Delivery of osteoinductive factors such as bone morphogenetic protein 2 (BMP-2) has emerged as a prominent strategy to improve regeneration in bone grafting procedures. However, it remains challenging to identify a carrier that provides the requisite loading efficiency and release kinetics without compromising the mechanical properties of the bone graft. Previously, we reported on porous, polymerized high internal phase emulsion (polyHIPE) microspheres fabricated using controlled fluidics. Uniquely, this solvent-free method provides advantages over current microsphere fabrication strategies including in-line loading of growth factors to improve loading efficiency. In the current study, we utilized this platform to fabricate protein-loaded microspheres and investigated the effect of particle size (~400 vs ~800 μm) and pore size (~15 vs 30 μm) on release profiles. Although there was no significant effect of these variables on the substantial burst release profile of the microspheres, the incorporation of the protein-loaded microspheres within the injectable polyHIPE resulted in a sustained release of protein from the bulk scaffold over a two-week period with minimal burst release. Bioactivity retention of encapsulated BMP-2 was confirmed first using a genetically-modified osteoblast reporter cell line. A functional assay with human mesenchymal stem cells established that the BMP-2 release from microspheres induced osteogenic differentiation. Finally, microsphere incorporation had minimal effect on the cure and compressive properties of an injectable polyHIPE bone graft. Overall, this work demonstrates that these microsphere-polyHIPE composites have strong potential to enhance bone regeneration through controlled release of BMP-2 and other growth factors.

Re-entrant arrhythmias—the leading cause of sudden cardiac death—are caused by diseased and delayed myocardial conduction. Access to the coronary veins that cross the “culprit” scarred regions where re-entry originates provides improved pacing to prevent ventricular arrhythmias and circumvent the need for painful defibrillation, risky cardiac ablation, or toxic and often ineffective antiarrhythmic medications. To date, this goal has not been achieved due to the lack of pacing electrodes which are small or focal enough to navigate these tributaries. We have developed an injectable conductive hydrogel that can fill the epicardial coronary veins and their mid-myocardial tributaries. When connected to a standard pacing lead, these injected hydrogels can be converted into flexible electrodes that directly pace the previously inaccessible mid-myocardial tissue. In our two-component system, hydrogel precursor solutions can be injected through a dual lumen catheter in a minimally invasive deployment strategy to provide direct access to the diseased regions with relative precision and ease. Mixing of the two solutions upon injection into the vein activates redox-initiated crosslinking of the gel for rapid in situ cure without an external stimulus. An ex vivo porcine model was used to identify the requisite viscosity and cure rate for gel retention and homogeneity. Ionic species added to the hydrogel precursor solutions conferred conductivity above target myocardium values that was retained after implantation. Successful in vivo deployment demonstrated that the hydrogel electrode filled the anterior interventricular vein with extension into the septal (mid-myocardial) venous tributaries, far deeper than current technologies allow. In addition to successful capture and pacing of the porcine heart, analysis of surface ECG tracings revealed a novel pacing paradigm not observed in traditional single-point pacing: capture of extensive swaths of the native conduction system. This is the first report of an injectable electrode used to successfully pace the mid-myocardium and mimic physiologic conduction. As such, this injectable hydrogel electrode can be deployed to any region affected by prior myocardial infarction and consequent scar tissue to provide a reliable pacing modality that most closely resembles native conduction.Abstract FigureOne Sentence SummaryInjectable hydrogel electrodes achieve pacing that mimics physiologic conduction by capturing midmyocardial tissue.