Dynamic matrix composition in engineered cartilage with stochastic supplementation of growth factors

Abstract

Dynamic extracellular matrix (ECM) synthesis is explored in a hypothesized engineered cartilage construct. Growth (α) and decay (β) rate parameters are developed from a previous engineered cartilage model. The presented mathematical model was constructed from the parameterized experimental data using a deterministic and stochastic examination of ECM synthesis based on a negative feedback control mechanism. A growth factor supplementation is incorporated in a probabilistic mathematical approach. The growth factor component modified an initial deterministic model through a Gaussian white noise fluctuation. As the primary constituents of ECM, the mathematical tool is intended to characterize the probable steady state distribution of glycosaminoglycan (GAG) and collagen molecules as well as mean mass accumulation at homeostasis. Computer simulation of the models is applied to reported data from four similar chondrocyte-polymer construct culture systems. The range in rate ratios reflect the differing nature of GAG and collagen synthesis (α GAG /β GAG = 4.2 to 148.6; α collagen /β collagen = 8.1 to 2590.4). This technique reduced the influencing synthesis factors to a few key descriptive parameters. Additional anabolic and catabolic factors may further be built into the models.

A Distinct Catabolic to Anabolic Threshold Due to Single-Cell Static Nanomechanical Stimulation in a Cartilage Biokinetics Model

“…Our results clearly indicate that anabolic actions of different growth factors are essentially dose and time dependent [29,30]. These works have culminated in characterizing molecular regulatory mechanisms influencing both anabolic and catabolic processes, which maintain matrix homeostasis [31].…”

“…The parameters characterizing ECM structural molecule and proteoglycan dynamics were determined previously through a deterministic approach where kinetic rate ratios of synthesis per decay contribute to steady state levels of ECM accumulation [30]. The parameters associated with mechanical stress and strain within isolated cartilage cells were also derived from previous analyses.…”

Periodic Nanomechanical Stimulation in a Biokinetics Model Identifying Anabolic and Catabolic Pathways Associated With Cartilage Matrix Homeostasis

“…The parameters related to ECM structural molecules and proteoglycans were determined previously through a deterministic approach, where kinetic rate ratios of synthesis per decay contribute to steady state levels of ECM accumulation [20]. Experimental and theoretical stresses were based on a microfluidic environment designed for biological cell investigations [36], where stresses applied to a suspended cell range from 0.02 Pa to 0.04 Pa.…”

“…Identification of these two molecules and their roles is a significant advancement in cartilage biology; however, there is still limited knowledge as to how these molecules are functionally active. Based on a system biological approach, we have recently predicted that anabolic actions of different growth factors are essentially dose and time dependent [19, 20]. Extending that work to a system dynamics mechanistic model, results strongly indicate that a balanced network of anabolic and catabolic pathways emerges out of cytokine and growth factor interactions, which helps the ECM to reach homeostasis [21].…”

Biokinetic Mechanisms Linked With Musculoskeletal Health Disparities: Stochastic Models Applying Tikhonov’s Theorem to Biomolecule Homeostasis

“…Reported results suggest that excessive release of basic fibroblast growth factors (bFGFs) from the cartilage matrix during injury, excessive loading, or osteoarthritis could contribute to increased proliferation and reduced anabolic activities in articular cartilage [10,11]. Previous predictions based on system dynamics modeling suggest that articular cartilage matrix synthesis clearly indicate that anabolic actions of different growth factors are essentially dose and time dependent [12,13]. In addition, applied mechanical stresses play an important role in healthy cartilage maintenance [6,7,14].…”