Griffiths, Leigh G

Current clinically used electronic implants, including cardiac pacing leads for epicardial monitoring and stimulation of the heart, rely on surgical suturing or direct insertion of electrodes to the heart tissue. These approaches can cause tissue trauma during the implantation and retrieval of the pacing leads, with the potential for bleeding, tissue damage, and device failure. Here, we report a bioadhesive pacing lead that can directly interface with cardiac tissue through physical and covalent interactions to support minimally invasive adhesive implantation and gentle on-demand removal of the device with a detachment solution. We developed 3D-printable bioadhesive materials for customized fabrication of the device by graft-polymerizing polyacrylic acid on hydrophilic polyurethane and mixing with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) to obtain electrical conductivity. The bioadhesive construct exhibited mechanical properties similar to cardiac tissue and strong tissue adhesion, supporting stable electrical interfacing. Infusion of a detachment solution to cleave physical and covalent cross-links between the adhesive interface and the tissue allowed retrieval of the bioadhesive pacing leads in rat and porcine models without apparent tissue damage. Continuous and reliable cardiac monitoring and pacing of rodent and porcine hearts were demonstrated for 2 weeks with consistent capture threshold and sensing amplitude, in contrast to a commercially available alternative. Pacing and continuous telemetric monitoring were achieved in a porcine model. These findings may offer a promising platform for adhesive bioelectronic devices for cardiac monitoring and treatment.

Abstract Whole organ tissue engineering encompasses a variety of approaches, including 3D printed tissues, cell-based self-assembly, and cellular incorporation into synthetic or xenogeneic extracellular matrix (ECM) scaffolds. This review article addresses the importance of whole organ tissue engineering for various solid organ applications, focusing on the use of extracellular (ECM) matrix scaffolds in such engineering endeavors. In this work, we focus on the emerging barriers to translation of ECM scaffold-based tissue-engineered organs and highlight potential solutions to overcome the primary challenges in the field. The 3 main factors that are essential for developing ECM scaffold-based whole organs are (1) recapitulation of a functional vascular tree, (2) delivery and orientation of cells into parenchymal void spaces left vacant in the scaffold during the antigen elimination and associated cellular removal processes, and (3) driving differentiation of delivered cells toward the appropriate site-specific lineage. The insights discussed in this review will allow the potential of allogeneic or xenogeneic ECM scaffolds to be fully maximized for future whole organ tissue-engineering efforts.

Surgical sealing and repair of injured and resected gastrointestinal (GI) organs are critical requirements for successful treatment and tissue healing. Despite being the standard of care, hand-sewn closure of GI defects using sutures faces limitations and challenges. In this work, we introduce an off-the-shelf bioadhesive GI patch capable of atraumatic, rapid, robust, and sutureless repair of GI defects. The GI patch integrates a nonadhesive top layer and a dry, bioadhesive bottom layer, resulting in a thin, flexible, transparent, and ready-to-use patch with tissue-matching mechanical properties. The rapid, robust, and sutureless sealing capability of the GI patch is systematically characterized using ex vivo porcine GI organ models. In vitro and in vivo rat models are used to evaluate the biocompatibility and degradability of the GI patch in comparison to commercially available tissue adhesives (Coseal and Histoacryl). To validate the GI patch’s efficacy, we demonstrate successful sutureless in vivo sealing and healing of GI defects in rat colon, stomach, and small intestine as well as in porcine colon injury models. The proposed GI patch provides a promising alternative to suture for repair of GI defects and offers potential clinical opportunities for the repair of other organs.

Currently, despite the success of percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) remains among the most commonly performed cardiac surgical procedures in the United States. Unfortunately, the use of autologous grafts in CABG presents a major clinical challenge as complications due to autologous vessel harvest and limited vessel availability pose a significant setback in the success rate of CABG surgeries. Acellular extracellular matrix (ECM) scaffolds derived from xenogeneic vascular tissues have the potential to overcome these challenges, as they offer unlimited availability and sufficient length to serve as “off-the-shelf” CABGs. Unfortunately, regardless of numerous efforts to produce a fully functional small diameter xenogeneic ECM scaffold, the combination of factors required to overcome all failure mechanisms in a single graft remains elusive. This article covers the major failure mechanisms of current xenogeneic small diameter vessel ECM scaffolds, and reviews the recent advances in the field to overcome these failure mechanisms and ultimately develop a small diameter ECM xenogeneic scaffold for CABG. Impact Statement Currently, the use of autologous vessel in coronary artery bypass graft (CABG) is common practice. However, the use of autologous tissue poses significant complications due to tissue harvest and limited availability. Developing an alternative vessel for use in CABG can potentially increase the success rate of CABG surgery by eliminating complications related to the use of autologous vessel. However, this development has been hindered by an array of failure mechanisms that currently have not been overcome. This article describes the currently identified failure mechanisms of small diameter vascular xenogeneic extracellular matrix scaffolds and reviews current research targeted to overcoming these failure mechanisms toward ensuring long-term graft patency.

PurposeThis case‐control retrospective discovery study is to identify antigenic bovine pericardium (BP) proteins that stimulate graft‐specific humoral immune response in patients implanted with glutaraldehyde fixed bovine pericardial (GFBP) heart valves.Experimental designBanked serum is collected from age‐ and sex‐matched patients who received either a GFBP or mechanical heart valve replacement. Serum IgG is isolated and used to generate poly‐polyclonal antibody affinity chromatography columns from each patient. Native and deglycosylated BP protein extracts are separately added to individual patient affinity chromatography columns, with unbound proteins washed through the column. Proteins captured in the affinity chromatography columns are submitted for proteomic identification. Differences between GFBP and mechanical heart valve replacement recipients are analyzed with Gaussian linearized modeling.ResultsCarbohydrate antigens overwhelm protein capture in the column, requiring BP protein deglycosylation prior to affinity chromatography. Nineteen BP protein antigens, which stimulated graft‐specific IgG production, are identified in patients who received GFBP valve replacements. Identified antigens are significantly over‐represented for calcium‐binding proteins.Conclusions and clinical relevancePatients implanted with GFBP valves develop a graft‐specific humoral immune response toward BP protein antigens, with 19 specific antigens identified in this work. The molecular functions of over‐represented antigens, specifically calcium‐binding proteins, may aid in understanding the underlying factors that contribute to structural valve deterioration.

New techniques able to monitor the maturation of tissue engineered constructs over time are needed for a more efficient control of developmental parameters. Here, a label‐free fluorescence lifetime imaging (FLIm) approach implemented through a single fiber‐optic interface is reported for nondestructive in situ assessment of vascular biomaterials. Recellularization processes of antigen removed bovine pericardium scaffolds with endothelial cells and mesenchymal stem cells were evaluated on the serous and the fibrous sides of the scaffolds, 2 distinct extracellular matrix niches, over the course of a 7 day culture period. Results indicated that fluorescence lifetime successfully report cell presence resolved from extracellular matrix fluorescence. The recellularization process was more rapid on the serous side than on the fibrous side for both cell types, and endothelial cells expanded faster than mesenchymal stem cells on antigen‐removed bovine pericardium. Fiber‐based FLIm has the potential to become a nondestructive tool for the assessment of tissue maturation by allowing in situ imaging of intraluminal vascular biomaterials.

Significance Cardiac arrhythmias often occur in heart failure (HF) patients, but drug therapies using selective ion channel blockers have failed clinical trials and effective drug therapies remain elusive. Here we systematically study the major ionic currents during the cardiac action potential (AP) and arrhythmogenic Ca 2+ release in postinfarction HF. We found that changes in any individual current are relatively small, and alone could mislead as to consequences. However, differential changes in multiple currents integrate to shorten AP in the infarct border zone but prolong AP in the remote zone, increasing AP repolarization inhomogeneity. Our findings help explain why single channel-blocker therapy may fail, and highlight the need to understand the integrated changes of ionic currents in treating arrhythmias in HF.

Abstract Background There are limited reports of severe tricuspid valve stenosis in dogs and limited data regarding treatment and outcome. Objective To evaluate clinical signs, echocardiographic features, and outcome of balloon valvuloplasty (BV) in dogs with severe tricuspid valve stenosis (TVS) in which BV was attempted. Animals Five client-owned dogs with severe TVS. Methods Records were retrospectively reviewed and data collected regarding signalment, clinical signs, diagnostic findings, procedures, and outcome. Results All dogs were Labrador Retrievers. Presenting complaints included episodic weakness/syncope (4/5), abdominal distension (4/5), lethargy (2/5), and exercise intolerance (2/5). The median and range of measurements before BV were as follows: TV mean velocity 1.5 m/s (range 1.4–1.7 m/s); velocity-time integral (VTI) 79.8 cm (42.4–99.1 cm); and TV maximum velocity 2.9 m/s (2.3–3.2 m/s). Measurements (available for 3 of 5 dogs) after BV were as follows: TV mean velocity 1.15 m/s (0.9–1.4 m/s); VTI 44.95 cm (41.4–54.8 cm); and TV maximum velocity 1.15 m/s (1.9–2.3 m/s). The procedure was attempted in all dogs and completed in 4/5 dogs. The largest balloon diameter ranged from 15 mm to 25 mm, and length ranged from 4 cm to 5 cm. Right atrial pressure decreased in 4/5 dogs. All but 1 dog had clinical improvement after BV, but recurrence of clinical signs occurred (2/5). Tricuspid regurgitation worsened in 1 dog culminating in right heart failure and euthanasia. Conclusions and Clinical Importance BV can be an effective treatment; however, clinical signs can recur. Right heart failure due to worsened TR is a potential complication in dogs with pre-existing moderate-to-severe TR.