Design of a Coupled Thermoresponsive Hydrogel and Robotic System for Postinfarct Biomaterial Injection Therapy

Abstract

Background In preclinical testing, ventricular wall injection of hydrogels has been shown to be effective in modulating ventricular remodeling and preserving cardiac function. For some approaches, early-stage clinical trials are under way. The hydrogel delivery method varies, with minimally invasive approaches being preferred. Endocardial injections carry a risk of hydrogel regurgitation into the circulation, and precise injection patterning is a challenge. An epicardial approach with a thermally gelling hydrogel through the subxiphoid pathway overcomes these disadvantages. Methods A relatively stiff, thermally responsive, injectable hydrogel based on N-isopropylacrylamide and N-vinylpyrrolidone (VP gel) was synthesized and characterized. VP gel thermal behavior was tuned to couple with a transepicardial injection robot, incorporating a cooling feature to achieve injectability. Ventricular wall injections of the optimized VP gel have been performed ex vivo and on beating porcine hearts. Results Thermal transition temperature, viscosity, and gelling time for the VP gel were manipulated by altering N-vinylpyrrolidone content. The target parameters for cooling in the robotic system were chosen by thermal modeling to support smooth, repeated injections on an ex vivo heart. Injections at predefined locations and depth were confirmed in an infarcted porcine model. Conclusions A coupled thermoresponsive hydrogel and robotic injection system incorporating a temperature-controlled injectate line was capable of targeted injections and amenable to use with a subxiphoid transepicardial approach for hydrogel injection after myocardial infarction. The confirmation of precise location and depth injections would facilitate a patient-specific planning strategy to optimize injection patterning to maximize the mechanical benefits of hydrogel placement.

Ventricular wall biomaterial injection therapy after myocardial infarction: Advances in material design, mechanistic insight and early clinical experiences

“…Cooled by a fluid sheath around the catheter, the hydrogel was kept in the liquid phase prior to the injections. Four injections in the planned square layout were made, as shown by photoacoustic imaging (Figure 10D, E) [107]. The HeartLander delivery system was considered suitable for a wide variety of injectable biomaterials.…”

“…Zhu et al increased the hydrophilicity of a polyNIPAAm-based hydrogel by incorporating a higher percentage of N-vinylpyrrolidone monomer in the polymer backbone, obtaining a low viscosity, slower gelling version. While the relatively hydrophobic hydrogel formed isolated masses in the myocardium, higher hydrophilicity allowed the hydrogel to diffuse through the tissue before gelling [107]. …”

“…(E) Match between pattern of injected hydrogel with planned injection sites. (F) Injected hydrogel in LV myocardium (arrow: hydrogel) [107]. …”

Tailoring Gelation Mechanisms for Advanced Hydrogel Applications

“…Furthermore, deep-tissue injection of thermoresponsive materials can still result in premature gelation and catheter obstruction. [190] The use of remote triggers, such as light or ultrasound, may be able to overcome some of the drawbacks associated with component mixing and thermal gelation. In this context, the choice of gelation trigger depends on the target location within the body.…”

Physiological motion modeling for organ‐mounted robots

“…Numerous interventions are possible using these devices, shown in Figure , including cell transplantation, gene therapy for angiogenesis, intrapericardial drug delivery, epicardial electrode placement for resynchronization, epicardial atrial ablation, and ventricle‐to‐coronary artery bypass (VCAB) . Interventions already demonstrated preclinically with these robots include myocardial injection, epicardial pacing, and epicardial ablation…”