A Cohesive Shear-Thinning Biomaterial for Catheter-Based Minimally Invasive Therapeutics

Abstract

Shear-thinning hydrogels are suitable biomaterials for catheter-based minimally invasive therapies; however, the tradeoff between injectability and mechanical integrity has limited their applications, particularly at high external shear stress such as that during endovascular procedures. Extensive molecular crosslinking often results in stiff, hard-to-inject hydrogels that may block catheters, whereas weak crosslinking renders hydrogels mechanically weak and susceptible to shear-induced fragmentation. Thus, controlling molecular interactions is necessary to improve the cohesion of catheter-deployable hydrogels. To address this material design challenge, we have developed an easily injectable, nonhemolytic, and noncytotoxic shear-thinning hydrogel with significantly enhanced cohesion via controlling noncovalent interactions. We show that enhancing the electrostatic interactions between weakly bound biopolymers (gelatin) and nanoparticles (silicate nanoplatelets) using a highly charged polycation at an optimum concentration increases cohesion without compromising injectability, whereas introducing excessive charge to the system leads to phase separation and loss of function. The cohesive biomaterial is successfully injected with a neuroendovascular catheter and retained without fragmentation in patient-derived three-dimensionally printed cerebral aneurysm models under a physiologically relevant pulsatile fluid flow, which would otherwise be impossible using the noncohesive hydrogel counterpart. This work sheds light on how charge-driven molecular and colloidal interactions in shear-thinning physical hydrogels improve cohesion, enabling complex minimally invasive procedures under flow, which may open new opportunities for developing the next generation of injectable biomaterials.

Sodium Phytate‐Incorporated Gelatin‐Silicate Nanoplatelet Composites for Enhanced Cohesion and Hemostatic Function of Shear‐Thinning Biomaterials

“…In the high strain regime after the breaking point, however, re‐association of the electrostatic network is postponed due to Phyt slowing down or disrupting the “house of cards” formation of SNs (because of Phyt blocking positive edges of SNs), which explains the accelerated softening of Phyt‐incorporated STBs post‐breaking point. This behavior renders higher shear‐stress sensitivity of STBs, which is in agreement with our previously published work [ 20 ] and can facilitate their injection while enhancing hydrogel cohesion.…”

Injectable Shear‐Thinning Hydrogels with Sclerosing and Matrix Metalloproteinase Modulatory Properties for the Treatment of Vascular Malformations

“…STB‐DOX 0.5% and STB‐DOX 1% were considerably softer than Gel‐SN at larger strain amplitudes (Figure 2D; Figure S1B, Supporting Information), which corresponds to lower loads for injection (injection force ≈7 N for STB‐DOX 0.5). [ 16 ] The amount of SN was optimized (4.5% w/w) based on higher storage moduli and higher cohesiveness with easier injection force. Increasing the amount of SN to 6% w/w increased the viscosity and storage moduli but also considerably increased the injection force and subsequently blocked the catheters (Figure S1C,D, Supporting Information).…”

“…Injectability is a fundamental requirement for the minimally invasive application of embolic agents. [13,14,16] STBs are appealing because they soften when shear-inducing injection forces are applied, making them easier to flow and for surgeons to inject. [17] The experimental setup depicted in Figure 2E was utilized to characterize the injectability of hydrogels.…”

Recent Progress in Advanced Hydrogel‐Based Embolic Agents: From Rational Design Strategies to Improved Endovascular Embolization

“…[171] Owing to these properties, the STBs are attracting considerable attention as a group of embolic agents that are easy to apply and suitable for treating various shape/size of vascular lesions. [172,173] Once they are injected into the target blood vessels, the viscosity of STB drops as a result of the decreased shear stress between the vicious fluids and the transcatheter lumen. Upon elimination of the shear stress with the STB entering the blood vessels, the viscosity of STB increases sharply and the materials return to solid-like gels to achieve endovascular embolization.…”

“…The physical and biological performance of STB, such as the mechanical strength, shear-thinning behavior, and hemostatic properties, are always adjusted by incorporation of functional nanomaterials to meet various clinical requirements. [172,174,175] Recently, Avery et al developed STB as an endovascular embolic agent, which is a nanocomposite hydrogel comprised of porcine gelatin and synthetic silicate nanoplatelets (Figure 13A). The developed STB demonstrated excellent injectability through a clinical catheter (Figure 13B).…”