Abstract:The
ongoing research to improve the clinical outcome of titanium
implants has resulted in the implemetation of multiple approches to
deliver osteogenic growth factors accelerating and sustaining osseointegration.
Here we show the presentation of human bone morphogenetic protein
7 (BMP-7) adsorbed to titanium discs coated with poly(ethyl acrylate)
(PEA). We have previously shown that PEA promotes fibronectin organization
into nanonetworks exposing integrin- and growth-factor-binding domains,
allowing a synergis… Show more
“…This simple engineering approach exploits the synergistic presentation of BMP-2 on the FN material-driven networks, and was shown to drive significant bone regeneration in a critical size defect in vivo [ 130 ]. This system has also been used to coat titanium implants to present ultralow doses of BMP-7, with the aim to improve the bio-integration of titanium implants [ 143 ], and further to this, by tethering vascular endothelial growth factor (VEGF) improved vascularization of biomaterial scaffolds was achieved in vivo [ 144 ]. Figure 4.…”
Mesenchymal stem cells, characterized by their ability to differentiate into skeletal tissues and self-renew, hold great promise for both regenerative medicine and novel therapeutic discovery. However, their regenerative capacity is retained only when in contact with their specialized microenvironment, termed the stem cell niche. Niches provide structural and functional cues that are both biochemical and biophysical, stem cells integrate this complex array of signals with intrinsic regulatory networks to meet physiological demands. Although, some of these regulatory mechanisms remain poorly understood or difficult to harness with traditional culture systems. Biomaterial strategies are being developed that aim to recapitulate stem cell niches, by engineering microenvironments with physiological-like niche properties that aim to elucidate stem cell-regulatory mechanisms, and to harness their regenerative capacity in vitro. In the future, engineered niches will prove important tools for both regenerative medicine and therapeutic discoveries.
“…This simple engineering approach exploits the synergistic presentation of BMP-2 on the FN material-driven networks, and was shown to drive significant bone regeneration in a critical size defect in vivo [ 130 ]. This system has also been used to coat titanium implants to present ultralow doses of BMP-7, with the aim to improve the bio-integration of titanium implants [ 143 ], and further to this, by tethering vascular endothelial growth factor (VEGF) improved vascularization of biomaterial scaffolds was achieved in vivo [ 144 ]. Figure 4.…”
Mesenchymal stem cells, characterized by their ability to differentiate into skeletal tissues and self-renew, hold great promise for both regenerative medicine and novel therapeutic discovery. However, their regenerative capacity is retained only when in contact with their specialized microenvironment, termed the stem cell niche. Niches provide structural and functional cues that are both biochemical and biophysical, stem cells integrate this complex array of signals with intrinsic regulatory networks to meet physiological demands. Although, some of these regulatory mechanisms remain poorly understood or difficult to harness with traditional culture systems. Biomaterial strategies are being developed that aim to recapitulate stem cell niches, by engineering microenvironments with physiological-like niche properties that aim to elucidate stem cell-regulatory mechanisms, and to harness their regenerative capacity in vitro. In the future, engineered niches will prove important tools for both regenerative medicine and therapeutic discoveries.
“…Using DED technology, the characteristics of the surface can be controlled to create ideal porous surfaces with ideal pore size and maximum roughness [9,41]. In addition, adding an antibacterial and bioactive coating to the titanium surface increases the efficiency of osseointegration and prevents infection [42][43][44].…”
Direct energy deposition (DED) technology has gained increasing attention as a new implant surface technology that replicates the porous structure of natural bones facilitating osteoblast colonization and bone ingrowth. However, concerns have arisen over osteolysis or chronic inflammation that could be caused by Cobalt-chrome (CoCr) alloy and Titanium (Ti) nanoparticles produced during the fabrication process. Here, we evaluated whether a DED Ti-coated on CoCr alloy could improve osteoblast colonization and osseointegration in vitro and in vivo without causing any significant side effects. Three types of implant CoCr surfaces (smooth, sand-blasted and DED Ti-coated) were tested and compared. Three cell proliferation markers and six inflammatory cytokine markers were measured using SaOS2 osteoblast cells. Subsequently, X-ray and bone histomorphometric analyses were performed after implantation into rabbit femur. There were no differences between the DED group and positive control in cytokine assays. However, in the 5-bromo-2′-deoxyuridine (BrdU) assay the DED group exhibited even higher values than the positive control. For bone histomorphometry, DED was significantly superior within the 1000 µm bone area. The results suggest that DED Ti-coated metal printing does not affect the osteoblast viability or impair osseointegration in vitro and in vivo. Thus, this technology is biocompatible for coating the surfaces of cementless total knee arthroplasty (TKA) implants.
“…The bioreactor system has already been sent to a number of research labs, running successful experiments with minimal training from the authors here and using a variety of cultureware formats, as validated in this paper. In fact, the first clinical evaluation of surgical bone graft using mechanically stimulated MSCs, created with this bioreactor platform, and a 3D polycaprolactone (PCL) construct coated in layers of poly(ethyl acrylate) (PEA), fibronectin (FN) and growth factor BMP-2 41–43 is scheduled for 2020/21, funded by the landmine charity Find A Better Way 44 . As well as the cost-effective production of the system, there is also the possibility of substantial cost savings to be made by healthcare organisations when using the bioreactor to produce cellular bone graft material for surgery in orthopaedic patients.…”
In regenerative medicine, techniques which control stem cell lineage commitment are a rapidly expanding field of interest. Recently, nanoscale mechanical stimulation of mesenchymal stem cells (MSCs) has been shown to activate mechanotransduction pathways stimulating osteogenesis in 2D and 3D culture. This has the potential to revolutionise bone graft procedures by creating cellular graft material from autologous or allogeneic sources of MSCs without using chemical induction. With the increased interest in mechanical stimulation of cells and huge potential for clinical use, it is apparent that researchers and clinicians require a scalable bioreactor system that provides consistently reproducible results with a simple turnkey approach. A novel bioreactor system is presented that consists of: a bioreactor vibration plate, calibrated and optimised for nanometre vibrations at 1 kHz, a power supply unit, which supplies a 1 kHz sine wave signal necessary to generate approximately 30 nm of vibration amplitude, and custom 6-well cultureware with toroidal shaped magnets incorporated in the base of each well for conformal attachment to the bioreactor’s magnetic vibration plate. The cultureware and vibration plate were designed using finite element analysis to determine the modal and harmonic responses, and validated by interferometric measurement. This helps ensure that the vibration plate and cultureware, and thus collagen and MSCs, all move as a rigid body, avoiding large deformations close to the resonant frequency of the vibration plate and vibration damping beyond the resonance. Assessment of osteogenic protein expression was performed to confirm differentiation of MSCs after initial biological experiments with the system, as well as atomic force microscopy of the 3D gel constructs during vibrational stimulation to verify that strain hardening of the gel did not occur. This shows that cell differentiation was the result of the nanovibrational stimulation provided by the bioreactor alone, and that other cell differentiating factors, such as stiffening of the collagen gel, did not contribute.
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