I have been asked by the IOM3 to provide feedback on your Nanoscience/Nanotechnology Report. Just for information, I sit on the IOM3 Nanotechnology Committee and am a medic by background.

Overall, I felt the Report was a pretty balanced, and not an over optimistic assessment of needs and future societal contribution. Where the Report become a little fuzzy, for very understandable reasons, was in regard to how harnessing of nanostructures as reporters, effective "materials" and systems modifiers was actually to be achieved. I wonder if in this context, some advice from ergonomic or design experts might come in handy. In my context, I will argue that many natural macromolecules, not least enzymes, possess a host of desirable properties, the difficulty is how to connect them up to information systems and, as appropriate, as harness-able agents. So maybe ideas about packaging, particle networking and non-contact monitoring might be of relevance. The following are responses to specific subcomponents:

NANOMATERIALS
I strongly support the notion of synergy between biostructures and nanomaterials. Nanovoids are probably as important as nanostructures as a route to better scaffolding. I am not aware of cells being used as scaffolding, however, and this should be confirmed by whoever stated the point. Quite the contrast, no artificial materials have been used as scaffolding, subsequently loaded with cells. Reference is made to inorganic surfaces, but equally valid would be organic/polymeric.

If micromachined silicon sensors are only to be limited to physical devices, we would be restricted, and chemical/biological “hybrid” sensors would be important to pursue and may offer earlier deliverables.

I am not clear why natural sympathetic routes for nanoparticles should have the heading “Biomaterials” unless such entities are to be used as implants.

I would dispute the proposition that it is not known how many of the particles will interact with proteins. Both in vivo and in vitro, there is experience on how colloidal scale particles adhere to, or indeed, flocculate proteins, which have a tendency to drop out of solution once unravelled. The term “misfolding” implies a protein folded up wrongly during synthesis, I suspect what is being meant is protein unfolding. Certainly there is no question that protein unfolding, i.e. denaturation, wrecks the performance of a protein, and it ceases to be functional. In fact not only does that happen at a great rate of knots naturally inside the body (that is why we have protein turnover), but any exposure to an artificial surface drastically distorts protein structure. With nanoparticles I can only suggest that the surface denaturation process with proteins might be more extensive. The other way to consider this issue is that outcomes will be affected by the relative size of the protein verses the nanoparticle.

With regard to toxicity, I absolutely agree about the parallel with asbestos. However, I would suggest that the specific issue here is that asbestos particles continue to be attacked by free radical generating lipocytes, and it is this which probably does the damage, whereas particulates that elicit a more benign body response are better tolerated. It is also a mute point as to whether molecular disperses the nanoscale would be toxic relative to each other. It needs to be emphasised, particularly given the public’s concern that we are surrounded by naturally and artificially generated atmospheres of nanoparticles, and that the white cell scavenging system, together with lympathics and lymph nodes have evolved over a long time to cope specifically with these hazards, i.e. we have specific partitioning systems that sequestrate particulates. These even operate at the molecular scale, thus ferric iron is extraordinarily toxic (a virtual free radical), but it is our protein masking systems that create nanobarriers around such iron particulates (haemosiderin is a classic toxic nanoparticle in this context that is packaged up by the body).

I agree strongly the point that surface chemistry matters, and is not well understood at the nanoparticle scale. In particular, I would suggest that the nanoscale might amplify the catalytic properties of materials and enhance toxicity in that way. One example of nanoparticles doing mischief irrespective of our lympathic handling system is the cascade of wear particles coming out of hip joints, which then move around the local tissues with subtle, adverse biological effects.


ELECTRONICS AND OPTOELECTRONICS

From my perspective I would suggest that once such devices reach the nanoscale, their internalisation into the body as a viable diagnostic, electrical stimulating and guidance materials should be considered.
I would not agree that smart dust is a long term venture, I am aware of some work on smart dust used to sample the atmosphere. I also would not agree the point about point of care health screening being a long-term proposition. Firstly there are already point of care systems available, and further miniaturisation of colour generating, biosensing, immobilised biological dipsticks etc., would not seem to be too far away. Indeed, one might argue that the latex particle tags on antibody used in pregnancy tests are already an exploitation of nanostructures – is quantum dot attachment all that farfetched?

I would support the notion of avoiding nanotechnology as an undergraduate
degree.

I would strongly support the notion of bionanotechnology as promising breakthrough area for nanotech.


BIONANOTECHNOLOGY AND NANOMEDICINE

I do not understand the point that “barriers that control drug release”. Yes, we need a better control over drug release, but that is not a prerogative of nanotechnology. Is the point intended to refer to tissue and cell membrane barriers that prevent location of the drug precisely where it is wanted?

The point about avoiding flocculation has some resemblance of truth, but I would argue that it is really not the main issue. If one wants selective targeting, the problem is how to stop nanoparticles from being taken up by phagocytic signals in the body which stop the particles from reaching desired locations. A more relevant issue might be how can we get particulates to move across natural tissue and biopolymer barriers, e.g., across the capillary bed? The point about targeting toxic drugs is fine, but the issue is not one of conventional verses non conventional routes, it is of exploiting nano-particles as safe packages for toxic agents until they arrived at their target tissue destination.

I am sure some use in tissue engineering, or better stated regenerative medicine, is likely, though I note the points made are pretty vague. I agree the point about textured surfaces, but I would prefer an example such as vascular stents rather than hips. In the context of drug discovery, it would be nice if reference is made to biosensors as well as miniature versions of existing laboratory apparatus (lab on a chip), but used for general analytical and biomedical measurement as apposed to simply drug discovery. Whilst drug discovery is a priority area, there are many other biomedical analytical needs. A classic target would be nanoscale lab on a chip devices that allowed in vivo monitoring and also could be integrated into implants
to monitor status.

I agree the applications, but again, feel citing the hip joint is maybe the wrong example and maybe vascular stents is better.

With regard to science fiction, I am not sure why the nanorobot is regarded as science fiction, given that it must be one of the near term targets, there are already molecular machines around. However the problem with nanorobots is that however sophisticated they maybe, they would be very rapidly attacked by the body’s response to invasion/infection. Is not a virus particle a nanorobot, and if so, we could mimic its structure?

I do not agree that drug targeting is science fiction, it maybe difficult, it maybe partially successful, but it is possible.


HEALTH, SAFETY, ENVIRONMENT AND SOCIAL ISSUES

The impression given is that of using the precautionary principle as a basis for going forward. I absolutely agree with this. Carbon nanotube structures would be a classic concern. Probably at stake is the speed at which a nanoparticle can be degraded. Thus, even a poly sugar (cotton) causes lung disease because it hangs around for some time. Also whilst toxicology is referred to, it is very likely that nanostructures are more immunogenic and more likely to cause allergies.


I hope these thoughts are of some use to you.

Regards.

Professor Pankaj Vadgama
Director, IRC in Biomedical Materials
Queen Mary, University of London