Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications

Abstract

Basic fibroblast growth factor (FGF)-2 has been shown to regulate many cellular functions including cell proliferation, migration, and differentiation, as well as angiogenesis in a variety of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve. These multiple functions make FGF-2 an attractive component for wound healing and tissue engineering constructs; however, the stability of FGF-2 is widely accepted to be a major concern for the development of useful medicinal products. Many approaches have been reported in the literature for preserving the biological activity of FGF-2 in aqueous solutions. Most of these efforts were directed at sustaining FGF-2 activity for cell culture research, with a smaller number of studies seeking to develop sustained release formulations of FGF-2 for tissue engineering applications. The stabilisation approaches may be classified into the broad classes of ionic interaction modification with excipients, chemical modification, and physical adsorption and encapsulation with carrier materials. This review discusses the underlying causes of FGF-2 instability and provides an overview of the approaches reported in the literature for stabilising FGF-2 that may be relevant for clinical applications. Although efforts have been made to stabilise FGF-2 for both in vitro and in vivo applications with varying degrees of success, the lack of comprehensive published stability data for the final FGF-2 products represents a substantial gap in the current knowledge, which has to be addressed before viable products for wider tissue engineering applications can be developed to meet regulatory authorisation.

Storable bFGF-Releasing Membrane Allowing Continuous Human iPSC Culture

“…A similar phenomenon was reported in our previous study [ 18 ]. The increased bFGF concentration in the presence of iPSCs was likely caused by autocrine bFGF [ 26 ] and/or bFGF-stabilizing molecules (such as heparin [ 9 , 13 , 17 ]) from iPSCs. Extracellular matrix components and other biomolecules from iPSCs may also increase the residual bFGF concentration through nonspecific adsorption onto the well surface, which reduces bFGF adsorption.…”

“…It is well-known that lyoprotectants and cryoprotectants can protect proteins during freeze-drying and freeze-thawing processes, respectively [ 19 ]. For bFGF, molecules such as sucrose, lactose, mannitol, glucose, polyethylene glycol, and glucose have been reported as effective lyoprotectants/cryoprotectants [ 13 , 25 ]. It is also known that certain types of molecules such as heparin, similar glucosaminoglycans, and heparin-like synthetic polymers can stabilize bFGF by binding to the heparin-binding site of bFGF [ 13 , 17 ].…”

“…For bFGF, molecules such as sucrose, lactose, mannitol, glucose, polyethylene glycol, and glucose have been reported as effective lyoprotectants/cryoprotectants [ 13 , 25 ]. It is also known that certain types of molecules such as heparin, similar glucosaminoglycans, and heparin-like synthetic polymers can stabilize bFGF by binding to the heparin-binding site of bFGF [ 13 , 17 ]. Conventional bFGF-releasing materials often contain these additives to ensure their sustained bFGF release.…”

“…These supplements allow sustained release of bFGF in a culture medium of human iPSCs, thereby reducing the frequency of medium refreshment to a biweekly basis. Not only for stem cell maintenance but also for therapeutic and tissue engineering applications, a variety of bFGF-releasing materials have been developed [ 13 , 14 , 15 , 16 ]. However, many conventional bFGF-releasing materials consist of degradable components and often contain additives such as heparin (a well-known bFGF stabilizer [ 9 , 13 , 17 ]) or similar molecules, which may leach into the culture media and affect stem cells directly or indirectly.…”

Potential aggregation hot spots in recombinant human keratinocyte growth factor; a computational study

“…using different stabilizers (heparin), osmolytes (like trehalose and sucrose) and salts (like ammonium sulfate, and sodium chloride) applied for KGF [12] and other FGFs [36] may be implemented for in vitro applications, but in vivo applications are limited to the naturally occurring solution environment. For the latter, aggregation management can be obtained by designing aggregation-resistant variants.…”