September 2017 CÚRAM Researcher Publishes Papers in Top International Journals on Lab-grown 3D Stem Cells to Benefit Orthopaedics

Dr Manus Biggs, Investigator at CÚRAM, the Science Foundation Ireland Centre for Research in Medical Devices based at NUI Galway, has just published two separate research papers in top tier international journals, one in the Nature journal Nature Biomedical Engineering and another in the prestigious materials journal, Advanced Materials.

Both research papers by Dr Biggs describe advances made in the fields of biomaterials and engineered bioreactor systems to direct the differentiation of mesenchymal stem cells (MSCs), in the laboratory. Advances in stem cells, gene therapy, biomaterials, medical device technology, growth and differentiation factors, as well as biomimetic environments have created unique opportunities to fabricate tissues in the laboratory from combinations of engineered extracellular matrices (scaffolds), cells, and biologically relevant stimulation or cues.

In the study published in Nature Biomedical Engineering, the researchers from NUI Galway and University of Glasgow describe how they have used measurement technology, based on the sophisticated laser interferometer systems built for gravitational wave detection of astrophysical objects, to grow three-dimensional samples of mineralised bone in the laboratory for the first time. These 3D living bone grafts, when implanted into patients in the future, will be able to repair or replace damaged sections of bone.

Mesenchymal stem cells, which are naturally produced by the human body in bone marrow, have the potential to differentiate into a range of specialised cell types such as bone, cartilage, ligament, tendon and muscle. Using patients’ own mesenchymal cells means surgeons will be able to prevent the problem of rejection, and can bridge larger gaps in bone.

Dr Biggs describes his research into the stimulation of bone formation from stem cells using a nanovibrational bioreactor. This study, conducted in conjunction with Professor Matt Dalby, at the University of Glasgow, was focused on identifying the roles of high-frequency, low-amplitude mechanical stimulation in inducing mesenchymal stem cells to differentiate into bone cells (the process by which a cell becomes specialised in order to perform a specific function, as in the case of a bone cell).

“After blood, bone is the most transplanted tissue used in patients in the form of bone graft. Autologous graft (bone grafts taken from the patient’s own body and commonly employed for the treatments of bone cancer, trauma or infection) is in short supply and can be associated with pain and donor site morbidity. Tissue engineered bone-like graft would help meet this clinical demand as well as provide researchers with a potential tissue model for drug screening”, Dr Manus Biggs explains. 

Dr Biggs research showed for the first time, that high-frequency vibrations of nanoscale amplitude alone can be used to differentiate patient derived stem cells, to form mineralised tissue in 3D. To achieve this, Professor Dalby designed and developed a totally new genre of vibrational bioreactor (a bench-top cell conditioner, which constantly vibrates lab-grown cells). Using this bioreactor, Dr Biggs and the team from the University of Glasgow demonstrated that vibrations which produce tiny nanoscale deformations (1 millionth of a millimetre), to stem cells encapsulated in a collagen gel - a process termed “Nanokicking”  can induce these stem cells to become bone-like cells without any further conditioning. By doing this they have provided a scalable pathway to control the differentiation of stem cells to bone cells for the generation of lab-grown bone tissue.

In his second study published in Advanced Materials, Dr Biggs and his team collaborated with Professor Shalom Wind at Columbia University. Speaking about the study, Dr Biggs said: “Pervious studies indicate that stem cells can be easily persuaded to become bone-like cells when grown on a material which physically and chemically resembles bone tissue. In particular, substrates posessing a rigidity similar to that of bone have been shown to be favourable in inducing stem-cells to become bone cells in the lab. Although tissues can easlily be classified as rigid (bone tissue) or easily deformable (brain tissue), microscopically, tissues are comprised of a variety of micron and nanoscale elements (such as fibres, cells, crystals) with widely differing rigidity. In this way an individual cell carrying out its work in a specific tissue is subjected to many kinds of small structures, some of these small features are rigid, like the mineral deposits found in bone, while some of these features are very elastic such as neighbouring cells.”

Dr Biggs and his team investigated whether a fine beam of electrons could be used to alter the rigidity at discrete regions on a soft polymer, thereby enabling the development of a new class of 2D materials possessing patterned features of increased rigidity, ranging from the micron to the nanoscale level. Electron-beam patterning allows for the fabrication of devices with nanoscale features, and has been used extensively in the microelectronics industry for the production of integrated circuits or microchips. In this work, the team showed for the first time that a beam of electrons can significantly alter the rigidity of an elastic polymer.

The team then went on to investigate the response of human mesenchymal stem cells when grown on electron-beam patterned polymers, which posessed millions of ordered dots of increased rigidity. Interestingly it was observed that cells were able to perceive the tiny ‘rigid’ features beneath them and responded by changing their function – becomning more bone and cartillage like when grown in the lab.

Commenting on Dr Biggs success, Professor Abhay Pandit, Scientific Director of CÚRAM at NUI Galway, said: “This work will establish the groundwork for a new generation of biomimetic materials. Tissue engineering and regenerative medicine is a key area of research at CÚRAM with a goal of finding solutions to chronic health problems and addressing unmet medical need and the use of these technologies to develop clinically translatable reparative and regenerative approaches to chronic illnesses is a major goal.”

To read the Advanced Materials paper in full, visit: http://onlinelibrary.wiley.com/doi/10.1002/adma.201702119/full

To read the Nature Biomedical Engineering paper in full, visit: http://rdcu.be/vMwt

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