In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2

Ribeiro, Filomena; Gómez‐Benito, María José; Folgado, João; Fernandes, Paulo R.; García-Aznar, J.M.

doi:10.1371/journal.pone.0127722

Cited by 47 publications

(43 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The apparent retention of BMP-2 was estimated from the measured release over time and expressed as a percentage of the total BMP-2 loaded [40]. BMP-2 release/retention kinetics have previously been represented using exponential decay [11, 40, 42]. Accordingly, BMP-2 retention data for each sample was fit to an exponential decay function, and the rate of decay λ was estimated [40].…”

Section: Methodsmentioning

confidence: 99%

Delivery vehicle effects on bone regeneration and heterotopic ossification induced by high dose BMP-2

et al. 2017

View full text Add to dashboard Cite

Bone morphogenetic protein-2 (BMP-2), delivered on absorbable collagen sponge, is frequently used to treat bone defects. However, supraphysiological BMP-2 doses are common and often associated with complications such as heterotopic ossification and inflammation, causing pain and impaired mobility. This has prompted investigations into strategies to spatially control bone regeneration, for example growth factor delivery in appropriate scaffolds. Our objective was to investigate the spatiotemporal effects of high dose BMP-2 on bone regeneration as a function of the delivery vehicle. We hypothesized that an alginate delivery system would spatially restrict bone formation compared to a collagen sponge delivery system. In vitro, BMP-2 release was accelerated from collagen sponge compared to alginate constructs. In vivo, bone regeneration was evaluated over 12 weeks in critically sized rat femoral segmental defects treated with 30 μg rhBMP-2 in alginate hydrogel or collagen sponge, surrounded by perforated nanofiber meshes. Total bone volume, calculated from micro-CT reconstructions, was higher in the alginate group at 12 weeks. Though bone volume within the central defect region was greater in the alginate group at 8 and 12 weeks, heterotopic bone volume was similar between groups. Likewise, mechanical properties from ex vivo torsional testing were comparable between groups. Histology corroborated these findings and revealed heterotopic mineralization at 2 weeks post-surgery in both groups. Overall, this study recapitulated the heterotopic ossification associated with high dose BMP-2 delivery, and demonstrated that the amount and spatial pattern of bone formation was dependent on the delivery matrix.

show abstract

Section: Methodsmentioning

confidence: 99%

Delivery vehicle effects on bone regeneration and heterotopic ossification induced by high dose BMP-2

et al. 2017

View full text Add to dashboard Cite

show abstract

“…On the other hand, simulations of the initial bone healing phases, such as inflammation, granulation tissue formation, and callus development have not been frequently modeled (Isaksson et al, 2007, Gómez-Benito et al, 2005a, Ribeiro et al, 2015). This may be partly due to mechanical factors playing a lessor role in this phase, while biological and chemical factors are much more significant (Pivonka and Dunstan, 2012, Claes et al, 2012).…”

Section: Steps Of Healing Included In Simulationmentioning

confidence: 99%

“…uniform or peripheral seeding) (Checa and Prendergast, 2010), type of growth factors (i.e. chondrogenic growth factors such as BMP-2/4 or osteogenic growth factor such as TGF-β1) (Geris et al, 2008, BailÓN-Plaza and Van Der Meulen, 2001, Bailón-Plaza and van der Meulen, 2003, Ribeiro et al, 2015, Geris et al, 2006), release duration (BailÓN-Plaza and Van Der Meulen, 2001, Bailón-Plaza and van der Meulen, 2003), scaffold implantation (Ribeiro et al, 2015, Checa and Prendergast, 2010), or mechanical loading effects (Geris et al, 2010a, Checa and Prendergast, 2010). …”

Section: Clinical Applicationmentioning

confidence: 99%

Bone fracture healing in mechanobiological modeling: A review of principles and methods

et al. 2017

View full text Add to dashboard Cite

Bone fracture is a very common body injury. The healing process is physiologically complex, involving both biological and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis, and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade, bone healing simulation and modeling has been employed to understand its details and mechanisms, to investigate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and the most recent work in bone healing simulations with an emphasis on both biological and mechanical properties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general mechanisms), biological modeling (considering only the biological factors and processes), and mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we evaluate different components and clinical applications of bone healing simulation such as mechanical stimuli, phases of bone healing, and angiogenesis.

show abstract

“…In this study area, finite element modeling (FEM) simulation can be a fundamental tool to predict the appropriate microenvironment formulation, to achieve an effective biochemical signal delivery within the scaffold per unit volume along all the cultivation time, both static than dynamic. Indeed, a great variety of mathematical tools have been developed for modeling 3D bioengineered scaffolds, in terms of both cellular behavior and their response to growth factors (Gómez‐Benito, García‐Aznar, Kuiper, & Doblaré, ; Ribeiro, Gomez‐Benito, Folgado, Fernandes, & Garçia‐Aznar, ). However, despite several FEM modeling approaches, proposed in the recent literature, for the prediction of nutrients and oxygen mass transfer (Curcio et al, ; Ye, Dasa, Triffitt, & Cui, ), a FEM simulation within 3D bioengineered scaffold with microcarriers for the growth factor controlled delivery study was never described.…”

Section: Introductionmentioning

confidence: 99%

Growth factor sustained delivery from poly‐lactic‐co‐glycolic acid microcarriers and its mass transfer modeling by finite element in a dynamic and static three‐dimensional environment bioengineered with stem cells

Trucillo

Bisceglia

Valdrè

et al. 2019

Biotech & Bioengineering

View full text Add to dashboard Cite

Poly-lactic-co-glycolic acid (PLGA) microcarriers (0.8 ± 0.2 μm) have been fabricated with a load of 20 μg/g PLGA by an emulsion-based-proprietary technology to sustained deliver human bone morphogenetic protein 2 (hBMP2), a growth factor largely used for osteogenic induction. hBMP2 release profile, measured in vitro, showed a moderate "burst" release of 20% of the load in first 3 days, followed by a sustained release of 3% of the load along the following 21 days. PLGA microbeads loaded with fluorescent marker (8 mg/g PLGA ) and hydroxyapatite (30 mg/g PLGA ) were also fabricated and successfully dispersed within three-dimensional (3D) alginate scaffold (Ca-alginate 2% wt/wt) in a range between 50 and 200 mg/cm 3 ; the presence of microcarriers within the scaffold induced a variation of its stiffness between 0.03 and 0.06 MPa; whereas the scaffold surface area was monitored always in the range of 190-200 m 2 /g. Uniform microcarriers dispersion was obtained up to 200 mg/cm 3 ;higher loading values in the 3D scaffold produced large aggregates. The release data and the surface area were, then, used to simulate by finite element modeling the hBMP2 mass transfer within the 3D hydrogel bioengineered with stem cells, in dynamic and static cultivations. The simulation was developed with COMSOL Multiphysics ® giving a good representation of hBMP2 mass balances along microbeads (bulk eroded) and on cell surface (cell binding). hBMP2 degradation rate was also taken into account in the simulations. hBMP2 concentration of 20 ng/cm 3 was set as a target because it has been described as the minimum effective value for stem cells stimulation versus the osteogenic phenotype. The sensitivity analysis suggested the best microbeads/cells ratio in the 3D microenvironment, along 21 days of cultivations in both static and dynamic cultivation (perfusion) conditions. The simulated formulation was so assembled experimentally using human mesenchymal stem cells and an improved scaffold stiffness up to 0.09 MPa (n = 3; p ≤ 0.01) was monitored after 21 days of cultivation; moreover a uniform extracellular matrix deposition within the 3D system was detected by Von Kossa staining, especially in dynamic

show abstract

In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2

Cited by 47 publications

References 104 publications

Delivery vehicle effects on bone regeneration and heterotopic ossification induced by high dose BMP-2

Delivery vehicle effects on bone regeneration and heterotopic ossification induced by high dose BMP-2

Bone fracture healing in mechanobiological modeling: A review of principles and methods

Growth factor sustained delivery from poly‐lactic‐co‐glycolic acid microcarriers and its mass transfer modeling by finite element in a dynamic and static three‐dimensional environment bioengineered with stem cells

Contact Info

Product

Resources

About