Drug-eluting resorbable scaffolds (DRS) are conceptually attractive for treatment of peripheral arterial disease, particularly below-the-knee. MOTIV is a peripheral variant of REVA Medical’s well-established, radiopaque tyrosine-polycarbonate (Tyrocore) sirolimus-eluting DRS. The purpose of this study was to provide imaging and histopathologic data on vascular response to MOTIV in porcine peripheral arteries. MOTIV scaffolds (3.0 or 3.5 × 12/24/36/48/60 mm) were implanted in 20 internal iliac arteries of 9 Yorkshire swine. At 30 and 90 days, vascular stenosis, strut coverage, and strut apposition were characterized using optical coherence tomography. Scaffold structure and vascular healing were assessed by histopathology and scanning electron microscopy. At termination, all vessels remained patent. The average neointimal thickness was 0.22 ± 0.05 mm in Group 1 (30 days) and 0.18 ± 0.10 mm in Group 2 (90 days); the percent area stenosis was 28 ± 6% and 24 ± 11%, respectively. All struts were fully covered by neointima. No malapposition, stent fracture or late strut discontinuity was observed. Adequate vessel wall healing at both time points was characterized by a typically fully mature neointima and complete reendothelialization at all sites. No unresorbed luminal thrombus was observed. The inflammation scores were low for all vessels on both time points, except for one animal. The average inflammation (excluding multinucleated giant cells [MNGCs]) was 0.6 (MNGCs score was 0.9) for the stented vessel segments at 30 days and 0.8 (MNGCs score of 1.0) at 90 days. Implantation of the MOTIV up to 60 mm long in small-caliber peripheral arteries of swine resulted in 100% patency rate and adequate vascular healing at 30-day and 90-day timepoints. The Tyrocore-based DRS retained the necessary structural integrity throughout the course of the study and confirmed their favorable biocompatibility in small-caliber porcine peripheral arteries.

Objectives: We aimed to evaluate the effectiveness of alternating magnetic fields AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone. Methods: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5- or 21-days post-implantation. Blood and tissue samples were collected at various time points post-AMF treatment. Results: In vivo efficacy studies demonstrated significant biofilm reduction on titanium and cobalt-chrome implants with AMF-linezolid combination treatment compared to controls. Significant bacterial reductions were also observed in surrounding tissues and bones. Cytokine analysis showed improved inflammatory responses with combination therapy, and histopathology confirmed reduced inflammation, necrosis, and bacterial presence, especially at 5 days post-implantation. Conclusions: This study demonstrates that combining AMF with antibiotics significantly reduces biofilm-associated infections on metal implants in a large animal model. Numerical simulations confirmed targeted heating, and in vivo results showed substantial bacterial load reduction and reduced inflammatory response. These findings support the potential of AMF as a non-invasive treatment for prosthetic joint infections. (c) 2024 Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Anterior cruciate ligament reconstruction (ACLR) is one of the more common procedures performed worldwide and perhaps the most widely studied construct in orthopedic literature. Interference screws are reliable and frequently used for ligament reconstruction, providing rigid fixation and facilitates graft incorporation allowing for the physiologic loads of early rehabilitation. The purpose of this study was to determine the bio-integration profile and quality of soft tissue graft when using mineral fiber-reinforced screws in an ACLR interference model. Nine sheep underwent ACLR using harvested autologous tendon graft fixated with 4.75 mm screws made of continuous mineral fibers. Histopathology and imaging evaluation at 28, 52, 104, 132-weeks (W) demonstrated mesenchymal tissue ingrowth into implant wall at 28 W, which increased at 52 W and peaked at 104 W. At 132 W, implants fully replaced by newly remodeled bone. Graft cellularity was evident at 28 W and continued to increase through 132 W as the tendon ossified at sites of bone contact. Pro-healing M2-macrophages and giant cells remained infrequent, with minor increases between 52 W and 104 W, attributed to expected phagocytic response. Pro-inflammatory cells (i.e., M1-macrophages, polymorphonuclears) were absent through the entire study course. In conclusion, bio-integrative screws provide secure soft tissue fixation with replacement by bone demonstrating graft cellularization over time.

One of the challenging aspects of minimal invasive surgery (MIS) is intracorporal suturing, which can be significantly time-consuming. Therefore, there is a rising need for devices that can facilitate the suturing procedure in MIS. Su2ura Approximation Device (Su2ura Approximation) is a novel device developed to utilize the insertion of anchors threaded with stitches to allow a single action placement of a suture. The objective of this study was to evaluate the long-term safety and tissue approximation of Su2ura Approximation in comparison to Endo Stitch + Surgidac sutures in female domestic pigs. All incision sites were successfully closed by both methods. Firm consolidation within and around the incision site was noted in several animals in both treatment groups, which corresponded histopathologically to islands of ectopic cartilage or bone spicules within the fibrotic scar. These changes reflect heterotopic ossification that is commonly seen in the healing of abdominal operation sites in pigs. No other abnormal findings were observed throughout the study period. In conclusion, the use of Su2ura Approximation under the present experimental conditions revealed no safety concerns.

Nonclinical implantation studies are a common and often critical step for medical device safety assessment in the bench-to-market pathway. Nonclinical implanted medical devices or drug-device combination products require complex macroscopic and microscopic pathology evaluations due to the physical presence of the device itself and unique tissue responses to device materials. The Medical Device Implant Site Evaluation working group of the Society of Toxicologic Pathology's (STP) Scientific and Regulatory Policy Committee (SRPC) was tasked with reviewing scientific, technical, and regulatory considerations for these studies. Implant site evaluations require highly specialized methods and analytical schemes that should be designed on a case-by-case basis to address specific study objectives. Existing STP best practice recommendations can serve as a framework when performing nonclinical studies under Good Laboratory Practices and help mitigate limitations in standards and guidances for implant evaluations (e.g., those from the International Organization for Standardization [ISO], ASTM International). This article integrates standards referenced by sponsors and regulatory bodies with practical pathology evaluation methods for implantable medical devices and combination products. The goal is to ensure the maximum accuracy and scientific relevance of pathology data acquired during a medical device or combination drug-device implantation study.

The study assessed chronic myocardial, coronary and systemic effects of intracoronary supersaturated oxygen (SSO 2 ) therapy. Left anterior descending coronary arteries of 40 swine were stented and randomized to 90-min selective intracoronary infusion of SSO 2 (pO 2 760–1000 mmHg) or normoxemic saline. In 20 out of 40 animals, SSO 2 delivery followed a 60-min balloon occlusion to induce myocardial infarction (MI). In both normal and MI models, intracoronary treatment with hyperoxemic SSO 2 therapy showed no evidence of coronary thrombosis. There were no biologically relevant differences between treatments at either time point in regard to coronary intervention site healing and neointimal growth. No signs of any myocardial or systemic toxicity were observed after 7 or 30 days. A trend was observed toward reduced incidence of microscopic MI scars and reduced infarct size in histopathology, as well as toward better recovery of echocardiographically evaluated global and regional contractility at 30 days. No treatment related infarcts or thromboemboli were observed in the downstream organs.

Significance: Intravascular photoacoustic (IVPA) imaging can identify native lipid in atherosclerotic plaques in vivo. However, the large number of laser pulses required to produce 3D images is a safety concern that has not been fully addressed. Aim: We aim to evaluate if irradiation at wavelengths and dosages relevant to IVPA imaging causes target vessel damage. Approach: We irradiate the carotid artery of swine at one of several energy dosages using radiation at 1064 or 1720 nm and use histological evaluation by a pathologist to identify dose-dependent damage. Results: Media necrosis was the only dose-dependent form of injury. Damage was present at a cumulative fluence of 50 J / cm2 when using 1720 nm light. Damage was more equivocally identified at 700 J / cm2 using 1064 nm. Conclusions: In prior work, IVPA imaging of native lipid in swine has been successfully conducted below the damage thresholds identified. This indicates that it will be possible to use IVPA imaging in a clinical setting without damaging vessel tissue. Future work should determine if irradiation causes an increase in blood thrombogenicity and confirm whether damaged tissue will heal over longer time points.

The aim of the study was to evaluate a balloon expandable transcatheter heart valve (THV) system (Myval) at 6-month follow-up in ovine banding model. Eleven THV systems were implanted via carotid approach. There were 2 procedure-related deaths and 2 premature deaths. At 6 months all valves that completed follow-up (n = 7) were functional, with no significant regurgitation, calcification, thrombi, or vegetation. Mean pressure gradient was 21.9 ± 11 mm Hg, maximum velocity = 3.3 ± 1 m/s, and ejection fraction was 53.3 ± 6%. Myval THV showed optimal hemodynamic performance and biocompatibility.

With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.

Objective This study aimed to evaluate the pharmacokinetic profile and tissue effects of everolimus delivered into arterial wall using biodegradable nanospheres. Background Delivery of everolimus into the arterial wall is challenging due to its low-lipophilic profile. Methods A pharmacokinetic study included 28 porcine coronary arterial segments initially injured with balloon angioplasty followed by the local delivery of everolimus encapsulated in nanospheres (EEN) via injection through a microporous delivery catheter. The animals were sacrificed at 1 hour, 1,7,28, and 90-day follow-up. In the tissue effects study 16 coronary bare metal stent (BMS) were implanted following EEN delivery, 15 BMS following nanospheres delivery without the drug (reference group) and 16 implanted BMS served as a control. Angiographic and histology follow-up was scheduled at 28 and 90-day. Results The study showed high-everolimus concentrations in arterial tissue early after nanoparticles delivery followed by its gradual decrease to 1.15 +/- 0.40 ng/mg at 90 days. Histology analysis showed favorable biocompatibility and healing profile with comparable area stenosis between groups at both time-points. Conclusions The present study demonstrates for the first time the safety, biocompatibility, and long-term retention of everolimus in arterial tissue after single local delivery of biodegradable nanospheres.

BackgroundLong-term evaluation of transcatheter heart valves (THV) in the pre-clinical setting and clinical translation of outcomes was limited.AimWe evaluate biocompatibility and durability of a balloon expandable THV system (Myval, Meril Lifesciences) at 6-month follow-up in the novel ovine aortic banding model.MethodsA surgical ascending aortic banding model was created in 11 sheep. Two weeks later, 11 Myval THV systems (20 and 23 mm) were introduced and implanted via carotid approach for a 6 month follow-up. Transthoracic echocardiography was performed at 30, 90, and 180 days. Subsequently, the animals were sacrificed and the valves with surrounding tissue harvested for pathological and radiographic evaluation.ResultsAll valves were implanted successfully. There were 2 procedure-related deaths. One sheep died prematurely on day 133 due to endocarditis and one on day 74 due to leaflet immobility caused by tight banding. Both these were not related to the device.At 6 months all valves that completed follow-up (n = 7) were functional, with no significant regurgitation, calcification, thrombi, or vegetation. At terminal follow-up mean pressure gradient was 21.9{plus minus}11 mm Hg, Vmax = 3.3{plus minus}1 m/s and ejection fraction of 53.3 {plus minus} 6%. In pathology, implant cusps were covered with endothelialized and fibrocellular neointima, whereas the conduits were fully integrated without inflammatory reaction. There were no signs of thrombus or calcifications.ConclusionsIn this novel aortic banding model, Myval THV showed optimal deployment and good hemodynamic performance at 6 months. There were no device related degenerations and healing was very advanced.

Re-endothelialization of vascular lumen after endovascular procedures is a critical healing milestone and is subjected to routine pathological evaluation during preclinical safety assessment of new cardiovascular devices. Gross evaluation, microscopic evaluation, and scanning electron microscopy (SEM) are the methods of choice for evaluation of vascular surfaces. In this article, we present a new digital imaging approach of surface topography herein referred to as topographical digital microscopy (TDM) that is able to meet the objectives of endovascular healing assessment in a single instrumental platform combined with the same sample preparation techniques as for histology or SEM. This platform is taking advantage of digitally managed illumination, X-Y stitching, and Z-stacking to enable direct optical imaging of tissue surfaces at levels of details ranging from the macroscopic to the cellular level. This technique is enabled by advances in digital optical microscopy and provides images in color and 3 dimensions that can help in the analysis, especially in distinguishing biologically meaningful observations from technical preparation artifacts and in visualizing surface topography.

Surgical site infections (SSIs) are a common surgical-related complication. To avoid these complications, a new biodegradable polymer–lipid encapsulation matrix that provides controlled release of doxycycline (doxycycline/polymer-lipid encapsulation matrix [D-PLEX]) has been developed. The aim of this comprehensive study was to evaluate the potential safety of D-PLEX100 in abdominal surgical site. D-PLEX100 was administered into incisions of abdominal surgical site in Yucatan miniature swine, which were followed for up to 6 months and compared to sham-control swine. The D-PLEX100 mass did not migrate from the incisional site, and there was no evidence for systemic toxicity or other safety concerns. Surgical incision sites, including the peritoneal surface, were fully healed at 6 months in all animals. Most of the D-PLEX100 mass was absorbed during the first 3 months, and by 6 months, D-PLEX100 was fully absorbed. Toxicokinetic evaluation revealed that doxycycline concentrations were evident at 30 minutes and persisted to 8 days (71 mg/kg) or at least 15 days (284 mg/kg) and were no longer present in plasma by day 29. This study supports the safety of D-PLEX100 and its favorable degradability profile. A clinical study is being performed to assess the safety and the efficacy of D-PLEX100 to prevent human abdominal SSIs.

Purpose: To evaluate the patency, cellular response, and thrombogenicity of a novel vascular stent graft. Materials and Methods: Test stent grafts, incorporating luminal spun polytetrafluoroethylene and a nonpenneable fluoropolymer layer, and control stent grafts, constructed of permeable expanded polytetrafluoroethylene, were implanted in the external iliac arteries of 14 adult sheep with a median weight of 73.4 kg ranging from 60.6-86.8 kg for 30 (n = 4), 90 (n = 4), and 180 (n = 6) days. Angiographic patency and percent diameter stenosis (%DS) were assessed at termination. Excised stent grafts were fixed and stained for histopathologic analysis, including neointimal coverage (NC) assessment. Results: Test and control device migration occurred in 1 animal, resulting in test device thrombosis. Both devices were excluded from analysis. Mean %DS in test and control implants was 4.6% and 8.2% (P = .563), 2.0% and 10.9% (P = .363), and 2.1% and 10.3% (P = .009) at 30, 90, and 180 days, respectively. Median NC scores at 30, 90, and 180 days were significantly lower in middle test device sections (P < .05). Proximal and distal test and control sections exhibited similar median NC scores at all time periods (P > .05). When present, test and control devices exhibited no neointimal detachment from the graft surface. Except for the migrated test device, no thrombus was observed. Transgraft cellular migration was absent in test devices but present in control devices with tissue accumulation around the stent struts. Conclusions: Test and control devices demonstrated excellent patency in an ovine model. Compared to the control, test devices exhibited significantly lower %DS values at 180 days and significantly lower mid-device NC scores at 30, 90, and 180 days.

AIMS:Peripheral arteries are constantly exposed to deformation (elongation, twisting, shortening, compression) making bioresorbable scaffolds (BRS) a potentially attractive therapeutic alternative to metallic stents. We conducted a long-term pilot preclinical study of a novel sirolimus-eluting BRS in peripheral arteries. METHODS AND RESULTS:Fourteen BRS were deployed in iliofemoral arteries of seven healthy Yucatan miniswine and examined with imaging, pharmacokinetic, histopathologic, and polymer degradation techniques at 0, 30, 90, 180 days, 1, 2, and 3.3 years. Angiographic late luminal loss remained unchanged at 30 and 180 days but significantly decreased from 1 to 3.3 years. optical coherence tomography (OCT) showed late increase in lumen area (1 year: 14.70 ± 3.58 mm2 , 2 years 22.04 ± 3.81 mm2 , and 3.3 years 23.45 ± 7.07 mm2 ; p < .05) primarily due to scaffold area enlargement between 1 and 3.3 years, while there was no difference in the percent area stenosis at all time points. Histologic evidence of scaffold degradation was observed starting at 2 years, with minimal inflammatory reaction. At 3.3 years, BRS struts were rarely discernible by OCT, confirmed by a nearly complete polymer degradation by molecular weight analysis. CONCLUSIONS:In this pilot study, novel sirolimus-eluting BRS showed promising acute and chronic performance in the iliofemoral arteries of Yucatan miniswine.

Dura mater defects are a common problem following neurosurgery. Dural grafts are used to repair these defects; among them are biodegradable polymeric synthetic grafts. ArtiFascia is a novel synthetic and fibrous Dural graft, composed of poly(l-lactic-co-caprolactone acid) (PLCL) and poly(d-lactic-co-caprolactone acid). In this study, the biodegradability and local tolerance of ArtiFascia was evaluated in rabbits and compared with a bovine collagen matrix as a reference control. ArtiFascia implantation resulted in the formation of neo-dura at the site of implantation and recovery of the dural damage and the calvaria bone above. The implanted graft was completely absorbed after 12 months and the remaining macrophages were morphologically consistent with the anti-inflammatory M2-like phenotype, which contributes to tissue healing and are not pro-inflammatory. The site of the drilled skull bone had a continuous smooth surface, without exuberant tissue or inflammation and a newly formed trabecular bone formation indicated the healing process of the bone. These results support the local tolerability and biodegradability of ArtiFascia when used as a dural graft in rabbits. This study suggests that PLCL-based grafts including ArtiFascia are safe and effective to repair Rabbit Dura.

Histology of medical devices poses a variety of unique challenges. Comprehensive histologic assessment of medical devices often requires spatial context and high-quality retention of the device-tissue interface. However, the composition of many medical devices is often not amenable to traditional paraffin embedding and thus alternative specialized methodologies such as hard resin embedding must be used. Hard resin embedding requires specialized laboratory technical expertise and equipment, and the fixation techniques and resin composition used markedly impact the feasibility of immunohistochemistry. For the continuity of spatial context during histologic evaluation, additional imaging methods such as macrophotography, radiography, micro-Computerized Tomography (microCT), or magnetic resonance imaging (MRI) can be used to guide sectioning and to complement histologic findings. Although standardized approaches are scarce for medical devices, important considerations specific to medical device histology are discussed, including general specimen preparation, special considerations for devices by organ system, and the challenges of immunohistochemistry. Histologic preparation of medical devices must be thoughtful, thorough, and tailored to achieve optimal histologic outcomes for complex, valuable, and often limited implant specimens.