Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation

Weaver, Jessica D.; Headen, Devon M.; Hunckler, Michael D.; Coronel, María M.; Stabler, Cherie L.; Garcı́a, Andrés J.

doi:10.1016/j.biomaterials.2018.04.047

Cited by 112 publications

(125 citation statements)

References 34 publications

(39 reference statements)

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“…The diameter of traditional islet encapsulation devices has been limited to a few hundred micrometers to enable sufficient oxygen diffusion from the surrounding environment. [4a,5b] By reducing the thickness of the shell structure through careful design of the coaxial printing nozzle of the 3D PICT system, the distance between every single islet and the surrounding environment can be controlled to less than 400 µm. Combined with appropriate porosity and high surface to volume ratios that can be achieved with a 3D structure design and printing process, a far more favorable microenvironment can be created inside the hydrogel scaffolds to enhance islet survival.…”

Section: Resultsmentioning

confidence: 99%

“…To improve the viability of transplanted islets, various islet encapsulation strategies have been investigated, including macro‐encapsulation of islets in retrievable devices and microencapsulation in hydrogel microspheres. [1b,6] Using the macroencapsulation device, islets can be physically isolated from the surrounding environment by semipermeable cell containment barriers.…”

Section: Introductionmentioning

confidence: 99%

“…[4a,7] However, it is difficult to control the localization of islets during implantation and ensure practical surgical implantation. [5b,8]…”

Section: Introductionmentioning

confidence: 99%

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Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet‐Containing Constructs

Liu

Carter

Renes

et al. 2019

Adv Healthcare Materials

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Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin‐based bioink formulation is optimized for islet and islet‐related cell encapsulation and 3D printing. In addition, a custom‐designed coaxial printer is developed for 3D printing of multicellular islet‐containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet‐Containing Constructs

Liu

Carter

Renes

et al. 2019

Adv Healthcare Materials

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“…Human MSC and Rat Islet Encapsulation and Viability Assay : Rat islets were isolated according to previously published protocols before being resuspended in 20 × 10 −3 m HEPES in PBS at 2× concentration (10 islet equivalent µL −1 ) . The rat islets were mixed at 1:1 ratio with a 2× macromer solution in PBS to achieve a final concentration of 4.0% w/v PEG‐4NB (aNB or eNB), 2.0 × 10 −3 m RGD (GRGDSPC, Genscript), 3.0 × 10 −3 m PEG‐DT, and 0.5 × 10 −3 m LAP.…”

Section: Methodsmentioning

confidence: 99%

Linkage Groups within Thiol–Ene Photoclickable PEG Hydrogels Control In Vivo Stability

Hunckler

Medina

Coronel

et al. 2019

Adv Healthcare Materials

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step-growth photopolymerization based on the orthogonal reaction between thiol and norbornene has emerged as an attractive strategy for many biomedical applications. [7,8] These step-growth photoinitiated (thiol-ene) hydrogels have shown great promise in 2D and 3D cell culture and organoid development, due, in part, to the low radical concentration and physiological pH required for crosslinking. [9] In addition, thiol-ene PEG hydrogels exhibit high cytocompatibility, precise spatiotemporal control of gelation, tunable degradation, and versatile modulation of biophysical and biochemical properties. The versatility of these hydrogels is demonstrated through extensive applications, ranging from protein and drug delivery, [10][11][12][13][14][15][16][17] cartilage development, [18,19] osteogenic differentiation, [20,21] endothelial tubulogenesis, [22] brain tumor models, [23] synthetic matrix mimics, [8,[24][25][26][27][28][29][30][31][32] 2D culture substrates, [33][34][35] and islet and cell encapsulation. [36][37][38][39][40][41][42][43] However, these applications have been exclusively conducted in vitro, yielding little insight into the in vivo behavior of these hydrogels. Our initial exploratory studies with these widely used 4-arm, ester-linked, thiol-ene PEG (PEG-4eNB) hydrogels implanted into the intraperitoneal space of mice unexpectedly showed that the hydrogels undergo rapid degradation in vivo ( Figure S1, Supporting Information). Hypothesizing that the poor in vivo stability may result from the hydrolysis of the ester linkage between the PEG backbone and norbornene functional end group, we replaced this connection with a more hydrolytically stable amide linkage. Here, we describe the characterization and implementation of 4-arm, amide-linked, thiol-ene PEG (PEG-4aNB) hydrogels that retain long-term stability in both in vitro and in vivo environments. We demonstrate rapid (<24 h) in vivo degradation of PEG-4eNB and gradual (>35 days) in vitro degradation. Conversely, PEG-4aNB retains long-term in vitro and in vivo stability while maintaining high cytocompatibility, and this material can be utilized as an appropriate replacement in many biomedical applications.The ester linkage in PEG hydrogels has been reported to be hydrolytically labile over the course of many weeks in cell culture. [44] This feature has been exploited further by introducing ester-containing poly(caprolactone) linkage groups to accelerate in vitro degradation of PEG hydrogels to within a Thiol-norbornene (thiol-ene) photoclickable poly(ethylene glycol) (PEG) hydrogels are a versatile biomaterial for cell encapsulation, drug delivery, and regenerative medicine. Numerous in vitro studies with these 4-arm ester-linked PEG-norbornene (PEG-4eNB) hydrogels demonstrate robust cytocompatibility and ability to retain long-term integrity with nondegradable crosslinkers. However, when transplanted in vivo into the subcutaneous or intraperitoneal space, these PEG-4eNB hydrogels with nondegradable crosslinkers rapidly degrade within 24 h. This char...

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“…Open macroporous encapsulation devices that allow revascularization of islets have demonstrated some promise but it still takes at least 7-14 days until a new functional vasculature is established in transplanted islets [3] and immunosuppressants are always required. Macro-and microencapsulation of islets and beta cells are an alternative to open devices that introduce a physical barrier to protect the transplanted islets from the host's immune system, potentially circumventing the need for immunosuppressive therapy [4] and mitigating some risks by protecting the patient from rogue cells in case of induced pluripotent-or embryonic stem cell-derived beta cell therapy [5][6][7][8][9][10][11]. Whatever the strategy chosen, the clinical success of encapsulation devices is hampered by a number of complex factors such as acute and long-term ischemia, limited vascularization and mass transport of crucial nutrients such as oxygen and insulin, and suboptimal biomaterial properties [12].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in alpha and beta cells as a selection criterion for biocompatible biomaterials

Sthijns

Jetten

Mohammed

et al. 2019

Preprint

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The clinical success of islet transplantation is limited by factors including acute ischemia, stress upon transplantation, and delayed vascularization. Islets experience high levels of oxidative stress due to delayed vascularization after transplantation and this can be further aggravated by their encapsulation and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, PEOT/PBT300 did not induce oxidative stress or reduce viability in MIN6 beta cells, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets. These data indicate that PEOT/PBT300 may be a suitable biomaterial for an islet encapsulation device. PEOT/PBT4000

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Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation

Cited by 112 publications

References 34 publications

Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet‐Containing Constructs

Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet‐Containing Constructs

Linkage Groups within Thiol–Ene Photoclickable PEG Hydrogels Control In Vivo Stability

Oxidative stress in alpha and beta cells as a selection criterion for biocompatible biomaterials

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