Abstract
We produced low-molecular-weight heparin/protamine micro (nano) particles (LMW-H/P MPs·NPs) as a carrier for heparin-binding growth factors (GFs), such as fibroblast growth factor (FGF)-2 and various GFs in platelet-rich plasma (PRP). A mixture of LMW-H (MW: approximately 5000 Da, 6.4 mg/ml) and protamine (MW: approximately 3000 Da, 10 mg/ml) at a ratio of 7:3 (vol:vol) yields a dispersion of micro (nano) particles (200 nm - 3 µm in diameter). The diluted LMW-H solution in saline (0.32 mg/ml) mixed with diluted protamine (0.5 mg/ml) at a ratio at 7:3 (vol:vol) resulted in soluble nanoparticles (approximately 100 nm in diameter). The generated NPs could be then stabilized by adding 2 mg/ml dextran (MW: 178-217 kDa) and remained soluble after lyophilization of dialyzed LMW-H /P NPs solution. The LMW-H/P MPs·NPs adsorb GFs, control their release, protect GFs and activate their biological activities. Furthermore, administration of GFs-containing F/P MPs·NPs exhibited significantly higher inductions of vascularization and fibrous tissue formation in vivo than GFs alone. LMW-H/P MPs·NPs can also efficiently bind to tissue culture plates and retain the binding of GFs. The LMW-H/P MPs·NP-coated matrix with various GFs or cytokines provided novel biomaterials that could control cellular activity such as proliferation and differentiation. Thus, LMW-H/P MPs·NPs are an excellent carrier for GFs and are a functional coating matrix for various kinds of cell cultures.
Highlights
Polyelectrolyte complexes (PECs) are produced by electrostatic interactions between oppositely charged polyelectrolytes
We described on the LMW-H/P MPs·NPs which we originally prepared as PECs, its characterizations and its potential medical applications as carriers for growth factors (GFs) such as fibroblast growth factor (FGF)-2 and GFs in platelet-rich plasma (PRP)
We demonstrated that recombinant hematopoietic cell growth factors (HCGFs) such as SCF, Tpo, and Flt-3 were immobilized onto LMW-H/P MPs·NPs-coated plates, and the immobilized cytokines were stabilized, were activated, and were gradually released into the medium
Summary
Polyelectrolyte complexes (PECs) are produced by electrostatic interactions between oppositely charged polyelectrolytes. LMW-H/P MPs·NPs are bound to FGF-2 and other various heparin-binding growth factors (GFs) in platelet-rich plasma (PRP) [10] through interaction between LMW-H molecules in LMWH/P MPs·NPs and those GFs. LMW-H/P MPs·NPs are able to protect those GFs from heat and proteolytic inactivation and to enhance those biological activities. We prepared water-insoluble micro (nano) particles (200 nm - 3 μm in diameter) by mixing LMW-H (6.4 mg/ml) with protamine (10 mg/ml) at a ratio of 7:3 (vol:vol), and reported the ability of the resulting injectable low-molecular-weight heparin/protamine micro (nano) particles (LMW-H/P MPs·NPs) to protect FGF-2 activity (see Figure 1) [8,9]. Because of the use of autologous materials, this method using PRP-containing LMW-H/P MPs·NPs is simpler, cheaper, and has no side effect compared with conventional methods
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