Growth factor delivery from hydrogel particle aggregates to promote tubular regeneration after acute kidney injury

Abstract

Local delivery of growth factors (GFs) can accelerate regeneration of injured tissue, but for many medical applications, injectable GF delivery systems are required for clinical success. Viscoelastic, injectable aggregates of micrometer-sized hydrogel particles made of multiarmed polyethylene glycol (starPEG) and heparin were prepared and tested for site-specific paracrine stimulation of tissue regeneration. Heparin was used as it binds, protects and releases numerous GFs. Hydrogel based delivery of basic fibroblast growth factor (bFGF) and murine epidermal growth factor (EGF) was monitored utilizing enzyme-linked immunosorbent assay (ELISA). bFGF was released slowly because of its high affinity to the heparin while the significantly higher release of the non-specific binding EGF was controlled by diffusion only. To investigate GF delivery in vivo, a hydrogel loaded with murine EGF or bFGF was injected subcapsularly into the left kidney of mice with experimental acute kidney injury caused by glycerol induced rhabdomyolysis. Visual examination confirmed sustained stability of the injected gel aggregates during the timescale of the experiment. The number of proliferating kidney tubular epithelial cells was quantified both in the injected kidney and the non-injected contralateral kidney. bFGF delivery from hydrogels induced a significant increase in cell proliferation in the injected kidney, although small effects were also seen in the non-injected kidney due to a systemic effect. EGF delivery strongly increased cell proliferation for both kidneys, but also showed a local effect on the injected kidney. The hydrogel without loaded GFs was used as a control and showed no increase in cell proliferation. Our results suggest that this novel starPEG-heparin hydrogel system can be an effective approach to deliver GFs locally.