Peer review of: Printable microscale interfaces for long-term peripheral nerve mapping and precision control (2019)


RR2
REVIEWERS' COMMENTS:
Reviewer #1 (Remarks to the Author):
  The paper is much improved, and the majority of my comments have been addressed. There are still two
 issues that should be strongly considered prior to publication.
 First, the addition of new control experiments in Figure 5 and S6, showing that the signal can be recorded
 from on the nerve but not immediately off the nerve is compelling. I am also very encouraged that the
 authors are very concerned about the possibility of artifact. My concern that this is artifactual still
 remains, and the comparison table highlights why. The closest similar design cited is Gonzalez-Gonzalez
 et al, where the present study states in error that they report 400 uVpp spontaneous signals. They
 actually report closer to 100 uV signals, which is particularly good for a nerve cuff. While the form factor,
 implantation method, etc are very different from other nerve cuffs, from an electrical perspective one
 might expect them to be very similar. It also appears that my question about the average spontaneous
 chronic Vpp across n=? birds was not answered in the response, and the 500 uV referred to throughout
 the paper could be exemplar, which is not appropriate.
 At minimum here, there needs to be a line of mechanistic, physics based reasoning about why these
 signals are so much larger than other devices. These signals would need to be larger still in the
 extracellular space within the epineurium. Is that likely to be true for some reason? The one sentence
 listing various differences isn’t enough. You should also consider the possibility of EMG invasion from the
 innervated muscle into the fluid of the nerve. I strongly recommend language in the Discussion
 suggesting that this may not ultimately be ENG., i.e. axonal recordings To summarize, the control
 experiments are exactly what one would think to do, but this paper could still become famously
 artifactual, and you may wish to hedge your interpretation of the results.
 Second, all reviewers had real concerns about the histological results, and I am still very concerned that
 exemplar data is being reported without being labeled as such. There is no n given in the Methods
 paragraph on immunohistology. If immohistology is outside the scope of this paper, which is a reasonable
 argument given the length, it should just be removed. If not, you should make a good faith effort to
 characterize other devices, report an n of attempts, and whether or not contradictory data to Figure 2b
 was ever observed. Cracked sections may not be good for figures, but they can still be evaluated in many
 cases.
 Reviewer #2 (Remarks to the Author):
Reviewer #3 (Remarks to the Author):
 The authors have meaningfully and compellingly addressed my concerns, and added in a figure of
 significant value to address possible EMG contamination. These additions greatly strengthen the paper,
 and demonstrate the novelty and utility of this approach. Now, if only these authors can start widely
 distributing this device, so that I can use it in my research! I recommend no further revisions to this
 manuscript.
 Cristin Welle
  As previously described, the technical developments presented in this manuscript are potentially
 impactful. The Reviewers put significant effort into evaluating the potential value of the nanoclip device
 and clearly communicated the additions that would convincingly support the use and further development
 of the nanoclip. Examples were showing the device’s feasibility as a chronic implant and its potential for
 application beyond one nerve, in one system, in one animal. Unfortunately, the authors decided not to
 address the Reviewers’ major comments and therefore didn’t significantly improve the manuscript.