How We Can Heal Fractures Faster

Where the cuboid fracture is located (left) and star player George Kittle (right).

The Problem

Biological Scaffolding

Summary of the bone scaffold process.
  • Be biocompatible — cells must adhere, function normally, and migrate onto the surface and eventually through the scaffold and begin to proliferate before laying down the next matrix
  • Be biodegradable — Scaffolds are not to be permanent, so it must be biodegradable as to allow cells to produce their own extracellular matrix at a certain point. The by-products of the degradation should also be non-toxic and able to exit the body without interference with other organs
  • Be mechanically strong — Ideally, the scaffold should have mechanical properties consistent with the anatomical site into which it is implanted in, and must be strong enough to allow surgical handling during implantation. They also need sufficient mechanical integrity to function from the time of implantation to the completion of the remodeling process
  • Be architecturally correct — The architecture of scaffolds should have interconnected pore structures and high porosity to ensure cellular penetration and adequate diffusion of nutrients to cells within the construct and to the extracellular matrix formed by these cells
  • Be easily manufactured — In order for a scaffold to be clinically and commercially viable, it should be cost effective and it should be possible to scale-up from making one at a time in a research lab to small batch production

The Proposed Solution

  • Materials — hydroxyapatite/HAp (ceramic), chitosan/CTS (natural polymer), and ultrahigh molecular weight polyethylene oxide/PEO (synthetic polymer)
  • Preparation — Using a co-precipitation method, the HAp/CTS nanoparticles were formed in a solution. The PEO was then added to this solution
  • Fabrication — The solution was then electrospun into thin fibers, which then were shaped into a fibrous scaffold with the HAp/CTS nanoparticles embedded into the fibers

Choosing Materials

Overview of what goes into choosing materials for bone scaffolds.
  • Hydroxyapatite(HAp) — This is a ceramic biomaterial whose nanoparticles must be formed via a certain preparation method. It is a major component and an essential ingredient of normal bone as it makes up bone mineral. It is this material that gives bones their rigidity. By getting a lot of it in a scaffold, you can help the bone get stronger by providing it with the biomaterial before hand, while stimulating surrounding cells to heal
  • Chitosan(CTS) — A natural polymer, this biomaterial has been long considered as one of the most attractive natural polymers for bone tissue engineering owing to its structural similarity to the glycosaminoglycan (play a crucial role in the cell signaling process, including regulation of cell growth, proliferation, promotion of cell adhesion, and wound repair) found in bone, biocompatibility, biodegradability and excellent mechanical properties.
  • Ultrahigh molecular weight polyethylene oxide (UHMWPEO) — A synthetic polymer. The purpose of this is to help fiber form stronger and better. The solution is added after the HAp/CTS solution is finished.

Co-Precipitation

Diagram of co-precipitation method.
  • Mixing Solution — Start off with mixing the two solutions together which then form into the HAp nanoparticles. In this case the solutions are a CTS/H3PO4 solution mixed with a Ca(OH)2 solution.
  • Nucleation and Growth — After the solutions have been added, vigorous stirring occurs, followed by a period of ripening. This is when a crystal forms from the solution, in which a small number of ions, atoms, or molecules become arranged in a pattern characteristic of a crystalline solid, forming a site upon which additional particles are deposited as the crystal grows.
  • Agglomeration — The sites made by nucleation, are where the HAp nanoparticles come and group themselves at these sites to form larger crystal HAp particles
  • Precipitation — No, not rain. A precipitate is a substance separated from the solution usually as an insoluble amorphous or, in our case, a crystalline solid. The precipitate, containing the HAp nanoparticles, is separated from the solution
  • Filtration — Pretty self explanatory, but essentially the precipitate is washed with deionized water for several times to neutral pH levels
  • Calcination — The last step is when you heat the precipitate to high temperatures in air for the purpose of removing impurities or volatile substances.

Electrospinning

Diagram of how electrospinning works along with the main components.
  • As a simple overview, electrospinning is a technique in which charging liquid under high voltage leads to the interaction between the surface tension and electrostatic repulsion. This causes droplets on the spinneret needle to erupt and stretch
  • A standard system contains 4 main components: a spinner with a syringe pump, a metallic needle(spinneret), a high-voltage power supply, and a ground collector (see above image)
  • The strength of the electric field exceeds the surface tension of the droplet to produce a liquid jet that is then extended and whipped continuously by electrostatic repulsion until it is deposited on the grounded collector
  • The solvent evaporates in the process, and the jet is solidified to form into a fibrous membrane

So…Does it Work?

The Good

  • The conductive effect of the incorporated HAp nanoparticles stimulated a more significant level of bone cell formation ability when using the nanocomposite nanofibers of HAp/CTS scaffolds, owing to primarily the intrinsic osteoconductivity of HAp. The osteoconductivity has fundamentally been understood that HAp can absorb more proteins such as fibronectin and vitronectin, which will promote better binding with integrins (receptors that bind to the extracellular matrix).
  • In addition to cell proliferation, mineral deposits were found to be much higher on the HAp/CTS fibers as compared to normal cell growth (ie. no scaffold). As higher amount of mineral deposits implies a higher degree of differentiation of the cells, enhanced bone formation ability can therefore be expected from the electrospun HAp/CTS scaffolds.

The Bad

Conclusion

Key Points

  • Bone regeneration methods are slow and inefficient. They can be improved via nanotech and biological scaffolding
  • For a scaffold to be successful it must have 5 main properties — be biocompatible, biodegradable, mechanically strong, architecturally correct, and easily manufactured
  • These scaffolds can be made by combining various materials, the major groups being ceramics, natural polymers, and synthetic polymers
  • The proposed solution uses a hydroxyapatite/chitosan nanoparticle mixture as the solution, which is then turned into fibers, which is then shaped into the scaffold
  • The HAp/CTS nanocomposite is prepared using a co-precipitation method which allows for better dispersion of the particles, along with stronger groups of them
  • The solution is then prepared with PEO (a fiber-forming additive) and then electrospun into thin fibers over a long period of time to create a huge sheet of them
  • The fiber sheet can then be used to shape the desired scaffold size and implanted into the body
  • Overall the results prove that the idea would work, however there is one major issue — in the early stages the PEO inhibits the cell growth. To battle this an extraction of the PEO after the fiber sheet has been formed would be required

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