Head to head comparison of optical coherence tomography, intravascular ultrasound echogenicity and virtual histology for the detection of changes in polymeric struts over time: insights from the ABSORB trial

To analyse and to compare the changes in the various optical coherence tomography (OCT), echogenicity and intravascular ultrasound virtual histology (VH) of the everolimus-eluting bioresorbable scaffold (ABSORB) degradation parameters during the first 12 months after ABSORB implantation. In the ABSORB study, changes in the appearance of the ABSORB scaffold were monitored over time using various intracoronary imaging modalities. The scaffold struts exhibited a progressive change in their black core area by OCT, in their ultrasound derived grey level intensity quantified by echogenicity, and in their backscattering ultrasound signal, identified as "pseudo dense-calcium" (DC) by VH.

In Vitro and In Vivo Imaging Characteristics Assessment of Polymeric Coils Compared with Standard Platinum Coils for the Treatment of Intracranial Aneurysms

BACKGROUND AND PURPOSE:Conventional platinum coils cause imaging artifacts that reduce imaging quality and therefore impair imaging interpretation on intraprocedural or noninvasive follow-up imaging. The purpose of this study was to evaluate imaging characteristics and artifact production of polymeric coils compared with standard platinum coils in vitro and in vivo.MATERIALS AND METHODS:Polymeric coils and standard platinum coils were evaluated in vitro with the use of 2 identical silicon aneurysm models coiled with a packing attenuation of 20% each. DSA, flat panel CT, CT, and MR imaging were performed. In vivo evaluation of imaging characteristics of polymeric coils was performed in experimentally created rabbit carotid bifurcation aneurysms. DSA, CT/CTA, and MR imaging were performed after endovascular treatment of the aneurysms. Images were evaluated regarding visibility of individual coils, coil mass, artifact production, and visibility of residual flow within the aneurysm.RESULTS:Overall, in vitro and in vivo imaging showed relevantly reduced artifact production of polymeric coils in all imaging modalities compared with standard platinum coils. Image quality of CT and MR imaging was improved with the use of polymeric coils, which permitted enhanced depiction of individual coil loops and residual aneurysm lumen as well as the peri-aneurysmal area. Remarkably, CT images demonstrated considerably improved image quality with only minor artifacts compared with standard coils. On DSA, polymeric coils showed transparency and allowed visualization of superimposed vessel structures.CONCLUSIONS:This initial experimental study showed improved imaging quality with the use of polymeric coils compared with standard platinum coils in all imaging modalities. This might be advantageous for improved intraprocedural imaging for the detection of complications and posttreatment noninvasive follow-up imaging.

Minimum ten year results of total hip arthroplasty with the acetabular reinforcement ring in avascular osteonecrosis

Total hip arthroplasty (THA) still carries a higher failure rate in patients with avascular necrosis of the femoral head (AVN) than in a similar patient population with THA for other reasons. This is particularly true for the acetabular component. One of the major factors accounting for this is the compromised acetabular bone quality with structural defects subsequent to collapsing of the femoral head in high-grade AVN. In this study we implanted an acetabular reinforcement ring with hook (ARRH), which had been used successfully for other indications with acetabular bone stock deficiency, in 32 consecutive THA's in 29 patients with AVN. Five patients died during the observation period of causes unrelated to the surgery, one patient was lost to follow-up and one patient could not be followed up due to chronic illness, leaving 25 hips (23 patients) with a minimum follow-up of ten years (mean: 11.8; range: 10-15). The mean Merle d'Aubigne score increased significantly from 7.7 preoperatively to 16.6 postoperatively (p < 0.001). One revision was performed for aseptic stem loosening. Of the unrevised hips, one acetabular component was classified as definitively loose. The cumulative 12-year survivorship for THA with ARRH in AVN was 95.2% (confidence interval: 86.1-100%) for both components, 100% for the cup and 95.2% for the stem (86.1-100%).

Preliminary results following reinforcement of the pulmonary autograft to prevent dilatation after the Ross procedure

OBJECTIVE: The Ross operation remains a controversially discussed procedure, because concern exists regarding late dilatation of the neoaortic root and progressive regurgitation of the autograft valve. We present our early experience with an external reinforcement of the autograft, which is inserted into a prosthetic Dacron graft with an artificial aortic root configuration. This detail should help to prevent neoaortic root dilatation. PATIENTS AND METHODS: Between 2006 and 2007, 12 patients (mean age 16 +/- 38 years; range 15-38 years) underwent a Ross procedure by this technique. Indications were aortic regurgitation (n = 2), aortic stenosis (n = 5), and combined aortic stenosis and insufficiency (n = 5). A bicuspid aortic valve was present in 9 patients. Balloon valvuloplasty had been performed in 7 patients. Follow-up was performed by clinical and echocardiographic examinations. RESULTS: No early or late deaths occurred in this small series, and freedom from reoperation is 100%. Echocardiographic follow-up confirmed absence of aortic insufficiency in 11 patients after a mean of 11 months (range 2-30 months). In 1 patient, a small asymmetric regurgitation jet was already observed at discharge echocardiography. As expected, no neoaortic root dilatation was observed during follow-up. All patients are in New York Heart Association class I. CONCLUSIONS: The present technique is a simple and reproducible technical step that does not require significant additional time. Inclusion of the autograft within a root prosthesis may be especially indicated in situations known for late autograft dilatation, namely, bicuspid aortic valve, predominant aortic insufficiency, and ascending aortic enlargement.

Acetabular reinforcement ring in primary total hip arthroplasty: a minimum 10-year follow-up

INTRODUCTION: We report the results of a titanium acetabular reinforcement ring with a hook (ARRH) in primary total hip arthroplasty (THA), which was introduced in 1987 and continues to be used routinely in our center. The favorable results of this device in arthroplasty for developmental dysplasia and difficult revisions motivated its use in primary THA. With this implant only minimal acetabular reaming is necessary, anatomic positioning is achieved by placing the hook around the teardrop and a homogenous base for cementing the polyethylene cup is provided. MATERIALS AND METHODS: Between April 1987 and December 1991, 241 THAs with insertion of an ARRH were performed in 178 unselected, consecutive patients (average age 58 years; range 30-84 years) with a secondary osteoarthrosis in 41% of the cases. RESULTS: At the time of the latest follow-up, 33 patients (39 hips) had died and 17 cases had been lost to follow-up. The median follow-up was 122 months with a minimum of 10 years. Eight hips had been revised, leaving 177 hips in 120 living patients without revision. Six cups were revised because of aseptic loosening. Two hips were revised for sepsis. The mean Merle d'Aubigné score for the remaining hips was 16 (range 7-18) at the latest follow-up. For aseptic loosening, the probability of survival of the cup was 0.97 (95% confidence interval, 0.94-0.99). However, analysis of radiographs implied loosening in seven other cups without clinical symptoms. CONCLUSIONS: The results of primary THA using an acetabular reinforcement ring parallel the excellent results of these implants often observed in difficult primary and revision arthroplasty at a minimum of 10 years. Survivorship is comparable to modern cementless implants. Medial migration that occurs with loosening of the acetabular component seems to be prevented with this implant. Radiographic loosening signs can exist without clinical symptoms.

Multiscale constitutive modeling of polymer materials

Materials are inherently multi-scale in nature consisting of distinct characteristics at various length scales from atoms to bulk material. There are no widely accepted predictive multi-scale modeling techniques that span from atomic level to bulk relating the effects of the structure at the nanometer (10-9 meter) on macro-scale properties. Traditional engineering deals with treating matter as continuous with no internal structure. In contrast to engineers, physicists have dealt with matter in its discrete structure at small length scales to understand fundamental behavior of materials. Multiscale modeling is of great scientific and technical importance as it can aid in designing novel materials that will enable us to tailor properties specific to an application like multi-functional materials. Polymer nanocomposite materials have the potential to provide significant increases in mechanical properties relative to current polymers used for structural applications. The nanoscale reinforcements have the potential to increase the effective interface between the reinforcement and the matrix by orders of magnitude for a given reinforcement volume fraction as relative to traditional micro- or macro-scale reinforcements. To facilitate the development of polymer nanocomposite materials, constitutive relationships must be established that predict the bulk mechanical properties of the materials as a function of the molecular structure. A computational hierarchical multiscale modeling technique is developed to study the bulk-level constitutive behavior of polymeric materials as a function of its molecular chemistry. Various parameters and modeling techniques from computational chemistry to continuum mechanics are utilized for the current modeling method. The cause and effect relationship of the parameters are studied to establish an efficient modeling framework. The proposed methodology is applied to three different polymers and validated using experimental data available in literature.

DESIGN AND SYNTHESIS OF MULTIFUNCTIONAL POLYMERIC MICELLES FOR GENE-DIRECTED ENZYME PRODRUG THERAPY

Gene-directed enzyme prodrug therapy is a form of cancer therapy in which delivery of a gene that encodes an enzyme is able to convert a prodrug, a pharmacologically inactive molecule, into a potent cytotoxin. Currently delivery of gene and prodrug is a two-step process. Here, we propose a one-step method using polymer nanocarriers to deliver prodrug, gene and cytotoxic drug simultaneously to malignant cells. Prodrugs acyclovir, ganciclovir and 5-doxifluridine were used to directly to initiate ring-opening polymerization of epsilon-caprolactone, forming a hydrophobic prodrug-tagged poly(epsilon-caprolactone) which was further grafted with hydrophilic polymers (methoxy poly(ethylene glycol), chitosan or polyethylenemine) to form amphiphilic copolymers for micelle formation. Successful synthesis of copolymers and micelle formation was confirmed by standard analytical means. Conversion of prodrugs to their cytotoxic forms was analyzed by both two-step and one-step means i.e. by first delivering gene plasmid into cell line HT29 and then challenging the cells with the prodrug-tagged micelle carriers and secondly by complexing gene plasmid onto micelle nanocarriers and delivery gene and prodrug simultaneously to parental HT29 cells. Anticancer effectiveness of prodrug-tagged micelles was further enhanced by encapsulating chemotherapy drugs doxorubicin or SN-38. Viability of colon cancer cell line HT29 was significantly reduced. Furthermore, in an effort to develop a stealth and targeted carrier, CD47-streptavidin fusion protein was attached onto the micelle surface utilizing biotin-streptavidin affinity. CD47, a marker of self on the red blood cell surface, was used for its antiphagocytic efficacy, results showed that micelles bound with CD47 showed antiphagocytic efficacy when exposed to J774A.1 macrophages. Since CD47 is not only an antiphagocytic ligand but also an integrin associated protein, it was used to target integrin alpha(v)beta(3), which is overexpressed on tumor-activated neovascular endothelial cells. Results showed that CD47-tagged micelles had enhanced uptake when treated to PC3 cells which have high expression of alpha(v)beta(3). The synthesized multifunctional polymeric micelle carriers developed could offer a new platform for an innovative cancer therapy regime.

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.

Annexin A5-Conjugated Polymeric Micelles For Dual SPECT and Optical Detection of Apoptosis

Apoptosis, a form of programmed cell death, is critical to homoeostasis, normal development, and physiology. Dysregulation of apoptosis can lead to the accumulation of unwanted cells, such as occurs in cancer, and the removal of needed cells or disorders of normal tissues, such as heart, neurodegenerative, and autoimmune diseases. Noninvasive detection of apoptosis may play an important role in the evaluation of disease states and response to therapeutic intervention for a variety of diseases. It is desirable to have an imaging method to accurately detect and monitor this process in patients. In this study, we developed annexin A5-conjugated polymeric micellar nanoparticles dual-labeled with a near-infrared fluorescence fluorophores (Cy7) and a radioisotope (111In), named as 111In-labeled annexin A5-CCPM. In vitro studies demonstrated that annexin A5-CCPM could strongly and specifically bind to apoptotic cells. In vivo studies showed that apoptotic tissues could be clearly visualized by both single photon emission computed tomography (SPECT) and fluorescence molecular tomography (FMT) after intravenous injection of 111In-labeled Annexin A5-CCPM in 6 different apoptosis models. In contrast, there was little signal in respective healthy tissues. All the biodistribution data confirmed imaging results. Moreover, histological analysis revealed that radioactivity count correlated with fluorescence signal from the nanoparticles, and both signals co-localized with the region of apoptosis. In sum, 111In-labeled annexin A5-CCPM allowed visualization of apoptosis by both nuclear and optical imaging techniques. The complementary information acquired with multiple imaging techniques should be advantageous in improving diagnostics and management of patients.

Personalized Tuning of a Reinforcement Learning Control Algorithm for Glucose Regulation

Artificial pancreas is in the forefront of research towards the automatic insulin infusion for patients with type 1 diabetes. Due to the high inter- and intra-variability of the diabetic population, the need for personalized approaches has been raised. This study presents an adaptive, patient-specific control strategy for glucose regulation based on reinforcement learning and more specifically on the Actor-Critic (AC) learning approach. The control algorithm provides daily updates of the basal rate and insulin-to-carbohydrate (IC) ratio in order to optimize glucose regulation. A method for the automatic and personalized initialization of the control algorithm is designed based on the estimation of the transfer entropy (TE) between insulin and glucose signals. The algorithm has been evaluated in silico in adults, adolescents and children for 10 days. Three scenarios of initialization to i) zero values, ii) random values and iii) TE-based values have been comparatively assessed. The results have shown that when the TE-based initialization is used, the algorithm achieves faster learning with 98%, 90% and 73% in the A+B zones of the Control Variability Grid Analysis for adults, adolescents and children respectively after five days compared to 95%, 78%, 41% for random initialization and 93%, 88%, 41% for zero initial values. Furthermore, in the case of children, the daily Low Blood Glucose Index reduces much faster when the TE-based tuning is applied. The results imply that automatic and personalized tuning based on TE reduces the learning period and improves the overall performance of the AC algorithm.

Temporal evolution of strut light intensity after implantation of bioresorbable polymeric intracoronary scaffolds in the ABSORB cohort B trial-an application of a new quantitative method based on optical coherence tomography.

BACKGROUND Quantitative light intensity analysis of the strut core by optical coherence tomography (OCT) may enable assessment of changes in the light reflectivity of the bioresorbable polymeric scaffold from polymer to provisional matrix and connective tissues, with full disappearance and integration of the scaffold into the vessel wall. The aim of this report was to describe the methodology and to apply it to serial human OCT images post procedure and at 6, 12, 24 and 36 months in the ABSORB cohort B trial. METHODS AND RESULTS In serial frequency-domain OCT pullbacks, corresponding struts at different time points were identified by 3-dimensional foldout view. The peak and median values of light intensity were measured in the strut core by dedicated software. A total of 303 corresponding struts were serially analyzed at 3 time points. In the sequential analysis, peak light intensity increased gradually in the first 24 months after implantation and reached a plateau (relative difference with respect to baseline [%Dif]: 61.4% at 12 months, 115.0% at 24 months, 110.7% at 36 months), while the median intensity kept increasing at 36 months (%Dif: 14.3% at 12 months, 75.0% at 24 months, 93.1% at 36 months). CONCLUSIONS Quantitative light intensity analysis by OCT was capable of detecting subtle changes in the bioresorbable strut appearance over time, and could be used to monitor the bioresorption and integration process of polylactide struts.