Materials
bone tissue) are an everyday occurrence in hospitals. But they do have their disadvantages, not least the risk of infection, blood loss and nerve damage. The “holy grail” in the field of artificial bone material is a composite that demonstrates an internal architecture capable of fully integrating with natural bone, while also stimulating the healing process as efficiently as an autologous graft. After decades of innovation in the fields of biochemistry and bioengineering, along with the assistance of 3D printing and computer aided design technology, that holy grail may soon be within reach. In order to reach this outcome and produce the formation of new bone – a process known as osteogenesis – a material must overcome two obstacles. It needs to be able to stimulate the body to attract, proliferate and differentiate mesenchymal stem cells or immature bone cells into osteoblasts to form healthy bone tissue (osteoinduction); and it needs a suitable scaffold for new bone to regrow (osteoconduction). Materials used in bone replacement fall into two categories: inorganic ceramics and organic synthesised polymers – both of which have different roles. Biologically inert ceramics have star quality in helping build scaffolding for new bone formation. On the other hand, synthetic polymers like poly methyl acrylate, polyethyl acrylate (PEA) and polycaprolactone – a tough biodegradable, semicrystalline and hydrophobic polyester with biocompatibility – stimulate new bone structure using stem cells and growth factors cultivated three dimensionally.
The University of Glasgow has a long tradition in bone research and Manuel Salmeron-Sanchez, the chair of its Centre for the Cellular Microenvironment, says it’s a challenge designing a material that is both osteinductive and osteoconductive. “Ceramics are fine for osteoconducting bone, but they lack the bioactivity to generate bone formation,” he says. “They cannot properly differentiate stem cells into osteoblasts.” At the Centre, Salmeron-Sanchez has been developing a material that is both osteoinductive and osteoconductive. “In our lab, we have been able to combine synthetic material with the activity provided by growth factor by using a combination of PEA, fibronectin (FN) and bone morphogenetic protein 2 (BMP-2),” he explains. “Fibronectin is an adhesive glycoprotein that is crucial for tissue repair and for regulating cell motility and also in embryogenesis. BMP-2 is associated with the genetic coding mechanism and cell differentiation for bone and cartilage.”
Good vibrations
Perhaps the most fascinating part of the process is the use of nanovibrational stimulation technology (NST) on the three-dimensional culture of PEA FN and BMP-
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2. Centred on the apparent ability of cells to react in their microenvironment through mechano- transduction systems, studies have shown that the growth and differentiation of stem cells can be controlled by NST – even in the absence of biochemical stimuli such as growth factors. “We find that low levels of BMP-2 bound to PEA+FN to allow local presentation of BMP-2 in a way that is highly bioactive yet does not compromise safety,” explains Salmeron-Sanchez. “Local BMP-2 triggers stem cells in the bone marrow to differentiate into osteoblasts, it is the trigger of the process of bone formation, and we’ve shown that it leads to bone regeneration. The late Adam Curtis, emeritus professor of cell biology at the University of Glasgow, first suggested the idea that nanovibration might kick-start activity at the cellular level, and it has been shown to be true in vitro.”
An illustration of the steps involved in osteogenesis.
“Our method has the potential to radically change current practice, reducing patient suffering and ultimately saving lives. It paves the way for numerous opportunities that could prove transformational.”
Kristopher Kilian
Original attempts were on 2D-layered culture plates and focused on vibrating single petri dishes with cells growing in monolayers. Rapid advances have given access to 3D skeletal tissue engineering that are bumped by the so-called “nanokick”. However, the vibration of culture plates and 3D hydrogels may in theory seem a simple task, but achieving consistent vibration transmission is problematic because creating the devices for inducing nanovibrations is a huge technical challenge. A whole sector of engineering design has evolved to deliver “good vibrations”. Experiments under vibrational conditions of an amplitude of 25μm and frequencies of 20–60Hz have been tried in pursuit of
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