S. Roberts, S. Hollenbeck, A. Chilkoti
inSoma Bio, Inc.,
United States
Keywords: elastin, soft tissue, reconstruction, intrinsically disordered, biomaterial, adipose
Summary:
The properties of natural biomaterials result from the collective effects of nanoscale interactions among ordered and disordered domains. Of particular interest in the last decade has been a growing understanding of the biological and mechanical importance of the interactions of disordered protein sequences. Intrinsically disordered proteins (IDPs) challenge the conventional paradigm that a protein's function is intrinsically linked to its specific structure. Unlike their structured counterparts, IDPs do not adopt a single, stable three-dimensional shape. Instead, they exist in a dynamic ensemble of conformations. This inherent flexibility and disorder enable IDPs to partake in a broad spectrum of functions and allows them to undergo conformational changes in response to various stimuli. Herein, we show that this flexibility and environmental response can be harnessed to allow de novo design of advanced protein-based materials for biomedical applications. Our Duke University-spinout, inSoma Bio Inc., is focused on the commercial development of a family of artificial IDPs that we call Fractomers that spontaneously form porous “fractal” networks reminiscent of native elastin when heated. Central to the innovation of Fractomers is their ability to transition from low viscosity liquids to solid networks at a sharp, tunable temperature. This ability can be exploited to created mechanically and thermodynamically stable scaffolds only after injection and exposure to body heat. By modulating concentration, molecular weight, and density of physically crosslinking, we can also control network pore sizes from 500 nm–20 μm, and mechanical stability, with elastic moduli (G’) ranging from 10 Pa to 500 kPa. Subcutaneous injections of Fractomer are exceptionally stable, forming depots that can be designed maintain shape and volume for up to one year. As Fractomers are derived from native elastin sequences, once injected they demonstrate rapid integration with surrounding tissue, allowing cell infiltration and local vascularization without local encapsulation or a harmful inflammatory response. Our core commercial development for Fractomers has focused on their ability to act as a moldable, stabilizing scaffold for autologous fat in reconstructive plastic surgery—particularly in post mastectomy and post-lumpectomy breast reconstruction where autologous fat, if properly stabilized, can provide an alternative to traditional implants and fillers. In pre-clinical models of this indication, Fractomer is able to double the effective volume of injected lipoaspirate, maintain adipose shape for over 6 months, and reduce incidence of detrimental fat necrosis by 50%. Looking beyond tissue scaffolding, Fractomer’s versatility can extend to controlled drug delivery systems where we have shown the ability to create stabilized microparticles and slow-release depots with unique architectures using mixtures of Fractomers with other IDPs. The development of Fractomers underscores the currently underutilized utility of functional disorder in protein biomaterial design, which offer a promising avenue for the creation of highly adaptable and responsive materials for biomedical applications.