While new biomaterials for regenerative therapies are being reported in the literature, clinical translation is slow. Some existing regenerative approaches rely on high doses of growth factors, such as bone morphogenetic protein‐2 (BMP‐2) in bone regeneration, which can cause serious side effects. An ultralow‐dose growth factor technology is described yielding high bioactivity based on a simple polymer, poly(ethyl acrylate) (PEA), and mechanisms to drive stem cell differentiation and bone regeneration in a critical‐sized murine defect model with translation to a clinical veterinary setting are reported. This material‐based technology triggers spontaneous fibronectin organization and stimulates growth factor signalling, enabling synergistic integrin and BMP‐2 receptor activation in mesenchymal stem cells. To translate this technology, plasma‐polymerized PEA is used on 2D and 3D substrates to enhance cell signalling in vitro, showing the complete healing of a critical‐sized bone injury in mice in vivo. Efficacy is demonstrated in a Münsterländer dog with a nonhealing humerus fracture, establishing the clinical translation of advanced ultralow‐dose growth factor treatment.
There is a pressing
clinical need to develop cell-based bone therapies
due to a lack of viable, autologous bone grafts and a growing demand
for bone grafts in musculoskeletal surgery. Such therapies can be
tissue engineered and cellular, such as osteoblasts, combined with
a material scaffold. Because mesenchymal stem cells (MSCs) are both
available and fast growing compared to mature osteoblasts, therapies
that utilize these progenitor cells are particularly promising. We
have developed a nanovibrational bioreactor that can convert MSCs
into bone-forming osteoblasts in two- and three-dimensional, but the
mechanisms involved in this osteoinduction process remain unclear.
Here, to elucidate this mechanism, we use increasing vibrational amplitude,
from 30 nm (N30) to 90 nm (N90) amplitudes at 1000 Hz and assess MSC
metabolite, gene, and protein changes. These approaches reveal that
dose-dependent changes occur in MSCs’ responses to increased
vibrational amplitude, particularly in adhesion and mechanosensitive
ion channel expression and that energetic metabolic pathways are activated,
leading to low-level reactive oxygen species (ROS) production and
to low-level inflammation as well as to ROS- and inflammation-balancing
pathways. These events are analogous to those that occur in the natural
bone-healing processes. We have also developed a tissue engineered
MSC-laden scaffold designed using cells’ mechanical memory,
driven by the stronger N90 stimulation. These mechanistic insights
and cell-scaffold design are underpinned by a process that is free
of inductive chemicals.
In the future it is envisaged that this technology may have beneficial therapeutic applications in the healthcare industry, for conditions whose overall phenotype maybe characterized by weak or damaged bones (e.g., osteoporosis and bone fractures), and which can benefit from having an increased number of osteoblastic cells in vivo.
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