MRI-guided, transrectal, intraprostatic steam application as potential focal therapeutic modality for prostatic diseases in a large animal translational model: A feasibility follow-up study

Parallel to establishment of diagnostic surveillance protocols for detection of prostatic diseases, novel treatment strategies should be developed. The aim of the present study is to evaluate the feasibility and possible side effects of transrectal, MRI-targeted intraprostatic steam application in dogs as an established large animal translational model for prostatic diseases in humans. Twelve healthy experimental, intact, male beagle dogs without evidence of prostatic pathology were recruited. An initial MRI examination was performed, and MRI-targeted steam was applied intraprostatically immediately thereafter. Serum levels of C-reactive protein (CRP), clinical and ultrasonographic examinations were performed periodically following the procedure to assess treatment effect. Four weeks after treatment, all dogs underwent follow-up MRI examinations and three needle-core biopsies were obtained from each prostatic lobe. Descriptive statistics were performed. MRI-guided intraprostatic steam application was successfully performed in the study population. The first day after steam application, 7/12 dogs had minimal signs of discomfort (grade 1/24 evaluated with the short-form Glasgow Composite Measure Pain Scale) and no dogs showed any sign of discomfort by day 6. CRP elevations were detected in 9/12 dogs during the first week post steam application. Mild to moderate T2 hyperintense intraparenchymal lesions were identified during follow-up MRI in 11/12 dogs four weeks post procedure. Ten of these lesions enhanced mild to moderately after contrast administration. Coagulative necrosis or associated chronic inflammatory response was detected in 80.6% (58/72) of the samples obtained. MRI-targeted intraprostatic steam application is a feasible technique and displays minimal side effects in healthy dogs as translational model for human prostatic diseases. This opens the possibility of minimally invasive novel treatment strategies for intraprostatic lesions

Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation.

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine

Blood oxygenation-level dependent cerebrovascular reactivity imaging as strategy to monitor CSF-hemoglobin toxicity

Objectives: Cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) may be one of the main drivers of secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Haptoglobin scavenging of CSF-Hb has been shown to mitigate cerebrovascular disruption. Using digital subtraction angiography (DSA) and blood oxygenation-level dependent cerebrovascular reactivity imaging (BOLD-CVR) the aim was to assess the acute toxic effect of CSF-Hb on cerebral blood flow and autoregulation, as well as to test the protective effects of haptoglobin. Methods: DSA imaging was performed in eight anesthetized and ventilated sheep (mean weight: 80.4 kg) at baseline, 15, 30, 45 and 60 minutes after infusion of hemoglobin (Hb) or co-infusion with haptoglobin (Hb:Haptoglobin) into the left lateral ventricle. Additionally, 10 ventilated sheep (mean weight: 79.8 kg) underwent BOLD-CVR imaging to assess the cerebrovascular reserve capacity. Results: DSA imaging did not show a difference in mean transit time or cerebral blood flow. Whole-brain BOLD-CVR compared to baseline decreased more in the Hb group after 15 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs -0.01 ± 0.02) and remained diminished compared to Hb:Haptoglobin group after 30 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs 0.0 ± 0.01), 45 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.01 vs 0.01 ± 0.02) and 60 minutes (Hb vs Hb:Haptoglobin: -0.03 ± 0.02 vs 0.01 ± 0.01). Conclusion: It is demonstrated that CSF-Hb toxicity leads to rapid cerebrovascular reactivity impairment, which is blunted by haptoglobin co-infusion. BOLD-CVR may therefore be further evaluated as a monitoring strategy for CSF-Hb toxicity after aSAH

A new-generation, low-permeability flow diverting device for treatment of saccular aneurysms

Objectives: We report a preclinical comparative study of a 96-strand braided flow diverter. Methods: The 96-strand braided device was compared with the currently commercially available flow diverter with 48 strands. The devices were implanted across the neck of 12 elastase-induced aneurysms in New Zealand White rabbits and followed for 1 and 3months (n = 6 respectively). Aneurysm occlusion rates, parent artery stenosis and patency of jailed branch occlusions were assessed by angiography, histology and scanning electron microscopy studies. Results: It was feasible to navigate and implant the 96-strand device over the aneurysm orifice in all cases. At follow-up two aneurysms in the 48-strand vs. one in the 96-strand group were not occluded. This aneurysm from the 96-strand group however had a tracheal branch arising from the sac and showed a reverse remodelling of the vascular pouch at 3months. In the occluded aneurysms, the parent artery was always completely reconstructed and the aneurysm orifice was sealed with neointimal tissue. No in-stent stenosis or jailed branch artery occlusion was observed. Conclusions: The 96-strand flow diverter proved to be safe, biocompatible and haemodynamically effective, induced stable occlusion of aneurysms and led to reverse remodelling of the parent artery. Key points : • Flow diversion has been introduced to improve endovascular treatment of cerebral aneurysms • A new low-permeability flow diverter is feasible for parent artery reconstruction. • The Silk 96 flow diverter appears effective at inducing aneurysm healing. • The covered branches remained patent at follow-up

Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine

Coronary optical frequency domain imaging (OFDI) for in vivo evaluation of stent healing: comparison with light and electron microscopy

Aims Coronary late stent thrombosis, a rare but devastating complication, remains an important concern in particular with the increasing use of drug-eluting stents. Notably, pathological studies have indicated that the proportion of uncovered coronary stent struts represents the best morphometric predictor of late stent thrombosis. Intracoronary optical frequency domain imaging (OFDI), a novel second-generation optical coherence tomography (OCT)-derived imaging method, may allow rapid imaging for the detection of coronary stent strut coverage with a markedly higher precision when compared with intravascular ultrasound, due to a microscopic resolution (axial ∼10-20 µm), and at a substantially increased speed of image acquisition when compared with first-generation time-domain OCT. However, a histological validation of coronary OFDI for the evaluation of stent strut coverage in vivo is urgently needed. Hence, the present study was designed to evaluate the capacity of coronary OFDI by electron (SEM) and light microscopy (LM) analysis to detect and evaluate stent strut coverage in a porcine model. Methods and results Twenty stents were implanted into 10 pigs and coronary OFDI was performed after 1, 3, 10, 14, and 28 days. Neointimal thickness as detected by OFDI correlated closely with neointimal thickness as measured by LM (r = 0.90, P < 0.01). The comparison of stent strut coverage as detected by OFDI and SEM analysis revealed an excellent agreement (r = 0.96, P < 0.01). In particular, stents completely covered by OFDI analysis were also completely covered by SEM analysis. All incompletely covered stents by OFDI were also incompletely covered by SEM. Analyses of fibrin-covered stent struts suggested that these may rarely be detected as uncovered stent struts by OFDI. Importantly, optical density measurements revealed a significant difference between fibrin- and neointima-covered coronary stent struts [0.395 (0.35-0.43) vs. 0.53 (0.47-0.57); P < 0.001], suggesting that differences in optical density provide information on the type of stent strut coverage. The sensitivity and specificity for detection of fibrin vs. neointimal coverage was evaluated using receiver-operating characteristic analysis. Conclusion The present study demonstrates that OFDI is a highly promising tool for accurate evaluation of coronary stent strut coverage, as supported by a high agreement between OFDI and light and electron microscopic analysis. Furthermore, our data indicate that optical density measurements can provide additional information with respect to the type of stent strut coverage, i.e. fibrin vs. neointimal coverage. Therefore, coronary OFDI analysis will provide important information on the biocompatibility of coronary stent

Coronary optical frequency domain imaging (OFDI) for in vivo evaluation of stent healing: comparison with light and electron microscopy

The present study demonstrates that OFDI is a highly promising tool for accurate evaluation of coronary stent strut coverage, as supported by a high agreement between OFDI and light and electron microscopic analysis. Furthermore, our data indicate that optical density measurements can provide additional information with respect to the type of stent strut coverage, i.e. fibrin vs. neointimal coverage. Therefore, coronary OFDI analysis will provide important information on the biocompatibility of coronary stents

Development of post-pump syndrome in a sheep after mitral valve stenting

A one-year-old healthy sheep received an implant stenting the mural ('posterior') leaflet of the mitral valve. The experiment was authorized by the Cantonal Ethical Committee. The surgery was performed on the open, beating heart during cardiopulmonary bypass (CPB). Management of anaesthesia was based on isoflurane with mechanical intermittent positive pressure ventilation (IPPV) of the lungs, combined with intercostal nerve blocks and intravenous fentanyl and lidocaine. Marked cardiovascular depression occurred towards the end of CPB time and required high doses of dopamine, dobutamine, lidocaine and ephedrine to allow for weaning off the CPB pump. Moreover, severe pulmonary dysfunction developed when IPPV was re-initiated after CPB. Hypoxaemia persisted throughout the recovery from general anaesthesia. Multiple organ failure developed gradually during the three postoperative days, leading to euthanasia of the animal. As described in this case, marked lung injury associated with some degree of failure of other vital organs may occur in sheep after CPB. Intraoperative cardiorespiratory complications when weaning-off may indicate the development of 'post-pump syndrome'

Ligature-induced peri-implantitis in minipigs revisited

Aim: The ligature-induced defect model still remains the model of first choice to experimentally investigate the cause, effect and treatment approaches of periimplantitis. It was the aim of the present in-vivo trail to revisit the ligature-induced peri-implantitis minipig model regarding its current scientific value and ethical justification in implant research. Materials and methods: Six minipigs were used for the analysis of peri-implant hard and soft tissue structures. Animals were randomly allocated to an experimental silk ligature-induced peri-implantitis group (n=4 animals) and a reference healthy group (n=2 animals). After six weeks mean pocket depths (PD) and bleeding on probing (BOP) measurements were performed just before animals were sacrificed. Results: Overall, ligature-induced peri-implantitis provoked a local inflammation around the experimental implants. Additionally, a loss of crestal bone surrounding the implants could be detected. Mean pocket depths (PD) were 2.2 ± 1.1 mm for healthy animals and 5.4 ± 1.9 mm for peri-implantitis sites. Healthy sites showed a BOP of 60%, whereas peri-implantitis sites disclosed a BOP of 90% within 10 s after probing. Conclusion: Clinical, radiological and histological findings of the present animal experiment supported the overall applicability of the ligature-induced periimplantitis minipig model. A rapid breakdown of peri-implant hard tissues could be detected mainly on the buccal side

Clinical evaluation of intranasal medetomidine-ketamine and medetomidine-S(+)-ketamine for induction of anaesthesia in rabbits in two centres with two different administration techniques

OBJECTIVE: The aim was to compare efficacy and side effects of induction with medetomidine-ketamine or medetomidine-S(+)-ketamine by intranasal (IN) instillation in rabbits and to evaluate both protocols during subsequent isoflurane anaesthesia. STUDY DESIGN: Prospective, blinded, randomized experimental study in two centres. ANIMALS: Eighty-three healthy New Zealand White rabbits undergoing tibial or ulnar osteotomy. METHODS: Medetomidine (0.2 mg kg-1 ) with 10 mg kg-1 ketamine (MK) or 5 mg kg-1 S(+)-ketamine (MS) was administered IN to each rabbit in a randomized fashion. In Centre 1 (n = 42) rabbits were held in sternal recumbency, and in Centre 2 (n = 41) in dorsal recumbency, during drug instillation. Adverse reactions were recorded. If a rabbit swallowed during endotracheal intubation, half of the initial IN dose was repeated and intubation was re-attempted after 5 minutes. Anaesthesia was maintained with isoflurane. Heart rate, blood pressure, end-tidal carbon dioxide concentration and blood gases were recorded. Data were analysed using Student's t-test, Mann-Whitney test and Fisher's exact test. RESULTS: In all, 39 animals were assigned to the MK group and 44 to the MS group. Two rabbits in the MS group held in dorsal recumbency died after instillation of the drug. Eight (MK) and 11 rabbits (MS) were insufficiently anaesthetized and received a second IN dose. One rabbit in MK and three in MS required an isoflurane mask induction after the second IN dose. There were no significant differences between treatments for induction, intraoperative data, blood gas values and recovery data. CONCLUSION AND CLINICAL RELEVANCE: This study indicated that medetomidine-ketamine and medetomidine-S(+)-ketamine were effective shortly after IN delivery, but in dorsal recumbency IN administration of S(+)-ketamine led to two fatalities. Nasal haemorrhage was noted in both cases; however, the factors leading to death have not been fully elucidated