhållen enhet för utvärdering av perifer neuropati samt hur processen att CE-märka en medicinteknisk produkt generellt går till för ett mindre eller nystartat företag. Arbetet syftar till att visa vilka utmaningar mindre bolag har i synnerhet vid processen att CE-märka sin första produkt samt vad företag kan göra för att effektivisera sin process. I arbetet visas att mindre företag kan effektivisera sin process genom att: Tidigt lägga grunden till CE-märkningen. Se till att rätt kompetens finns eller införskaffas utifrån Redan i produktutvecklingen säkerställa att väsentliga krav uppfylls, gärna genom att följa harmoniserade standarder. Arbetet visar även att kraven inom det regulatoriska området för medicintekniska produkter blir hårdare med tiden och att den utvecklingen förväntas fortsätta. / The regulatory framework for medical devices is extensive and the medical device industry spends considerable resources on ensuring that their products comply with existing laws and requirements. This paper describes the authors’ contribution to the CE marking process of the very first product from the startup company LARA Diagnostics, a handheld device for the evaluation of peripheral neuropathy, as well as how the process of CE marking a medical device is carried out in general for a small or startup business. The work aims to point out the challenges for smaller companies in particular to get their first product certified, but also what can be done to streamline that process. The paper shows that small companies can improve the process by: Laying the foundation for CE marking early in the process. Ensure that the right skills exist internally or are acquired externally. Making sure that essential requirements are met early in the product development life cycle, preferably by adhering to harmonized standards. The paper also shows that the requirements within the regulatory framework for medical devices are becoming stricter over time and that this trend is expected to continue.

This study is concerned with the differences in career patterns and characteristics between the medical technology program graduates who remain in practice and those who leave the profession. The subjects of the study are the 155 graduates of the program for the period from 1970 through 1978. This study has three purposes. The first is to determine the retention rate of the graduates. The second is to assess the factors related to attrition of these professionals. The third is to describe a programming methodology that would enhance career retention.

The novel contribution of this research is the development of a supervised algorithm that extracts relevant attributes from The Health Improvement Network database to detect prescription side effects. Prescription drug side effects are a common cause of morbidity throughout the world. Methods that aim to detect side effects have historically been limited due to the data available, but some of these limitations may be overcome by incorporating longitudinal observational databases into pharmacovigilance. Existing side effect detecting methods using longitudinal observational databases have shown promise at becoming a fundamental component of post marketing surveillance but unfortunately have high false positive rates. An extra step is required to further analyse and filter the potential side effects detected by existing methods due to their high false positive rates, and this reduces their efficiency. In this thesis a novel methodology, the supervised adverse drug reaction predictor (SAP) framework, is presented that learns from known side effects, and identifies patterns that can be utilised to detect unknown side effects. The Bradford-Hill causality considerations are used to derive suitable attributes as inputs into a learning algorithm. Both supervised and semi-supervised techniques are investigated due to the limited number of definitively known side effects. The results showed that the SAP framework implementing a random forest classifier outperformed the existing methods on The Health Improvement Network longitudinal observational database, with AUCs ranging between 0.812-0.937, an overall MAP of 0.667, precision values between 0.733-1 and a false positive rate ≤ 0.013. When applied to the standard reference the SAP framework implementing a support vector machine obtained a MAP score of 0.490, an average AUC of 0.703 and a false positive rate of 0.16. The false positive rate is lower than that obtained by existing methods on the standard reference.

The field of nanomedicine has progressed to a stage where a diverse set of materials are available for controlling how a drug is delivered in the body. Although these materials can be engineered to overcome many of the obstacles associated with drug delivery, the complexity of cellular trafficking mechanisms means controlling intracellular delivery remains a major challenge. The primary portal for the cellular internalisation of nanomedicines is endocytosis, which involves transport through a network of highly complex intracellular compartments undergoing a dynamic process of acidification. As a result, nanoparticle-based pH sensors offer a new perspective from which to investigate this process. In this study, ratiometric polyacrylamide pH nanosensors were utilised to probe fundamental aspects of intracellular trafficking with the view of developing biological insights to aid the rational design of nanomedicines. Nanosensors were fabricated with a dynamic range covering the entire range of the endocytic pathway (4.0 – 7.5), with sizes between 50 and 100 nm. Endocytic uptake of nanosensors was induced in four different cell types (HeLa, 3T3, MRC-5 and JAWS II) by increasing the surface charge on the nanosensor. Dynamic pH measurements were found to be highly sensitive to experimental methodology for performing ratiometric measurements, particularly image analysis. Consequently an optimised procedure for performing ratiometric measurements was developed, and subsequently validated by correlating pH measurements with intracellular location using 3D structured illumination microscopy (3D-SIM). Application of pH nanosensors in studies investigating fundamental aspects of intracellular trafficking resulted in three key findings: 1) HeLa, 3T3 and JAWS II cells process material in different ways with respect to the extent and rate of acidification in endocytic organelles, 2) surface charge does not affect the final intracellular location of polyacrylamide nanoparticles internalised by endocytosis, and 3) lipid-mediated transfection of siRNA is associated with a greater degree of lysosomal disruption compared to cationic polymer-mediated transfection, with the former observed to show increased toxicity. These findings represent biological insights, which can be utilised to provide a rational basis for tailoring the response of pH-sensitive nanomedicines to a specific cell type, tuning the physicochemical properties of a material for more efficient intracellular trafficking and optimising siRNA formulations for endo-lysosomal release.

This thesis explores the political and ethical response to the development of new medical technology in the 1980s through the governmental commission Utredningen om det ofödda barnet [the commission regarding the unborn child] and its final report Den gravida kvinnan och fostret – två individer: om fosterdiagnostik, om sena aborter: slutbetänkande av Utredningen om det ofödda barnet [The Pregnant Woman and the Foetus – two individuals. On prenatal diagnosis. On late abortions: final report on the commission on the unborn child]. This governmental commission, alongside the late 1980s more broadly, have been described as a conservative backlash and reaction to the feminist movement and the fight for women’s right to their bodies. However, a close reading of the report shows that though it draws controversial connections between abortion, prenatal diagnosis and ability variations, the governmental commission advocated an extension of the law, not a limitation of rights. Through a biopolitical perspective this thesis shows how power was distributed between the state, the society and the individual. Unlike previous research’s polarisation, this thesis’s take on medicalisation shows that medicalisation is not something that necessarily opposes moralisation, but that they can be used to legitimate each other. Finally it discusses what this means for our understanding of the political climate in Sweden during the 1980s and how this changes our perception of what makes a human being.

Die Transplantation eines Organes ist in der Medizin oftmals die letzte Möglichkeit zur Behandlung einer terminalen Organinsuffizienz. Das grundlegende Problem der internationalen Transplantationsmedizin ist die stetig wachsende Diskrepanz zwischen Bedarf und Angebot von Transplantaten. Die Situation wird dramatisiert durch einen Trend der Marginalisierung von Spenderorganen. Marginale Spenderorgane werden häufig aufgrund mangelnder Möglichkeiten zur Funktionsbewertung verworfen. Die Technik der ex-vivo Organperfusion kann maschinell physiologienahe Bedingungen bereitstellen, um ein isoliertes Transplantat zu rekonditionieren und sogar eine Bewertung seines Zustands zu ermöglichen. Perfusionsprozesse sind organsystemindividuell durch eine hohe Komplexität ihrer biologisch-technisch verkoppelten Vorgänge gekennzeichnet. Für nutzer- und sicherheitsorientierte, klinisch taugliche Perfusionssysteme ist eine Prozessautomatisierung unumgänglich. Hier sind in klassischer anwendungsindividueller Entwicklung hohe Kosten die Folge. Auf Basis von Recherchen zum aktuellen Stand von Medizin und Technik konnten Eigenschaften von Perfusionsprozessen für die Organsysteme Herz, Lunge, Leber und Niere bestimmt werden. Aus ähnlichen Anwendungen der extrakoporalen Lebensunterstützung sind Erkenntnisse zur Systemautomatisierung zusammengetragen worden. In Fortführung der Arbeit sind die Organperfusionsprozesse abstrahiert und verallgemeinert worden. Beteiligte Prozessgrößen, sowie deren funktioneller Verkopplungen wurden identifiziert und evaluiert, um schließlich eine generalisierte, organunabhängige Strategie zur dezentralen Mehrgrößenregelung abzuleiten. Die abgeleitete Regelungsstrategie wurde folgend speziell für die ex-vivo Nierenperfusion umgesetzt. Dazu wurde zunächst auf Basis des generalisierten Organperfusionsprozesses ein Gerätesystem zur Nierenperfusion abgeleitet, entwickelt und aufgebaut. Für das entstandene Perfusionssystem wurden Modellbildungen und Parameteridentifikationen des Temperatursystems, des hämodynamischen Systems und des Blutgassystems durchgeführt. Die entstandenen Zustandsraummodelle wurden jeweils in Simulink implementiert und mittels realer Perfusionsexperimente an Schweinenieren im Tiermodell validiert. Simulativ und analytisch wurden für die drei Subsysteme Regelungsstrategien zur robusten Einzelgrößenregelung entwickelt und im realen Perfusionssystem implementiert. Im Zuge von weiteren Perfusionsexperimenten im Tiermodell konnten die Regelungen ebenfalls validiert und deren Robustheit im Mehrgrößenfall evaluiert werden. Die Erkenntnisse der speziellen Umsetzung des generalisierten Mehrgrößenregelungsansatzes zur Organperfusion wurden auf die Organsysteme Herz, Lunge und Leber projiziert. Die Hypothese dieser Arbeit, dass eine organübergreifende generalisierte Regelungsstrategie zur ex-vivo Perfusion bei Nutzung mit verschiedenen speziellen Organsystemen tauglich ist, konnte bestätigt werden. Auf dieser Basis ist eine vereinfachte und kostenreduzierte Entwicklung von Perfusionssystemen für verschiedene Organsysteme möglich. / In many cases the transplantation of an organ is the last way to treat a terminal organ insuffiency. The basic problem of international transplant medicine is a continiously increasing gap between the demand and the proposal of sufficient organ grafts. The situation is compounded by the actual trend of marginalization of organ grafts. Marginal donor grafts often are discarded due to absent options to test their vitality and viability. The technique of ex-vivo organ perfusion provides near physiologic conditions in order to recondition and even to evaluate the state of an isolated organ graft. Perfusion processes are organ individual characterized by highly complex coupled biological-technical processes. For achieving an user- and safety-focussed, clinical suitable perfusion system, an automation of the system is inavoidable. Within classical development of technologies, high costs were following. On the base of research according to the actual status quo of medicine and technology, characteristics of the perfusion processes for the heart, the lungs, the liver and the kidneys could be determined. Knowledge about similar processes of extracorporeal life support were gathered. Subsequently the organ perfusion processes were abstracted and generalized. Participating process values, as well as their couplings, were identified and evaluated in order to extract a generalized, organ independent strategy for decentral multivariable control. The extracted control strategy was then transfered specificly for ex-vivo kidney perfusion. Therefore a device for ex-vivo kidney perfusion was developed and built from the generalized organ perfusion process. According to the implemented device, the temperature system, the hemodynamic system and the blood gas system were modelled mathematically and parameter estimations were performed. The resulted state space models were implemented to Simulink and validated by comparing simulations to the results of experiments on real procine kidneys. Within the simulations and based on analytical methods, robust single variable control strategies for the control of the three subsystems temperature, hemodynamic and blood gases were developed and implemented into the real kidney perfusion device. During further perfusion experiments within the large animal model, the control strategies could be validated an their robustness could be evaluated in the multivariable case. The findings of the special implementation of the generalized multivariableapproach for organ perfusion were projected on the organ systems heart, lungs and liver. The hypothesis of this work, in detail, that a generalized, organ independent control strategy for organ perfusion processes is suitable for the use with several special organ systems, could be confirmed. On this basis, simplified and cost reduced developments of perfusion systems for different organ systems are possible.

Aus der Einleitung: "Im Tissue Engineering und in der Medizintechnik gewinnt das Rapid Prototyping (RP), das zu den additiven Fertigungsverfahren zählt, zunehmend an Bedeutung (Zhang, et al. 2015) (Li, et al. 2014). Für die Verarbeitung von thermoplastischen Biopolymeren ist das Fused Deposition Modeling (FDM, schematische Darstellung in Abbildung 1) von zentralem Stellenwert. ..."

The aim of this thesis is to develop a theoretical model to explore how sociomaterial networks, involving large-scale automation, come into being, persist and change over time, within a healthcare environment. It does so by bridging the gap between design, implementation and use of large-scale pathology automation (LSPA) within two United Kingdom (UK) National Health Service (NHS) laboratories. A longitudinal, multi-site, ethnographic approach was used, along with semi-structured interviews, template analysis and participant observation of LSPA ‘in-practice’. This research has suggested that design features, embedded within the material properties of LSPA, were purposefully intended to bring about organisational change. In both user organisations, the material affordances of LSPA resulted in anticipated skill mix changes. However, material constraints required the enforcement of changes to organisational routines, creating operational difficulties, which were then subsequently transferred across organisational boundaries by the researcher/manager. The identification of these sociomaterial affordances and constraints, in conjunction with humans acting as boundary objects, had the unintended consequence of influencing strategic decision making and initiating structural and cultural change. The development and practical application of the resulting SociomANTerial model allowed the researcher to trace the analytical history of these organisational changes over time and consider the impact of broader social structures such as power. Ultimately it is suggested that a greater emphasis on collaboration between users, designers and corporate agents will result in more innovative approaches for technology adoption and improved organisational design.

An estimated 15 million individuals in the United States have been formally diagnosed with dysphagia, defined as swallowing dysfunction -- the fifth leading cause of death in Americans over the age of 65. Statistical findings indicate that at least 50% of these individuals have limited access to treatment. However, despite the rapid expansion of telepractice (defined as the use of telecommunications technology to provide services at a distance) as a statistically valid online method for the provision of medical and clinical intervention to those without access, telepractice has yet to consistently incorporate online dysphagia service delivery (referred to as tele-dysphagia) into its clinical scope. This investigation compared the outcomes of traditional face-to-face intervention to online tele-dysphagia intervention by measuring the correct and incorrect responses to visual and auditory cues presented by a clinician during dysphagia intervention sessions. Data analysis conducted via t-test indicated that there was no significant difference in the mean scores from tele-dysphagia method (M = 9.67, SD = 3.74) as compared to face-to-face method (M = 9.00, SD = 2.70), t (28) = - 0.56, p = 0.580. Additionally, inter-rater reliability scores were obtained by determining a Cohen’s kappa coefficient in order to measure the degree of agreement between the two raters. Findings indicated a kappa statistic of k=1 for all items, given a 100% agreement for all trials. Additionally, results of a mixed-design analysis of variance suggested a significant within-subject effect with the use of cues, but there were no significant main effects of between-subject factors (gender, delivery type, etiology, or age) on the patients’ responses. Given that there was no significant statistical difference between the two delivery methods and inter-rater reliability scores demonstrated perfect agreement, we can suggest that the online tele-dysphagia method can potentially yield clinical outcomes similar to a traditional face-to-face method. Results from a mixed-design analysis of variance additionally suggested that there is a significant within-subject effect given the use of cues (F (1, 29)=14.99, p = .001) on patients’ responses. However, there were no significant main effects of between-subject factors (gender, delivery type, etiology, or age) on the patients’ responses. It is hoped that the results of this study will lend validity and direction to future attempts to provide much-needed dysphagia intervention via online service methods. Such attempts, in turn, would have the potential to promote increased longevity and quality of life in those populations currently unable to access such services.

Cardiac diseases and conduction disorders are associated with stroke, heart failure and sudden cardiac death and are a major health concern worldwide. In the US alone, more than 14 million people suffer from heart rhythm disorders. Current mapping and characterization techniques in the clinic involve invasive procedures, which are time-consuming, costly, and may involve ionizing radiation. In this dissertation, we introduce Electromechanical Wave Imaging (EWI) as a non-invasive, ultrasound-based treatment planning tool for pre-procedure characterization and assessment of arrhythmia in the clinic. In particular, standard EWI processing methods for mapping the electromechanical wave (EW), i.e. the onset of the mechanical activity following the depolarization of the heart, are described and detailed. Next, validation of EWI is performed with 3D electromechanical mapping and the EW propagation is shown to follow the electrical activation in all four chambers of the heart. Demonstration of the value of EWI for the characterization of cardiac arrhythmia is accomplished in vivo in a large animal model. First, EWI is shown capable of localizing the earliest region of activation in the ventricles during pacing from a standard pacemaker lead, as well as during pacing from a novel biological pacemaker. Repeatability is also demonstrated between consecutive cardiac cycle during normal sinus rhythm and during pacing. Then, in the atria, we demonstrate that EWI is capable of accurately identifying focal sources while pacing from several locations in both the left and right atria. In addition to being capable of localizing the focal source, EWI is also shown capable of differentiating between endocardial and epicardial focal sources. Finally, it is shown that EWI can correctly identify regions of infarction and monitor formation of infarcts over several days, after ligation of the left anterior descending coronary artery of canine hearts. Novel processing techniques aimed at extracting quantitative parameters from EWI estimates are then developed and implemented. Details of the implementation of processing methods for estimating the velocity of the EW propagation are presented, and a study of the EW velocity values in a canine heart before and after infarct formation is conducted. Electromechanical cycle length mapping (ECLM), which is aimed at extracting local rates of electromechanical activation in the heart, is then introduced and its implementation detailed. ECLM is subsequently validated in a paced canine heart in vivo. Finally, initial clinical feasibility is demonstrated. First, in the study of treatment of chaotic arrhythmia such as in the case of atrial fibrillation patients undergoing direct current cardioversion, ECLM is shown to be able to confirm acute treatment success. Then, the clinical value of EWI in the electrophysiology lab as a treatment planning tool for the characterization of focal arrhythmia is shown in ventricular tachycardia and Wolff-Parkinson-White patients. EWI is currently only a step away from real-world clinical application. As a non-invasive, ultrasound-based imaging modality, EWI is capable of providing relevant insights into the origins of an arrhythmia and has the potential to position itself in the clinic as a uniquely valuable pre-procedure planning tool for the non-invasive characterization of focal arrhythmias.