While industry is assessing the potential of advanced manufacturing techniques, the medical sector is already using them, making items precisely tailored to a patient’s body. Dental implants and most hearing-aid earpieces are made by additive-layer manufacturing, while bone prostheses are built and adapted using advanced techniques.
But additive manufacturing is on the verge of breaking into a more startling area. Using the techniques of 3D printing, doctors may soon be able to produce soft-tissue implants such as blood vessels. And following on from that could be the ability to build a whole organ - such as a liver or kidney - complete with all its blood vessels. Additive manufacturing could make the transplant list a thing of the past.
The first ’3D bio-printer’ for making human tissue and organs became available at the end of last year. Produced for a San Diego biotechnology company, Organovo, by Australian automation specialist Invetech, the machine is being evaluated by research institutions studying regenerative medicine - the technique of growing organs using cultures of a patient’s own cells.
The bio-printer is based on research by a group led by Prof Gabor Forgacs at the University of Missouri. It combines two separate disciplines: the layer-by-layer building of solid objects through a printing-related technology; and the still mysterious ability of proteins and other biological materials to organise and self-assemble into complex structures.
Forgacs’ work, which formed the basis for the prototype of the bio-printer, centred around building simple cylinders of living cells, analogous to blood vessels. The printer has two heads, one that prints biopaper - a biocompatible water-based gel, such as collagen, gelatine or hyaluronic acid - and the other bioink, made up of aggregates of 60,000-80,000 cells.
The bioink contains many different cell types - endothelial cells, which form the lining of blood vessels; smooth muscle cells, which make vessels expand and contract; and fibroblasts, the cells that form the tough connective tissue of the vessel’s skin. To make these into the ink aggregates, they are treated like a sausage: packed into tube, extruded and chopped into bits. The separate bits then spontaneously round up into spheres and are transferred into a printing cartridge.
The printer then works in two stages. The first part of the printing head deposits a sheet of biopaper gel onto a printing surface, then the second part prints a circle of bioink spheres onto that. The surface is moved down and the printing head returns for a second pass, depositing another sheet of biopaper and a circle of bioink on top of the first. The sequence continues until a stack of sheets has been built, supporting a cylinder of bioink blobs.
It is here that nature takes over. The cell soup of the bioink blobs begins to reorganise itself. The endothelial cells migrate to the inner edge of the cylinder, the smooth muscle cells move to the middle, and the fibroblasts take up position on the outside. The cells then self-assemble and fuse to form the structure of a blood vessel.
Forgacs admits he’s baffled by this. ’I’m still fascinated by the fact they know what to do,’ he said. While he can manipulate the positions of the cell aggregates, he can’t reproduce their function.
“Researchers can form adjacent layers of epithelial and stromal soft tissue that grow into a mature tooth”
However, the research that produced this effect is now forming the basis for the bio-printer. This takes Forgacs’ work and combines it with industrial automation to increase its flexibility, allowing it to make different types of structures. This is why Organovo - which Forgacs co-founded - turned to Invetech. The company operates in the medical industry, producing medical devices, diagnostics and clean-room technologies. ’We selected Invetech because of its capabilities for sophisticated engineering and automation, cultural fit as a long-term partner and its consideration towards protecting Organovo’s IP,’ explained Keith Murphy, Organovo’s chief executive. ’It has good processes for product development and project management, and it was apparent that project evaluation would be handled well.’
The printer is housed in the unprepossessing metal and glass box of a standard sterile biosafety cabinet. It contains two print heads, one for biopaper and the other for bioink; the capillary tip of the print heads, which places the cells, is a high-precision part connected to a laser-based calibration system to allow it to place cells with a precision within a few microns.
The software controlling the print heads has been designed so that the operators can design the tissue construct easily within three dimensions. Although the machines will initially only be used to build relatively simple stretches of tissue - such as skin, muscle fibres and small sections of blood vessels - this software will allow scientists and eventually surgeons or a new breed of medical engineers to design a complicated network of branched tubes, such as the scaffolding of blood vessels that supports a whole organ.
“Ultimately, the idea is for surgeons to have tissue on demand for various uses.”
Keith Murphy, Organovo
’Scientists and engineers can use the bio-printer to enable placing cells of almost any type into a desired pattern in 3D,’ Murphy added.
Researchers can place liver cells on a pre-formed scaffold, support kidney cells with a co-printed scaffold, or form adjacent layers of epithelial and stromal soft tissue that grow into a mature tooth.’
Organovo’s first machines, which cost $200,000 (£138,000), are destined for research laboratories. However, Murphy hopes that in a few years they will be used to produce materials for surgery; arterial grafts for heart surgery, which have a relatively simple structure, are likely to be the first. Currently, biocompatible polymers are used for these grafts, but these can cause blood clots. ’Ultimately, the idea would be for surgeons to have tissue on demand for various uses, and the best way to do that is to get a number of bioprinters into the hands of researchers and give them the ability to make 3D tissues,’ Murphy said.
in depth bio-printers
A bio-printer under development aims to make skin for burn victims
Organovo’s system is unlikely to be a lone entrant into the bio-printer market. Anthony Atala, of the Wake Forest Institute for Regenerative Medicine in North Carolina, is also working on a system that can print new skin directly onto burns, making it suitable for use in war zones.
Atala has already grown organs by seeding cells onto a cast polymer scaffold; his team has produced bladders, skin and erectile tissue. But bioprinting allows the scaffold to be eliminated and speeds up the process from six weeks to almost instantly.
The new system, still in an early experimental phase, starts with a laser scanner that maps the wound, producing a 3D map of the topography and shape of the burned area. The print head then sprays cells onto the wound, using the laser map to determine which type of cells should be deposited into which parts of the area, and the appropriate cell thickness.
Atala’s team has been conducting animal studies and has achieved promising results; burns treated with the skin printer heal about two weeks faster than those treated conventionally. There are also indications that skin printing is less painful than grafting.
The research aims to identify the best type of cell for the system. Options include: using a patient’s own cells; establishing a skin-cell bank; or using stem cells, which would transform into the appropriate cell-type once in place.
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