Tunable bifunctional silyl ether cross-linkers for the design of acid-sensitive biomaterials

Abstract

Responsive polymeric biomaterials can be triggered to degrade using localized environments found in vivo. A limited number of biomaterials provide precise control over the rate of degradation and the release rate of entrapped cargo and yield a material that is intrinsically nontoxic. In this work, we designed nontoxic acid-sensitive biomaterials based on silyl ether chemistry. A host of silyl ether cross-linkers were synthesized and molded into relevant medical devices, including Trojan horse particles, sutures, and stents. The resulting devices were engineered to degrade under acidic conditions known to exist in tumor tissue, inflammatory tissue, and diseased cells. The implementation of silyl ether chemistry gave precise control over the rate of degradation and afforded devices that could degrade over the course of hours, days, weeks, or months, depending upon the steric bulk around the silicon atom. These novel materials could be useful for numerous biomedical applications, including drug delivery, tissue repair, and general surgery.

Figure 1

Scanning electron micrographs of 5 μm cubes (1A, 1B) and 3 μm hexnut particles (1C, 1D) fabricated using PRINT. (Scale bar: 10 μm)

Figure 2

Percent rhodamine-B release verses time for 5 μm cube particles fabricated from (A) DMS, (B) DES, and (C) DTS cross-linkers.

Figure 3

Transmission electron micrographs of PRINT hexnut particles incubated in HeLa cells. Rapidly degrading hexnut particles fabricated from the DMS crosslinker (A, scale bar: 10 μm and B–F, scale bar: 0.5 μm), and non-degrading hexnut particles fabricated from the DTS crosslinker (G–H, scale bar: 0.5 μm).

Figure 4

Confocal laser scanning micrographs of HeLa cells incubated with rapidly degrading hexnut particles (green) and non-degrading hexnut particle (red). Micrographs highlight the phases of particle degradation: swelling (a), fragmentation (b), and complete degradation (c). The non-degradable particles showed no change when exposed to intracellular conditions (d) (scale bar: 10 μm).

Figure 5

Cell viability assay (CellTiter-Glo^®) of hexnut particles fabricated from DMS, DES, DIS and DTS crosslinkers. The assay was performed using HeLa (A) and SKOV3 (B).

Figure 6. Biomedical devices fabricated from silyl ether crosslinkers

A, A silyl ether suture fabricated from DMS and rhodamine-B was degraded in media buffered at pH 7.4 and pH 5.0 (scale bar: 1 cm). B, Silyl ether stents fabricated from compounds 1, 2, 3 and 4 (from left to right). Each stent was placed in a medium buffered at pH 5.0 and allowed to degrade (scale bar: 1 cm).

Scheme 1

Synthesis of bifunctional silyl ether (BSE) cross-linkers.