Alternative Implantation Site Research Articles

Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets.

Type 1 diabetes (T1D) is an autoimmune disease caused by the immune system attacking and destroying insulin-producing β cells in the pancreas. Islet transplantation is becoming one of the most promising therapies for T1D patients. However, its clinical use is limited by substantial cell loss after islet infusion, closely related to immune reactions, including instant blood-mediated inflammatory responses, oxidative stress, and direct autoimmune attack. Especially the grafted islets are not only exposed to allogeneic immune rejection after transplantation but are also subjected to an autoimmune process that caused the original disease. Due to the development and convergence of expertise in biomaterials, nanotechnology, and immunology, protective strategies are being investigated to address this issue, including exploring novel immune protective agents, encapsulating islets with biomaterials, and searching for alternative implantation sites, or co-transplantation with functional cells. These methods have significantly increased the survival rate and function of the transplanted islets. However, most studies are still limited to animal experiments and need further studies. In this review, we introduced the immunological challenges for islet graft and summarized the recent developments in immune-protective strategies to improve the outcomes of islet transplantation.

Epicardial implantation of a leadless pacemaker in a lamb model.

Pacemaker used in small children typically consist of an abdominally placed generator and epicardially affixed leads, making such a system prone to lead dysfunction during growth. Aim of this study was to investigate the feasibility of epicardial pacing with a leadless pacemaker in a lamb model. Seventeen lambs underwent epicardial implantation of a Micra transcatheter pacing system (TPS) (Medtronic, Minneapolis, MN, USA) via left-lateral thoracotomy to the left ventricle (LV) surface (n=11/17) and to the left atrial appendage (n=6). Ventricular devices were fixated with the tines within the pericardium, whereas the tines of the atrial devices penetrated the myocardium of the left atrial appendage. After 31weeks, animals were sacrificed and hearts were explanted for histological analysis. Following implantation, median P/R amplitude was 4.25/5.5mV while median pacing threshold was 1.1/1.9V at 0.24ms. After 31weeks, median P/R amplitude was 3.3/4.2mV. Median atrial pacing threshold was 0.5/0.24ms. Eight of 10 ventricular pacemakers had lost capture at standard impulse width even at maximum impulse amplitude. On explantation, firm adhesion of the device to the thoracic wall and dislodgement of the electrode tip was found in those ventricular devices. Firm fixation of the Micra electrode to the epicardial surface as applied to the atrial devices resulted in excellent electrical properties during midterm follow up. Pericardial fixation as in the ventricular devices was associated with loss of capture. Therefore, it is important to embed the tines in the myocardium and to choose an alternative implantation site allowing for safe fixation of the Micra TPS in a position perpendicular to ventricular epimyocardium.

Function and Gene Expression of Islets Experimentally Transplanted to Muscle and Omentum

Islet transplantation to the liver is a potential curative treatment for patients with type 1 diabetes. Muscle and the greater omentum are two alternative implantation sites, which can provide excellent engraftment and hold potential as future sites for stem-cell-derived beta-cell replacement. We evaluated the functional outcome after islet transplantation to muscle and omentum and found that alloxan-diabetic animals were cured with a low number of islets (200) at both sites. The cured animals had a normal area under the curve blood glucose response to intravenous glucose, albeit animals with intramuscular islet grafts had increased 120-min blood glucose levels. They also demonstrated an exaggerated counter regulatory response to hypoglycemia. The expression of genes important for beta-cell function was, at both implantation sites, comparable to that in native pancreatic islets. The gene expression of insulin (INS1 and INS2) and glucose transporter-2 was even increased, and the expression of lactate dehydrogenase decreased, at both sites when compared to native islets. We conclude that muscle and omentum provide excellent conditions for engraftment of transplanted islets. When compared to control, 200 islets implanted to the omentum displayed a restored glucose tolerance, whereas animals with intramuscular islet grafts of similar size displayed mild glucose intolerance.

Unsurpassed Intrahepatic Islet Engraftment - the Quest for New Sites for Beta Cell Replacement.

The liver is currently the site of choice for clinical islet transplantation, even though many alternative implantation sites have lately been proposed as more ideal for graft survival. The suggested sites, for example intramuscular space, omentum, bone marrow, and spleen, are sometimes difficult to compare due to differences in animal model, islet isolation procedure, and islet quality. In addition, the variation in transplanted islet mass is vast. The aim of this commentary is to review alternative implantation sites tested experimentally as well as in clinical islet transplantation. Although many sites have been investigated, none have convincingly proved better suited for clinical islet transplantation than intraportal injection to the liver, regardless of whether it is autologous or allogeneic transplantation. However, in order to fully evaluate upcoming bioengineering techniques, such as scaffolds containing insulin-producing cells derived from stem cells, the need of an alternative site has arisen to enable cellular monitoring, which currently cannot be achieved within the liver.

Quantification of β-Cell Mass in Intramuscular Islet Grafts Using Radiolabeled Exendin-4.

BackgroundThere is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor β-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular β-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4.MethodsOne hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry.ResultsIntramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving β cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated α cell mass.Conclusions[177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify β-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.

Rapid Restoration of Vascularity and Oxygenation in Mouse and Human Islets Transplanted to Omentum May Contribute to Their Superior Function Compared to Intraportally Transplanted Islets.

Transplantation of islets into the liver confers several site-specific challenges, including a delayed vascularization and prevailing hypoxia. The greater omentum has in several experimental studies been suggested as an alternative implantation site for clinical use, but there has been no direct functional comparison to the liver. In this experimental study in mice, we characterized the engraftment of mouse and human islets in the omentum and compared engraftment and functional outcome with those in the intraportal site. The vascularization and innervation of the islets transplanted into the omentum were restored within the first month by paralleled ingrowth of capillaries and nerves. The hypoxic conditions in the islets early posttransplantation were transient and restricted to the first days. Newly formed blood vessels were fully functional, and the blood perfusion and oxygenation of the islets became similar to that of endogenous islets. Furthermore, islet grafts in the omentum showed at 1 month posttransplantation functional superiority to intraportally transplanted grafts. We conclude that in contrast to the liver the omentum provides excellent engraftment conditions for transplanted islets. Future studies in humans will be of great interest to investigate the capability of this site to also harbor larger grafts without interfering with islet functionality.

Femoral placement of totally implantable venous power ports as an alternative implantation site for patients with central vein occlusions

To evaluate the indication, technical success, clinical outcome and safety of percutaneously placed totally implantable venous power ports (TIVPPs) in a femoral position in patients with contraindications to implantation in a standard position. Retrospectively, we screened our interventional radiology department database between 12/2,009 and 3/2,013 to identify 1,729 patients with a port implantation. In 8/1,729 (0.47%) patients (1 male, 7 female, mean age 55.5 ± 9.6years) the TIVPP was implanted via the common femoral vein with the port placed in the anterior thigh. All devices were high-pressure injectable, implanted under local anaesthesia with sonographic as well as fluoroscopic guidance, and were tunnelled subcutaneously. Indication, technical success and complications were retrospectively analysed according to the Society of Interventional Radiology (SIR) criteria. Indications were planned chemotherapy for breast (n = 6) and oesophagus cancer (n = 1) as well as need for long-term central venous access for intravenous therapy (n = 1) with a contraindication to or failed implantation in a standard position owing to central vein occlusions. Technical success was 100%. A number of five devices were placed in the right, three in the left thigh. Altogether 1,979 catheter days were analysed. One device was explanted owing to infection after 84days (late complication, 0.05/100 catheter days). No early complication was observed. Our data suggest that if implantation of a TIVPP is not favourable in a standard chest, upper arm or forearm position, femoral placement of the device may alternatively be used safely and with high technical success.

Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation.

OBJECTIVENo previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells.RESEARCH DESIGN AND METHODSAfter intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1-day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO2 <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections.RESULTSIn the native pancreas of nontransplanted animals, ∼30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets.CONCLUSIONSThe vascular engraftment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site.

Striated Muscle as Implantation Site for Transplanted Pancreatic Islets

Islet transplantation is an attractive treatment for selected patients with brittle type 1 diabetes. In the clinical setting, intraportal transplantation predominates. However, due to extensive early islet cell death, the quantity of islets needed to restore glucose homeostasis requires in general a minimum of two donors. Moreover, the deterioration of islet function over time results in few insulin-independent patients after five-year followup. Specific obstacles to the success of islet transplantation include site-specific concerns for the liver such as the instant blood mediated inflammatory reaction, islet lipotoxicity, low oxygen tension, and poor revascularization, impediments that have led to the developing interest for alternative implantation sites over recent years. Within preclinical settings, several alternative sites have now been investigated and proven favorable in various aspects. Muscle is considered a very promising site and has physiologically properties and technical advantages that could make it optimal for islet transplantation.

GLP-1–Receptor Scanning for Imaging of Human Beta Cells Transplanted in Muscle

To the Editor: Cell therapy is emerging as a realistic treatment for type 1 diabetes, on the basis of the prolonged success of intraportal islet transplantation in selected patients.1 Key improvements include the development of alternative implantation sites and new tools for in vivo detection of transplanted cells. In the absence of reliable beta-cell markers, previous clinical attempts to visualize transplanted islets have relied on magnetic resonance imaging2 and positron-emission tomography.3 However, these techniques necessitate the in vitro manipulation of islets and are limited by the short half-life of available labeling agents. Glucagon-like peptide 1 (GLP-1)–receptor scanning has been successfully . . .

Auditory Midbrain Implant: Present Clinical Results and Future Directions

Introduction: Tumor-induced damage in the cochlear nucleus may be responsible for the limited success of the auditory brainstem implant (ABI) in neurofibromatosis type 2 (NF2) patients. Therefore, an alternative implantation site that bypasses the damaged pathways in the brainstem may provide better hearing performance in NF2 patients. The central nucleus of the inferior colliculus (ICC) provides access to almost all ascending auditory information and has a well-defined tonotopic organization, which is important for an auditory prosthesis. The auditory midbrain implant (AMI) is a single-shank multielectrode array designed according to the dimensions of the human ICC with the goal of stimulating the different frequency layers of its central nucleus.

Reversal of Diabetes by Pancreatic Islet Transplantation into a Subcutaneous, Neovascularized Device

Transplantation of pancreatic islets for the treatment of type 1 diabetes allows for physiologic glycemic control and insulin-independence when sufficient islets are implanted via the portal vein into the liver. Intrahepatic islet implantation requires specific infrastructure and expertise, and risks inherent to the procedure include bleeding, thrombosis, and elevation of portal pressure. Additionally, the relatively higher drug metabolite concentrations in the liver may contribute to the delayed loss of graft function of recent clinical trials. Identification of alternative implantation sites using biocompatible devices may be of assistance improving graft outcome. A desirable bioartificial pancreas should be easy to implant, biopsy, and retrieve, while allowing for sustained graft function. The subcutaneous (SC) site may require a minimally invasive procedure performed under local anesthesia, but its use has been hampered so far by lack of early vascularization, induction of local inflammation, and mechanical stress on the graft. Chemically diabetic rats received syngeneic islets into the liver or SC into a novel biocompatible device consisting of a cylindrical stainless-steel mesh. The device was implanted 40 days prior to islet transplantation to allow embedding by connective tissue and neovascularization. Reversal of diabetes and glycemic control was monitored after islet transplantation. Syngeneic islets transplanted into a SC, neovascularized device restored euglycemia and sustained function long-term. Removal of graft-bearing devices resulted in hyperglycemia. Explanted grafts showed preserved islets and intense vascular networks. Ease of implantation, biocompatibility, and ability to maintain long-term graft function support the potential of our implantable device for cellular-based reparative therapies.