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A network of small intrabody prosthetic nanodevices

Image credit: K_E_N/shutterstock.com

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J
Juran Feb 12, 2021
Inspired by the Neuralink and Starlink (session) by Elon Musk, diabetes patches and recent advences in wearable electronics, I want to revive the idea of microsensors on/inside our bodies. For the sake of the session, let's call it the BodyLink and try to define the main areas of focus.

Please contribute with your ideas and comments on:
  • defining the categories of nanobodies according to the target molecule/process
  • body localization (which organs, tissues, fluids, ...)
  • types of microsensors (biodegradable, life-lasting, stationary, circulating, ...)
  • signal-detecting devices (simple phone app, an independent external device that collects data, ...)
  • materials (titan-based nanostructures, natural polymers, simple cells, plasmids, ...)
  • insertion methods (implantation, everyday intake through fluids and food, genetic engineering, ...)
  • maintenance (if needed)
  • sensor-linking methods (out-of-the-body processing, sensor crosstalk, tissue conductance...)
I'm talking about sensors or detectors only, not the executor bodies.
Let's not talk about ethics. Imagine it's only for a good cause.


The background

Humanity developed networks of almost everything. Except for the most known network of computers - the Internet, we had networks long before, too. It all started with civilization. We first developed families (the network of people), cities (the network of houses), and countries (the network of cities). Parallelly, we developed water pipelines (the water network), we invented electricity (the power network), and developed multiple communication networks (post, phones, apps). But we never developed any network inside our bodies (tell me if I am wrong).

Starlink was built to offer a satellite internet network, especially in underserved areas, with competitive prices. Why will it succeed? Because it's a network of things. When all the known satellites would be available for everyone, the signal could be transmitted faster, further, and cheaper (that's the general idea of Starlink, OneWeb, etc.). That's similar to how Uber "won" the market, right? By better networking.

Could we help to diagnose diseases when we would invest in developing the network of sensory nanobodies that would circulate or be stationary in our bodies, in tactically important and information-full places?

Why would we do that?

I think it's not necessary to highlight the increasing need to develop new tools for early-stage diagnosis and prediction of diseases and disorders. The mentioned system of body "satellites" could allow us the detection of the "signals" and compounds that cells emit.

The idea

So, the idea is to create a start-up that would develop specific small (e.g. bacteria-sized) artificial or natural nanobodies or linking methods of already existing body mechanisms of detection and sensing that would collect the information in real-time. We would also be able to read the collected information and keep the track of changes inside our bodies via an AI-powered app. The company would focus on developing the nanosensors/detectors in five main areas:
  • virus and foreign nucleic-acid
  • proteins and proteostasis
  • bacteria
  • sugars and acidity
  • DNA damage and senescence


What are your thoughts on this?
What are the biggest problems?
What other areas would you cover?
What materials would you use?
Where would you plant them and how?
How can we make the network of small body satellites?
What kind of structures would that be? Natural or artificial?
Do we just need a better detection and connecting method? Are all the detectors already there?

Update:
Some of the sessions dealing with specific nanotechnological solutions:
Can we develop a cellular nano-sensing mechanism to specifically detect and target viral markers (NA and proteins) to fight viral infections in vivo?
Are “backpack” armed macrophages the next big thing in cellular immunotherapy?
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Creative contributions

Can we use storage cells as specialized sites for the nanobodies integration?

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Subash Chapagain
Subash Chapagain Feb 15, 2021
Interesting session, @Juran. The idea of a "network" of nanodevices sounds fascinating. Though not as a network of nanosensors, I had posted this session where I asked whether we could install in-vivo nanosensors that specifically target viral nucleic acids and proteins. Within this category (the devices that sense viral infections), one approach could be to use the inducible promoters that are specifically expressed as detection systems upon viral infection. Please go through the session and see if it fits into one of the applications of such type of networks. Talking about the kind of material that we would use to build these nano-devices, it is obvious that they should be bio-compatible, non-toxic and produce the lowest level of the immune response in the body. In another session where I summarized seemingly groundbreaking research in the field of cancer immunotherapy (using backpack nano-particles with macrophages to target cancer cells), @Shubhankar had put a list of the options of (bio)materials that we can start as candidates to build such nanoparticles. However, there are few things like the expected half-life, the system within the body for which the device is designed and similar other considerations prior to choosing a ype of material over the others. To address one issue of the site of plantation, the first thing that occurred to me was if we could exploit the adipocytes in our body. Adipose cells are the natural storage cells of our body, and if we could engineer these nanodevices to integrate into the adipose tissue, it would be easier for us to maintain/edit the devices as we need. Localizing the nanobodies in the storage cells, could it be possible to let them loose periodically, go for the targeted patrolling around the body (via blood) and after session of inspection return back to the adipose tissue? Imagine housing these nanobodies together in the adipose tissues in different organ locations and then deploying the subsets (as we need) to go around the body looking for infections/anomalies and after a successful reporting, them returning back to the initial site of plantation-the adipocytes in this case. Since most of these nanodevices can be expected to contain a fair amount of lipid content, content I think the idea of storage cells as a 'parking lot' for these devices could work. Now, talking about the 'network' side of things. The signalling system is clearly expected to transmit the data out of the body, most probably via using the Internet of Things (as seen in the BioStamp). However, there is one concern that bothers me. What if the link between the nanodevice and the external information processing system is intercepted? In other words, how do we make these nano-networks non-hackable? This is imperative because since proposed devices are intra-body, the damage they could do if they are hacked/destabilized could be astounding. Hence, what kind of biological as well as computing safety precautions could be used to prevent any kind of breaching?
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Juran5 months ago
Hi Subash Chapagain! Thank You!

I am sorry for not contributing to your session before. I read and posted my contribution - hope you like it.
The Shubhankar Kulkarni's list is very useful in terms of materials. I will add links to both sessions at the bottom of this one.

The adipose tissue indeed seems suitable for such implants or storage cells. Also, the idea of a "nanoparticle garage" is very cool. It would be awesome if we could control, deploy and recall the nanoparticles whenever we want.
The first solutions that occurred to me are:
1) lipid nanoparticles stored in the adipose tissue; deployed on electrical/hormonal signal
2) nanoparticles from artificial material (metals, polymers) that can be collected in implanted "garage" by changes in charge of the "garage" (stents could also be such "garages" - see my contribution to your session)

The problem you mentioned in the third paragraph is real. This data could be intercepted and used against you if the nanoparticles are so smart. If they are just collecting data (e.g. conjugated antibodies), then they are just reporters and there is no fear. If they are also effectors (affecting the blood content, on-site action, ...), then yes, we have a problem. I guess we can stop it by firewalls that block the outside signal or allow only one "connected" user. But it's a good question, tricky one.


In vivo real-time wireless temperature sensing at sub-0.1 mm3 scale is here!

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Juran May 23, 2021
For years, nanomedicine is trying to develop small implantable medical devices that would monitor physiological parameters inside the body. Although the idea sounds great, scientists encountered several serious problems that need to be solved.

The main problems of nanomedical devices
Up-to-date electronics are:
1) bulky --> problems with implantation inside the tissue, precise measurements of the parameters on the spot, and tissue damage and rejection
2) multicomponent --> require several parts (wires, external transducers, batteries, ...), which often limits the signal


A step forward
The solutions for both of these problems were thoroughly described in a recent paper, in a form of injectable sub-0.1 mm3 integrated wireless temperature sensing mote [Figure 1] .

Scientists monolithically integrated a 0.18-μm CMOS chip with temperature sensor IC with a piezoelectric zirconate titanate (PZT) transducer. When a commercial device produces an ultrasound, an output voltage generates across the two sides of the transducer and the power for the IC is generated. The sensor chip contains a front-end block that converts the incoming AC from the transducer into a stable DC supply for the rest of the chip, a temperature-sensing block that measures and modulation block that transfers the information back to the ultrasound source by modifying the input impedance of the PZT transducer.
Figure 1. (A) A schematic illustration of the device structure (B-E), size comparison, and (F) the operating principles (described in the text). Taken from .

The scientists also implanted the device inside the brain and the hindlimb of the mouse. To measure the temperature, they needed to keep a commercial ultrasound device 5 mm from the mice's head. The results were similar to the results of the reference probe. The testing was then performed in a dynamical environment where continuous precise temperature measurements are needed (FUS neuromodulation of the sciatic nerve) and it performed beyond expectations.

Limits
Although many problems have been solved, some of them require certain technological advances. One of them is that the mote operates up to 2 cm deep in the tissue. Scientists proposed solutions like reduction of the mote's energy consumption, a reduction in the ultrasound operating frequency, or 2D ultrasound imaging array that would focus the energy to exactly to the implanted mote.

This paper shows the direction which will eventually lead towards the development of the network of nanodevices of different kinds being implanted all over the body and routinely scanned for biomarkers on every medical examination.

The additional ideas and questions
  • an ultrasound device that scans the whole body (similar to the CT device)
  • an ultrasound device in your phone
  • what would be the best place to plant temperature sensing mote?

[1]https://advances.sciencemag.org/content/7/19/eabf6312

Nanobodies monitoring the function of sensors

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 13, 2021
Great session @Juran! Here is an idea to monitor the functioning of some of the bodily processes. Our body has sensors that detect changes such as, for example, a change in arterial blood pressure. Baroreceptors are located in the carotid sinus and the aortic arch. They sense (measure) the blood pressure and relay the information to the brain. The brain then employs other mechanisms such as constriction or the relaxation of the capillaries in order to maintain the required blood pressure. With age or as a manifestation of other comorbidities, the sensing and information relay mechanisms of these baroreceptors function sub-optimally. What if, as a part of the BodyLink, we could install nanobodies adjacent to these baroreceptors? They could sense the blood pressure the same way as the baroreceptors and alert the person when things go south.

Such receptors are the first to know when there is a problem and they are the point of initiation of the repair or the maintenance pathways. Knowing whether or not they are working properly can be the preliminary diagnosis. This can be expanded to include nanobodies for all other sensors (thermoreceptors, osmoreceptors, etc.).
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Juran6 months ago
Hi Shubhankar Kulkarni! Thank You!
That's exactly the idea I was looking for. You highlighted the importance of the already integrated body sensory systems (baroreceptors) and that's, in my opinion, one out of two main approaches. Blood pressure is indeed the biggest problem of today's medicine, so it makes sense to develop such a product.

So, the option could be the implementation of these small nanobodies adjacent to baroreceptors which would then sense the blood pressure the same way as baroreceptors. By going this road, we need to 1) develop the technology that senses the changes in pressure the same way (or more sensitive) as baroreceptors, 2) make the nanobodies from the "body-acceptable" materials, 3) localize them right next to the baroreceptors, and 4) develop the detection system for these nanobodies.

The other way could be to attach small detectors next to the baroreceptors, which would then read and transmit the signal of "natural" baroreceptors. That way the problem of mimicking the baroreceptor sensory mechanism, could be avoided (one step less). The only problem would be the "shelf life" of the baroreceptors.
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Shubhankar Kulkarni
Shubhankar Kulkarni5 months ago
Juran I like the other way, too. Yes, it saves a big step of detecting the blood pressure and can rely on the natural baroreceptor for that. There is a slight difference in the kind of data we acquire using the two approaches. Using the first approach where the nanobodies sense the blood pressure on their own and transmit these blood pressure values, we have the changed blood pressure data and the therapy can be started immediately. Using the second approach, if the natural baroreceptors stop functioning optimally, they will detect a changed blood pressure value (which is not correct), which will be copied by the nanobody sensor and transmitted to the device/doctor. Now this changed value is not reliable since the natural baroreceptors are not functioning properly. Therefore, before starting any therapy, the then blood pressure will need to be measured. Here is that additional step.
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Juran5 months ago
Shubhankar Kulkarni True, true. A good way of thinking.
I would suggest classical blood pressure measurement either way, but yes, the data should be interpreted differently. Although the first could detect the blood pressure changes and help to act in a timely manner, the second one could be used to detect certain disorders and diseases related to the blood pressure changes.

A potential downside: Carrying a large extra set of equipment

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 13, 2021
I am not sure if this can be a potential downside but something to think about. If we have microsensors for all or even most of the molecules, cell secretions in the body, it will mean carrying a large set of those sensors inside the body. One unit of sensor would not be sufficient; we are talking in terms of magnitudes of 10 for each single measurable bodily molecule. Will they not hamper the functioning of the body? The most proximate effect I can imagine is an increase in the density of blood if we have circulating nanobodies. An increase in density may increase blood pressure. An increase in the density of blood also means greater pressure on the kidneys to filter it.

If the nanobodies are embedded in tissues, they might probably affect the density and the arrangement of the extracellular matrix. I don't know, it seems like carrying a large pathogenic load or allergens, except for the fact that it is inert and will, probably, not elicit any reaction. However, on the other hand, they will always be there and the body might get used to it.
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Juran6 months ago
It's the real potential threat, I agree, but it depends on the system we choose.

If we develop a network of nanobodies circulating the bloodstream and implanted in certain tissues in large quantities, then we have to deal with this. With the last sentence, you already said the same thing I would say on this. I think the body would get used to it, the same way it gets used to high sugar levels, low iron, high copper, etc. Yes, it can result in certain disorders and yes, it could be lethal and therefore needs to be treated. But by having these sensors, we can treat it in time, and the risk: benefit ratio could be close to one or even smaller, especially in cases of people with serious diseases.

If, on the other hand, we choose to go with a smaller number of wisely-positioned sensors (like mentioned in Biostamp contribution), then we do not need to worry.


A network of wirelessly-powered virus-detecting stents

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Juran Feb 17, 2021
The idea of wirelessly-powered virus-detecting stents was described in my contribution to this session.
Shortly, the idea is to develop a system of two parts:
  • the moving part - nanobodies made of antibody-conjugated Qdots
  • the stationary part - small microfluidic channels inside the stent each specifically coated with antibodies used in nanobodies
Once the "moving part" binds to the virus in the blood, it subsequently enters the stent channel coated with the same antibody, forms the immuno-sandwich, and emits a signal to the detector.


The upgraded idea

Here, I present an upgrade to the mentioned idea.
What if we implanted many stents, with each individual stent having different antibodies in different microchannels and simultaneously having various antibody-conjugated Qdots circulating the bloodstream? (read the contribution for better understanding) We could use one device to read the data, evaluate it and act accordingly.

That way we could detect various viral pathogens with high sensitivity or read blood parameters in real-time, with high accuracy.

Inter-connected Biostamp patches as a primitive solution

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Juran Feb 12, 2021
Biostamp (Figure 1.) is a flexible electronic chip designed by MC10 company to specifically detect changes inside the body. It can measure body temperature, heart rate, muscle movement, blood pressure, metabolite levels, and more. If put all over your body and connected, they could give your doctor, trainer, or yourself much important information about your health in real-time.

It's not intrabody, but rather an on-body network of devices. It could be a problem in the future, but with technology advances and chips getting smaller, it could lead us to sustainable health tracking. The only step we need to take is the one towards the wider scope of body parameters being collected.

Figure 1. Biostamp (taken from http://cargocollective.com/futurehealth/BioStamp)





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