What is bioelectronic medicine defined as?
A branch of science that deals with electronic control of physiological function as applied in medicine to compensate for defects of the nervous system.
What is the basis of bioelectronic medicines?
All cells have electrical behaviour. When disease occurs, this behaviour changes, either in the production of currents or in membrane voltage difference.
By restoring this electrical malfunctioning we can either treat the disease directly or the symptoms of the disease to make it more manageable.
How is electricity used in cochlear implants?
- An external microphone picks up audio and a sound processor converts the audio to a radio frequency signal.
- This is transmitted to receiver under the skin behind the ear.
- Here, the signal is converted to electrical currents which pass through a wire which has been surgically inserted into the cochlea.
- Here, it mimics the action of functioning cochlear cells and stimulates the auditory nerve, allowing the person to hear.
How is electricity used in pacemakers/ICDs?
A pacemaker/ICD, an electrical device which interfaces with the heart and sends out electrical impulses to restart the heart if it stops (ICD – implantable cardioverter defibrillators) or modify heart rate due to arrythmias (pacemaker).
What are the 2 key biological currents?
Ionic current (action potential) – bulk movement of charge. For example, a sodium-potassium ion channel which modulates the flux of sodium and potassium into and out of the cell. Voltage difference is generated across the membrane which can be modified by bioelectronic medicines.
Faradaic current – free electrons are generated through redox reactions and move across membranes. Can also be modified by bioelectronic medicines.
What is an action potential?
The movement of charge across a neuronal/nerve cell via controlling the influx of sodium into a cell and the outflow of potassium out of the cell.
Describe an action potential.
- At rest, there is a resting membrane potential of -60mV due to the outflow of potassium through open K+ channels down its concentration gradient, but lack of sodium influx due to closed/deactivated Na+ channels.
- A change in voltage causes the voltage-gated sodium channels to open and potassium channels to close, causing an influx of Na+ ions and decreased efflux of K+ ions, as well as a subsequent increase in membrane potential.
- More sodium channels open, causing an even further increase in intracellular Na+ ions and membrane potential. As the potential becomes more positive and the membrane depolarises, the potential surpasses -40mV (threshold potential) which initiates an action potential.
- At a certain membrane potential, sodium channels start to close, and potassium channels start to open, meaning less Na+ ions are flowing in, and more K+ ions are flowing out, causing the membrane to repolarise. When the potential dips below resting potential (-60mV) this is known as hyperpolarisation.
- The sodium-potassium pump works to re-establish the resting state
Who is involved in the development of bioelectronic medicines?
- Clinicians and molecular biologists identify the target of disease/health.
- Neuroscientists identify the neural pathway to manipulate the target.
- Engineers and computer scientists design a device to modulate the appropriate pathway
Why is control of the immune system tightly regulated?
Overstimulation of the anti-inflammatory pathway can lead to infection and cancer, while overstimulation of the pro-inflammatory pathway can lead to autoimmune and inflammatory conditions.
What is tumour necrosis factor (TNF)
A multifunctional pro-inflammatory cytokine which plays important beneficial roles in cell survival, proliferation, differentiation, and death
What can overproduction of TNF lead to?
Blood pressure to plummet leadinf to organ failure due to lack of oxygen, resulting in lethal shock (septic shock).
How can bioelectronic medicine be used to reduce TNF or replace anti-TNF antibodies?
- Efferent activity in the vagus nerve leads to an increase in the number of propagated action potentials towards the organs.
- Action potential at the end of the nerve near the spleen is translated into chemical signals which activate T-cells to produce acetylcholine.
- ACh interacts with the α-bungarotoxin-sensitive nicotinic receptors (ACh receptors) on tissue macrophages in these organs to inhibit the release of TNF (and other cytokines).
Therefore, a device on the vagus nerve could be implanted to use electrons to prevent septic shock and inflammatory conditions.
Describe the composition of the nervous system.
Human nervous system:
Central nervous system – brain and spinal cord. Interneurons.
Peripheral nervous system – Everything else. Sensory and motor neurones.
o Somatic nervous system – voluntary, Input from sense organs, output from skeletal muscles.
o Autonomic nervous system – involuntary. Input from internal receptors, output to smooth muscles and glands.
Sympathetic motor system – Adrenergic system (neurotransmitter - noradrenaline). Fight or flight responses.
Parasympathetic motor system – Cholinergic system (neurotransmitter – acetylcholine). Relaxing responses.
Name 3 advantages of bioelectronic medicines.
Standard electronic components are cheap, so they could be preassembled to allow the development cost to be lower.
Side effects may be lower than conventional medicines.
May not need as thorough regulatory approval which could make costs cheaper.
How does toll like receptor 4 (TLR4) contribute to immune repsonses.
TLR4 is found on macrophages and detects lipopolysaccharide, a cell surface glycolipid found on gram negative bacteria. Upon detection, it stimulates production on inflammatory cytokines such as TNF and IL6, and recruits other immune cells leading to an innate immune response. These pro-inflammatory cytokines are balanced by anti-inflammatory cytokines such as IL10, TGF-beta, and soluble cytokines.
What are some issues associated with bioelectronic medicines?
- Resolution – difficult to target a specific neuronal cell in a bundle of nerves to target that particular pathway, rather than the electrical input being exposed to all cells.
- Invasiveness – increased infection and patient discomfort. For example, the vagus nerve stimulator is an invasive surgery meaning it can lead to an increased risk of infection, as well as physical and mental discomfort for the patient.
- Intimacy of electronics with biology/rigidity – if there is a gap between the electrical input and the biology, there will be a resistance to current. This means that a current in the electronic will not be felt by the biology. Materials which are soft and can bend with biology and are 3D, allow them to blend with biology and reduce this.
- Biocompatibility – materials used should not invoke a biological reaction and extend the implant life.
- Immune reactions – materials should not invoke an immune reaction and extend the implant life.
- Lack of understanding of closed loop bio-electrical circuits – finely tuned electrical responses require a record using a feedback loop to ensure they remain tuned.
How do bionic eyes work?
A chip with 264 electrodes is implanted into the back of the eye to the retina with a wire attached to a camera which is worn in glasses. When the image is fed from the camera to the electrodes in the retina, it feeds back through the optic nerve allowing them to see.
Why do bionic eyes have poor resolution?
The 264 electrodes can only interact with a small number of neuronal cells, so the patient’s vision will have poor resolution. So, they may be able to look at a face in an audience but not distinguish them.
What 3 issues do the bionic eye have?
Biocompatability
Invasiveness
Resolution
How have issues with biocompatability and ivasiveness of the bionic eye been improved?
New diamond-based electrodes can prevent immune responses and fibrogenesis (encapsulation) so they do not have to be replaced as often, hence improving biocompatibility and reducing the regularity of invasiveness
How might the resolution of the bionic eye be improved in the future?
Arrays of nano-electrodes which enable interface with single cells are being produced to allow stimulation of one particular cell. In theory, this means we can interface with every cell of the optic nerve to create vision with improved resolution.
How can electronic wires self-assemble in situ?
Cellular redox sensing:
Patient wears a conductive patch on the skin and either takes an oral dose of conductive nanoparticles or is injected with conductive microparticles. You can then direct an electric field to self-assemble electronic wires.
How does NoVo-cure electrical treatment for glioblastoma work?
The patient wears a cap containing transducer arrays which delivers an electric field (alternating current of 200kiloherts). This causes deformation of microtubules which results in abnormal DNA segregation during cell division, leading to cell death, and migration of organelles leads to cell fragmentation.
How does NoVo-cure electrical treatment cause microtubule abnormalities and cell death?
Dipoles are molecules in which the electric charge is separated. In a uniform alternating electric field, dipoles oscillate in sync with the field. At high frequencies, motion diminishes as dipoles align with the field.
During metaphase, mitotic spindles forms from microtubules, which in turn are produced by polymerisation of tubulin dimers which experience large dipole moments. The uniform fields cause the tubulin dimers to align with the field, thus inhibiting microtubule formation and leading to metaphase arrest, prolonged mitosis, and cell death. The deformed microtubules cause abnormal DNA segregation between daughter cells, also ultimately causing cell death
