Extrahepatic transplant sites for islet xenotransplantation

Contreras, Juan L.

doi:10.1111/j.1399-3089.2008.00461.x

Cited by 16 publications

(9 citation statements)

References 26 publications

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“…Biomaterial-based approaches have traditionally involved encapsulation and isolation; however, some scaffolds have been developed that encourage host integration [17, 22, 23]. A biomaterial scaffold can provide a support that enables transplantation at extrahepatic and extravascular sites, which will avoid the negative influences of the liver environment and the IBMIR [24, 25]. Importantly, biomaterial scaffolds implanted extrahepatically may be retrievable, which could facilitate the adoption of insulin-producing cells derived from stem cells.…”

Section: Engraftmentmentioning

confidence: 99%

Advancing islet transplantation: from engraftment to the immune response

Gibly¹,

Graham²,

Luo³

et al. 2011

Diabetologia

127

108

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The promise and progress of islet transplantation for treating type 1 diabetes has been challenged by obstacles to patient accessibility and long-term graft function that may be overcome by integrating emerging technologies in biomaterials, drug delivery and immunomodulation. The hepatic microenvironment and traditional systemic immunosuppression stress the vulnerable islets and contribute to the limited success of transplantation. Locally delivering extracellular matrix proteins and trophic factors can enhance transplantation at extrahepatic sites by promoting islet engraftment, revascularisation and long-term function while avoiding unintended systemic effects. Cell- and cytokine-based therapies for immune cell recruitment and reprogramming can inhibit local and systemic immune system activation that normally attacks transplanted islets. Combined with antigen-specific immunotherapies, states of operational tolerance may be achievable, reducing or eliminating the long-term pharmaceutical burden. Integration of these technologies to enhance engraftment and combat rejection may help to advance the therapeutic efficacy and availability of islet transplantation.

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Section: Engraftmentmentioning

confidence: 99%

Advancing islet transplantation: from engraftment to the immune response

Gibly¹,

Graham²,

Luo³

et al. 2011

Diabetologia

127

108

View full text Add to dashboard Cite

show abstract

“…The hepatic and intravascular site of islet transplantation has been identified as contributing to poor islet survival posttransplant due to the immediate damage caused by the instant blood-mediated inflammatory reaction (IBMIR) that occurs when islets encounter whole blood and a foreign hepatic environment that provides additional challenges to engraftment and long-term survival (3,23). Extrahepatic and extravascular sites have been challenging because of the need for creating space to accommodate the relatively large mass of donor cells required while facilitating survival and function (8,17,30). Biomaterial scaffolds provide an opportunity to define an extrahepatic site beyond a surgical pouch and enhance the site for maximal islet engraftment, survival, and function, significantly improving the efficiency of islet cell delivery as a therapy for type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Porous Scaffolds Support Extrahepatic Human Islet Transplantation, Engraftment, and Function in Mice

et al. 2013

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Islet transplantation as a therapy or cure for type 1 diabetes has significant promise but has been limited by islet mass requirements and long-term graft failure. The intrahepatic and intravascular site may be responsible for significant loss of transplanted islets. Nonencapsulating biomaterial scaffolds provide a strategy for architecturally defining and modulating extrahepatic sites beyond the endogenous milieu to enhance islet survival and function. We utilized scaffolds to transplant human islets into the intraperitoneal fat of immunodeficient mice. A smaller human islet mass than previously reported reversed murine diabetes and restored glycemic control at human blood glucose levels. Graft function was highly dependent on the islet number transplanted and directly correlated to islet viability, as determined by the ATP-to-DNA ratio. Islets engrafted and revascularized in host tissue, and glucose tolerance testing indicated performance equivalent to healthy mice. Addition of extracellular matrix, specifically collagen IV, to scaffold surfaces improved graft function compared to serum-supplemented media. Porous scaffolds can facilitate efficient human islet transplantation and provide a platform for modulating the islet microenvironment, in ways not possible with current clinical strategies, to enhance islet engraftment and function.

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“…Importantly, the omentum has gained significant attention as a pancreatic islet transplantation site, because it provides a large implantation volume, easy accessibility, and immunological privilege from host rejection of the implanted islets [34, 37]. However, there is still significant islet death in the omentum which is most likely associated with ischemia and inadequate nutrient supply due to incomplete revascularization [38]. Thus, rapid islet revascularization is important to provide sufficient nutrients and oxygen to the implanted islets; this is also essential for the survival of any other implanted tissues in the omentum.…”

Section: Introductionmentioning

confidence: 99%

“…As an angiogenic tissue engineering scaffold, the hybrid nanosack is expected to recruit and connect blood vessels from the host to the graft at the omentum by providing multi-stage release of FGF-2 and enhanced porous structures. Besides enhancing vascularization, the hybrid nanosack also prevents the leakage of implanted tissues from the omentum, which is another issue for the utilization of the omentum site [38]. By combining the desirable qualities of hydrogel and electrospun materials, we have developed a new class of tissue scaffold which can be applied to improve outcomes of tissue grafts requiring vascularization in the omentum.…”

Section: Introductionmentioning

confidence: 99%

A bio-inspired hybrid nanosack for graft vascularization at the omentum

et al. 2016

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For three-dimensional tissue engineering scaffolds, the major challenges of hydrogels are poor mechanical integrity and difficulty in handling during implantation. In contrast, electrospun scaffolds provide tunable mechanical properties and high porosity; but, are limited in cell encapsulation. To overcome these limitations, we developed a “hybrid nanosack” by combination of a peptide amphiphile (PA) nanomatrix gel and an electrospun poly (ε-caprolactone) (ePCL) nanofiber sheet with porous crater-like structures. This hybrid nanosack design synergistically possessed the characteristics of both approaches. In this study, the hybrid nanosack was applied to enhance local angiogenesis in the omentum, which is required of tissue engineering scaffolds for graft survival. The ePCL sheet with porous crater-like structures improved cell and blood vessel penetration through the hybrid nanosack. The hybrid nanosack also provided multi-stage fibroblast growth factor-2 (FGF-2) release kinetics for stimulating local angiogenesis. The hybrid nanosack was implanted into rat omentum for 14 days and vascularization was analyzed by micro-CT and immunohistochemistry; the data clearly demonstrated that both FGF-2 delivery and porous crater-like structures work synergistically to enhance blood vessel formation within the hybrid nanosack. Therefore, the hybrid nanosack will provide a new strategy for engineering scaffolds to achieve graft survival in the omentum by stimulating local vascularization, thus overcoming the limitations of current strategies.

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Extrahepatic transplant sites for islet xenotransplantation

Cited by 16 publications

References 26 publications

Advancing islet transplantation: from engraftment to the immune response

Advancing islet transplantation: from engraftment to the immune response

Porous Scaffolds Support Extrahepatic Human Islet Transplantation, Engraftment, and Function in Mice

A bio-inspired hybrid nanosack for graft vascularization at the omentum

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