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Cited by 67Neuroscience and Neural EngineeringTissue Engineering and Regenerative MedicineNerve injury and regeneration

Regenerative Electrode Interfaces for Neural Prostheses.

Open access
Thompson, Cort H., Zoratti, Marissa J., Langhals, Nicholas B., Purcell, Erin K.·2016·Tissue Engineering Part B: Reviews
DOI 10.1089/ten.teb.2015.0279
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Abstract

This review categorizes tissue-engineering strategies for regenerative electrode interfaces and discusses selective interfacing with specific neuronal subpopulations.

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys tissue-engineering strategies intended to improve electrode–neuron integration in peripheral and central neural prostheses, grouping them into architectural redesign, bioactive/material coatings, and biohybrid cell or tissue grafts. It argues that regenerative interfaces could improve device stability, longevity, and subtype selectivity, while noting that translation and long-term durability remain unresolved.

Key findings

  • The review organizes regenerative interfaces into three broad approaches: (1) electrode architecture with finer geometries or topographical guidance, (2) material coatings and incorporated bioactive molecules, and (3) cellular grafts or biohybrid devices; these are discussed separately for the peripheral and central nervous systems.
  • In the CNS, implantation is linked to neuronal loss near the electrode surface, with about a 40% decrease in neuronal density reported within the estimated recordable radius; in the PNS, axons have been observed to retract more than 1 cm from the wound after penetrating electrode implantation.
  • Examples include flexible polyimide sieve electrodes that supported regenerating fibers in all 30 implanted rats; microchannel electrode arrays with roughly 100 × 100 µm channels that supported miniature fascicles up to 5 mm; PDMS/SU-8 microchannel scaffolds that recorded in vivo for 5 months; and regenerative peripheral nerve interfaces that recorded compound muscle action potentials over 7 months and 14 months, with unpublished rodent viability beyond 20 months and 50–100× signal amplification compared with state-of-the-art peripheral nerve interfaces.
  • L1-coated probes were associated with no evident reduction in neuronal density around implants over 8 weeks and improved density/neurofilament staining within the first 100 µm; a laminin nanoscale coating reduced gliosis at 4 weeks but did not affect local neuronal density; parylene-C coated versus uncoated arrays showed no significant differences over 12 weeks.

Methods

  • Narrative review, not a primary experimental study. It synthesizes published work on regenerative electrode interfaces for the PNS and CNS, with literature summarized in Supplementary Figs. S1 and S2.
  • The main organizing analysis is thematic: approaches are categorized by strategy (architecture, coatings/biologics, biohybrid devices) and by nervous system region, with selected in vitro and in vivo examples.
  • No systematic search strategy, inclusion criteria, or quantitative meta-analysis is described.

Limitations

  • Stated: the review notes ongoing challenges including translating in vitro coating benefits to in vivo outcomes, long-term electrical and mechanical stability of bioactive conductive polymers, limited survival or detection of grafted cells beyond early time points, and unclear mechanisms behind improved neuronal responses.
  • Stated: several cited findings are preliminary or proof-of-concept, and some data are unpublished; longer-term studies are called for.
  • Evident: as a narrative review, it lacks a formal systematic search and risk-of-bias assessment, and its conclusions rely on selected examples rather than comprehensive quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/ten.teb.2015.0279

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

48 of 112 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    Signal instability and signal loss may undermine the detection and decoding efficacy of brain-machine interfaces and closed-loop neurostimulation applications in which the stimulus is conditioned on a recorded neural signal.

    “This may undermine the detection and decoding efficacy of brain-machine interfaces and closed-loop neurostimulation applications in which the stimulus is conditioned on a recorded neural signal.1,15”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] 1. Rosin, B., Slovik, M., Mitelman, R., Rivlin-Etzion, M., Haber, S.N., Vaadia, E., et al. Closed-loop deep brain stimulation is superior in ameliorating parkinsonism. Neuron 72, 370, 2011. source
    • cites [15] 15. Perge, J.A., Homer, M.L., Malik, W.Q., Cash, S., Eskandar, E., Friehs, G., et al. Intra-day signal instabilities affect decoding performance in an intracortical neural interface system. J Neural Eng 10, 036004, 2013. source

      The passage immediately before Methods reports that within-day signal changes caused decoding errors and degraded neural cursor control in people with tetraplegia. The paper supports the concern for brain–machine interface decoding, but the cited passages do not address detection efficacy or closed-loop neurostimulation conditioned on a recorded signal. Page numbers are not provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Neural injury and inflammation that accompany device implantation are key contributing factors to signal loss and instability.

    “but the neural injury and inflammation that accompany device implantation are key contributing factors.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] 16. Prasad, A., Xue, Q.-S., Sankar, V., Nishida, T., Shaw, G., Streit, W.J., et al. Comprehensive characterization and failure modes of tungsten microwire arrays in chronic neural implants. J Neural Eng 9, 056015, 2012. source
    • cites [17] 17. Prasad, A., Xue, Q.-S., Dieme, R., Sankar, V., Mayrand, R.C., Nishida, T., et al. Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants. Front Neuroeng 7, 2, 2014. source

      The Discussion identifies vascular disruption and intraparenchymal hemorrhage during implantation as a major biotic factor likely contributing to electrode failure. But the paper reports that electrode performance was not correlated with microglial activation (neuroinflammation), so it does not support inflammation as a key contributor to signal loss. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    After implantation in severed rat sciatic nerves, Bellamkonda microchannel scaffolds guided the growth of axons and supporting cells along the length of the embedded microchannels.

    “scaffolds guided the growth of axons and supporting cells along the length of the embedded microchannels”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] 33. Srinivasan, A., Tahilramani, M., Bentley, J.T., Gore, R.K., Millard, D.C., Mukhatyar, V.J., et al. Microchannel-based regenerative scaffold for chronic peripheral nerve inter- facing in amputees. Biomaterials 41, 151, 2015. source

      The implantation methods describe scaffolds placed in transected rat sciatic nerves, and Results §3.3 reports axon regeneration inside most of the larger microchannels. Results §3.2 shows Schwann cells migrating along microchannels, but that experiment used cultured tissue rather than implanted nerves; Results §3.5 locates axons and Schwann cells together distal to the implant. The copy therefore does not establish that supporting cells grew along the length of the embedded channels after implantation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Koppes et al. observed positive effects of electrically guided proximal Schwann cells on neurite outgrowth.

    “Koppes et al. observed positive effects of electrically guided proximal Schwann cells on neurite outgrowth.57”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] 57. Koppes, A.N., Nordberg, A.L., Paolillo, G.M., Goodsell, N.M., Darwish, H.A., Zhang, L., et al. Electrical stimula- tion of schwann cells promotes sustained increases in neurite outgrowth. Tissue Eng Part A 20, 494, 2014. source

      The Results report that electrically prestimulated Schwann cells supported significantly greater neurite outgrowth than unstimulated Schwann cells. The study describes cultured Schwann cells, but does not identify them as proximal Schwann cells or show that electrical guidance, rather than prestimulation, caused the increased outgrowth. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Bellamkonda microchannel scaffolds stimulated the growth of essential Schwann cells and structural fibroblasts.

    “scaffolds stimulated the growth of essential Schwann cells and structural fibroblasts, potentially enhancing the integrity of regenerated neural tissue”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] 33. Srinivasan, A., Tahilramani, M., Bentley, J.T., Gore, R.K., Millard, D.C., Mukhatyar, V.J., et al. Microchannel-based regenerative scaffold for chronic peripheral nerve inter- facing in amputees. Biomaterials 41, 151, 2015. source

      The Results (§3.5) describe regenerating axons and Schwann cells within fibroblast sheaths, and the Discussion (§4) says the scaffold supports a microenvironment for proliferating Schwann cells and chronic nerve stability. These passages support cell-associated regeneration and structural organization, but do not show that the scaffold stimulated fibroblast growth specifically. Page numbers were not supplied. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Neuronal loss, signatures of neurodegeneration, and activation of neuronal cell death pathways have been observed in tissue local to devices implanted in the CNS.

    “Neuronal loss, signatures of neurodegeneration, and activation of neuronal cell death pathways have been observed in the tissue local to devices implanted in the CNS.[18][19][20]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [18] 18. Biran, R., Martin, D.C., and Tresco, P.A. Neuronal cell loss accompanies the brain tissue response to chronically im- planted silicon microelectrode arrays. Exp Neurol 195, 115, 2005. source
    • cites [19] 19. Kozai, T.D.Y., Li, X., Bodily, L.M., Caparosa, E.M., Ze- nonos, G.A., Carlisle, D.L., et al. Effects of caspase-1 knockout on chronic neural recording quality and longev- ity: insight into cellular and molecular mechanisms of the reactive tissue response. Biomaterials 35, 9620, 2014. source
    • cites [20] 20. McConnell, G.C., Rees, H.D., Levey, A.I., Gutekunst, C.A., Gross, R.E., and Bellamkonda, R.V. Implanted neural electrodes cause chronic, local inflammation that is corre- lated with local neurodegeneration. J Neural Eng 2009, 6, 056003. source

  • May combine two claims.

    Premisecitation

    In the CNS, small signal amplitudes, signal instability, and signal loss over time are often observed.

    “In the CNS, small signal amplitudes, signal instability, and signal loss over time are often observed.14,15”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] 14. Chestek, C.A., Gilja, V., Nuyujukian, P., Foster, J.D., Fan, J.M., Kaufman, M.T., et al. Long-term stability of neural prosthetic control signals from silicon cortical arrays in rhesus macaque motor cortex. J Neural Eng 8, 045005, 2011. source

      The Results (sections 3.1 and 3.2; page not provided) report declining action-potential amplitudes in three of four cortical arrays and waveform variation over hours and days. The Discussion (section 4; page not provided) says these changes make single units difficult to maintain, but it does not establish that small amplitudes or complete signal loss are often observed across the CNS; recorded neural activity and decoder performance could persist. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [15] 15. Perge, J.A., Homer, M.L., Malik, W.Q., Cash, S., Eskandar, E., Friehs, G., et al. Intra-day signal instabilities affect decoding performance in an intracortical neural interface system. J Neural Eng 10, 036004, 2013. source

      The Introduction describes commonly observed instability in intracortical recordings, declining spike amplitudes, and fewer recorded action potentials over months. Section 3.3 discusses units with small spike amplitudes, but does not establish that small amplitudes are often observed throughout the CNS. The claim generalizes beyond the intracortical interface recordings the paper discusses. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Common sources of recording failures in the CNS include demyelination of adjacent neurons, breakdown of the blood-brain barrier around the implant site, neuronal loss, degradation of the electrode, and formation of a glial sheath around implanted electrodes.

    “Common sources of recording failures in the CNS include demyelination of the adjacent neurons, breakdown of the blood-brain barrier around the implant site, neuronal loss, degradation of the electrode, and formation of a glial sheath around implanted electrodes.64,65”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [64] 64. Polikov, V.S., Tresco, P.A., and Reichert, W.M. Response of brain tissue to chronically implanted neural electrodes. J Neurosci Methods 148, 1, 2005. source
    • cites [65] 65. Kozai, T.D.Y., Jaquins-Gerstl, A.S. Vazquez, A.L., Mi- chael, A.C., and Cui, X.T. Brain tissue responses to neural implants impact signal sensitivity and intervention strate- gies. ACS Chem Neurosci 6, 48, 2015. source

  • May combine two claims.

    Premisecitation

    Mesenchymal stem cells are a promising alternative cell source for deriving Schwann-like cells and can be readily obtained from bone marrow or adipose tissue.

    “mesenchymal stem cells are a promising alternative cell source for deriving Schwann-like cells and can be readily obtained from bone marrow or adipose tissue.56”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [56] 56. Rodrigues, M.C.O., Rodrigues, A.A., Glover, L.E., Vol- tarelli, J., and Borlongan, C.V. Peripheral nerve repair with cultured schwann cells: getting closer to the clinics. Sci- entificWorldJournal 2012, 1, 2012. source

      Section 4 says bone-marrow MSCs can differentiate into Schwann-like cells and describes their ease of access; it also identifies adipose tissue as an alternative source and discusses adipose-derived Schwann cells. The Conclusions describe minimally invasive bone-marrow harvesting. Our copy does not establish that adipose-derived MSCs are readily obtained, so that part of the claim is not fully supported. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Lotfi et al. results indicated preferential neurite outgrowth of subtypes of neurons toward the expected target locations, providing proof-of-concept support for selective neuronal regeneration.

    “The results presented indicated preferential neurite outgrowth of subtypes of neurons toward the expected target locations, providing a proof-of-concept support for this type of approach.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] 34. Lotfi, P., Garde, K., Chouhan, A.K., Bengali, E., and Romero-Ortega, M.I. Modality-specific axonal regenera- tion: toward selective regenerative neural interfaces. Front Neuroeng 4, 1, 2011. source

  • May combine two claims.

    Interpretationcitation

    The microchannel array design allowed for a considerable quantity of neural tissue regeneration with minimal scar tissue and inflammation.

    “This study concluded that the microchannel array design allowed for a considerable quantity of neural tissue regeneration with minimal scar tissue and inflammation”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] 33. Srinivasan, A., Tahilramani, M., Bentley, J.T., Gore, R.K., Millard, D.C., Mukhatyar, V.J., et al. Microchannel-based regenerative scaffold for chronic peripheral nerve inter- facing in amputees. Biomaterials 41, 151, 2015. source

      The Discussion reports robust axon regeneration in the larger microchannels and says the implants were generally well tolerated with little to no scar tissue. It does not report minimal inflammation for this scaffold; its references to inflammation concern other electrode designs. Page numbers were not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Regenerated fibers in the Stoyanova arrays contained both myelinated and unmyelinated fibers of varying diameter, suggesting the possible presence of motor, autonomic, and sensory neurites.

    “These regenerated fibers contained both myelinated and unmyelinated fibers of varying diameter, which suggests the possible presence of motor, autonomic, and sensory neurites.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] 35. Stoyanova, I.I., van Wezel, R.J.A., and Rutten, W.L.C. In vivo testing of a 3D bifurcating microchannel scaffold in- ducing separation of regenerating axon bundles in periph- eral nerves. J Neural Eng 10, 066018, 2013. source

  • May combine two claims.

    Premisecitation

    PEDOT/CNT-coated electrodes exhibited improved neuronal responses at the interface and decreased expression of neuronal apoptosis markers following implantation into the DRG of rats.

    “PEDOT/CNT films were assessed for their utility in modifying a PNS interface, and it was found that coated electrodes exhibited improved neuronal responses at the interface and decreased expression of neuronal apoptosis markers following implantation into the DRG of rats.43”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] 43. Kolarcik, C.L., Catt, K., Rost, E., Albrecht, I.N., Bourbeau, D., Du, Z., et al. Evaluation of poly(3,4-ethylenediox- ythiophene)/carbon nanotube neural electrode coatings for stimulation in the dorsal root ganglion. J Neural Eng 12, 016008, 2015. source

  • May combine two claims.

    Premisecitation

    Vascular endothelial growth factor is known to promote revascularization, axonal outgrowth, and Schwann cell proliferation.

    “Vascular endothelial growth factor (VEGF) is known to promote revascularization, axonal outgrowth, and Schwann cell proliferation.58”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] 58. Sondell, M., Lundborg, G., and Kanje, M. Vascular endo- thelial growth factor has neurotrophic activity and stimu- lates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous sys- tem. J Neurosci 19, 5731, 1999. source

      The Abstract (page not provided) reports VEGF-induced axonal outgrowth and increased Schwann cell proliferation in cultured adult mouse ganglia. It also says VEGF promotes angiogenesis in vivo, but does not specifically establish revascularization—the restoration of a blood supply—so that part of the claim is more specific than the source supports. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Microchannel-based devices guide regenerating axons and parcel outgrowth toward distinct target locations.

    “Microchannel-based devices guide regenerating axons and parcel outgrowth toward distinct target locations.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [95] 95. Srinivasan, A., Liang, G., and Bellamkonda, R.V. ''Re- generative microchannel electrode array for peripheral nerve interfacing.'' Neural Engineering (NER), 2011 5th International IEEE/EMBS Conference on. IEEE, 2011. source
    • cites [34] 34. Lotfi, P., Garde, K., Chouhan, A.K., Bengali, E., and Romero-Ortega, M.I. Modality-specific axonal regenera- tion: toward selective regenerative neural interfaces. Front Neuroeng 4, 1, 2011. source
    • cites [35] 35. Stoyanova, I.I., van Wezel, R.J.A., and Rutten, W.L.C. In vivo testing of a 3D bifurcating microchannel scaffold in- ducing separation of regenerating axon bundles in periph- eral nerves. J Neural Eng 10, 066018, 2013. source

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

    Premisecitation

    Parylene C is a biocompatible polymer commonly used to insulate recording electrodes, and it has been shown to reduce attachment of microglia and macrophages to an underlying substrate in vitro.

    “Likewise, parylene C is a biocompatible polymer commonly used to insulate recording electrodes, and it is has been shown to reduce attachment of microglia and macrophages to an underlying substrate in vitro, 76”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [76] 76. Winslow, B.D., Christensen, M.B., Yang, W.K., Solzba- cher, F., and Tresco, P.A. A comparison of the tissue re- sponse to chronically implanted Parylene-C-coated and uncoated planar silicon microelectrode arrays in rat cortex. Biomaterials 31, 9163, 2010. source

      The Introduction describes Parylene-C as a common insulating coating for cortical recording electrodes. The Results (§3.1) and Discussion (§4) report a 95% reduction in activated microglial attachment to Parylene-C-coated coverslips in vitro; the Introduction also describes reduced brain macrophage attachment. Our copy does not explicitly establish the additional characterization of Parylene-C as biocompatible. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    While typical neuronal loss occurred at the device interface surrounding control implants, no such reduction in neuronal density was evident surrounding L1-coated implants.

    “Remarkably, while there was evidence of typical neuronal loss at the device interface surrounding control implants, no such reduction in neuronal density was evident surrounding L1-coated implants.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] 77. Azemi, E., Lagenaur, C.F., and Cui, X.T. The surface im- mobilization of the neural adhesion molecule L1 on neural probes and its effect on neuronal density and gliosis at the probe/tissue interface. Biomaterials 32, 681, 2011. source

  • May combine two claims.

    Premisecitation

    Next-generation devices fabricated from parylene-insulated carbon fibers with antibiofouling poly(ethylene glycol) methacrylate coatings have demonstrated robust recording quality and a minimal accompanying tissue response.

    “Next-generation devices fabricated from parylene-insulated carbon fibers with antibiofouling poly(ethylene glycol) methacrylate coatings have demonstrated robust recording quality and a minimal accompanying tissue response (Fig. 3C).71”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [71] 71. Kozai, T.D.Y., Langhals, N.B., Patel, P.R., Deng, X., Zhang, H., Smith, K.L., et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat Mater 11, 1065, 2012. source

  • May combine two claims.

    Premisecitation

    In a follow-up study, the nanoscale coating in vivo following implantation in rat brains showed a positive impact on reducing gliosis at the 4 week time point, but no apparent effect on the neuronal density local to the implant.

    “In a follow-up study, He and colleagues evaluated the nanoscale coating in vivo following implantation in rat brains, where it showed a positive impact on reducing gliosis at the 4 week time point, but no apparent effect on the neuronal density local to the implant.75”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [75] 75. He, W., McConnell, G.C., and Bellamkonda, R.V. Na- noscale laminin coating modulates cortical scarring re- sponse around implanted silicon microelectrode arrays. J Neural Eng 3, 316, 2006. source

  • May combine two claims.

    Premisecitation

    Smaller electrode sites necessitated by finer-scale geometries have the drawback of increased impedance, but inclusion of conductive polymers mitigates this effect and allows improved signal detection.

    “While the smaller electrode sites necessitated by finer-scale geometries have the drawback of increased impedance, inclusion of conductive polymers mitigates this effect and allows improved signal detection.71,72”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [71] 71. Kozai, T.D.Y., Langhals, N.B., Patel, P.R., Deng, X., Zhang, H., Smith, K.L., et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat Mater 11, 1065, 2012. source
    • cites [72] 72. Ludwig, K.A., Langhals, N.B., Joseph, M.D., Richardson- Burns, S.M., Hendricks, J.L., and Kipke, D.R. Poly (3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes. J Neural Eng 8, 014001, 2011. source

  • May combine two claims.

    Interpretationnone given

    Bioengineering strategies to stabilize or regenerate the neuronal interface of implanted devices are amenable to the naturally regenerative environment of the PNS, and applications in the more challenging CNS environment have also exhibited success.

    “Such strategies are amenable to the naturally regenerative environment of the PNS, but applications in the more challenging environment of the CNS have also exhibited success.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Instability and poor patency in the tissue-electrode interface undermine the longevity and performance of neural prostheses.

    “but instability and poor patency in the tissue-electrode interface undermines the longevity and performance of these devices”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A natural spatial separation occurred between regenerating motor and sensory axons, with larger-diameter, slower-growth motor axons tending to occupy the periphery of the sieve and smaller, faster-regenerating sensory axons found primarily in the center.

    “A natural spatial separation occurred between regenerating motor and sensory axons, where larger-diameter, slowergrowth motor axons tended to occupy the periphery of the device, and smaller, faster-regenerating sensory axons were found primarily in the center of the sieve.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 27. Lago, N., Ceballos, D., Rodrı ´guez, F.J., Stieglitz, T., and Navarro, X. Long term assessment of axonal regeneration through polyimide regenerative electrodes to interface the peripheral nerve. Biomaterials 26, 2021, 2005. source

  • May combine two claims.

    Premisecitation

    Bioactive NGF delivered from PEDOT doped with p-toluene sulfonate promoted neurite outgrowth from PC12 cells, but results with a laminin peptide-doped material were less encouraging in both physical and biological assessment.

    “while bioactive NGF delivered from PEDOT doped with paratoluene sulfonate (p-TS) promoted neurite outgrowth from PC12 cells, results with a laminin peptide-doped material were less encouraging, both in terms of the physical and biological assessment of the material.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] 45. Green, R.A., Lovell, N.H., and Poole-Warren, L.A. Impact of co-incorporating laminin peptide dopants and neuro- trophic growth factors on conducting polymer properties. Acta Biomater 6, 63, 2010. source

  • May combine two claims.

    Premisecitation

    In chronic studies in rats, the muscle is reinnervated by the peripheral nerve, and the formation of new neuromuscular junctions is evident.

    “In chronic studies in rats, the muscle is reinnervated by the peripheral nerve, and the formation of new neuromuscular junctions is evident.62”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] 62. Kung, T.A., Langhals, N.B., Martin, D.C., Johnson, P.J., Cederna, P.S., and Urbanchek, M.G. Regenerative periph- eral nerve interface viability and signal transduction with an implanted electrode. Plast Reconstr Surg 133, 1380, 2014. source

  • May combine two claims.

    Premisecitation

    An initial report demonstrated enhanced neurite outgrowth from SGNs cultured on PPy that incorporated NT3, and outcomes were further improved by applying electrical stimulation in a paradigm mimicking normal cochlear implant function.

    “An initial report demonstrated enhanced neurite outgrowth from SGNs cultured on PPy that incorporated NT3, and outcomes were further improved by applying electrical stimulation in a paradigm mimicking normal cochlear implant function.47”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] 47. Richardson, R.T., Thompson, B., Moulton, S., Newbold, C., Lum, M.G., Cameron, A., et al. The effect of poly- pyrrole with incorporated neurotrophin-3 on the promotion of neurite outgrowth from auditory neurons. Biomaterials 28, 513, 2007. source

  • May combine two claims.

    Premisecitation

    In the PNS, nerve growth factor supports neuronal survival and neurite outgrowth.

    “In the PNS, nerve growth factor (NGF) supports neuronal survival and neurite outgrowth, 52”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] 52. Chan, K.M., Gordon, T., Zochodne, D.W., and Power, H.A. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol 261, 826, 2014. source

  • May combine two claims.

    Premisenone given

    The CNS has little natural capacity to regenerate, and insertion trauma, inflammation, and secondary injury response associated with chronically implanted microelectrode arrays present significant challenges to achieving effective long-term device function.

    “The CNS has little natural capacity to regenerate, and the insertion trauma, inflammation, and secondary injury response associated with chronically implanted microelectrode arrays present significant challenges to achieving effective long-term device function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Grafting muscle to the end of a severed peripheral nerve results in a minimal overall neural regeneration time because peripheral nerves continue to regenerate following injury at about 1 mm per day.

    “Since peripheral nerves continue to regenerate following an injury at *1 mm per day, grafting the muscle to the end of the nerve results in a minimal overall neural regeneration time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    By grafting muscle to the end of the nerve, the standard signal pathway is disrupted, making the RPNI interface appropriate for amputees and distal nerve injuries.

    “By grafting muscle to the end of the nerve, the standard signal pathway is disrupted, making this interface appropriate for amputees and distal nerve injuries.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In an in vivo assessment of chronically implanted polyimide arrays, regenerating fibers were observed in all 30 implanted rats with little evidence of axonopathy, marking an improvement over silicon arrays.

    “In an in vivo assessment of chronically implanted polyimide arrays, regenerating fibers were observed in all 30 implanted rats with little evidence of axonopathy, marking an improvement over silicon arrays.27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] 27. Lago, N., Ceballos, D., Rodrı ´guez, F.J., Stieglitz, T., and Navarro, X. Long term assessment of axonal regeneration through polyimide regenerative electrodes to interface the peripheral nerve. Biomaterials 26, 2021, 2005. source

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

    Interpretationnone given

    Given a small muscle harvest size of less than three centimeters, there is limited resultant donor site morbidity, which may regenerate from nearby myocytes.

    “Given a small muscle harvest size of less than three centimeters, there is limited resultant donor site morbidity, which may regenerate from nearby myocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A longer-term assessment over 14 months demonstrated that RPNIs had positive histological outcomes and robust signal detection over the duration of the study.

    “A longer-term assessment over 14 months again demonstrated that RPNIs had positive histological outcomes and robust signal detection over the duration of the study.63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] 63. Langhals, N.B., Member, I., Woo, S.L., Moon, J.D., Larson J.V, Leach, M.K., et al. Electrically stimulated signals from a long-term regenerative peripheral nerve interface. In Engineering in Medicine and Biology Society (EMBC), 2014 36th Annual International Conference of the IEEE, 1989, 2014. source

  • May combine two claims.

    Interpretationreasoning

    RPNIs do not record signals as large as healthy muscles, but the muscle tissue serves as a biological amplifier by increasing the signal amplitude by 50-100 times compared with what can currently be recorded from state of the art peripheral nerve interfaces.

    “While RPNIs do not record signals as large as healthy muscles, due to the regeneration and reinnervation process, the muscle tissue serves as a biological amplifier by increasing the signal amplitude by 50-100 times compared to what can currently be recorded from state of the art peripheral nerve interfaces.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Smaller, less invasive device designs may produce a more favorable neuronal response to implanted CNS prostheses.

    “It is intuitive that smaller, less invasive device designs may produce a more favorable neuronal response to implanted CNS prostheses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Improved recording quality may be related to reduced non-neuronal density near the lateral features, and reactive glia can produce inflammatory cytokines and chemokines with neurotoxic potential.

    “This may be related to reduced non-neuronal density near the lateral features; reactive glia can produce inflammatory cytokines and chemokines with neurotoxic potential.18,68,69”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] 18. Biran, R., Martin, D.C., and Tresco, P.A. Neuronal cell loss accompanies the brain tissue response to chronically im- planted silicon microelectrode arrays. Exp Neurol 195, 115, 2005. source
    • cites [68] 68. Karumbaiah, L., Saxena, T., Carlson, D., Patil, K., Patkar, R., Gaupp, E.A., et al. Relationship between intracortical electrode design and chronic recording function. Bioma- terials 34, 8061, 2013. source
    • cites [69] 69. Skousen, J.L., Bridge, M.J., and Tresco, P.A. A strategy to passively reduce neuroinflammation surrounding devices implanted chronically in brain tissue by manipulating de- vice surface permeability. Biomaterials 36, 33, 2015. source

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

    Premisecitation

    Seymour and Kipke reported increased neuronal density adjacent to finer-scale, lateral features of an open-architecture polymer neural probe implanted in the motor cortex of rats compared with tissue adjacent to the main shank.

    “In 2007, Seymour and Kipke reported increased neuronal density adjacent to finer-scale, lateral features of FIG. 2. Regenerative peripheral nerve interface (RPNI) to record prosthetic control signals from severed peripheral nerves.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] 66. Seymour, J.P., and Kipke, D.R. Neural probe design for reduced tissue encapsulation in CNS. Biomaterials 28, 3594, 2007. source

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

    Premisecitation

    An alternative strategy for incorporating neural progenitors on neural prostheses immobilizes laminin on the surface of silicon arrays to facilitate cellular attachment to the device.

    “An alternative strategy for incorporating neural progenitors on neural prostheses immobilizes laminin on the surface of silicon arrays to facilitate cellular attachment to the device.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] 88. Azemi, E., Gobbel, G.T., and Cui, X.T. Seeding neural progenitor cells on silicon-based neural probes. J Neuro- surg 113, 673, 2010. source

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

    Interpretationnone given

    Current designs suffer from poor integration between electrodes and neurons, with an extreme mismatch between the properties of biological and synthetic substrates at the device interface.

    “Nonetheless, current designs suffer from poor integration between electrodes and neurons, where an extreme mismatch exists between the properties of the biological and synthetic substrates at the device interface.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Smaller device designs offer the dual benefit of reduced insertion damage due to a smaller footprint and the capability to tap into neural circuitry with higher spatial resolution in a more distributed manner.

    “These designs offer the dual benefit of reduced insertion damage due to a smaller footprint of the implanted device, as well as the capability to tap into neural circuitry with higher spatial resolution in a more distributed manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    L1 promotes neuronal growth and neurite extension.

    “L1 has also been shown to promote neuronal growth and neurite extension, as well as reducing attachment of glial cells in vitro.79”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] 79. Azemi, E., Stauffer, W.R., Gostock, M.S., Lagenaur, C.F., and Cui, X.T. Surface immobilization of neural adhesion molecule L1 for improving the biocompatibility of chronic neural probes: in vitro characterization. Acta Biomater 4, 1208, 2008. source

  • May combine two claims.

    Premisecitation

    The neurotrophic cone electrode developed by Kennedy was a pioneering example of a biohybrid central neural prosthesis: a section of nerve housed within a glass electrode assembly was used to encourage neurite ingrowth near the gold recording wire.

    “The neurotrophic cone electrode developed by Kennedy was a pioneering example of a biohybrid central neural prosthesis: a section of nerve housed within a glass electrode assembly was used to encourage neurite ingrowth near the gold recording wire.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] 82. Kennedy, P.R. The cone electrode: a long-term electrode that records from neurites grown onto its recording surface. J Neurosci Methods 29, 181, 1989. source
37 of 37

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Most commonly the nerve lesion for regenerative implants is a full nerve transection where the two ends are cleanly separated and a gap forms.

    “Most commonly this is in the form of a full nerve transection, where the two ends of the nerve are cleanly separated and a gap forms between the two (Navarro et al., 2005; Thompson et al., 2015).”

    From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Thompson et al., 2015

    The Biohybrid devices section (page unavailable) describes a regenerative interface attached to a transected nerve, and the Fig. 2 caption describes grafting muscle to the end of a divided or severed nerve. Neither passage says that full transection is the most common lesion for regenerative implants or that it leaves two cleanly separated ends with a gap. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Cuff electrodes can be inserted into the gap of a nerve lesion and the nerve allowed to grow through it, rather than wrapping the cuff around a healthy nerve.

    “Cuff electrodes can be inserted into the gap of a nerve lesion and the nerve allowed to grow through it, rather than wrapping the cuff around a healthy nerve (Lotfi et al., 2011; Stoyanova et al., 2013; Thompson et al., 2015).”

    From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Thompson et al., 2015

    The Peripheral Regenerative Nerve Interfaces section says cuff electrodes wrap around the exterior of a nerve. The Electrode architecture section describes axons regenerating through sieve electrodes, but does not say that a cuff electrode can be placed in a lesion gap for the nerve to grow through. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Microchannel structure maximises the amplitude of recorded biopotentials and reduces the currents required to activate nerves without reliance on the position of the nodes of Ranvier in myelinated fibers.

    “This maximises the amplitude of the recorded biopotentials and reduces the currents required to activate nerves without reliance on the position of the nodes of Ranvier in myelinated fibers [23], [35].”

    From Active Neural Interface Circuits and Systems for Selective Control of Peripheral Nerves: A Review (2024) · cites this paper as [23]

    The Electrode architecture section (page unavailable) says insulated microchannels may boost recorded signals by reducing shunt loss. It does not establish that they maximise biopotential amplitude, reduce the current needed to activate nerves, or make activation independent of node-of-Ranvier position. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Cites

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Related

Authors
Thompson, C. H., Zoratti, M. J., Langhals, N. B., & Purcell, E. K.
Affiliations
Michigan State University (US)
Corresponding author
Purcell, Erin K.
ORCID
Venue
Tissue Engineering Part B: Reviews
Publisher
SAGE Publications
Published
2015-11-23
Volume
22
Issue
2
Pages
125-135
ISSN
  • 1937-3368 (ISSN-L)
  • 1937-3376
DOI
10.1089/ten.teb.2015.0279
OpenAlex
W2175643771
Cited by
67
References
93
Citations by year
2026: 1 · 2025: 5 · 2024: 4 · 2023: 12 · 2022: 1 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 5 · 2017: 11 · 2016: 2
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations
  • Tissue Engineering Part B Reviews (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Michigan State University
  • College of Engineering, Michigan State University
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
neural prostheses, electrode-tissue interface, nerve regeneration, electrode arrays, biohybrid devices, neuronal growth, topographical cues, bioactive coatings, peripheral nervous system, central nervous system
MeSH terms
Electrodes, Implanted, Humans, Nerve Regeneration, Peripheral Nerves, Neural Prostheses

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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