A Fast pH‐Switchable and Self‐Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Abstract

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model. yield a further rise in mortality and morbidity. [ 1 ] New strategies are aiming at the prevention of the progression of postmyocardial infarction toward heart failure. Catheter-based drug delivery injection approaches [ 2 , 3 ] are substantially less invasive than for example surgical implantation of in vitro engineered tissues, [ 4 ] patches, [ 5 , 6 ] or drug delivery carriers. [ 7 ] Therefore, catheter-injection strategies are the method of choice with regard to clinical applicability. State-of-the-art is the NOGA catheter that enables precise control over the injection location via a special mapping system. [ 8 ] A 3D electromechanical image of the myocardium can be obtained using an ultralow magnetic-fi eld energy source and a sensor-tipped catheter to locate the catheter position. This mapping allows for the accurate identifi cation of normal and infarcted myocardium, and in this way, enables excellent spatial control over the injection of drugs. Generally, the injected drugs are substantially fast removed from the pulsatile heart when not delivered via a solid or gelated carrier material. Therefore, the

Biomaterial‐Enhanced Cell and Drug Delivery: Lessons Learned in the Cardiac Field and Future Perspectives

“…At four week follow up, treated animals showed areas of viable myocardium suggesting that more favourable myocardial remodelling may have occurred in these animals. (129) These Multimodal approaches show particular promise for myocardial regeneration.…”

pH‐Responsive Drug‐Delivery Systems

“…Basak et al [7] prepared hydrogels of poly(vinyl alcohol) by crosslinking with maleic acid; they found that the swelling of the hydrogels was highest in intestinal fluid (pH 7.5) and lowest in simulated gastric fluid (pH 1.2); hydrogels loaded with vitamin B12 and salicylic acid exhibited colon-specific drug release behavior with a higher drug release in intestinal fluid (pH 7.5) than that in simulated gastric fluid (pH 1.2). Bastings et al [8] reported a pH-switchable supramolecular hydrogel by using fourfold hydrogen-bonding supramolecular ureidopyrimidinone (UPy) units coupled with alkyl urea spacers to poly(ethylene glycol) (PEG) chains. These UPy-modified PEG hydrogels formed fibers in aqueous solution that could cross-link to form transient supramolecular networks, and these unique UPy-transient networks were pH-responsive, which enabled a sol-to-gel switch in a subtle pH range.…”

Supramolecular hydrogels cross-linked by preassembled host–guest PEG cross-linkers resist excessive, ultrafast, and non-resting cyclic compression

“…Liu et al employed Hbond and dipole-dipole interactions to enhance the mechanical strength and fatigue resistance of physical hydrogels 11,12 . Meijer et al fabricated tough supramolecular hydrogels cross-linked by the H-bonds between selfcomplementary UPy units 13,14 . Scherman et al demonstrated the fabrication of supramolecular cross-linked hydrogels by the host-guest interactions of cucurbit [n] uril complexes [15][16][17] .…”