Application of robotics in abdominal organ transplantation: A bibliometric analysis.

BACKGROUND: Robotic transplant surgery has garnered worldwide attention since 2002. Discussions on this issue have led to more publications over the past decade. This study assessed global robotic organ transplantation studies using bibliometric analysis. METHOD: The study sample was robotic technique use in organ transplantation publications from 2002 to 2021 in the Web of Science database. We analysed top-cited authors, countries, institutions, journals, and keywords. Citations were used to visualise and analyse target literature in VOSviewer. RESULTS: 160 articles were included in the bibliometric study. Among the nations that are presently involved in the use of robotics in organ transplantation research, the United States of America leads robotic organ transplantation studies. The American Journal of Transplantation published the most articles overall. CONCLUSION: Based on publication and citation numbers, robotic organ transplantation techniques are becoming more global attention. This robotic abdominal organ transplant surgery bibliometric analysis review covers research output and hotspots.

Visualizing hypoxic modulation of beta cell secretions via a sensor augmented oxygen gradient.

One distinct advantage of microfluidic-based cell assays is their scalability for multiple concentrations or gradients. Microfluidic scaling can be extremely powerful when combining multiple parameters and modalities. Moreover, in situ stimulation and detection eliminates variability between individual bioassays. However, conventional microfluidics must combat diffusion, which limits the spatial distance and time for molecules traveling through microchannels. Here, we leveraged a multilayered microfluidic approach to integrate a novel oxygen gradient (0-20%) with an enhanced hydrogel sensor to study pancreatic beta cells. This enabled our microfluidics to achieve spatiotemporal detection that is difficult to achieve with traditional microfluidics. Using this device, we demonstrated the in situ detection of calcium, insulin, and ATP (adenosine triphosphate) in response to glucose and oxygen stimulation. Specifically, insulin was quantified at levels as low as 25 pg/mL using our imaging technique. Furthermore, by analyzing the spatial detection data dynamically over time, we uncovered a new relationship between oxygen and beta cell oscillations. We observed an optimum oxygen level between 10 and 12%, which is neither hypoxic nor normoxic in the conventional cell culture sense. These results provide evidence to support the current islet oscillator model. In future applications, this spatial microfluidic technique can be adapted for discrete protein detection in a robust platform to study numerous oxygen-dependent tissue dysfunctions.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Compared with calcineurin inhibitor-based immunosuppression, belatacept (BELA)-based treatment has been associated with better renal function but higher acute rejection rates. This phase 2 study (NCT02137239) compared the antirejection efficacy of BELA plus everolimus (EVL) with tacrolimus (TAC) plus mycophenolate mofetil (MMF), each following lymphocyte-depleting induction and rapid corticosteroid withdrawal. Methods: Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Results: Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. Conclusions: A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

Clinically translatable cytokine delivery platform for eradication of intraperitoneal tumors.

Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable cytokine delivery platform composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines. Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling predicts clinical translatability to humans. Notably, this platform elicited T cell responses in NHPs, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.

Robotic Assisted Living Donor Nephrectomies: A Safe Alternative to Laparoscopic Technique for Kidney Transplant Donation.

OBJECTIVE: To review outcomes after laparoscopic, robotic-assisted living donor nephrectomy (RLDN) in the first, and largest series reported to date. SUMMARY OF BACKGROUND DATA: Introduction of minimal invasive, laparoscopic donor nephrectomy has increased live kidney donation, paving the way for further innovation to expand the donor pool with RLDN. METHODS: Retrospective chart review of 1084 consecutive RLDNs performed between 2000 and 2017. Patient demographics, surgical data, and complications were collected. RESULTS: Six patients underwent conversion to open procedures between 2002 and 2005, whereas the remainder were successfully completed robotically. Median donor age was 35.7 (17.4) years, with a median BMI of 28.6 (7.7) kg/m2. Nephrectomies were preferentially performed on the left side (95.2%). Multiple renal arteries were present in 24.1%. Median operative time was 159 (54) minutes, warm ischemia time 180 (90) seconds, estimated blood loss 50 (32) mL, and length of stay 3 (1) days. The median follow-up was 15 (28) months. Complications were reported in 216 patients (19.9%), of which 176 patients (81.5%) were minor (Clavien-Dindo class I and II). Duration of surgery, warm ischemia time, operative blood loss, conversion, and complication rates were not associated with increase in body mass index. CONCLUSION: RLDN is a safe technique and offers a reasonable alternative to conventional laparoscopic surgery, in particular in donors with higher body mass index and multiple arteries. It offers transplant surgeons a platform to develop skills in robotic-assisted surgery needed in the more advanced setting of minimal invasive recipient operations.

Liver Transplantation With Grafts From Super Obese Donors.

There are limited data on liver transplant (LT) outcomes with grafts from super obese donors. The present study aims to evaluate a unique cohort of recipients following LT using grafts from donors with body mass index (BMI) ≥50. METHODS: Patients receiving grafts from donors with BMI ≥50 and BMI <50 from 2010 to 2019 were identified. A 1:2 case-control match was conducted to compare outcomes between the groups. Survival was analyzed using the Kaplan-Meier curves. RESULTS: Six hundred sixty-five adult LTs were performed in the study period. Eighteen patients receiving a graft from a donor with BMI ≥50 were identified and matched to 36 patients receiving a graft from a donor with BMI <50. Grafts from male donors were significantly lower in the donor BMI ≥50 group when compared with the donor BMI <50 group (16.7% versus 66.7%, P = 0.001). Liver biopsy was performed in 77.8% of grafts in the donor BMI ≥50 group, whereas only in 38.8% of the grafts in the donor BMI <50 group (P = 0.007). Recipients in the donor BMI ≥50 group had a significantly higher diagnosis rate of hepatocellular carcinoma pretransplant versus the donor BMI <50 group (38.9% versus 8.3%, respectively; P = 0.006). Major complications within 30 d did not differ statistically between groups. Biliary complications within the first 30 d were equal among groups (16.7%). Subanalysis comparing the super obese donor group versus the nonobese donor group showed no differences in terms of postoperative complications, readmission rate, graft rejection, or major complications including the need for reoperation, retransplantation, or mortality. Graft and patient survival at 1-, 3-, and 5-y graft were similar between the donor BMI ≥50 group versus donor BMI <50 group (94%/89%/89% versus 88%/88%/88%, P = 0.89, and 94%/94%/94% versus 88%/88%/88%, P = 0.48, respectively). CONCLUSIONS: LT with carefully selected grafts from super obese donors can be safely performed with outcomes comparable with non-super obese donor livers. Therefore, these types of grafts could represent a safe means to expand the donor pool.

Inhibition of PHLPP1/2 phosphatases rescues pancreatic ß-cells in diabetes.

Pancreatic ß-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to ß-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic ß-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate ß-cell death. PHLPPs directly dephosphorylate and regulate activities of ß-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control ß-cell apoptosis. Genetic inhibition of PHLPPs markedly improves ß-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our study presents PHLPPs as targets for functional regenerative therapy of pancreatic ß cells in diabetes.

Robot-assisted kidney transplantation is a safe alternative approach for morbidly obese patients with end-stage renal disease.

BACKGROUND: Many centres deny obese patients with a body mass index (BMI) >35 access to kidney transplantation due to increased intraoperative and postoperative complications. METHODS: From August 2017 to December 2019, 73 consecutive cases of kidney transplantation in morbidly obese patients were enrolled at a single university at the initiation of a robotic transplant surgery program. Outcomes of patients who underwent robotic assisted kidney transplant (RAKT) were compared to frequency-matched patients undergoing open kidney transplant (OKT). RESULTS: A total of 24 morbidly obese patients successfully underwent RAKT, and 49 obese patients received an OKT. The RAKT group developed fewer surgical site infections (SSI) than the OKT group. Graft function, creatinine, and glomerular filtration rate (GFR) were similar between groups 1 year after surgery. Graft and patient survival were 100% for both groups. CONCLUSIONS: RAKT offers a safe alternative for morbidly obese patients, who may otherwise be denied access to OKT.

Reduced replication fork speed promotes pancreatic endocrine differentiation and controls graft size.

Limitations in cell proliferation are important for normal function of differentiated tissues and essential for the safety of cell replacement products made from pluripotent stem cells, which have unlimited proliferative potential. To evaluate whether these limitations can be established pharmacologically, we exposed pancreatic progenitors differentiating from human pluripotent stem cells to small molecules that interfere with cell cycle progression either by inducing G1 arrest or by impairing S phase entry or S phase completion and determined growth potential, differentiation, and function of insulin-producing endocrine cells. We found that the combination of G1 arrest with a compromised ability to complete DNA replication promoted the differentiation of pancreatic progenitor cells toward insulin-producing cells and could substitute for endocrine differentiation factors. Reduced replication fork speed during differentiation improved the stability of insulin expression, and the resulting cells protected mice from diabetes without the formation of cystic growths. The proliferative potential of grafts was proportional to the reduction of replication fork speed during pancreatic differentiation. Therefore, a compromised ability to enter and complete S phase is a functionally important property of pancreatic endocrine differentiation, can be achieved by reducing replication fork speed, and is an important determinant of cell-intrinsic limitations of growth.

Robotic kidney transplantation in the obese patient: 10-year experience from a single center.

Despite increasing obesity rates in the dialysis population, obese kidney transplant candidates are still denied transplantation by many centers. We performed a single-center retrospective analysis of a robotic-assisted kidney transplant (RAKT) cohort from January 2009 to December 2018. A total of 239 patients were included in this analysis. The median BMI was 41.4 kg/m2 , with the majority (53.1%) of patients being African American and 69.4% of organs sourced from living donors. The median surgery duration and warm ischemia times were 4.8 hours and 45 minutes respectively. Wound complications (mostly seromas and hematomas) occurred in 3.8% of patients, with 1 patient developing a surgical site infection (SSI). Seventeen (7.1%) graft failures, mostly due to acute rejection, were reported during follow-up. Patient survival was 98% and 95%, whereas graft survival was 98% and 93%, at 1 and 3 years respectively. Similar survival statistics were obtained from patients undergoing open transplant over the same time period from the UNOS database. In conclusion, RAKT can be safely performed in obese patients with minimal SSI risk, excellent graft function, and patient outcomes comparable to national data. RAKT could improve access to kidney transplantation in obese patients due to the low surgical complication rate.

Genetically Encoded, Photostable Indicators to Image Dynamic Zn2+ Secretion of Pancreatic Islets.

As an essential element for living organisms, zinc (Zn2+) exerts its biological functions both intracellularly and extracellularly. Previous studies have reported a number of genetically encoded Zn2+ indicators (GEZIs), which have been widely used to monitor Zn2+ in the cytosol and intracellular organelles. However, it is challenging to localize existing GEZIs to the extracellular space to detect secreted Zn2+. Herein, we report two photostable, green fluorescent protein (GFP) based indicators, ZIBG1 and ZIBG2, which respond to Zn2+ selectively and have affinities suited for detecting Zn2+ secretion from intracellular vesicles. In particular, ZIBG2 can be effectively targeted to the extracellular side of plasma membrane. We applied cell surface-localized ZIBG2 to monitor glucose-induced dynamic Zn2+ secretion from mouse insulinoma MIN6 cells and primary mouse and human pancreatic islets. Because Zn2+ is co-released with insulin from ß-cells, the fluorescence of cell surface-localized ZIBG2 was shown to be a strong indicator for the functional potency of islets. Our work here has thus expanded the use of GEZIs to image dynamic Zn2+ secretion in live tissue. Because it is convenient to use genetically encoded indicators for expression over extended periods and for in vivo delivery, we envision future applications of ZIBG2 in development of induced ß-cells or islets to advance cell replacement therapies for diabetes and in direct imaging of Zn2+ secretion dynamics in vivo.

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived ß cells.

Despite advances in the differentiation of insulin-producing cells from human embryonic stem cells, the generation of mature functional ß cells in vitro has remained elusive. To accomplish this goal, we have developed cell culture conditions to closely mimic events occurring during pancreatic islet organogenesis and ß cell maturation. In particular, we have focused on recapitulating endocrine cell clustering by isolating and reaggregating immature ß-like cells to form islet-sized enriched ß-clusters (eBCs). eBCs display physiological properties analogous to primary human ß cells, including robust dynamic insulin secretion, increased calcium signalling in response to secretagogues, and improved mitochondrial energization. Notably, endocrine cell clustering induces metabolic maturation by driving mitochondrial oxidative respiration, a process central to stimulus-secretion coupling in mature ß cells. eBCs display glucose-stimulated insulin secretion as early as three days after transplantation in mice. In summary, replicating aspects of endocrine cell clustering permits the generation of stem-cell-derived ß cells that resemble their endogenous counterparts.

In situ graphene liquid cell-transmission electron microscopy study of insulin secretion in pancreatic islet cells.

BACKGROUND: Islet cell transplantation is one of the key treatments for type 1 diabetes. Understanding the mechanisms of insulin fusion and exocytosis are of utmost importance for the improvement of the current islet cell transplantation and treatment of diabetes. These phenomena have not been fully evaluated due either to the lack of proper dynamic imaging, or the lack of proper cell preservation during imaging at nanoscales. METHODS: By maintaining the native environment of pancreatic ß-cells between two graphene monolayer sheets, we were able to monitor the subcellular events using in situ graphene liquid cell (GLC)-transmission electron microscopy (TEM) with both high temporal and high spatial resolution. RESULTS: For the first time, the nucleation and growth of insulin particles until the later stages of fusion were imaged at nanometer scales. The release of insulin from plasma membrane involves the degradation of plasma membrane and drastic reductions in the shorter axis of the insulin particles. Sequential exocytosis results indicated the nucleation, growth and attachment of the new insulin particles to the already anchored ones, which is thermodynamically favorable due to the reduction in total surface, further reducing the Gibbs free energy. The retraction of the already anchored insulin toward the cell is also monitored for the first time live at nanoscale resolution. CONCLUSION: Investigation of insulin granule dynamics in ß-cells can be investigated via GLC-TEM. Our findings with this technology open new realms for the development of novel drugs on pathological pancreatic ß-cells, because this approach facilitates observing the effects of the stimuli on the live cells and insulin granules.

Minimally invasive, robot-assisted procedure for kidney transplantation among morbidly obese: Positive outcomes at 5 years post-transplant.

The pre-transplant weight loss required of end-stage renal disease patients is often unachievable. Though robot-assisted procedures among extremely obese have shown minimal complication, long-term outcomes are understudied. Previously, we reported no difference in 6-month patient and graft survival among 28 robot-assisted transplant cases (2009-2013) and 28 open controls (2004-2010). Groups were frequency-matched on age, sex, race, donor compatibility, disease, and dialysis history. Cases had greater median pre-transplant body mass index (BMI; 42.3 (31.1-64.3) vs 36.8 (30.0-51.1)). Here, we compared patient and graft survival through 5 years post-transplant. Infection, wound complications, and significant re-hospitalizations were collected. One-, three-, and five-year graft survival were 100%, 100%, and 89.3% among cases, and 96.4%, 85.7%, and 78.6% among controls. Rejection within 1 year was greater among cases (11 vs 8). Five-year rates were similar (P = 0.54). Post-transplant BMI remained comparable. No cases and eight controls experienced surgical site infection (SSI). Two cases and one control experienced hernias. Post-transplant diabetes was documented among five cases and six controls. Three deaths occurred among cases, two among controls. This is the most extensive known follow-up of such obese recipients of robot-assisted transplant. Our procedure is a promising pathway to transplant and decreased mortality for those deemed too high risk for conventional surgery.

Robotic pancreas transplantation: the state of the art.

PURPOSE OF REVIEW: Robotic pancreas transplantation is a novel procedure that aims to reduce surgical invasiveness, and thereby limit complications related to the surgical access. Given that few centers are providing robotic transplantation, this review serves as a state of the science article to outline early experiences and highlight areas for future research. RECENT FINDINGS: Pancreas transplantation results in relatively high rates of wound and other surgical complications that are known to deleteriously impact outcomes. The minimally invasive, robotic-assisted approach decreases wound complications. Because of the obesity epidemic, overweight and obese status is encountered in an increasing number of transplant candidates. These candidates are subject to increased wound-related complications and most benefit from a robotic approach. The first clinical reports on laparoscopic, robotic-assisted kidney and pancreas transplantation indicate a significant decrease in wound complications and excellent outcomes in obese patients otherwise denied access to transplantation. SUMMARY: With excellent results achieved in surgically challenging patients and further accumulation of experience, laparoscopic, robotic-assisted pancreas and kidney transplantation may evolve to a new standard approach.

Robotic Pancreas Transplantation.

Obesity is considered a relative contraindication to pancreas transplantation due to an overall increased risk in wound-related complications and surgical site infections. The rationale for performing pancreas transplantation in a minimally invasive fashion is to reduce these risks, which can be associated with inferior patient and graft survival following pancreas transplantation in morbidly obese patients. At the University of Illinois at Chicago, the initial series of robotic-assisted pancreas transplantation in obese patient with type 1 and 2 diabetes has been performed. In this article, surgical technique and world experience in robotic pancreas transplantation are described.

Report of the Key Opinion Leaders Meeting on Stem Cell-derived Beta Cells.

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

ß-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

ß-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into ß-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide-positive cells, expressing markers of mature ß-cells, including MAFA and NKX6.1. Upon transplantation in immunodeficient mice, grafted cells form vascularized islet-like structures containing MAFA/C-peptide-positive cells. These ß-cells adapt insulin secretion to ambient metabolite status and show normal insulin processing. Importantly, NT-ES-ß-cells maintain normal blood glucose levels after ablation of the mouse endogenous ß-cells. Cystic structures, but no teratomas, were observed in NT-ES-ß-cell grafts. Isogenic induced pluripotent stem cell lines showed greater variability in ß-cell differentiation. Even though different methods of somatic cell reprogramming result in stem cell lines that are molecularly indistinguishable, full differentiation competence is more common in ES cell lines than in induced pluripotent stem cell lines. These results demonstrate the suitability of NT-ES-ß-cells for cell replacement for type 1 diabetes and provide proof of principle for therapeutic cloning combined with cell therapy.

Long-term outcomes of living-related small intestinal transplantation in children: A single-center experience.

Pediatric patients with irreversible intestinal failure present a significant challenge to meet the nutritional needs that promote growth. From 2002 to 2013, 13 living-related small intestinal transplantations were performed in 10 children, with a median age of 18 months. Grafts included isolated living-related intestinal transplantation (n=7), and living-related liver and small intestine (n=6). The immunosuppression protocol consisted of induction with thymoglobulin and maintenance therapy with tacrolimus and steroids. Seven of 10 children are currently alive with a functioning graft and good quality of life. Six of the seven children who are alive have a follow-up longer than 10 years. The average time to initiation of oral diet was 32 days (range, 13-202 days). The median day for ileostomy takedown was 77 (range, 18-224 days). Seven children are on an oral diet, and one of them is on supplements at night through a g-tube. We observed an improvement in growth during the first 3 years post-transplant and progressive weight gain throughout the first year post-transplantation. Growth catch-up and weight gain plateaued after these time periods. We concluded that living donor intestinal transplantation potentially offers a feasible, alternative strategy for long-term treatment of irreversible intestinal failure in children.