Realizing flexible bioelectronic medicines for accessing the peripheral nerves – technology considerations

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

To deliver personalised therapy based on electricity, BEms need to target various sites in the human body and operate in a closed-loop manner.

“To deliver this personalised therapy based on electricity, BEms need to target various sites in the human body and operate in a closed-loop manner.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A flexible BEm for the PNS requires a compact unibody design including a three-dimensional neural interface and the electronics, wireless operation, and closed-loop stimulating, biomarker sensing and neural recording capabilities.

“These BEms, belong to a new generation of implants: they have to be of a compact unibody design (including a three-dimensional neural interface and the electronics), operate wirelessly (either standalone or in a distributed system), and in a closed-loop fashion, having stimulating, biomarker sensing and neural recording possibilities.”

Probably not a substantial claim: may not pass S4 (based).

For a distributed wireless system of BEms to restore full control of the urinary tract, miniature (<1cm3) BEms placed close to their targeted nerves are required.

“For such an implementation, miniature (<1cm3) BEms placed close to their targeted nerves are required.”

Probably not a substantial claim: may not pass S4 (based).

The specific conditions and anatomy of the targeted sites pose unique challenges in the development of BEms.

“The specific conditions and anatomy of the targeted sites pose unique challenges in the development of BEms.”

May combine two claims.

Peripheral nerve size and composition varies greatly; the major and minor diameters of the compound femoral nerve are about 10.5 mm and 2.3 mm, respectively, while pelvic splanchnic nerve bundles can be smaller than 0.05 mm or larger than 0.2 mm.

“for example, the major and minor diameters of the compound femoral nerve are about 10.5 mm and 2.3 mm, respectively. In contrast, the diameter of pelvic splanchnic nerve bundles can be smaller than 0.05 mm, or larger than 0.2 mm”

• cites Gustafson et al. 2009 sourceNot checked yet

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• cites Jang et al. 2015 sourceNot checked yet

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May combine two claims.

Extraneural interfaces leave the nerve intact but usually target several bundles of axons or fascicles within it, hence offer lower selectivity.

“Extraneural interfaces leave the nerve intact but usually target several bundles of axons or fascicles within it, hence offer lower selectivity.”

• cites Brindley 1972 sourceNot checked yet

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• cites Koller et al. 1992 sourceNot checked yet

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• cites Loeb and Peck 1996 sourceNot checked yet

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May combine two claims.

Silicon-based implants are stiff and rigid, and micromotion of the device might cause tissue damage.

“They are, however, stiff and rigid, and micromotion of the device might cause tissue damage”

• cites Alexander Arts et al. 2003 sourceNot checked yet

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May combine two claims.

Softer materials match much better the mechanical properties of the surrounding tissue, and several have shown excellent performance during chronic implantation with only mild to minor foreign body reactions.

“Softer materials match much better the mechanical properties of the surrounding tissue, and several of them have shown excellent performance during chronic implantation, with only mild to minor foreign body reactions (25).”

• cites [25] Chuang CL, Liao QA, Li HT, Liao SJ, Huang GS. Increasing the bonding strength of chips on flex substrates using thermosonic flip-chip bonding process with nonconductive paste. Microelectron Eng. 2010;87:624–30. sourceNot checked yet

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May combine two claims.

Titanium nitride coated electrodes have exhibited good electrochemical stability and charge injection limits similar to that of iridium oxide, but the biocompatibility of the coating still needs to be investigated further.

“Titanium nitride (TiN) coated electrodes have exhibited good electrochemical stability and charge injection limits similar to that of iridium oxide, but the biocompatibility of the coating still needs to be investigated further (Brunton et al. 2015).”

• cites Brunton et al. 2015 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Denser electrode integration is desirable as it offers higher spatial resolution, both for the stimulating and sensing operation mode.

“Generally, denser electrode integration is desirable as it offers higher spatial resolution, both for the stimulating and sensing operation mode.”

May combine two claims.

PEDOT is a conductive polymer known to exhibit low electrochemical impedance due to its porous film surface, can be modified by the addition of bioactive molecules, exhibits large charge injection capacity, and has proven to be stable in vivo without causing any toxic effect.

“Poly (3,4 – ethylene dioxytiophene) (PEDOT) is a conductive polymer known to exhibit low electrochemical impedance due to its porous film surface. PEDOT is interesting as it can be modified by the addition of bioactive molecules to e.g. promote cell adherence to the electrode surface. It exhibits large charge injection capacity and has proven to be stable in vivo without causing any toxic effect (”

• cites Charkhar et al. 2015 sourceNot checked yet

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May combine two claims.

Roughening the surface of electrodes increases the electrochemical surface area while keeping the geometric surface area constant, reducing electrode impedance.

“One popular technique is roughening the surface of electrodes, in order to increase the electrochemical surface area (Cogan 2008), while keeping the geometric surface area constant.”

• cites Cogan 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Off-the-shelf components could provide a rapid prototyping solution, but these are neither area nor power optimised.

“Systems assembled from off-the-shelf components could provide a rapid prototyping solution, but these are neither area nor power optimised.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Existing technologies for realising flexible implants are mainly polymer-based.

“Existing technologies for realising flexible implants are mainly polymer-based.”

Classified as probably not a substantial claim. May combine two claims.

Bi-directional communication and programmability are necessary for BEms, while safe and secure chronic operation is of utmost importance.

“To this end, bi-directional communication and programmability are necessary, while safe and secure chronic operation is of utmost importance.”

May combine two claims.

Platinum black and nanostructured platinum grass coatings have both shown significant improvements in electrode impedance, due to an increased surface area.

“More specifically, platinum black (Tand et al. 2014) and nanostructured platinum grass (Liu et al. 2012) coatings have both shown significant improvements in electrode impedance, due to an increased surface area.”

• cites Tand et al. 2014Not checked yet

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• cites Liu et al. 2012 sourceNot checked yet

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May combine two claims.

Small electrode sizes come at the expense of higher impedances, an undesired feature both in the recording as well as in the stimulation domain.

“One major bottleneck limiting the achievable electrode density is that small electrode sizes come at the expense of higher impedances, an undesired feature both in the recording as well as in the stimulation domain.”

May combine two claims.

Flexible transistors can incorporate some on-site intelligence, but their level of maturity is not yet sufficient to meet the foreseen processing complexity or the strict requirements for clinical use.

“Despite the fact that some on-site intelligence can be incorporated with the use of flexible transistors (Viventi et al. 2011), the level of maturity of such technologies is not yet sufficient to meet neither the foreseen processing complexity nor the strict requirements for clinical use.”

• cites Viventi et al. 2011 sourceNot checked yet

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May combine two claims.

Polymers have limited working temperatures (< 350 °C), which makes them incompatible with several important processing methods, such as chemical vapour deposition and baking, but also with conventional assembly methods, such as bonding and soldering.

“Challenges of the use of polymers as substrate materials for BEms relate to their limited working temperatures (< 350 °C), which makes them incompatible with several important processing methods, such as chemical vapour deposition and baking, but also with conventional assembly methods, such as bonding and soldering.”

Probably not a substantial claim: may not pass S4 (based).

The development of active implants is, in many ways, more challenging compared to their passive counterparts.

“The development of active implants is, in many ways, more challenging compared to their passive counterparts.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Air can be trapped in the polymer during fabrication and manifest itself as air bubbles, which can gradually compromise adhesion between layers and promote delamination.

“Air can be trapped in the polymer during fabrication and manifest itself as air bubbles, which can gradually compromise adhesion between layers and promote delamination.”

May combine two claims.

Iridium oxide coating is corrosion resistant and exhibits, in general, good biocompatibility and higher charge delivery capacity, but its exact properties depend greatly on the fabrication method, which affects the stability of the coating.

“Iridium oxide (IrO2) coating is corrosion resistant and exhibits, in general, good biocompatibility and higher charge delivery capacity (Wang et al. 2009). Nevertheless, its exact properties depend greatly on the fabrication method – activated, sputtered and electrodeposited variants have been reported – which, in turn, affects the stability of the coating.”

• cites Wang et al. 2009 sourceNot checked yet

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May combine two claims.

Deposition processes for platinum black have reportedly caused cytotoxic reactions due to lead traces found in the electroplating electrolyte, whereas this was not observed for nanostructured platinum grass.

“The deposition processes for platinum black have reportedly caused cytotoxic reactions due to lead traces found in the electroplating electrolyte (Schuettler et al. 2005b). This was not observed for nanostructured platinum grass (Boehler et al. 2015).”

• cites Schuettler et al. 2005bNot checked yet

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• cites Boehler et al. 2015 sourceNot checked yet

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May combine two claims.

Although dissimilar metals are generally desired to be avoided because galvanic corrosion could occur if exposed to body liquid, failures for the gold-platinum intermetallic combination are unlikely to occur because their galvanic potentials are close to each other.

“It is generally desired that dissimilar metals are avoided, as galvanic corrosion could occur if exposed to body liquid. However, as the galvanic potentials of gold and platinum are close to each other, such failures for this intermetallic combination are unlikely to occur.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Thinner devices are preferred as these usually can withstand larger bending radii.

“Although thicker substrates can be fabricated, thinner devices are preferred as these usually can withstand larger bending radii.”

May combine two claims.

Thinned ASICs will add to the flexibility of the BEm, but may have to be bent and conform to the features or structures of the implantation site, and care should be taken that the resulting mechanical strength of the thin die is adequate for the application.

“Thinned ASICs will add to the flexibility of the BEm, but may have to be bent and conform to the features or structures of the implantation site. Care should therefore be taken that the resulting mechanical strength of the thin die is adequate for the application.”

May combine two claims.

It is foreseen that the first generation of flexible BEms will feature several, up to tens of electrodes, rather than hundreds, with relatively larger sizes, recording compound neural activity as closed-loop control signals, rather than single-unit action potentials.

“Based on the above, it is foreseen that the first generation of flexible BEms will feature several, up to tens of electrodes, rather than hundreds, with relatively larger sizes, recording compound neural activity as closed-loop control signals, rather than single-unit action potentials – which are anyway difficult to acquire chronically.”

May combine two claims.

Due to the softer nature of the polymeric substrates, deformation due to motion from nearby organs is likely to occur, and the mechanical properties of interconnects and their substrates should allow the implant to withstand the expected deformation over millions or even billions of cycles without failing.

“Due to the softer nature of the polymeric substrates, in which these interconnects need to be embedded, however, deformation due to motion from nearby organs is likely to occur. The degree of this deformation will of course vary depending on the implantation site. Therefore, the mechanical properties of these interconnects (and their substrates) should be such that they allow the implant to withst”

• AssumptionRests on an assumption: The implantation site will subject the implant to deformation over millions or even billions of cycles.

Probably not a substantial claim: may not pass S2 (checkable).

Due to the limited available space around the peripheral nerves it is desirable that the majority of components required for the operation of the system are integrated on chip.

“Due to the limited available space around the peripheral nerves it is desirable that the majority of components required for the operation of the system are integrated on chip, as in Fig. 1.”

May combine two claims.

Current state-of-the-art silicon-based in vivo systems do not commonly feature more than hundreds of electrodes, with recent improvements bringing this number closer to one thousand, even on a single probe.

“Current state-of-the-art silicon-based in vivo systems do not commonly feature more than hundreds of electrodes (Campbell et al. 1991), with recent improvements bringing this number closer to one thousand (Shobe et al. 2015; Scholvin et al. 2016; Buszáki et al. 2015), even on a single probe (Jun et al. 2017).”

• cites Campbell et al. 1991 sourceNot checked yet

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• cites Shobe et al. 2015Not checked yet

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• cites Jun et al. 2017 sourceNot checked yet

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May combine two claims.

Fail-safe blocking capacitor-free stimulator designs have been reported and could be employed instead of blocking capacitors.

“Blocking capacitors are still useful to block direct currents (DCs), but fail-safe blocking capacitor-free stimulator designs have been reported (Liu et al. 2008; Sit and Sarpeshkar 2007), and could be employed instead.”

• cites Liu et al. 2008 sourceNot checked yet

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• cites Sit and Sarpeshkar 2007 sourceNot checked yet

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May combine two claims.

Denser electrode integration can be achieved using multiple metal layers, but flexible systems are rarely multi-layered, due to the more complex fabrication process and the higher chance of failure.

“Denser electrode integration can be achieved using multiple metal layers (Suaning et al. 2007), but flexible systems are rarely multi-layered, due to the more complex fabrication process this implies and the higher chance of failure.”

• cites Suaning et al. 2007Not checked yet

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May combine two claims.

Blocking capacitors do not offer the protection the community thought they did; they introduce a voltage offset across the electrode-tissue interface, which is often neglected and needs to be properly characterised to ensure safe operation.

“Complete elimination of blocking capacitors could be an option, as they anyway do not offer the protection the community thought they did–they introduce a voltage offset across the electrode-tissue interface, which is often neglected and needs to be properly characterised to ensure safe operation (van Dongen and Serdijn 2016).”

• cites van Dongen and Serdijn 2016 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

When large capacitors are still needed, for example for energy storage purposes, silicon integration of such structures could be another viable alternative.

“When large capacitors are still needed, for example for energy storage purposes, silicon integration of such structures could be another viable alternative (Lallemand and Voiron 2013).”

• cites Lallemand and Voiron 2013Not checked yet

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May combine two claims.

Even after thinning and die separation, millimeter-small, micrometer-thin individual dice have to be handled, mounted, aligned and assembled on the flexible substrates, and related challenges are far from trivial as they are radically different from wafer level processes.

“However, even after thinning and die separation, millimeter-small, micrometer-thin individual dice have to be handled, mounted, aligned and assembled on the flexible substrates, and related challenges are far from trivial as they are radically different from wafer level processes (Bosman et al. 2011).”

• cites Bosman et al. 2011 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Platinum is preferred as stimulating electrode material due to its higher charge storage capacity, but its low conductivity (more than four times lower compared to gold) renders it undesirable for narrow, thin and long interconnects.

“Generally, although platinum is preferred as stimulating electrode material due to its higher charge storage capacity, its low conductivity (more than four times lower compared to gold) renders it undesirable for narrow, thin and long interconnects.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The hybrid nature of flexible BEms implies that the custom designed ASICs required for the performance of the system will have to be assembled on the flexible substrates in a heterogeneous process.

“The hybrid nature of flexible BEms implies that the custom designed ASICs required for the performance of the system will have to be assembled on the flexible substrates in a heterogeneous process.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In flip-chip bonding with polymeric adhesives, the adhesive acts as the interconnection medium between the bumped chip and the substrate.

“The adhesive acts as the interconnection medium between the bumped chip and the substrate, while it at the same time protects the contacts and provides mechanical support.”

• cites Lai and Liu 1999Not checked yet

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• cites Chen et al. 2000 sourceNot checked yet

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• cites Lu and Chen 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Polymeric adhesives are very popular for flip-chip bonding on flexible substrates.

“Polymeric adhesives are also very popular for flip-chip bonding on flexible substrates (Lai and Liu 1999; Chen et al. 2000; Lu and Chen 2010; Chiang et al. 2006; Chuang et al. 2010) as they can eliminate the need for underfill.”

• cites Lai and Liu 1999Not checked yet

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• cites Chen et al. 2000 sourceNot checked yet

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• cites Lu and Chen 2010 sourceNot checked yet

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May combine two claims.

In flip-chip bonding with polymeric adhesives, the adhesive protects the contacts and provides mechanical support.

“The adhesive acts as the interconnection medium between the bumped chip and the substrate, while it at the same time protects the contacts and provides mechanical support.”

• cites Lai and Liu 1999Not checked yet

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• cites Chen et al. 2000 sourceNot checked yet

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• cites Lu and Chen 2010 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Flip-chip bonding has been extensively used on flexible substrates in several variations, including reflow soldering and thermocompression processes for thin dice (50 μm).

“Flip-chip bonding has been extensively used on flexible substrates in several variations, including reflow soldering and thermocompression processes for thin dice (50 μm) (Banda et al. 2008; Zhang et al. 2009), but dispensing the underfill without allowing the material to flow on top of the very thin die is challenging.”

• cites Banda et al. 2008 sourceNot checked yet

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• cites Zhang et al. 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Soldering would probably not be suitable for very fine pitches.

“When thick film rather than thin film is used options could include soldering, which provides reliable results, although it would probably not be suitable for very fine pitches (Schuettler et al. 2008), parallel-gap welding (Schuettler et al. 2008) and laser welding, which can be used to weld dissimilar materials with very different thicknesses (ratio 50:1) (Rischall and Shackleton 1964).”

• cites Schuettler et al. 2008Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The microflex assembly technique is based on biocompatible materials.

“Another interesting approach is the microflex assembly technique (Stieglitz et al. 2000), which is based on biocompatible materials and can be used both with thick but also thin films.”

• cites Stieglitz et al. 2000Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The microflex assembly technique can be used both with thick and thin films.

“Another interesting approach is the microflex assembly technique (Stieglitz et al. 2000), which is based on biocompatible materials and can be used both with thick but also thin films.”

• cites Stieglitz et al. 2000Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Laser welding can be used to weld dissimilar materials with very different thicknesses (ratio 50:1).

“When thick film rather than thin film is used options could include soldering, which provides reliable results, although it would probably not be suitable for very fine pitches (Schuettler et al. 2008), parallel-gap welding (Schuettler et al. 2008) and laser welding, which can be used to weld dissimilar materials with very different thicknesses (ratio 50:1) (Rischall and Shackleton 1964).”

• cites Rischall and Shackleton 1964 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Soldering provides reliable results for thick film assembly.

“When thick film rather than thin film is used options could include soldering, which provides reliable results, although it would probably not be suitable for very fine pitches (Schuettler et al. 2008), parallel-gap welding (Schuettler et al. 2008) and laser welding, which can be used to weld dissimilar materials with very different thicknesses (ratio 50:1) (Rischall and Shackleton 1964).”

• cites Schuettler et al. 2008Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

Substrate processing steps might adversely affect the overall biocompatibility of the implant.

“Nevertheless, substrate processing steps need careful consideration, as they might adversely affect both the reliability, but also the overall biocompatibility of the implant.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some polymer candidates for flexible implants stand out because of their proven biocompatibility.

“Technologies for developing flexible implants are clearly focusing on polymer processing, with some clear prominent candidates standing out because of their proven biocompatibility.”

Classified as probably not a substantial claim.

Substrate processing steps might adversely affect the reliability of the implant.

“Nevertheless, substrate processing steps need careful consideration, as they might adversely affect both the reliability, but also the overall biocompatibility of the implant.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Technologies for developing flexible implants are focusing on polymer processing.

“Technologies for developing flexible implants are clearly focusing on polymer processing, with some clear prominent candidates standing out because of their proven biocompatibility.”

May combine two claims.

Reduced impedance and/or increased electrochemical surface of electrode coatings allow for denser electrode integration.

“Their reduced impedance and/or increased electrochemical surface allow for denser electrode integration, hence higher specificity and further miniaturisation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Electrode materials have moved from noble metals to advanced coatings.

“Electrode materials have moved from noble metals to advanced coatings, constructed by either different materials, or different geometries.”