Bob Stevens

Fabricating electrospun cellulose nanofibre adsorbents for ion-exchange chromatography

Highlights • Optimised chemistry protocols of DEAE and COO functionalisations.• Compression applied after electrospinning improved mechanical strength.• Increasing compression and bed layers lowered binding capacities.

Nanofiber adsorbents for high productivity downstream processing

Electrospun polymeric nanofiber adsorbents offer an alternative ligand support surface for bioseparations. Their non‐woven fiber structure with diameters in the sub‐micron range creates a remarkably high surface area. To improve the purification productivity of biological molecules by chromatography, cellulose nanofiber adsorbents were fabricated and assembled into a cartridge and filter holder format with a volume of 0.15 mL, a bed height of 0.3 mm and diameter of 25 mm. The present study investigated the performance of diethylaminoethyl (DEAE) derivatized regenerated cellulose nanofiber adsorbents based on criteria including mass transfer and flow properties, binding capacity, and fouling effects. Our results show that nanofibers offer higher flow and mass transfer properties. The non‐optimized DEAE‐nanofiber adsorbents indicate a binding capacity of 10% that of packed bed systems with BSA as a single component system. However, they operate reproducibly at flowrates of a hundred times that of packed beds, resulting in a potential productivity increase of 10‐fold. Lifetime studies showed that this novel adsorbent material operated reproducibly with complex feed material (centrifuged and 0.45 µm filtered yeast homogenate) and harsh cleaning‐in‐place conditions over multiple cycles. DEAE nanofibers showed superior operating performance in permeability and fouling over conventional adsorbents indicating their potential for bioseparation applications. Biotechnol. Bioeng. 2013; 110: 1119–1128.

Electrodeposition of indium for bump bonding

Indium bump bonding has been employed to realize very high density interconnection used for hybrid pixel detector systems. The connection pitch sizes to achieve this may be below 50 mum for these assembly applications, such that the packaging density, i.e. I/Os, may exceed 40,000/cm2. Electrodeposition is a promising approach to enable a low- cost and high yield bump bonding process, compared with conventional sputtering or evaporation which is currently utilized for small-scale production. This paper reports an initial investigation of the alternative electroplating indium bumping process focusing on the challenge of this process in terms of uniformity and consistency across the wafer at ultra- fine pitches to achieve the highest yield. Fundamentally, it has been concerned that the current distribution and associated mass transport during the electroplating process are the main factors for determining the indium deposit growth. Therefore, in this study, the effects of pulsed current and ultrasonic agitation on the deposit growth are investigated through an initial plating trial. Indium bumps with finer grain size have been achieved by using pulsed current plating, which demonstrated the potential improvement of uniformity. It is known that ultrasonic agitation is beneficial to enhance the mass transport, and is expected to be able to penetrate the solution into the patterned apertures formed by the photoresist at a microscopic scale. The experimental study has shown a positive effect of ultrasonic agitation in terms of an increase of pre-wetting of the ultra-fine apertures with electrolyte. However, caution must be taken since there may exist a danger of damaging the photoresist layer due to severe vibration induced by the ultrasonic waves. Future work will consider the possible optimization of the waveform of the pulsed current and utilization of higher frequency ultrasonic agitation with a robust photoresist mask.

Microcrystal manipulation with laser tweezers

Optical trapping has successfully been applied to select and mount microcrystals for subsequent X-ray diffraction experiments.

Nanofiber adsorbents for high productivity continuous downstream processing

An ever increasing focus is being placed on the manufacturing costs of biotherapeutics. The drive towards continuous processing offers one opportunity to address these costs through the advantages it offers. Continuous operation presents opportunities for real-time process monitoring and automated control with potential benefits including predictable product specification, reduced labour costs, and integration with other continuous processes. Specifically to chromatographic operations continuous processing presents an opportunity to use expensive media more efficiently while reducing their size and therefore cost. Here for the first time we show how a new adsorbent material (cellulosic nanofibers) having advantageous convective mass transfer properties can be combined with a high frequency simulated moving bed (SMB) design to provide superior productivity in a simple bioseparation. Electrospun polymeric nanofiber adsorbents offer an alternative ligand support surface for bioseparations. Their non-woven fiber structure with diameters in the sub-micron range creates a remarkably high surface area material that allows for rapid convective flow operations. A proof of concept study demonstrated the performance of an anion exchange nanofiber adsorbent based on criteria including flow and mass transfer properties, binding capacity, reproducibility and life-cycle performance. Binding capacities of the DEAE adsorbents were demonstrated to be 10mg/mL, this is indeed only a fraction of what is achievable from porous bead resins but in combination with a very high flowrate, the productivity of the nanofiber system is shown to be significant. Suitable packing into a flow distribution device has allowed for reproducible bind-elute operations at flowrates of 2,400 cm/h, many times greater than those used in typical beaded systems. These characteristics make them ideal candidates for operation in continuous chromatography systems. A SMB system was developed and optimised to demonstrate the productivity of nanofiber adsorbents through rapid bind-elute cycle times of 7s which resulted in a 15-fold increase in productivity compared with packed bed resins. Reproducible performance of BSA purification was demonstrated using a 2-component protein solution of BSA and cytochrome c. The SMB system exploits the advantageous convective mass transfer properties of nanofiber adsorbents to provide productivities much greater than those achievable with conventional chromatography media.

Electrodeposition of Indium Bumps for Ultrafine Pitch Interconnection

Electroplating is a promising method to produce ultrafine pitch indium bumps for assembly of pixel detectors in imaging applications. In this work, the process of indium bumping through electrodeposition was demonstrated and the influences of various current waveforms on the bump morphology, microstructure and height uniformity were investigated. Electron microscopy was used to study the microstructure of electroplated indium bumps and a Zygo white light interferometer was utilised to evaluate the height uniformity. The results indicated that the bump uniformities on wafer, pattern and feature scales were improved by using unipolar pulse and bipolar pulse reverse current waveforms.

High density indium bumping through pulse plating used for pixel X-Ray detectors

High density indium bump bonding is in high demand for devices which operate under cryogenic environments, such as pixellated X-ray detectors for high energy physics, due to the outstanding ductility of indium even at liquid helium temperatures. For these assembly applications, the connection pitch size is shifting to below 50 μm, such that the packaging density, i.e. I/Os, may exceed 40,000/cm2. Electrodeposition is a promising approach to enable a low-cost and high yield bump bonding process, compared with conventional sputtering or evaporation which is currently utilized for small-scale production. Previous studies have shown the capability of electrodeposition to achieve high yield and high density indium bumps. The challenge exists to improve the bump height uniformity and consistency of electroplated indium bumps across the wafer at ultra-fine pitches with the highest yield. This paper is an initial investigation of the application of pulsed plating to the indium plating process and considers the influence of various current waveforms on the morphology and uniformity of the bumps. The results indicated that change in frequency and duty cycle did not have a significant influence on the indium bump morphology, but, together with the addition of a thief ring to the wafer design, pulse plating did have a noticeable impact on the bump height uniformity.

High density indium bumping using electrodeposition enhanced by megasonic agitation

Electrodeposition has been utilized to fulfill the demand of high density indium bumping used in high energy physics applications. Previous studies have shown the capability of electrodeposition to achieve high yield and high density indium bumps. The challenge exists to improve the bump height uniformity and consistency of electroplated indium bumps across the wafer at ultra-fine pitches with the highest yield. This paper reports progress towards the electroplating indium bumping process assisted by megasonic agitation. Electroplating of indium onto non-patterned substrates was initially conducted to investigate the performance of the solution with megasonic agitation. Further trials were carried out on 4 inch silicon dummy wafers to create indium bumps at 50 μm pitch. The results reflect that bubbles created during the plating process with megasonic agitation can affect the quality of the deposit and the yield of indium bumping, under the experimental conditions used in this study.

Megasonic enhanced wafer bumping process to enable high density electronics interconnection

The assembly of hybrid pixel detectors requires direct interconnection between the readout chip and sensor chip. In such systems, the connection pitch size may be below 50 mum, such that the packing density (i.e. I/Os) may exceed 40,000/cm2. Electroplating is a promising approach to enable low-cost, high yield and ultra-fine pitch bumping. This paper reports an ultra-fine pitch electroplating bumping process which can be enhanced by incorporating megasonic agitation. Acoustic agitation at above 1 MHz frequencies is able to significantly reduce the diffusion boundary layer of electroplating to a thickness less than 1 mum, as compared to tens of microns under conventional plating conditions. The initial experimental results presented here demonstrate an enhanced polycrystalline growth other than dendrite deposition under a very high current density through megasonic agitation deposition, thereby allowing a significant acceleration of the electrodeposition process. For the electroplating wafer bumping process, megasonic agitation can also accelerate the bump growth rate under the same current density, due to the increase of cathodic current efficiency. Also, megasonic agitation appears not to damage the photoresist pattern, which is often the case when ultrasonic agitation is used.

Investigation of high speed micro-bump formation through electrodeposition enhanced by megasonic agitation

Electroplating has been employed to produce metallic micro-bumps to meet the demand of high density flip chip interconnections for high-end electronic devices. Previous studies indicated that megasonic agitation is a promising approach to enable high speed electrodeposition and bumping which therefore can increase the productivity and reduce the cost of the process. This paper takes indium bumping as an example and reports further investigation of the electroplating bumping enhanced by megasonic agitation. Experimental results demonstrate that the bumping process could be accelerated to five times faster than the ordinary DC electroplating situation without any significant effect on the bump height uniformity.