silicon and Diabetes-Mellitus--Type-1

Materials advances enabled by nanotecbnology have brought about promising approaches to improve the encapsulation mechanism for immunoisolated cell-based drug delivery. Cell-based drug delivery is a promising treatment for many diseases but has thus far achieved only limited clinical success. Treatment of insulin dependent diabetes mellitus (IDDM) by transplantation of pancreatic beta-cells represents the most anticipated application ofcell-based drug delivery technology. This review outlines the challenges involved with maintaining transplanted cell viability and discusses how inorganic nanoporous membranes may be useful in achieving clinical success.

Topics: Aluminum Oxide; Animals; Diabetes Mellitus, Type 1; Drug Compounding; Drug Delivery Systems; Humans; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Membranes, Artificial; Nanostructures; Porosity; Silicon; Titanium

Type 1 diabetic patients with severe hypoglycemia unawareness have benefitted from cellular therapies, such as pancreas or islet transplantation; however, donor shortage and the need for immunosuppression limits widespread clinical application. We previously developed an intravascular bioartificial pancreas (iBAP) using silicon nanopore membranes (SNM) for immunoprotection. To ensure ample nutrient delivery, the iBAP will need a cell scaffold with high hydraulic permeability to provide mechanical support and maintain islet viability and function. Here, we examine the feasibility of superporous agarose (SPA) as a potential cell scaffold in the iBAP. SPA exhibits 66-fold greater hydraulic permeability than the SNM along with a short (<10 μm) diffusion distance to the nearest islet. SPA also supports short-term functionality of both encapsulated human islets and stem-cell-derived enriched β-clusters in a convection-based system, demonstrated by high viability (>95%) and biphasic insulin responses to dynamic glucose stimulus. These findings suggest that the SPA scaffold will not limit nutrient delivery in a convection-based bioartificial pancreas and merits continued investigation.

Topics: Adult; Diabetes Mellitus, Type 1; Glucose; Graft vs Host Disease; Humans; Insulin-Secreting Cells; Islets of Langerhans; Islets of Langerhans Transplantation; Membranes, Artificial; Nanopores; Pancreas, Artificial; Sepharose; Silicon; Stem Cell Transplantation; Tissue Scaffolds

Accumulating evidence indicates much higher failure rates for biomedical titanium implants in diabetic patients. This phenomenon is attributed to impaired osteoblastic function, suppressed angiogenesis capacity, and abnormal osteoclast activation in diabetic patients. Our previous study demonstrated that titanium implants coated with highly crystalline nanostructured hydroxyapatite (nHA) promoted the osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone-implant osseointegration under healthy conditions. Furthermore, recent studies showed that silicon-substituted biomaterials exhibited excellent osteogenesis and angiogenesis performance while repressing osteoclastogenesis. Hence, we proposed that a combination of nanostructural modification and Si substitution might produce synergetic effects to mitigate the impaired osseointegration of bone implants under diabetes mellitus (DM) conditions. To confirm this hypothesis, titanium implants coated with highly crystalline Si-substituted nHA (Si-nHA) were successfully fabricated via atmospheric plasma spraying combined with hydrothermal treatment. An in vitro study demonstrated that compared to the original HA coating, the nHA coating improved osteogenic and angiogenic differentiation and altered the OPG/RANKL ratio of DM-BMSCs. In addition, the Si-nHA coating further enhanced cell proliferation, improved osteogenic and angiogenic differentiation, and repressed osteoclastogenesis in DM-BMSCs. An in vivo study confirmed that the titanium implants coated with nHA or Si-nHA effectively promoted bone formation and bone-implant osseointegration in a diabetic rabbit model, with the Si-nHA coating exhibiting the best stimulatory effect. Collectively, the results suggest that the nanostructured topography and Si substitution act synergistically to ameliorate the poor bone regeneration and osseointegration associated with DM. Thus, the results provide a promising coating method for dental and orthopedic applications under diabetic conditions.

Topics: Alloxan; Animals; Coated Materials, Biocompatible; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Durapatite; Hypoglycemic Agents; Male; Nanostructures; Osseointegration; Particle Size; Rabbits; Silicon; Surface Properties

Problems associated with islet transplantation for Type 1 Diabetes (T1D) such as shortage of donor cells, use of immunosuppressive drugs remain as major challenges. Immune isolation using encapsulation may circumvent the use of immunosuppressants and prolong the longevity of transplanted islets. The encapsulating membrane must block the passage of host's immune components while providing sufficient exchange of glucose, insulin and other small molecules. We report the development and characterization of a new generation of semipermeable ultrafiltration membrane, the silicon nanopore membrane (SNM), designed with approximately 7 nm-wide slit-pores to provide middle molecule selectivity by limiting passage of pro-inflammatory cytokines. Moreover, the use of convective transport with a pressure differential across the SNM overcomes the mass transfer limitations associated with diffusion through nanometer-scale pores. The SNM exhibited a hydraulic permeability of 130 ml/hr/m(2)/mmHg, which is more than 3 fold greater than existing polymer membranes. Analysis of sieving coefficients revealed 80% reduction in cytokines passage through SNM under convective transport. SNM protected encapsulated islets from infiltrating cytokines and retained islet viability over 6 hours and remained responsive to changes in glucose levels unlike non-encapsulated controls. Together, these data demonstrate the novel membrane exhibiting unprecedented hydraulic permeability and immune-protection for islet transplantation therapy.

Topics: Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Membranes, Artificial; Nanopores; Nanotechnology; Particle Size; Silicon

The normal pancreatic beta-cell membrane depolarizes in response to increasing concentrations of glucose in a bursting pattern. At <7 mM (126 mg/dl), the cell is electrically silent. The bursting pulse width increases as glucose rises >7 mM (126 mg/dl) until a continuous train of bursting is seen at >25 mM (450 mg/dl). A bio-inspired silicon device has been developed using analogue electronics to implement membrane depolarization of the beta cell. The device is ultralow powered, miniaturized (5 x 5 mm), and produces a bursting output identical to that characterized in electrophysiological studies.. The goal of this study was to demonstrate the ability of silicon implementation of beta-cell electrophysiology to respond to a simulated glucose input and to drive an infusion pump in vitro.. The silicon device response to a current source was recorded at varying simulated glucose concentrations. Subsequently, the bursting response to a changing analyte concentration measured by an amperometric enzyme electrode was converted to a voltage, driving a syringe pump loaded with a 50-ml syringe containing water.. Bursting responses are comparable to those recorded in electrophysiology. Silicon beta-cell implementation bursts with a pulse width proportional to concentration and is able to drive an infusion pump.. This is the first in vitro demonstration of closed loop insulin delivery utilizing miniaturized silicon implementation of beta-cell physiology in analogue electronics.

Topics: Algorithms; Blood Glucose; Diabetes Mellitus, Type 1; Diagnostic Equipment; Equipment Design; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin-Secreting Cells; Materials Testing; Membrane Potentials; Miniaturization; Models, Biological; Monitoring, Physiologic; Silicon; Time Factors

A microfabricated silicon-based biocapsule for the immunoisolation of cell transplants is presented. The biocapsule-forming process employs bulk micromachining to define cell-containing chambers within single crystalline silicon wafers. These chambers interface with the surrounding biological environment through polycrystalline silicon filter membranes. The membranes are surface micromachined to present a high density of uniform pores, thus affording sufficient permeability to oxygen, glucose, and insulin. The pore dimensions, as small as 20 nm, are designed to impede the passage of immune molecules and graft-borne viruses. The underlying filter-membrane nanotechnology has been successfully applied in controlled cell culture systems (Ferrari et al., 1995), and is under study for viral elimination in plasma fractionation protocols. Here we report the encouraging results of in vitro experiments investigating the biocompatibility of the microfabricated biocapsule, and demonstrate that encapsulated rat neonatal pancreatic islets significantly outlive and outperform controls in terms of insulin-secretion capability over periods of several weeks. These results appear to warrant further investigations on the potential of cell xenografts encapsulated within microfabricated, immunoisolating environments for the treatment of insulin-dependent diabetes.

Topics: Animals; Biotechnology; Capsules; Diabetes Mellitus, Type 1; In Vitro Techniques; Islets of Langerhans; Islets of Langerhans Transplantation; Materials Testing; Membranes, Artificial; Rats; Silicon