Intraventricular Implantation Research Articles

A Soft Robotic Actuator System for In Vivo Modeling of Normal Pressure Hydrocephalus.

The intracranial pressure (ICP) affects the dynamics of cerebrospinal fluid (CSF) and its waveform contains information that is of clinical importance in medical conditions such as hydrocephalus. Active manipulation of the ICP waveform could enable the investigation of pathophysiological processes altering CSF dynamics and driving hydrocephalus. A soft robotic actuator system for intracranial pulse pressure amplification was developed to model normal pressure hydrocephalus in vivo. Different end actuators were designed for intraventricular implantation and manufactured by applying cyclic tensile loading on soft rubber tubing. Their mechanical properties were investigated, and the type that achieved the greatest pulse pressure amplification in an in vitro simulator of CSF dynamics was selected for application in vivo. A hydraulic actuation device based on a linear voice coil motor was developed to enable automated and fast operation of the end actuators. The combined system was validated in an acute ovine pilot in vivo study. in vitro results show that variations in the used materials and manufacturing settings altered the end actuator's dynamic properties, such as the pressure-volume characteristics. In the in vivo model, a cardiac-gated actuation volume of 0.125 mL at a heart rate of 62 bpm caused an increase of 205% in mean peak-to-peak amplitude but only an increase of 1.3% in mean ICP. The introduced soft robotic actuator system is capable of ICP waveform manipulation. Continuous amplification of the intracranial pulse pressure could enable in vivo modeling of normal pressure hydrocephalus and shunt system testing under pathophysiological conditions to improve therapy for hydrocephalus.

Intraventricular placement of a spring expander does not attenuate cardiac atrophy of the healthy heart induced by unloading via heterotopic heart transplantation.

An important complication of the prolonged left ventricle assist device support in patients with heart failure is unloading-induced cardiac atrophy which proved resistant to various treatments. Heterotopic heart transplantation (HTx) is the usual experimental model to study this process. We showed previously that implantation of the newly designed intraventricular spring expander can attenuate the atrophy when examined after HTx in the failing heart (derived from animals with established heart failure). The present study aimed to examine if enhanced isovolumic loading achieved by implantation of the expander would attenuate cardiac post-HTx atrophy also in the healthy heart. Cardiac atrophy was assessed as the ratio of the transplanted-to-native heart weight (HW) and its degree was determined on days 7, 14, 21 and 28 after HTx. The transplantation resulted in 32±3, 46±2, 48±3 and 46±3 % HW loss when measured at the four time points; implantation of the expander had no significant effect on these decreases. We conclude that enhanced isovolumic loading achieved by intraventricular implantation of the expander does not attenuate the development of cardiac atrophy after HTx in the healthy heart. This indicates that such an approach does not represent a useful therapeutic measure to attenuate the development of unloading-induced cardiac atrophy.

Isovolumic loading of the failing heart by intraventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation.

Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF). Our aim was to evaluate the course of unloading-induced cardiac atrophy in rats with failing hearts, and to examine if increased isovolumic loading obtained by intraventricular implantation of an especially designed spring expander would attenuate this process. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart (HW) to the control heart. Isovolumic loading was increased by intraventricular implantation of a stainless steel three-branch spring expander. The course of cardiac atrophy was evaluated on days 7, 14, 21, and 28 after HTx. Seven days unloading by HTx in failing hearts sufficed to substantially decrease the HW (−59 ± 3%), the decrease progressed when measured on days 14, 21, and 28 after HTx. Implantation of the spring expander significantly reduced the decreases in whole HW at all the time points (−39 ± 3 compared with −59 ± 3, −52 ± 2 compared with −69 ± 3, −51 ± 2 compared with –71 ± 2, and −44 ± 2 compared with −71 ± 3%, respectively; P<0.05 in each case). We conclude that the enhanced isovolumic heart loading obtained by implantation of the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing rat heart.

Modulation of Diastolic Filling Using an Epicardial Diastolic Recoil Device

Diastolic dysfunction likely contributes to all cases of congestive heart failure and is solely responsible for many. Existing cardiac support devices largely ignore diastolic dysfunction and may exacerbate it. Current diastolic devices in development rely on either extensive extraventricular fixation or intraventricular implantation with complications associated with blood contact. A diastolic recoil device is proposed that pneumatically locks to the outside of the heart wall. The end-diastolic total biventricular pressure-volume relationship (EDTBPVR) was used to evaluate, in vitro, the ability of a recoil device to modulate filling mechanics through pneumatic locking as the method of fixation. The pressure in a model heart was incremented and the corresponding volume changes were measured. The heart model and device were pneumatically locked together using a vacuum sac to model the pericardium. The diastolic recoil component shifted the EDTBPVR towards lower pressures at low volumes, providing up to 0.9 kPa (9 cm H2O) of suction, demonstrating enhanced diastolic recoil at beginning diastole. We conclude that pneumatic locking appears to be a viable method for a recoil device to engage the heart.

Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic mouse model of Alzheimer's disease

Encapsulated human mesenchymal stem cells(MSC) are studied in a double transgenic mouse model of Alzheimer's disease (AD) after intraventricular implantation at 3 months of age. Abeta 40/42 deposition, and glial (GFAP) and microglial (CD11b) immunoreactivity were investigated 2 months after transplantation of either native MSC or MSC transfected with glucagon-like peptide-1 (GLP-1). CD11b immunostaining in the frontal lobes was significantly decreased in the GLP-1 MSC group compared to the untreated controls. Also, the plaque associated GFAP immunoreactivity was only observed in one of four animals in the GLP-1 MSC group. Abeta 40 whole brain ELISA was decreased in the MSC group: 86.06±5.2pg/ml (untreated control) vs. 78.67±11.2pg/ml (GLP-1 MSC group) vs.70.9±11.1pg/ml (MSC group, p<0.05). Intraventricular transplantation of native and GLP-1 transfected MSC has been shown effective. Decreased amyloid deposition or suppression of glial and microglial responses were observed. However, encapsulation of MSC may alter their biological activity.

Microglial downregulation in a double transgenic mouse model associated with early-onset Alzheimer's disease (AD) after intraventricular implantation of alginate encapsulated Glukagon-like-peptide-1 (GLP-1) producing human mesenchymal stem-cells

ss Open Acce Oral presentation Microglial downregulation in a double transgenic mouse model associated with early-onset Alzheimer's disease (AD) after intraventricular implantation of alginate encapsulated Glukagon-like-peptide-1 (GLP-1) producing human mesenchymal stem-cells Kathrin Harmening1, Anna Heile1, Miles Miller2, Conrad E Johanson2, Christine Wallrapp3, Thomas Brinker1, Gerald D Silverberg2 and Petra M Klinge*2

Delivery of recombinant gene product to canine brain with the use of microencapsulation

An alternative approach to somatic gene therapy is to deliver a therapeutic protein by implanting “universal” recombinant cells that are immunologically protected from graft rejection with alginate microcapsules. This strategy has proved successful in reversing pathologic conditions in several rodent models of human disease (dwarfism, lysosomal storage disease, hemophilia, cancer). In particular, neurologic disease and behavioral deficit in the mouse model of a neurodegenerative disease (mucopolysaccharidosis [MPS] VII) were significantly improved through the intraventricular implantation of the recombinant encapsulated cells. Here we report the feasibility of delivering recombinant gene products to the central nervous systems (CNSs) of dogs, first using human growth hormone as a marker for delivery in normal dogs and then using α-iduronidase as a therapeutic product for delivery in the MPS I dog that is genetically deficient in this lysosomal enzyme. Madin-Darby canine kidney cells were genetically modified to express either human growth hormone or canine α-iduronidase, then enclosed in alginate-poly- l-lysine-alginate microcapsules of about 500 μm in diameter. The encapsulated cells were implanted into the brain under steoreotaxic guidance. The brains were monitored with computed tomographic scans before and after surgery and examined biochemically and histologically. Delivery of gene products, as measured in the plasma and cerebrospinal fluid sampled periodically through 21 days or in various regions of the brain after death showed that the delivery of both gene products was extremely low but detectable. However, we noted extensive inflammatory reactions, both at the sites of implantation and in the immediate vicinity of the implanted microcapsules. Hence for this technology to be applicable to the CNSs of larger animals and human beings, a more accurate and less invasive neurosurgical procedure, more biocompatible microcapsule–recombinant cell combinations, and higher output of recombinant products must be developed.

Seizure Suppression in Kindled Rats by Intraventricular Grafting of an Adenosine Releasing Synthetic Polymer

Adenosine, an endogenous inhibitory neuromodulator in the central nervous system, exerts anticonvulsant activity that is largely based on the inhibition of the release of excitatory amino acids. As a novel approach to treat pharmacoresistant partial epilepsies, the grafting of adenosine-releasing cells is foreseen to provide a local and sustained source of adenosine. The feasibility of this cell-based therapy was investigated in the present study by the intraventricular implantation of synthetic polymers that release adenosine. Kindled rats with a ventricular implant of an adenosine-releasing polymer showed a profound reduction of seizure activity. This was demonstrated not only by a 75% reduction of grade 5 seizures but also by a reduction of the amplitude and duration of afterdischarges in electroencephalographic (EEG) recordings. Kindled control rats that were implanted with bovine serum albumin (BSA)-containing polymers or were sham operated, continued to show their presurgery seizure pattern. Adenosine displayed antiepileptic activity when released in an amount of 20–50 ng per day. This finding sets the target for the required amount of adenosine to be released from future adenosine-releasing cells for antiepileptic therapy. The present results clearly support the feasibility of a novel therapy for epilepsy based on adenosine-releasing cells.

Effects of basic fibroblast growth factor on in vivo cerebral tumorigenesis in rats.

In vitro evidence suggests that basic fibroblast growth factor (bFGF) promotes tumor cell proliferation and angiogenesis. In this study, we evaluated the early and delayed effects of recombinant human bFGF on the early and late phases of in vivo, in situ tumorigenesis in rats. Brain tumors were induced by transplacentally exposing fetal rats to N-nitrosoethylurea on Day 17 of pregnancy. On postnatal (PN) Day 60 or 90, N-nitrosoethylurea-exposed rats underwent stereotactic intraventricular implantation of Gelfoam saturated with bFGF (60 micrograms) or vehicle; the rats were killed 4 days (early group) or 30 days (delayed group) later. The early and delayed effects of bFGF on the early phase of tumorigenesis (PN Day 60) were evaluated in 14 and 10 rats, respectively; early and delayed effects on the late phase of tumorigenesis (PN Day 90) were evaluated in 12 rats each. Histological examination 30 days after implantation showed a significantly higher tumor rate in rats that had been treated with bFGF on PN Day 90, compared with vehicle-treated control rats (P < 0.05); furthermore, in the bFGF-treated animals there was significantly greater intratumoral and periventricular glial fibrillary acidic protein expression, as determined immunohistochemically. Increased vascularity in the tumor ipsilateral to the implant was found in 2 of 14 rats that had been treated with bFGF on PN Day 60. These findings support in vitro evidence that bFGF and its receptor complex are implicated in the genesis and progression of N-nitrosoethylurea-induced brain tumors in this animal model.

Transplantation of a Polymer-Encapsulated Cell Line Genetically Engineered to Release NGF

The delivery of nerve growth factor (NGF) to the lateral ventricle of a fimbria-fornix-lesioned rat prevents the lesion-induced reduction in choline acetyltransferase (ChAT) expression by medial septal cells. Although delivery has been achieved through neural grafting of genetically engineered cell lines which release NGF, transplanted cells have grown beyond the implantation site and formed tumors. The encapsulation of cells within a permselective polymer capsule prior to transplantation allows cell growth only within the capsule space, while allowing molecular exchange between the host tissue and enclosed cells. Rat fibroblasts from the parent cell line (R208F) or fibroblasts genetically modified to produce NGF (R208N.8) were loaded within a thermoplastic hollow fiber-based capsule. Only the capsules loaded with the genetically engineered cells released measurable amounts of NGF in culture. Adult rats received unilateral aspirative fimbria-fornix lesions, followed by intraventricular implantation of a R208F capsule (n = 6) or a R208N.8 capsule (n = 6). After 2 weeks, rats receiving encapsulated cells showed no undue reaction to the implants. With both cell types, the cells remained viable and confined to the capsule space. R208N.8 capsules released sufficient NGF to prevent the lesion-induced loss of septal ChAT expression, whereas R208F capsules did not. This study suggests that encapsulated genetically engineered cells can provide an efficient means for future applications involving delivery of neurotrophic factors.

Pituitary cell transplants to the cerebral ventricles promote growth of hypophysectomized rats.

SummaryImplantation of acutely dispersed adenohypophysial cells into the lateral ventricles of hypophysectomized rats resulted in partial growth restoration for periods of one to three months. Weight gain by experimental animals was consistently 20%-60% greater than among hypophysectomized control rats; the response was related to the number of cells implanted. The weight gain reflected increases of both protein and fat in body composition. A significant increase in long bone lengths was also observed among rats bearing intraventricular cells. Intraventricular implantation of either heat-killed anterior pituitary cells or subcellular organelles, or implantation of pituitary cells into the peritoneal cavity or anterior chamber of the eye, did not promote significant growth in hypophysectomized recipients. The results suggest that transplanted growth hormonesecreting cells are provided with a suitable functional milieu by the cerebrospinal fluid of the hypophysectomized rat.