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The extracellular environment controls many cellular activities thereby linking external material cues to internal cell function. By better understanding these processes, synthetic extracellular material niches can be tailored to present cells with highly regulated physical and/or chemical cues that promote or suppress selected cell functions. Here, poly(ethylene glycol) (PEG) hydrogels were functionalized with fluvastatin-releasing grafts and growth factor binding heparin domains to enable the dynamic exchange of information between the material and cells from the outside-in and inside-out (i.e., bidirectional signaling). By incorporating a fluvastatin-releasing graft and carefully controlling the dose and temporal release, materials were designed to promote bone morphogenic protein (BMP2) and alkaline phosphatase (ALP) production by human mesenchymal stem cells (hMSCs). When the release of fluvastatin was controlled to occur over 2 weeks, BMP2 and ALP production was increased 2.2-fold and 1.7-fold, respectively, at day 28 compared to hMSCs cultured in the absence of fluvastatin. By introducing a heparin functionality into the gel to sequester and localize the hMSC-produced BMP2, the osteogenic differentiation of hMSCs was further augmented over fluvastatin delivery alone. Osteopontin and core binding factor α1 gene expression was 6-fold and 4-fold greater for hMSCs exposed to fluvastatin in the presence of the heparin functionalities, respectively. These results demonstrate how multifunctional gels that interact with cells in a bidirectional manner can efficiently promote selected cell functions, such as the osteogenic differentiation of hMSCs.

On-lattice kinetic Monte Carlo (KMC) simulations have extensively been applied to numerous systems. However, their applicability is severely limited to relatively short time and length scales. Recently, the coarse-grained MC (CGMC) method was introduced to greatly expand the reach of the lattice KMC technique. Herein, we extend the previous spatial CGMC methods to multicomponent species and/or site types. The underlying theory is derived and numerical examples are presented to demonstrate the method. Furthermore, we introduce the concept of homogenization at the stochastic level over all site types of a spatially coarse-grained cell. Homogenization provides a novel coarsening of the number of processes, an important aspect for complex problems plagued by the existence of numerous microscopic processes (combinatorial complexity). As expected, the homogenized CGMC method outperforms the traditional KMC method on computational cost while retaining good accuracy.

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BackgroundAn adaptive coarse-grained (kinetic) Monte Carlo (ACGMC) simulation framework is applied to reaction and diffusion dynamics in inhomogeneous domains. The presented model is relevant to the diffusion and dimerization dynamics of epidermal growth factor receptor (EGFR) in the presence of plasma membrane heterogeneity and specifically receptor clustering. We perform simulations representing EGFR cluster dissipation in heterogeneous plasma membranes consisting of higher density clusters of receptors surrounded by low population areas using the ACGMC method. We further investigate the effect of key parameters on the cluster lifetime.ResultsCoarse-graining of dimerization, rather than of diffusion, may lead to computational error. It is shown that the ACGMC method is an effective technique to minimize error in diffusion-reaction processes and is superior to the microscopic kinetic Monte Carlo simulation in terms of computational cost while retaining accuracy. The low computational cost enables sensitivity analysis calculations. Sensitivity analysis indicates that it may be possible to retain clusters of receptors over the time scale of minutes under suitable conditions and the cluster lifetime may depend on both receptor density and cluster size.ConclusionsThe ACGMC method is an ideal platform to resolve large length and time scales in heterogeneous biological systems well beyond the plasma membrane and the EGFR system studied here. Our results demonstrate that cluster size must be considered in conjunction with receptor density, as they synergistically affect EGFR cluster lifetime. Further, the cluster lifetime being of the order of several seconds suggests that any mechanisms responsible for EGFR aggregation must operate on shorter timescales (at most a fraction of a second), to overcome dissipation and produce stable clusters observed experimentally.