Red blood cell-mimicking synthetic biomaterial particles

Abstract

Biomaterials form the basis of current and future biomedical technologies. They are routinely used to design therapeutic carriers, such as nanoparticles, for applications in drug delivery. Current strategies for synthesizing drug delivery carriers are based either on discovery of materials or development of fabrication methods. While synthetic carriers have brought upon numerous advances in drug delivery, they fail to match the sophistication exhibited by innate biological entities. In particular, red blood cells (RBCs), the most ubiquitous cell type in the human blood, constitute highly specialized entities with unique shape, size, mechanical flexibility, and material composition, all of which are optimized for extraordinary biological performance. Inspired by this natural example, we synthesized particles that mimic the key structural and functional features of RBCs. Similar to their natural counterparts, RBC-mimicking particles described here possess the ability to carry oxygen and flow through capillaries smaller than their own diameter. Further, they can also encapsulate drugs and imaging agents. These particles provide a paradigm for the design of drug delivery and imaging carriers, because they combine the functionality of natural RBCs with the broad applicability and versatility of synthetic drug delivery particles.

Fig. 1.

Synthesis technique of RBC-mimicking particles. (A) RBC-shaped particles prepared from hollow PS template. Complementary layers of proteins and polyelectrolytes were deposited by LbL technique on the template surface followed by cross-linking of the layers to increase stability. PS core was dissolved to yield RBC-shaped particles, which can be loaded with therapeutic and imaging agents. (B) Biocompatible RBC-mimicking particles prepared from PLGA template particles. PLGA RBC-shaped templates were synthesized by incubating spheres synthesized from electrohydrodynamic jetting in 2-propanol. LbL coating on template, protein cross-linking, and dissolution of template core yielded biocompatible sRBCs.

Fig. 2.

SEM micrographs of RBC-mimicking particles synthesized using hollow PS template particles. (A) BSA/PAH was deposited on template particles by LbL technique, and the layers were cross-linked. Particles were exposed to THF to yield sRBCs. Inset shows close up. (B) Hb/PSS-based sRBCs prepared by LbL technique. (C) sRBCs prepared by adsorption of Hb on template particles. (Scale bars, 1 μm.) (Inset, 500 nm.)

Fig. 3.

SEM images of biocompatible sRBCs. (A) RBC-shaped PLGA templates fabricated by electrohydrodynamic jetting. (B) Biocompatible sRBCs prepared from PLGA template particles by LbL deposition of PAH/BSA and subsequent dissolution of the polymer core. (C) Cross-linked mouse RBCs. sRBCs demonstrate striking resemblance to the natural counterparts. Insets show close up images. (Scale bars, 5 μm.) (Insets, 2 μm.)

Fig. 4.

Mechanical properties of sRBCs measured using AFM. (A) Comparison of elastic modulus of sRBCs with mouse RBCs and PLGA particles (*, P < 0.001, n = 5). (B) sRBCs (7 ± 2 μm) flowing through glass capillary (5-μm inner diameter). The image also shows a particle outside the capillary. (Scale bar, 5 μm.)

Fig. 5.

Biomedical applications of sRBCs. (A) Oxygen carrying capacity of sRBCs demonstrated based on the chemiluminescence reaction of luminol. Cross-linking and exposure to the organic solvent reduces the oxygen carrying capacity, but coating the sRBCs with uncross-linked Hb increased the oxygen-binding capacity to levels comparable to mouse blood (S-RBC, t = 0). Ninety percent of oxygen carrying capacity was retained after 1 week (S-RBC, t = 1 wk). BSA-coated particles were included as negative control (*, P < 0.01, n = 3). (B) Controlled release of radiolabeled heparin from sRBCs over a period of 10 days (n = 5). (C) TEM micrograph showing encapsulation of 30 nm iron oxide nanoparticles in RBC-shaped PLGA templates. The Inset shows PLGA particles loaded with iron oxide nanoparticles before conversion into RBC-like templates. (Scale bars, 1 μm.)