Quantitative analysis of exogenous IGF-1 administration of intervertebral disc through intradiscal injection
Introduction
The homoeostasis of the intervertebral disc (IVD) is regulated by a delicate balance between catabolic and anabolic cellular processes. Unbalanced metabolic activity leads to the degeneration of the IVD tissue (Masuda and An, 2004). Several growth factors are known to up-regulate the anabolic activity of disc cells (e.g., TGF-β, IGF, BMPs, etc.) (Masuda and An, 2004). In particular, it has been reported that IGF-1 stimulates the production of proteoglycans (PG) composing the extracellular matrix (ECM) of the IVD (Osada et al., 1996, Thompson et al., 1991). Therefore, the exogenous administration of IGF-1 has been proposed as a therapy for disc degeneration (Osada et al., 1996, Thompson et al., 1991). Since the response of IVD cells to IGF-1 stimulation is dose-dependent (Osada et al., 1996, Thompson et al., 1991), knowledge and control of the distribution of this molecule in the IVD is crucial for the success of the therapy. However, molecular transport in the IVD is very complex and involves a series of coupled mechano-electrochemical events. In particular, transport of IGF-1 is regulated by reversible binding reactions with binding sites (mainly IGFBP-3) present on the ECM of cartilaginous tissues (Bhakta et al., 2000, Garcia et al., 2003, Osada et al., 1996). In order to optimise the administration of IGF-1 for a successful therapy, analysing the complex molecular transport is necessary and requires the aid of a numerical tool.
Administration of IGF-1 has been shown to promote cell proliferation and ECM production (Osada et al., 1996; Pratsinis and Kletsas, 2007b), which in turn increases demand for nutrients. Thus, after injection, tissue regions infused by exogenous IGF-1 might require higher nutritional supply. Since the IVD is the largest avascular tissue in the body, increasing nutritional demand may further worsen the condition of malnutrition within the IVD, which could be detrimental to cell viability. The investigation on the effect of IGF-1 administration on nutritional supply would provide crucial information for optimising this therapeutic strategy for disc degeneration. Therefore, the objectives of this study were to develop a numerical model for quantitatively analysing exogenous administration of IGF-1 of the IVD via intradiscal injection and to test the following hypotheses:
- (1)
Binding reactions affect the effective volume of IGF-1 injection in the degenerated IVD by intradiscal injection;
- (2)
Intradiscal IGF-1 injection may not improve nutritional conditions in the degenerated IVD.
Section snippets
Theoretical model
The theoretical model developed in this study was based on the mechano-electrochemical mixture theory (Lai et al., 1991, Gu et al., 1998, Ateshian, 2007) and an extension of the theoretical framework reported in our previous study (Huang and Gu, 2008). The IVD tissue was considered as a mixture of an elastic, porous, permeable, negatively charged solid phase with IGF binding proteins, an interstitial fluid phase, and six solute phases (i.e., sodium and chloride ions, oxygen, glucose, lactate,
Finite element analysis
Human lumbar IVD was schematized as a 2D axisymmetric object consisting of two anatomical regions, the NP and the AF, with dimensions and properties similar to those reported in our previous study (Huang and Gu, 2008) (Fig. 1). All numerical simulations were performed on degenerated disc and the data were compared to those for healthy disc in some cases. The solute exchange area of the cartilaginous endplate (CEP) above the NP was 50% and 25% for healthy and degenerated discs, respectively(
Distribution of IGF-1 after intradiscal injection in degenerated discs
After injection of IGF-1 solution containing no glucose, lactate, or oxygen at the centre of NP region, IGF-1 transports through the IVD by diffusion and convention. The distribution of IGF-1 depended on the initial concentration of binding proteins (Fig. 2, Fig. 3). Compared to the IVD without binding proteins, IGF-1 spread slower in the IVD containing binding proteins after injection (Figs. 2a and 3a) since part of injected IGF-1 molecules were bound to binding proteins to form complexes (
Discussion
This study quantitatively analysed intradiscal IGF-1 injection and its effects on the distributions of pH, glucose, and lactate in the IVD. A finite element model, based on the mixture theory for charged hydrated soft tissues, was developed to describe the coupled convective, diffusive, and reactive IGF-1 transport in the disc. This study was the first to demonstrate the effects of binding reaction on distribution of IGF-1 after intradiscal IGF-1 injection and the influence of IGF-1 on
Conflict of interest statement
No financial support or benefits have been or will be received from any commercial source related directly or indirectly to the scientific work reported in this manuscript.
Acknowledgements
This study was supported by grants from NIH (AR050609, AR056101, and EB008653).
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