Quantitative MR imaging study of intravitreal sustained release of VEGF in rabbits.

PURPOSE: To determine whether sustained elevation of vascular endothelial growth factor (VEGF) in the vitreous cavity causes retinal hyperpermeability [blood-retinal barrier (BRB) breakdown] before the development of retinal neovascularization (NV) and to document the kinetics of the integrity of BRB breakdown versus time. METHODS: Poly(L-lactide-co-glycolide)based devices loaded with VEGF were implanted intravitreally in rabbit eyes. Contrast-enhanced magnetic resonance imaging (MRI) methods were used to identify and quantitate the retinal permeability at various time points after implantation. This was done with the newly developed MR tracer AngioMARK (Epix Medical, Boston, MA). After the MRI measurements, fundus photography and fluorescein angiography (FA) also were performed on the same set of animals. RESULTS: At 3 days after implantation, the MR images showed a significant retinal leakage into the vitreous cavity (BRB breakdown) of the VEGF-implanted eyes. To quantitate this leakage, the permeability surface area product (PS) was measured. At 3 days, the mean PS product was 1.25 +/-0.25 x 10(-5) cm3/min. Based on the VEGF in vitro release study, this 3-day BRB breakdown corresponded to a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. The fundus and FA photographs of these VEGF-implanted eyes taken at 4 days after implantation also showed a considerable level of retinal vascular dilation and tortuosity. By 12 days after implantation, the mean PS product decreased to 5.83 +/- 1.38 x 10(-6) cm3/min. However, the retinal NV was observed only after the second week after implantation. By this time, a total of 10.70 +/- 0.92 microg/ml of VEGF was released in a sustained fashion. Also, after the retinal NV development, retinal detachment also was observed. The control eyes, however, which were implanted with blank devices, remained unchanged and normal during the entire course of this study (PS = 5.57 +/- 0.66 x 10(-7) cm3/min). CONCLUSIONS. The findings indicate that sustained delivery of elevated amounts of VEGF in the vitreous cavity induces a BRB breakdown even earlier than 3 days after implantation. This was achieved after a total sustained release of 7.42 +/- 0.54 microg/ml of VEGF. This retinal leakage regressed by more than half by the time the retinal NV developed. Furthermore, a retinal detachment occurred after this retinal NV. These results are similar to proliferative diabetic retinopathy (PDR). The sustained elevation of VEGF in the vitreous cavity of rabbit eyes is potentially a good model to test VEGF antagonists to treat or prevent PDR in humans. The quantifiable change of BRB breakdown by the contrast-enhanced MRI method is ideal to assess the therapeutic intervention in vivo without killing the animal and may prove to be clinically useful in humans.

Tissue reactions to polypyrrole-coated polyesters: A magnetic resonance relaxometry study.

The electrically conductive properties of polypyrrole (PPy) as a coating on polyester material are very attractive for the manufacture of small diameter blood conduits. However, before these PPy-coated materials can be investigated for their capacity to generate endothelialized luminal surfaces, they must first be studied for their innocuousness in a living environment. The specific goal of the present study was to investigate the in vivo interactions of PPy-coated and noncoated woven polyester materials implanted subcutaneously in rats for prescheduled periods of 2, 5, 10, 20, and 30 days. The in vivo magnetic resonance (MR) relaxation times were computed for a small area of muscle tissue adjacent to the implants. A correlation was concurrently attempted with blood monocyte activation studies as well as histological observations of the tissue-material interface. The progressive pattern of the slower transversal relaxation time (T2s) values revealed a more persistent tissue reaction for the most conductive PPy-coated materials and a shorter acute tissue response as the surface resistivity increased. Similarly, the blood monocyte activation studies indicated that the thickness of the PPy coating, which correlated with the conductivity, was directly related to tissue response. Furthermore, both the MR and biological studies showed that the PPy-coated material with a high surface resistivity displayed the lowest tissue reaction over the entire period of implantation. The results obtained from the blood monocyte activation studies and histological observations correlate well with the noninvasive MR measurements of the body's healing process. The conductive materials with high surface resistivities must be further investigated. Finally, the noninvasive nature of MR relaxometry reveals its outstanding potential for future in vivo investigations of the body's tissue interactions with polymers and nonferromagnetic biomaterials.

Multinuclear solid-state NMR spectroscopy of envelopes from virgin and explanted silicone breast prostheses: an exploratory study.

The structure and dynamics of silicone envelopes from virgin and explanted breast prostheses have been studied by 1H, 13C, and 29Si high-resolution solid-state NMR spectroscopy. The results indicate that this combination of techniques can be used to unambiguously identify the presence of methyltrifluoropropylsiloxane units and diphenylsiloxane units at concentrations of about 2.0% and 3.5%, respectively, in some of the envelopes. The presence of about 10% silica also was detected and a trace of lipids was found in the explanted silicone envelopes. We have also measured the proton T2 and T1 relaxation times of the envelopes to characterize the dynamics of the silicone in the envelopes.

Will it be feasible to insert endoprostheses under interventional MRI?

PURPOSE: Recent advances in magnetic resonance imaging (MRI) technology may provide a safer and more sensitive monitoring modality than X-ray imaging for endovascular surgical procedures. The purpose of this study was to investigate the feasibility of using MRI to monitor the insertion of endoprostheses. METHODS: The endoprostheses we studied were composed of a nitinol stent encased in a polyester sheath. These were characterized with four different MRI techniques: the fast spin-echo; spin-echo; gradient-recalled echo; and the spoiled gradient-recalled echo. The deployment of the endoprosthesis into an artery was simulated in an in vitro model and viewed using a fast spin-echo MRI technique. RESULTS: Image artifacts produced by the nitinol framework in these endoprostheses were minimal when fast spin-echo or spin-echo imaging techniques were used, improving the visibility of the device. In in vitro tests, the catheters and endoprostheses were visualized by MRI with sufficient clarity to guide the placement of a device in the model artery. CONCLUSIONS: Insertion of this type of endoprosthesis under interventional MRI guidance is feasible. The convenience and improved safety provided by interventional MR systems and "real-time" imaging capabilities are expected to make this technology an attractive alternative to X-ray imaging techniques.

High resolution solid-state 29Si NMR spectroscopy of silicone gels used to fill breast prostheses.

We have used 29Si solid-state nuclear magnetic resonance (NMR) spectroscopy to study the chemical structure of the silicone gels in virgin and explanted breast prostheses. Despite evidences of alteration in the morphological appearance of the silicone gel inside the breast prosthesis, our results do not reveal changes in the chemical nature and structure of the silicone gels after implantation. In addition to the main 29Si resonance peak at -22.26 ppm that corresponds to the resonance frequency of the D repeat unit of the polysiloxane chains, the high sensitivity of our NMR technique allows the detection of very low concentrations of silicone compounds. Within our experimental detection limit of 0.2%, no signal between -90 ppm and -150 ppm are observed. This indicates that no silica products are present inside the gel of the prostheses. Furthermore, our 29Si NMR spectra indicate differences in the chemical compositions of the silicone gels from different manufacturers.

Noninvasive follow-up of tissue encapsulation of foreign materials. Are magnetic resonance imaging and spectroscopy breakthroughs?

The development of sensitive and noninvasive magnetic resonance (MR) techniques for the long- and short-term evaluation of vascular prostheses requires detailed knowledge of the evolutionary trend of the MR properties of the perigraft tissue during the healing process. To characterize changes in water MR properties, the water proton relaxation times, T1 and T2, of the muscle in the vicinity of an implanted polyester material were measured as a function of implantation time. To provide better insight into interpretation of the MR results, we carried out histologic and peripheral blood cell activation studies and tissue water content measurements. The MR results illustrated the sensitivity of the relaxation times to changes in cellular response to the presence of an implant. The evolutionary trend of these MR parameters exhibited two distinct phases. The crossover from phase I to phase II occurred around 10 days postimplantation. This crossover is attributed to the transition in the inflammatory response from the acute phase to the chronic phase. During the acute phase, the very high initial T1 and T2s (the slower relaxing component of the transverse relaxation time) values decreased significantly and steadily. The value of T1 dropped by a factor of 2, whereas T2s went down by a factor of 6. During the same time, the diffusion parameter, beta, remained constant. However, during the chronic phase, the diffusion parameter increased sharply. By 30 days postimplantation, the value of beta had increased by a factor of 10. The relaxation times, on the other hand, increased steadily with implantation time. Because the current MR results provide an in vivo and noninvasive follow-up of the healing process around the polyester implant material, they will be of considerable value in the early detection of vascular graft complications by MR imaging.

Magnetic resonance study of virgin and explanted silicone breast prostheses. Can proton relaxation times be used to monitor their biostability?

The development of sensitive and non invasive magnetic resonance (MR) techniques for monitoring the fate of silicones in breast prostheses in vivo requires detailed knowledge of the MR properties of these silicones. To characterize changes in the proton dynamics, relaxation time measurements (T1 and T2) were obtained on virgin and explanted breast prostheses using both spectroscopic and imaging techniques in a magnetic field of 1.5 Tesla. Averaged transverse relaxation times (T2) were observed to depend neither on the measurement technique employed (virgin silicone, T2 = 160 +/- 5 msec with imaging and 154 +/- 9 msec spectroscopically) nor on the effect of being implanted in the body for various periods of time ranging from 4 months to 17 years (explanted silicone, T2 = 164 +/- 16 msec with imaging and 159 +/- 25 msec spectroscopically). Average longitudinal relaxation times (T1) were also found to be similar for virgin and explanted prostheses (virgin silicone T1 = 899 +/- 32 msec, explanted silicone T1 = 879 +/- 75 msec, measured with imaging), but appeared to depend on the measurement technique employed (virgin silicone T1 = 764 +/- 17 msec, explanted silicone T1 = 765 +/- 23 msec, measured spectroscopically). Although the measured relaxation times did not reveal any differences between virgin and explanted prostheses, marginal differences were detected between the relaxation times of explanted prostheses from different manufacturers. More reference data on standard silicone products may be required before changes in implanted silicone can be assessed using proton magnetic relaxation times.