Implantable Electrodes for Upper Limb Prosthetic Control

This thesis describes a study investigating implantable interfaces with muscles and peripheral nerves. Current prostheses for upper limb amputees do not provide intuitive control over hand, wrist and elbow motion. By implanting electrodes for recording and stimulating onto muscles and into nerves in the amputation stump a greater number of control signals may be made available, signals which will be used to control dextrous hand movements. An implantable epimysial interface was developed using a bone-anchored device to hard-wire signals across the skin barrier. In a single ovine model pilot study the bone-anchor was implanted transtibially and the epimysial electrode was place superficially to m. peroneus teritus. Physiological signals were obtained over 12 weeks during treadmill walking. The external connector on the bone-anchor failed at 12 weeks, correlating with a drop in signal quality in an otherwise robust interface integrated with bone and skin tissue. The ovine bone-anchor model was repeated in 6 sheep for 19 weeks, with epimysial recordings made regularly. Increasing signal quality was seen during the study and was significantly greater from implanted electrodes compared with skin surface electrodes at 19 weeks (p = 0.016). Some complications with skin-implant integration were observed in proximally located implants. Crosstalk between muscles was assessed using pre-terminal nerve stimulation, and was found to be dependent upon muscle location and innervation. The ovine m. peroneus teritus model was used to assess recovery following targeted muscle reinnervation. Muscle signal recovery was observed approximately one month after surgery correlating with the start of functional recovery (assessed by force plate analysis). These studies indicate that a suitably modified bone-anchored device may be suitable for signal transmission in human patients, providing a stable, long-term solution to both prosthesis attachment and control. The potential of nerve interfaces for prosthetic control was investigated. The microchannel neural interface (MNI) was chosen because it overcomes limitations with other neural microarray designs: signal strength; cross-talk, and the locations of Nodes of Ranvier. MNIs confine regenerating nerves to small, ∼ 100 µm diameter, insulating tubes, this increases the length within which nerve signals can be recorded and amplifies the recorded signals. However, in vivo MNIs can become occluded by fibrosis that reduces or prevents axon regeneration. Two in vitro studies of neurocompatibility were carried out to investigate strategies for improving axon regeneration within microchannels. The first in vitro study compared the effect of different adsorbed endoneurial basement membrane proteins on PC-12 cell neurite extension on silicone substrates. The optimal protein coating concentrations for poly-D-lysine, collagen-IV and laminin-2,(-4) were determined. The optimal concentrations were compared with mixtures of basement membrane proteins, the effect of mixture coating order and constitution were investigated. It was found that endoneurial BM proteins significantly enhance neurite outgrowth compared with controls. Two coatings were suggested as most suited for improving neural regeneration within microchannels: a single layer coating of 10 µg/cm2 collagen-IV; and a mixed coating of 10 µg/cm2 collagen-IV, 1 µg/cm2 laminin-2,(-4), and 0.175 µg/cm2 nidogen-1. The second in vitro study investigated the effect of grooved, roughened and multi-scale silicone surfaces on on PC-12 cell neurite extension. Deeper, narrower grooves were shown to increase the extent of neurite alignment, while resulting in fewer, longer, neurites. Roughening surfaces was shown to increase the amount of protein (collagen-IV) which adsorbed from solution and increase the number of neurites each cell extended. Surfaces with multiscale topographies synergistically increased the number and length of neurites and guided neurite growth along the groove direction. MNIs were manufactured for in vivo testing. These MNIs were used to determine the effect of adsorbed endoneurial basement membrane proteins on nerve regeneration in vivo, but the multiscale topographies were not applied during manufacturing. Four alternative manufacturing methods were investigated and iterative improvements were made to create a stacked interface with multiple microchannel layers. Microchannel layers were created by laser patterning silicone and metal foil components, followed by plasma bonding to create a 3-dimensional structure with 150 µm deep, 200 µm wide microchannels. Electrode impedances of 27.2 ± 19.8 kΩ at 1kHz were achieved by DC etching. The method overcomes some current limitations on electrode connectivity and microchannel sealing, and may improve recording capabilities over single layer designs by increasing the ratio of electrodes to microchannels. Manufactured MNIs were tested in a rat sciatic nerve transection model. Following implantation nerves were allowed to regenerate for one and two months. First, suture and fibrin glue were compared as MNI fixation methods for one month, the nerve regenerated within the fibrin glue, outside the interface lumen, therefore sutures were chosen as a long term fixation method. The influence of endoneurial basement membrane protein coatings, identified previously, on nerve regeneration with MNIs was investigated. Nerves regenerated through the MNIs over two months and began to reinnervate the distal limb. Improvements in the sciatic function index were observed over two months, with no significant differences between protein coated and control interfaces. Some weak histological evidence for the use of protein coatings was found, with axon diameters increased distal to protein coated MNIs. Electromyographic and electroneurographic recordings demonstrated similar signal amplitudes to previous studies. In order to bring the research described in this thesis to clinical practice further engineering improvements to the design and manufacture of electrodes, which utilise materials or coatings to enhance neurocompatibility, is required. Avenues for further research are discussed and additional experiments and investigations are described. By combining developments in implantable muscle and nerve interfaces with surgical techniques and improvements in neurocompatibility the promise of upper limb prosthetic control may be realised

The biomechanics of human locomotion

Includes bibliographical references. The thesis on CD-ROM includes Animate, GaitBib, GaitBook and GaitLab, four quick time movies which focus on the functional understanding of human gait. The CD-ROM is available at the Health Sciences Library

Ultrasound Imaging

In this book, we present a dozen state of the art developments for ultrasound imaging, for example, hardware implementation, transducer, beamforming, signal processing, measurement of elasticity and diagnosis. The editors would like to thank all the chapter authors, who focused on the publication of this book

Electrospun Nanofibers for Biomedical Applications

Electrospinning is a versatile and effective technique widely used to manufacture nanofibrous structures from a diversity of materials (synthetic, natural or inorganic). The electrospun nanofibrous meshes’ composition, morphology, porosity, and surface functionality support the development of advanced solutions for many biomedical applications. The Special Issue on “Electrospun Nanofibers for Biomedical Applications” assembles a set of original and highly-innovative contributions showcasing advanced devices and therapies based on or involving electrospun meshes. It comprises 13 original research papers covering topics that span from biomaterial scaffolds’ structure and functionalization, nanocomposites, antibacterial nanofibrous systems, wound dressings, monitoring devices, electrical stimulation, bone tissue engineering to first-in-human clinical trials. This publication also includes four review papers focused on drug delivery and tissue engineering applications

Hepatic Surgery

Longmire, called it a "hostile" organ because it welcomes malignant cells and sepsis so warmly, bleeds so copiously, and is often the ?rst organ to be injured in blunt abdominal trauma. To balance these negative factors, the liver has two great attributes: its ability to regenerate after massive loss of substance, and its ability, in many cases, to forgive insult. This book covers a wide spectrum of topics including, history of liver surgery, surgical anatomy of the liver, techniques of liver resection, benign and malignant liver tumors, portal hypertension, and liver trauma. Some important topics were covered in more than one chapter like liver trauma, portal hypertension and pediatric liver tumors

Trial efficacy vs real world effectiveness in first line treatment of multiple myeloma

Background: Large randomized clinical trials (RCT) are the foundation of the registration of newly developed drugs. A potential problem with RCTs is that the inclusion/exclusion criteria will make the population different from the actual population treated in real life. Hence, it is important to understand how the results from the RCT can be generalized to a general population. Aims: The primary aim of the present study was to assess the generalizability of the large 1st line RCTs in Multiple Myeloma (MM) to the Nordic setting and to understand potential difference and magnitude in outcomes between RCTs and patients treated in standard care in the Nordics. Methods: A retrospective analysis was performed on an incident cohort of 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics, treatments and outcomes. Data from relevant 1st line MM RCTs was selected from the treatment MP (Waage, A., et al., Blood. 2010], MPT (Waage, A., et al., Blood. 2010) and VMP (San Miguel, J.F., et al., N Engl J Med, 2008) and baseline characteristics were compared to newly diagnosed Nordic MM treated patients. Potential difference in response and overall survival (OS) was estimated by adjusting the RWE population to the RCT population using matching adjusted indirect comparisons. Patients were matched on age (median approximated to mean), gender, calcium, beta2-microglobulin and ISS score 3. These variables were selected because they were reported in all trials and have previously been identified as having prognostic value. Results: Patients in the Nordic database treated with MP (n=880) had a response rate of (PD, NR, PR, VGPR, ≥nCR) of (13%, 39%, 38%, 6%, 4%). After matching (n=347), the response rate was slightly worse (12%, 43%, 36%, 6%, 3%). This can be compared to the response rate from the RCT of (7%, 53%, 33%, 3%, 4%). OS for Nordic MP treated patients was 2.67 years (2.25-3.17). After matching the OS was 3.37 years (2.86-3.96) and this can be compared to the trial with OS 2.40 years (2.23-2.66). Patients treated with MPT (n=283) in the Nordic countries had a response rate of (5%, 14%, 52%, 20%, 9%). After matching (n=179) the response rate was slightly changed to (6%, 20%, 50%, 13% 11%). The corresponding RCT response results were 14%, 29%, 34%, 10%, and 13% respectively. OS for Nordic MPT treated patients was 4.15 years (3.73- 4.74). After matching the OS was 4.28 years (3.98-NA) years and compared to 2.42 years (2.08-3.17) OS observed in the corresponding trial. Patients treated with VMP (n=59) in the Nordic countries had a response rate of (4%, 5%, 40%, 18%, 33%). After matching (n=31) the response rate was improved to (8%, 11%, 28%, 8%, 45%). This corresponding response rates shown in the trial are 1%, 23%, 33%, 8%, and 33% respectively. OS for Nordic MP treated patients was 4.86 years (3.79-NA). After matching the OS was 4.86 years (4.86-NA) and this can be compared to the trial with OS 4.70 years. Summary and Conclusions: Surprisingly Nordic treated MM patients do very well compared to, and even better than, patients treated in RCTs. Since the OS for all tested treatments improves after matching to the RCT baseline characteristics, patients recruited to the RCTs seems to be a bit better than ordinary Nordic patents. The database used in the present study, and the used method, can be valuable for generalizing the results to the Nordic setting and estimating potential difference for future RCTs and Nordic MM treated patients. Future research should include different data cuts to see whether the analyses are biased by differences subsequent treatments applied in RCTs and clinical practice

Micro-costing study of rituximab subcutaneous injection versus intravenous infusion in dutch setting

Background: Rituximab for subcutaneous (SC) administration has recently been approved for use in common forms of diffuse large B-cell lymphoma (DLBCL). This form of rituximab is supplied in ready-to-use vials that do not require individual dose adjustment. It is expected that SC-injection will shorten the treatment time per administration of rituximab in comparison with currently available intravenous (IV) infusion. Aims: The goal of this study is to identify and compare all direct costs of IV and SC rituximab given to the DLBCL patients in the Netherlands. Methods: Using a prospective, observational, bottom up, micro-costing study we collected primary data on the direct medical costs of the preparation, administration and acquisition of rituximab. Drug costs and spillage, labor costs, material costs and remaining daycare costs were identified using standardized forms, structured using guideline prices and compared for the IV and SC forms of rituximab. Results: Measurements were done on 53 administrations (33 IV and 20 SC). The mean total costs of the IV infusion were €2174, and €1907 for the SC injection. The estimated difference of €267 per administration was mainly due to spillage costs and differences in chair time, related daycare costs and drug costs. Summary and Conclusions: Rituximab administered in the form of SC injection is less costly than its IV form. Taking into account their equal effectiveness, favorable pharmacoeconomic profile of SC rituximab can result in significant savings when transferred to the total DLBCL population in the Netherlands