A Microfluidic Platform to design crosslinked Hyaluronic Acid Nanoparticles (cHANPs) for enhanced MRI

Abstract

Recent advancements in imaging diagnostics have focused on the use of nanostructures that entrap Magnetic Resonance Imaging (MRI) Contrast Agents (CAs), without the need to chemically modify the clinically approved compounds. Nevertheless, the exploitation of microfluidic platforms for their controlled and continuous production is still missing. Here, a microfluidic platform is used to synthesize crosslinked Hyaluronic Acid NanoParticles (cHANPs) in which a clinically relevant MRI-CAs, gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA), is entrapped. This microfluidic process facilitates a high degree of control over particle synthesis, enabling the production of monodisperse particles as small as 35 nm. Furthermore, the interference of Gd-DTPA during polymer precipitation is overcome by finely tuning process parameters and leveraging the use of hydrophilic-lipophilic balance (HLB) of surfactants and pH conditions. For both production strategies proposed to design Gd-loaded cHANPs, a boosting of the relaxation rate T1 is observed since a T1 of 1562 is achieved with a 10 μM of Gd-loaded cHANPs while a similar value is reached with 100 μM of the relevant clinical Gd-DTPA in solution. The advanced microfluidic platform to synthesize intravascularly-injectable and completely biocompatible hydrogel nanoparticles entrapping clinically approved CAs enables the implementation of straightforward and scalable strategies in diagnostics and therapy applications.

A Microfluidic Platform to design Multimodal PEG - crosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications

“…In batch processes, the only driving force for reaction occurrence and group interaction is thermal motion. In a flow focusing regimen, the middle stream is squeezed by lateral flows to a width related to the flow rate ratio (FR 2 ), defined as the ratio between the volumetric flow rate of the solvent phase (middle channel) and the non-solvent phase (side channels) 41 . Thus, tuning the FR 2 , it is possible to reduce the τ mix of the components improving the probability of reaction occurrence 28 .…”

“…An efficient implementation of nanoprecipitation for particle production in microfluidics is the hydrodynamic flow focusing (HFF) regimen [39][40][41][42] . Indeed, as reported by Liu et al 38 the HFF can be used to improve different component mixing and to induce nanoprecipitation.…”

“…Starting from the evidence of the previous works related to the crosslinked Hyaluronic Acid NanoParticles (cHANPs) 41,48 we are proposing an innovative process based on HFF to obtain in a ONE-STEP process the crosslinking reaction between thiolated Hyaluronic Acid (HA-SH) and Polyethylene glycol-vinyl sulfone (PEG-VS producing pegylated cHANPs (PEG-cHANPs), to produce multimodal probes for diagnostic applications.…”

Current developments and applications of microfluidic technology toward clinical translation of nanomedicines

“…The precipitation of PLGA-b-PEG diblock copolymers has been controlled by a tunable mixing through 2D-HFF [27]. In addition to PLGA-b-PEG nanoparticles, poloxamer [113,114], hydrophobically modified chitosan [115], hyaluronic acid [116,117], poly-2-vinylpyridine-b-poly(ethylene oxide) [118], and alginate [119] nanoparticles have also been successfully prepared by the 2D-HFF. The poloxamer block-copolymer micelles were designed for the co-delivery of dexamethasone and ascorbyl-palmitate for the combined induction of osteogenic differentiation [120].…”

Microfluidics Mediated Production of Foams for Biomedical Applications

“…Scaffolds are obtained through solidification of these preformed liquid foams [36]. The ability to control biomaterial physico-chemical properties down to micrometer and nanometer scales [47] has opened new routes in biomedicine for cell transplantation [48], drug release [9,49], health monitoring [50][51][52], diagnostics [53], and therapeutic treatments in situ [54,55].…”