First-time visitors to Asia are often surprised to see construction workers on modern buildings, even skyscrapers, climbing up flimsy-looking bamboo scaffolding. These traditional structures are not as ramshackle as they might appear. Bamboo poles are lighter, more flexible and cheaper to erect than Western-style metal scaffolding, though they are more likely to buckle in humid conditions. These days, the poles are usually secured with strong nylon straps for safety.
Researchers working with scaffolds at a far smaller scale are now exploring the use of similar hybrid structures, made using a combination of biological and synthetic elements. Three-dimensional scaffolds are often implanted or injected into the body as part of the process of tissue engineering. They have many uses: to target cancers with localised drugs, repair the effects of trauma or disease and maybe even to help regrow entire organs and bones.
Much of the miniature scaffolding in use today is purely natural in origin. Many commercially available scaffolds use material normally found in the human body, harvested from animals or human donors. Others have more exotic origins, such as spider webs, silk, algae, seaweed and the chitinous shells of crabs and shrimp.
Scaffolds made from these natural materials tend to have good “biocompatibility”—the ability to play well with the body’s own cells—and usually biodegrade gracefully when their work is done. But they have drawbacks, too. Biological materials vary from batch to batch, can be hard to obtain, may carry disease and can break down too quickly in the hot, moist environment inside the body.
Purely synthetic materials are not always a perfect alternative. True, they can be produced in volume and engineered to degrade at very consistent rates. But their limited ability to interact with living tissue is a mixed blessing. It minimises the risk of an immune response or cross-contamination, but synthetic materials are less good at encouraging the cell growth essential for successful implantation or healing. So tissue engineers have been pursuing a hybrid approach, developing new scaffolds that combine biological and synthetic aspects.
Consider an accidentally severed nerve in a hand, for example. Today, a small tube made from bovine collagen would be surgically attached to the nerve endings. Because the collagen tube resembles the body’s own nerve guides, cells will grow through and around it to rebuild the nerve gradually. Although the collagen guides are structurally weak and occasionally provoke an immune response, they are still preferable to tough polyester scaffolds that cannot support natural regeneration.
At the University of Washington in Seattle, a research group led by Miqin Zhang is weaving nanoscale nerve-guide scaffolds from a mixture of natural chitosan and an industrial polyester polymer, using a process called electrospinning. The raw materials are dissolved in solvents and placed into a syringe, the needle of which is attached to a high-voltage supply. Charged liquid is then expelled from the needle towards an earthed collector plate. Like a spark between a cloud and a lightning conductor, the liquid stretches out to the collector, and the molecules within it form into a solid but incredibly thin thread.
The resulting minuscule fibres accrete into a dense mesh whose texture is similar to that of the body’s own connective tissue. In laboratory tests, prototype nerve guides built from this nanomaterial sustained the growth of new neural cells, produced no immune reactions and were much stronger and more flexible than commercial collagen tubes. By adjusting the electrospinning process, the orientation of the nanofibres can be controlled to build scaffolds suitable for cultivating cells that need precise alignment, such as elongated muscle fibres and heart tissue.
Ms Zhang’s team is also combining natural and synthetic polymers for use in drug delivery. Some cancer drugs are extremely potent and will harm healthy cells if not applied carefully. Wrapping such drugs in a scaffold allows doctors to keep them close to a tumour and control their rate of release. One promising approach involves super-absorbent polymer scaffolds called hydrogels. These are jelly-like materials made up of a bundle of highly water-absorbent polymer chains. This makes them liquid enough to be injected, carrying a pharmaceutical payload with them. Both of her team’s composite biomaterials are now heading towards commercialisation.
Another approach to making hybrid scaffold materials is to convert a natural material into an artificial one while retaining its structure. Over 2m bone grafts are performed worldwide each year to replace bone lost to damage or disease. If only a small amount of bone is needed, it can often be harvested, painfully, from the patient’s own pelvis. When more bone is needed, donor bones can be used. But they are limited in supply and carry the risk of rejection or transmitting disease. Biologically inert metal bones are strong, but are a poor substitute for living bone and often require further surgical interventions.
Over the past few years attention has focused instead on calcium-based ceramics such as hydroxyapatite. These have a chemical composition close to that of natural bone and can encourage some regeneration. Hydroxyapatite is extremely brittle, however, and cannot sustain the stresses experienced by arms and legs. But researchers at the Institute of Science and Technology for Ceramics (ISTEC) in Faenza, Italy, noticed that some woods, in particular rattan, shared the complex porous structure of human bone, and were similarly strong and lightweight.
This inspired Simone Sprio and his colleagues at ISTEC to try to convert the cellulose of wood into something suitable for implantation. Their process starts by heating rattan in the absence of oxygen, preserving the wood’s structure while reducing its organic molecules to pure carbon. It is then infused with calcium, oxygen and phosphorous in a series of chemical steps, to create a hydroxyapatite scaffold with the same structure as the original wood. In tests using sheep, this novel scaffold was completely colonised by host bone cells in one month and new bone began to form.
Microscopic sites for sore eyes
A different “biomimetic” approach (in other words, inspired by nature) is to engineer a material from scratch to have characteristics found in natural materials. Tissue engineers in Britain are doing just that to treat corneal scarring, a painful eye condition that affects millions of people, particularly in the developing world. When the cornea, the transparent front part of the eye, is damaged seriously enough to wipe out its resident repair team of limbal stem cells, scarring and blindness can result.
The most successful existing treatment involves extracting limbal stem cells from a healthy eye, cultivating them on human amniotic membrane (harvested from human placentas) and then surgically grafting this to the damaged eye. But this requires a well-stocked tissue bank and a biological clean room, both of which are in short supply in many developing countries. And the implants are often rejected: the long-term success rate for this operation is less than 50% after three years.
Sheila MacNeil, a professor of tissue engineering at the University of Sheffield, wondered whether this was due to damage to tiny niches in the cornea where limbal stem cells are thought to reside. Without these refuges, colourfully known as the palisades of Vogt, the transplanted stem cells could not survive. Ms MacNeil and her colleagues created a scaffold that incorporates artificial palisades of Vogt by building up an electrospun polymer called PGLA, commonly used in dissolvable sutures, on a carefully designed template created using a form of 3D printing called micro-stereolithography.
“Biological materials vary from batch to batch, can carry disease and may break down too quickly”
The resulting structure provides a welcoming environment for stem cells, some of which are placed into the scaffold, which is immediately implanted, thus avoiding the need for a sterile clean room. The hope is that the polymer scaffold will biodegrade in the eye slowly enough for the stem cells to find a permanent home. The first test in human patients is planned in collaboration with the LV Prasad Eye Institute in Hyderabad, India, later this year.
Designing for biocompatibility does not have to mean slavish biomimicry, however. Healionics, a start-up based in Seattle and Wallonia, Belgium, has developed a material called STAR that stimulates the body’s natural immune defences to occupy it. When dense objects such as implants or medical devices are implanted in the body, they provoke a reaction that usually encapsulates them in dense scar tissue. This can be dangerous, isolating bacteria within the encapsulated region from infection-busting white blood cells.
Andrew Marshall, Healionics’ chief technology officer, speculated that a scaffold with pores large enough to permit macrophages (the largest white blood cells, over 20 microns wide) to pursue bacteria (typically 2 microns wide) would reduce encapsulation and sepsis. He experimented with tissue scaffolds made by fusing billions of tiny acrylic spheres, filling the gaps with silicone, then dissolving the spheres, leaving just the silicone structure behind. By altering the size of the spheres, he could control the dimensions of the pores. In tests in mice, Mr Marshall found that pores of 25-40 microns (about half the diameter of a human hair) resulted in the formation of about twice as many blood vessels.
When white blood cells encounter the STAR material, instead of kick-starting inflammation and scarring, they make themselves at home in the highly porous structure. They then send out chemical signals that cause capillary blood vessels to grow into the material, creating a permanent hybrid scaffold within days. The result is much less scarring, and an encapsulated region into which macrophages can travel. Through its Belgian spin-out, iSTAR Medical, Healionics recently launched its first product, a small device that is implanted into the eye to treat glaucoma. One benefit of Healionics’ approach is that its innovations are structural rather than chemical. Because silicone is widely used and well understood, obtaining regulatory approval was relatively simple, says Mr Marshall.
Many of the scaffolds that have already been commercialised for wound repair, bone grafts and surgical aids are comparatively simple. Moving to the next generation of scaffolds for the delivery of drugs, cells and eventually genes will require extensive safety testing and lengthy clinical trials. But Robert Langer of the Massachusetts Institute of Technology, who pioneered modern tissue engineering in the 1980s, says he is confident that the industry will ultimately deliver. Hybrid scaffolding, in which man-made and biological elements work together, could then become as widespread on the insides of human bodies as it is on the outsides of Asian buildings.