A highly compact packaging concept for ultrasound transducer arrays embedded in neurosurgical needles

State-of-the-art neurosurgery intervention relies heavily on information from tissue imaging taken at a pre-operative stage. However, the data retrieved prior to performing an opening in the patient’s skull may present inconsistencies with respect to the tissue position observed by the surgeon during intervention, due to both the pulsing vasculature and possible displacements of the brain. The consequent uncertainty of the actual tissue position during the insertion of surgical tools has resulted in great interest in real-time guidance techniques. Ultrasound guidance during neurosurgery is a promising method for imaging the tissue while inserting surgical tools, as it may provide high resolution images. Microfabrication techniques have enabled the miniaturisation of ultrasound arrays to fit needle gauges below 2 mm inner diameter. However, the integration of array transducers in surgical needles requires the development of advanced interconnection techniques that can provide an interface between the microscale array elements and the macroscale connectors to the driving electronics. This paper presents progress towards a novel packaging scheme that uses a thin flexible printed circuit board (PCB) wound inside a surgical needle. The flexible PCB is connected to a probe at the tip of the needle by means of magnetically aligned anisotropic conductive paste. This bonding technology offers higher compactness compared to conventional wire bonding, as the individual electrical connections are isolated from one another within the volume of the paste line, and applies a reduced thermal load compared to thermo-compression or eutectic packaging techniques. The reduction in the volume required for the interconnection allows for denser wiring of ultrasound probes within interventional tools. This allows the integration of arrays with higher element counts in confined packages, potentially enabling multi-modality imaging with Raman, OCT, and impediography. Promising experimental results and a prototype needle assembly are presented to demonstrate the viability of the proposed packaging scheme. The progress reported in this work are steps towards the production of fully-functional imaging-enabled needles that can be used as surgical guidance tools

Enhancing bacterial production of a recombinant cetuximab-Fab by partial humanization and its utility for drug conjugation

Cetuximab is a murine-human chimeric monoclonal antibody (mAb) that is clinically used to treat epidermal growth factor receptor (EGFR)-positive cancers. As antibody fragment engineering has emerged as an economic alternative to mAb drugs via bacterial production, we have previously generated FM318, a recombinant Fab adopted from cetuximab. Here, in an effort to facilitate industrial development, we searched for useful mutations that could increase its production yields. Amino acid substitutions were selected to resemble the humanized sequence to avoid unexpectedly raising immunogenic problems by the mutations. As a result, FM329, which accommodates L3Q/L4 M mutations in the light chain and S15G/Q16G in the heavy chain Fd, showed a high production yield in a fed-batch operation, reaching approximately 3.5 times FM318 productivity, with its structure and EGFR-binding affinity being maintained. Additionally, for a potential application to antibody-drug conjugates, a cytotoxic agent, DM1 was successfully linked to FM329 with an average drug-to-antibody ratio of 1.4. The conjugate showed dramatically increased anticancer activity with retention of EGFR-binding affinity. Collectively, we suggest that the partially humanized recombinant cetuximab Fab, FM329, and its DM1 conjugate would serve as promising platforms to develop an economic alternative to cetuximab and/or an improved drug candidate for a potent anti-cancer therapy

Anatomical attributes of clinically relevant diagonal branches in patients with left anterior descending coronary artery bifurcation lesions

AIMS: This study aimed to investigate the anatomical attributes determining myocardial territory of diagonal branches and to develop prediction models for clinically relevant branches using myocardial perfusion imaging (MPI) and coronary CT angiography (CCTA). METHODS AND RESULTS: The amount of ischaemia and subtended myocardial mass of diagonal branches was quantified using MPI by percent ischaemic myocardium (%ischaemia) and CCTA by percent fractional myocardial mass (%FMM), respectively. In 49 patients with isolated diagonal branch disease, the mean %ischaemia by MPI was 6.8+/-4.0%, whereas in patients with total occlusion or severe disease of all diagonal branches it was 8.4+/-3.3%. %ischaemia was different according to the presence of non-diseased diagonal branches and dominant left circumflex artery (LCx). In the CCTA cohort (306 patients, 564 diagonal branches), mean %FMM was 5.9+/-4.4% and 86 branches (15.2%) had %FMM >/=10%. %FMM was different according to LCx dominance, number of branches, vessel size, and relative dominance between two diagonal branches. The diagnostic accuracy of prediction models for %FMM >/=10% based on logistic regression and decision tree was 0.92 (95% CI: 0.85-0.96) and 0.91 (95% CI: 0.84-0.96), respectively. There was no difference in the diagnostic performance of models with and without size criterion. CONCLUSIONS: LCx dominance, number of branches, vessel size, and dominance among diagonal branches determined the myocardial territory of diagonal branches. Clinical application of prediction models based on these anatomical attributes can help to determine the clinically relevant diagonal branches in the cardiac catheterisation laboratory. CLINICAL TRIAL REGISTRATION: NCT0393554