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Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant–tissue interfaces1–4. Here we demonstrate that an adhesive implant–tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant–tissue interface compared to the non-adhesive implant–tissue interface. Histological analysis shows that the adhesive implant–tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo. In vitro protein adsorption, multiplex Luminex assays, quantitative PCR, immunofluorescence analysis and RNA sequencing are additionally carried out to validate the hypothesis. We further demonstrate long-term bidirectional electrical communication enabled by implantable electrodes with an adhesive interface over 12 weeks in a rat model in vivo. These findings may offer a promising strategy for long-term anti-fibrotic implant–tissue interfaces.

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.

Bovine pericardium (BP) is a vascular biomaterial used in cardiovascular surgery that is typically cross-linked for masking antigenicity and enhance stability. There is a need for biochemical evaluation of the tissue properties prior to implantation to ensure that quality and reliability standards are met. Here, engineered antigen removed BP (ARBP) that was cross-linked with 0.2% and 0.6% glutaraldehyde (GA), and further calcified in vitro to simulate graft calcifications upon implantation was characterized nondestructively using fluorescence lifetime imaging (FLIm) to identify regions of interest which were then assessed by Raman spectroscopy. We observed that the tissue fluorescence lifetime shortened, and that Raman bands at 856, 935, 1282, and 1682 cm–1decreased, and at 1032 and 1627 cm–1increased with increasing GA cross-linking. Independent classification analysis based on fluorescence lifetime and on Raman spectra discriminated between GA-ARBP and untreated ARBP with an accuracy of 91% and 66%, respectively. Pearson’s correlation analysis showed a strong correlation between pyridinium cross-links measured with high-performance liquid chromatography and fluorescence lifetime measured at 380–400 nm (R= −0.76, p= 0.00094), as well as Raman bands at 856 cm–1for hydroxy-proline (R= −0.68, p= 0.0056) and at 1032 cm–1for hydroxy-pyridinium (R= 0.74, p= 0.0016). Calcified areas of GA cross-linked tissue showed characteristic hydroxyapatite (959 and 1038 cm–1) bands in the Raman spectrum and fluorescence lifetime shortened by 0.4 ns compared to uncalcified regions. FLIm-guided Raman imaging could rapidly identify degrees of cross-linking and detected calcified regions with high chemical specificity, an ability that can be used to monitor tissue engineering processes for applications in regenerative medicine.

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 StatementCurrently, 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.

Current heart valve prostheses are associated with significant complications, including aggressive immune response, limited valve life expectancy, and inability to grow in juvenile patients. Animal derived “tissue” valves undergo glutaraldehyde fixation to mask tissue antigenicity; however, chronic immunological responses and associated calcification still commonly occur. A heart valve formed from an unfixed bovine pericardium (BP) extracellular matrix (ECM) scaffold, in which antigenic burden has been eliminated or significantly reduced, has potential to overcome deficiencies of current bioprostheses. Decellularization and antigen removal methods frequently use sequential solutions extrapolated from analytical chemistry approaches to promote solubility and removal of tissue components from resultant ECM scaffolds. However, the extent to which such prefractionation strategies may inhibit removal of antigenic tissue components has not been explored. We hypothesize that presence of magnesium in prefractionation steps causes DNA precipitation and reduces removal of nuclear-associated antigenic proteins. Keeping all variables consistent bar the addition or absence of magnesium (2 mM magnesium chloride hexahydrate), residual BP ECM scaffold antigenicity and removed antigenicity were assessed, along with residual and removed DNA content, ECM morphology, scaffold composition, and recellularization potential. Furthermore, we used proteomic methods to determine the mechanism by which magnesium presence or absence affects scaffold residual antigenicity. This study demonstrates that absence of magnesium from antigen removal solutions enhances solubility and subsequent removal of antigenic nuclear-associated proteins from BP. We therefore conclude that the primary mechanism of action for magnesium removal during antigen removal processes is avoidance of DNA precipitation, facilitating solubilization and removal of nuclear-associated antigenic proteins. Future studies are necessary to further facilitate solubility and removal of nuclear-associated antigenic proteins from xenogeneic ECM scaffolds, in addition to an in vivoassessing of the material.

Effective solubilization of proteins by chaotropes in proteomic applications motivates their use in solubilization-based antigen removal/decellularization strategies. A high urea concentration has previously been reported to significantly reduce lipophilic antigen content of bovine pericardium (BP); however, structure and function of the resultant extracellular matrix (ECM) scaffold were compromised. It has been recently demonstrated that in vivoECM scaffold fate is determined by two primary outcome measures as follows: (1) sufficient reduction in antigen content to avoid graft-specific adaptive immune responses and (2) maintenance of native ECM structural proteins to avoid graft-specific innate responses. In this work, we assessed residual antigenicity, ECM architecture, ECM content, thermal stability, and tensile properties of BP subjected to a gradient of urea concentrations to determine whether an intermediate concentration exists at which both antigenicity and structure–function primary outcome measures for successful in vivoscaffold outcome can simultaneously be achieved. Alteration in tissue structure–function properties at various urea concentrations with decreased effectiveness for antigen removal makes use of urea-mediated antigen removal unlikely to be suitable for functional scaffold generation.

Chronic vascular diseases affect over 25 million patients in the U.S, alone. While non-invasive therapies are available, approximately 4.5 million individuals are estimated to require a vascular bypass annually, worldwide. Autologous vascular grafts remain the standard of care; yet the absence of a suitable donor vessel results in approximately one third of patients being ineligible for autologous grafting. “Off-the-shelf” alternatives have been proposed, but have had limited pre-clinical success, primarily due to graft failure via thrombosis. Thrombotic failure risk has been shown to be dramatically reduced by the formation of a luminal quiescent endothelial cell monolayer. Recently, our group engineered an unfixed, antigen-removed (AR) extracellular matrix (ECM) scaffold from bovine saphenous vein (SV) which is minimally immunogenic and avoids in vivothrombosis. However, the mechanism by which AR-ECM SV scaffolds prevent thrombosis remains unknown. In this study, we utilized cell culture, immunofluorescence, and RNA-seq to assess the hypothesis that hAECs seeded on the basement membrane (BM) surface of AR-ECM SV scaffolds adopt a quiescent phenotype. Cells seeded on the BM surface proliferated and underwent significantly greater XY migration than those seeded on the non-BM surface. Additionally, unlike non-BM seeded cells, BM seeding resulted in quiescent hAEC phenotype (i.e., apical polarization of podocalyxin and adherence junction protein (i.e., cadherin and β-catenin) colocalization). Finally, the transcriptional phenotype of hAECs seeded on the BM surface was similar to cells treated with simvastatin (i.e. “quiescent”) and significantly different from those treated with TNFα (i.e. “activated”) (n=6/group), as assessed by gene set enrichment and t-SNE analysis. We conclude that seeding hAECs on the BM surface of AR-SV ECM scaffolds induces a favorable “quiescent” phenotype, while an unfavorable “activated” phenotype is avoided. Ultimately, these results show that the BM surface of AR-SV-ECM scaffolds possesses inherent characteristics which promote quiescent hAEC behavior and resultant vascular homeostasis and will help inform future pre-clinical studies of this novel small diameter vascular grafting biomaterial.

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.

The feasibility of surgical correction for almost all canine congenital or acquired cardiac diseases has been demonstrated. Current surgical success rates are remarkably high considering the infrequency with which such procedures are performed. Such results are a testament to the dedication and skill of the various cardiac surgical teams offering these procedures worldwide. However, experience from the medical field indicates that the only way to increase success rates above those presently achieved will be to dramatically increase the frequency with which cardiac surgical teams perform these procedures. Fortunately, lack of case load does not appear to be the limiting factor to such efforts. Rather, lacks of infrastructure and manpower are the major obstacles for expansion of cardiac surgical programs.

To compare the clinical effects of unilateral thyroarytenoid lateralization versus unilateral cricoarytenoid laryngoplasty for the treatment of canine laryngeal paralysis.A prospective, clinical trial.Twenty client-owned dogs admitted to Glasgow University Veterinary Hospital (GUVH) between 1997 and 1999 with a diagnosis of laryngeal paralysis.A thorough evaluation of each dog was undertaken that included history, physical and neurologic examinations, complete blood count, serum biochemistry profile, serum thyroxine (T4) level, and thyroid-stimulating hormone (TSH) assay. The exercise tolerance of each dog was investigated by assessing respiratory rate and arterial blood gas analysis at rest and after 5 minutes of mild exercise. Animals were included in the study on the basis of a definitive diagnosis of laryngeal paralysis made by endoscopic observation of the larynx in the lightly anesthetized patient. The animals were randomly assigned to 1 of 2 treatment groups: unilateral thyroarytenoid lateralization or unilateral cricoarytenoid laryngoplasty, with all procedures being performed by the same surgeon. Video images of the rima glottidis were recorded pre- and postoperatively using video endoscopy. Video images were digitized and the area of the rima glottidis measured using image-analysis software. An increase in the area of the rima glottidis was expressed as a percentage of the preoperative area. All animals were reassessed 6 weeks' postoperatively, and exercise tolerance tests were repeated. The mean increase in the area of the rima glottidis postoperatively when compared with the preoperative area was 140% for those animals undergoing unilateral thyroarytenoid lateralization (range, 120%-158%) and 207% for those animals undergoing unilateral cricoarytenoid laryngoplasty (range, 183%-228%). This difference was statistically significant ( P < .0001 ). At the 6-week postoperative examination, there was no significant difference in improvement between the 2 groups when compared on either a clinical basis or exercise tolerance tests. The mean surgical time in the 2 groups was 25 minutes for thyroarytenoid lateralization and 43 minutes for cricoarytenoid laryngoplasty. This was a statistically significant difference ( P= .002 ). Although increase in area of the rima glottidis was significantly greater after unilateral cricoarytenoid laryngoplasty compared with unilateral thyroarytenoid lateralization, no difference in clinical outcome could be detected. However, the cricoarytenoid laryngoplasty procedure required significantly more surgical time.Both unilateral cricoarytenoid laryngoplasty and unilateral thyroarytenoid lateralization are successful methods for the treatment of laryngeal paralysis; however, thyroarytenoid lateralization requires less surgical time to perform.

To summarize the presenting complaints and clinical signs associated with traumatic penetrating injuries to the canine oropharynx. To determine how the site of injury, causative agent, and duration of disease affect the presentation and clinical outcome of treatment.Retrospective study.50 client-owned dogs.The medical records of 50 dogs with oropharyngeal penetrating injuries referred to Glasgow University Veterinary Hospital (GUVH) between 1979–1999 were reviewed. Data regarding signalment, owners' presenting complaint, history, physical examination, radiographic and endoscopic findings, surgical findings, and outcome were recorded and compared with the GUVH population. Estimates of individual breed-specific odds ratios were calculated. Outcome was evaluated by reexamination 6 weeks after surgery with recurrence of disease recorded as failure.Oropharyngeal injuries occurred most often in medium to large breed dogs. The majority of dogs presented with chronic disease (82%). The common findings on clinical examination were discharging sinus (72%) and swelling (70%). Acute cases typically presented with dysphagia and oral pain. The original site of injury was evident in only 34% of dogs, with the sublingual area the most frequently traumatized. The apparent cause of injury to the oropharynx was most commonly a piece of wood (72%). Other causes were metallic foreign bodies (3 dogs) and bones (2 dogs). In the remaining 9 dogs, the cause was not determined. The clinical signs resolved in all dogs that presented acutely compared with only 62% in dogs with chronic signs.Medium to large breed dogs appear to be prone to oropharyngeal injuries caused mainly by wooden foreign bodies. This may be attributable to stick chewing or retrieving behavior in these animals.History of trauma, stick retrieval, submandibular/cervical swelling, and discharging sinus are commonly encountered in the presentation of this condition. The sublingual area was the most frequent portal of entry recorded, although in chronic cases the initial site of injury was often unclear. Radiography and endoscopy, while offering definitive diagnosis with positive findings, often provide false negative findings. Aggressive surgical debridement of all sinus tracts is essential in obtaining a successful result, but recovery of a foreign body is not necessarily a determinant of success.

Introduction:Left heart disease (LHD) leads to pulmonary venous hypertension (PVH) and isolated post-capillary (IpcPH) or combined post-capillary and pre-capillary (CpcPH) pulmonary hypertension (PH). While CpcPH is usually attributed to pulmonary arterial remodeling, we hypothesized that in a large animal model of PVH, remodeling of pulmonary veins also occurs and is associated with PH severity.Methods:Domestic swine (10 PVH and 9 Sham) underwent baseline right heart catheterization (RHC). PVH was produced by superior and common inferior pulmonary vein banding just proximal to the left atrium. All pigs underwent monthly RHC. PVH pigs were sacrificed at end-study (ES), defined as clinical instability (n=3), severe CpcPH (n=6) at RHC or 4 months post-banding (n=1). Sham pigs were sacrificed at similar time points to PVH pigs. Pulmonary arteries and veins were specifically labeled at sacrifice using pressurized perfusion with microbead- or barium-agarose solution for quantitative histomorphometry.Results:(See Table) At ES, mean PAP, TPG, PVR, and Cpa differed between groups, while PAWP, CO and body weight did not. Wall thickness relative to external diameter (% Wall Th) was increased in arteries and veins (Figure) and both arterial and venous % Wall Th correlated with mean PAP, TPG and PVR (R2?0.60, p?0.0014 for all).Conclusion:Arterial and venous pulmonary vascular remodeling is associated with CpcPH severity in a large animal model of CpcPH due to chronic PVH (as occurs in LHD). Further study in this model is needed to characterize potentially unique mediators of pulmonary arterial versus venous remodeling and thus novel therapies in CpcPH associated with LHD.

Naturally occurring diseases in companion animals represent an underused resource that holds promise for providing predictive proof of efficacy in the evaluation of new therapeutics and devices.