Optimal conditions for slow passive release of heparin-binding growth factors from an affinity-based delivery system

TL;DR

This paper develops a simplified mathematical model to optimize the slow passive release of heparin-binding growth factors from an affinity-based delivery system, validated with experimental data and identifying key parameters for controlled release.

Contribution

It introduces a reduced two-equation model that predicts conditions for slow growth factor release and explains the two-stage release behavior observed experimentally.

Findings

Slow release occurs when peptide concentration exceeds the dissociation constant.

Heparin concentration must be much higher than its dissociation constant from the growth factor.

The model matches experimental release profiles, explaining initial rapid and subsequent slow release stages.

Abstract

We consider a mathematical model that describes the release of heparin-binding growth factors from an affinity-based delivery system. In the delivery system, heparin binds to a peptide which has been covalently cross-linked to a fibrin matrix. Growth factor in turn binds to the heparin, and growth factor release is governed by both binding and diffusion mechanisms, the purpose of the binding being to slow growth factor release. The governing mathematical model, which in its original formulation consists of five partial differential equations, is reduced to a system of just two equations. We identify the governing non-dimensional parameters that can be varied to tune the growth factor release rate. In particular, we identify a parameter regime that ensures slow passive release (usually desirable) of at least a fraction of the growth factor. It is found that slow release is assured if the matrix is prepared with the concentration of cross-linked peptide greatly exceeding the dissociation constant of heparin from the peptide, and with the concentration of heparin greatly exceeding the dissociation constant of the growth factor from heparin. Also, for the first time, in vitro experimental release data is directly compared with theoretical release profiles generated by the model. We propose that the two stage release behaviour frequently seen in experiments is due to an initial rapid out-diffusion of free growth factor over a diffusion time scale (typically days), followed by a much slower release of the bound fraction over a time scale depending on both diffusion and binding parameters (frequently months).