Although cellular therapies represent a promising strategy for a number of conditions, current approaches face major translational hurdles, including limited cell sources and the need for cumbersome pre-processing steps (for example, isolation, induced pluripotency). In vivo cell reprogramming has the potential to enable more-effective cell-based therapies by using readily available cell sources (for example, fibroblasts) and circumventing the need for ex vivo pre-processing.
Existing reprogramming methodologies, however, are fraught with caveats, including a heavy reliance on viral transfection. Moreover, capsid size constraints and/or the stochastic nature of status quo approaches (viral and non-viral) pose additional limitations, thus highlighting the need for safer and more deterministic in vivo reprogramming methods.
Here, we report a novel yet simple-to-implement non-viral approach to topically reprogram tissues through a nanochannelled device validated with well-established and newly developed reprogramming models of induced neurons and endothelium, respectively. We demonstrate the simplicity and utility of this approach by rescuing necrotizing tissues and whole limbs using two murine models of injury-induced ischaemia.
With this technology, we can convert skin cells into elements of any organ with just one touch. This process only takes less than a second and is non-invasive, and then you’re off. The chip does not stay with you, and the reprogramming of the cell starts. Our technology keeps the cells in the body under immune surveillance, so immune suppression is not necessary,” said Sen, who also is executive director of Ohio State’s Comprehensive Wound Center.
TNT technology has two major components: First is a nanotechnology-based chip designed to deliver cargo to adult cells in the live body. Second is the design of specific biological cargo for cell conversion. This cargo, when delivered using the chip, converts an adult cell from one type to another, said first author Daniel Gallego-Perez, an assistant professor of biomedical engineering and general surgery who also was a postdoctoral researcher in both Sen’s and Lee’s laboratories.
TNT doesn’t require any laboratory-based procedures and may be implemented at the point of care. The procedure is also non-invasive. The cargo is delivered by zapping the device with a small electrical charge that’s barely felt by the patient.
Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes. These include using electric and magnetic fields, temperature, ultrasound or light to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis).
More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications. Here we show that molecular machines can drill through cellular bilayers using their molecular-scale actuation, specifically nanomechanical action.
Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells.
We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitro applications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation.
The machines are so tiny that 50,000 of them together is still about the width of a single strand of human hair. Each machine is engineered to be sensitive to a protein located on a specific type of cell, which helped them find their target. Once you add light, they spin up to 3 million times per second, and this spinning provides the power needed to break into a cell. Without light, the nanomachines can still find the molecule, but just remain on the surface.
When scientists let these nanomachines loose in a dish full of human kidney cells, the nanomachines made holes in the cells and killed them within minutes. The same thing happened when the nanomachines were unleashed on cancerous prostate cells.
These little robots are powered by an electromagnetic field, similar to how you would wirelessly charge a cell phone. By changing the frequency of the magnetic field, the researchers are able to precisely control the exact movement of their prototype.
For instance, one triangular robot that’s no bigger than a quarter is composed of three triangular pieces of thin plastic, attached with hinges to a middle triangle that has a circuit. The hinges are controlled by coils of a metal called “shape-memory alloy,” which changes its form when it’s exposed to heat. When an electric current starts running through the central circuit, these coils heat up and contract, causing the three triangles to fold up toward the center of the robot. When the current stops, the hinges return to their flat state.
Two hundred million years ago, our mammal ancestors developed a new brain feature: the neocortex. This stamp-sized piece of tissue (wrapped around a brain the size of a walnut) is the key to what humanity has become. Now, futurist Ray Kurzweil suggests, we should get ready for the next big leap in brain power, as we tap into the computing power in the cloud.
Speaking of AI augmenting human intelligence rather than replacing, Ray Kurzweil popularized the idea in 2014 suggesting that nanorobotics could do the trick in just a few decades.
Remember that he works for Google.
An international team of researchers has developed miniscule, self-propelled devices that mimic the way cells move. These “nanoswimmers” cross the blood–brain barrier highly efficiently, and could lead to the development of drug delivery systems that navigate through tissues and organs to target specific sites precisely.
…penetrating the blood–brain barrier, which prevents microbes, toxins and large molecules from entering the brain, has proved hugely challenging. One major goal is to develop self-guided polymersomes that traverse this barrier to deliver their cargo to a specific brain area.
Nanotechnology is the science, engineering, and technology conducted at the nanoscale, which is about 1 to 100 nanometers.
Essentially, it’s manipulating and controlling materials at the atomic and molecular level.
To give you perspective, here’s how to visualize a nanometer:
- The ratio of the Earth to a child’s marble is roughly the ratio of a meter to a nanometer.
- It is a million times smaller than the length of an ant.
- A sheet of paper is about 100,000 nanometers thick.
- A red blood cell is about 7,000-8,000 nanometers in diameter.
- A strand of DNA is 2.5 nanometers in diameter.
A nanorobot, then, is a machine that can build and manipulate things precisely at an atomic level.
These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria — and therefore self-propelled — and loaded with drugs that moved by taking the most direct path between the drug’s injection point and the area of the body to cure,” explains Professor Sylvain Martel, holder of the Canada Research Chair in Medical Nanorobotics and Director of the Polytechnique Montréal Nanorobotics Laboratory, who heads the research team’s work. “The drug’s propelling force was enough to travel efficiently and enter deep inside the tumours.”
When they enter a tumour, the nanorobotic agents can detect in a wholly autonomous fashion the oxygen-depleted tumour areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumour cells.