Hyperglycemic Conditions Enhance the Mechanosensitivity of Proinflammatory RAW264.7 Macrophages.

Macrophages are a primary contributor to the orchestration and severity of the foreign body response. As phagocytes and antigen-presenting cells, macrophages engage foreign objects, producing chemokines, degrading enzymes, and proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Encapsulated islet transplantation (EIT) is a return of function therapy in which donor insulin-secreting cells are encased in a biomaterial and implanted into a diabetic patient to regulate blood glucose levels. However, the foreign body response by macrophages to the encapsulated islet allograft may cause rejection. Recent studies have shown that substrate stiffness affects macrophage activity, which can inform EIT capsule design. However, due to the dysregulation of glucose maintenance in diabetic patients, varying from normoglycemic to hypoglycemic or hyperglycemic conditions, it is imperative to determine if glucose dysregulation affects macrophage mechanosensitivity to EIT biomaterials. This study explores the relationship between glucose metabolism and mechanosensitivity and the ultimate impact on proinflammatory macrophage function in static hyperglycemic and normoglycemic conditions. Using a 2-dimensional (2D) polyacrylamide model of 3-order magnitude in stiffness, 2, 15, and 274 kPa Young's moduli, the effect of glycemic condition on the mechanosensitive characteristics of unstimulated and proinflammatory RAW264.7 macrophage function in vitro using lipopolysaccharide (LPS) was examined. Hyperglycemic conditions were found to impact macrophage response to substrate stiffness significantly. Notably, TNF-α secretion was significantly reduced as substrate stiffness increased in LPS-stimulated hyperglycemic conditions, whereas normoglycemic macrophages held similar secretion across all stiffnesses. Stiffness-influenced differences in cytokine secretion were also induced in IL-6 secretion by hyperglycemic conditions. Hyperglycemic conditions promoted a biphasic trend in IL-6 cytokine secretion and gene expression by proinflammatory macrophages with significantly decreased production when cultured on 15 kPa compared to production on 2 and 274 kPa. Although hyperglycemic conditions drastically increased IL-10 secretion, stiffness-influenced differences were not shown when compared to the same glycemic condition. Furthermore, under LPS stimulation, lactate secretion had an inverse relationship to TNF-α secretion. However, no significant stiffness-influenced difference was demonstrated in glucose transporter 1 (GLUT1) expression, glucose uptake, or GAPDH. These findings suggest that hyperglycemic conditions enhance the mechanosensitivity of proinflammatory macrophages and should be explored further. Impact statement The work presented increases our understanding of the effect of glycemic condition on macrophage mechanosensitivity related to substrate stiffness. This has ramifications on the design of material-based therapies, such as encapsulated islet transplantation, for type 1 diabetic patients who experience glycemic dysregulation.

A Case for Material Stiffness as a Design Parameter in Encapsulated Islet Transplantation.

Diabetes is a disease that plagues over 463 million people globally. Approximately 40 million of these patients have type 1 diabetes mellitus (T1DM), and the global incidence is increasing by up to 5% per year. T1DM is where the body's immune system attacks the pancreas, specifically the pancreatic beta cells, with antibodies to prevent insulin production. Although current treatments such as exogenous insulin injections have been successful, exorbitant insulin costs and meticulous administration present the need for alternative long-term solutions to glucose dysregulation caused by diabetes. Encapsulated islet transplantation (EIT) is a tissue-engineered solution to diabetes. Donor islets are encapsulated in a semipermeable hydrogel, allowing the diffusion of oxygen, glucose, and insulin but preventing leukocyte infiltration and antibody access to the transplanted cells. Although successful in small animal models, EIT is still far from commercial use owing to necessary long-term systemic immunosuppressants and consistent immune rejection. Most published research has focused on tailoring the characteristics of the capsule material to promote clinical viability. However, most studies have been limited in scope to biochemical changes. Current mechanobiology studies on the effect of substrate stiffness on the function of leukocytes, especially macrophages-primary foreign body response (FBR) orchestrators, show promise in tailoring a favorable response to tissue-engineered therapies such as EIT. In this review, we explore strategies to improve the clinical viability of EIT. A brief overview of the immune system, the FBR, and current biochemical approaches will be elucidated throughout this exploration. Furthermore, an argument for using substrate stiffness as a capsule design parameter to increase EIT efficacy and clinical viability will be posed.

Cervical cerclage in delayed interval delivery in a multifetal pregnancy: a review of seven case series.

OBJECTIVE: To examine whether cervical cerclage after the first delivery prolongs the inter-delivery interval in delayed interval deliveries. STUDY DESIGN: We identified 66 case reports and case series of delayed interval delivery published between 1880 and 2002. We selected seven case series that identified all cases of delayed interval delivery in their institutions during a specified period. RESULTS: Despite routine use of broad-spectrum prophylactic antibiotics, the average incidence of clinical intrauterine infection after the first delivery was 36% (95% confidence interval (CI): 26-46%). The incidence of maternal sepsis was 4.9% (95% CI: 0.2-9.6%). Studies in which cerclage was infrequently used reported a shorter inter-delivery interval compared to studies where cerclage was used in all cases (median is equal to 9 days versus 26 days, respectively, P<0.001) despite similar gestational ages at the first delivery, types of antibiotics, tocolytics, and incidence of infection. After controlling for other factors, the use of cerclage did not significantly increase the risk of intrauterine infection (adjusted relative risk=1.1, 95% CI: 0.4-3.5). CONCLUSION: Cervical cerclage after the first delivery is associated with a longer inter-delivery interval without increasing the risk of intrauterine infection.

Survival of other fetuses after a fetal death in twin or triplet pregnancies.

OBJECTIVE: To estimate the frequency of fetal death in multifetal pregnancies and the probability of survival to age 1 year for twins or triplets in which at least one fetal death occurred at 20 weeks' gestation or more. METHODS: We used the Matched Multiple Birth File from the US National Center for Health Statistics, which included 152,233 sets of twins and 5356 sets of triplets registered from 1995 to 1997. The Cox proportional hazards model was used to estimate the adjusted relative risk of death before age 1 year for remaining twins and triplets. RESULTS: Fetal death at 20 weeks' gestation or later was uncommon, occurring in 2.6% of twin and 4.3% of triplet gestations. After adjustment for confounders, the survival of the remaining fetuses was inversely related to the time of the first fetal demise. Same-sex twins were two times more likely than opposite-sex twins to die after an intrauterine demise at 25-32 weeks' gestation and were more than three times more likely to die after a death at 33 weeks' gestation or more. CONCLUSION: After a fetal death in a multifetal pregnancy at 20 weeks' gestation or later, the survival of the remaining fetuses is inversely related to the time the death occurred. Among twins, survival also depends on sex concordance, with opposite-sex twins more likely than same-sex twins to survive.

Methodologic considerations for population-based research on fetal deaths: overcoming data gaps.

Fetal deaths comprise a large component of perinatal mortality and remain an understudied pregnancy outcome, especially from a population perspective. Interpretation of the findings from clinical or community-based studies can be difficult without a clear understanding of fetal death at the population level. This article addresses the critical data gaps underlying population-based research on fetal deaths, including the magnitude and scope of the problem, the probability of occurrence, the populations at risk, and the importance of accounting for prior reproductive history. Suggestions are given for new avenues of population-based research such as prospective inquiry of couples attempting pregnancy and newer analytic and modeling strategies for assessing risk and for addressing the lack of independence in pregnancy outcomes.