BackgroundUnderstanding the effects of capsule composition and transplantation site on graft outcomes of encapsulated islets will aid in the development of more effective strategies for islet transplantation without immunosuppression.MethodsHere, we evaluated the effects of transplanting alginate (ALG)-based microcapsules (Micro) in the confined and well-vascularized epididymal fat pad (EFP) site, a model of the human omentum, as opposed to free-floating in the intraperitoneal cavity (IP) in mice. We also examined the effects of reinforcing ALG with polyethylene glycol (PEG). To allow transplantation in the EFP site, we minimized capsule size to 500 ± 17 μm. Unlike ALG, PEG resists osmotic stress, hence we generated hybrid microcapsules by mixing PEG and ALG (MicroMix) or by coating ALG capsules with a 15 ± 2 μm PEG layer (Double).ResultsWe found improved engraftment of fully allogeneic BALB/c islets in Micro capsules transplanted in the EFP (median reversal time [MRT], 1 day) versus the IP site (MRT, 5 days; P < 0.01) in diabetic C57BL/6 mice and of Micro encapsulated (MRT, 8 days) versus naked (MRT, 36 days; P < 0.01) baboon islets transplanted in the EFP site. Although in vitro viability and functionality of islets within MicroMix and Double capsules were comparable to Micro, addition of PEG to ALG in MicroMix capsules improved engraftment of allogeneic islets in the IP site, but resulted deleterious in the EFP site, probably due to lower biocompatibility.ConclusionsOur results suggest that capsule composition and transplant site affect graft outcomes through their effects on nutrient availability, capsule stability, and biocompatibility.

This work combines the power of 3D additive manufacturing with clinically advantageous minimally invasive delivery. We obtain porous, highly compressible and mechanically rugged structures by optimizing a cryogenic 3D printing process. Only a basic commercial 3D printer and elementary control over reaction rate and freezing are required. The porous hydrogels obtained are capable of withstanding delivery through capillaries up to 50 times smaller than their largest linear dimension, an as yet unprecedented compression ratio. Cells seeded onto the hydrogels are protected during compression. The hydrogel structures further exhibit excellent biocompatibility 3 months after subcutaneous injection into mice. We finally demonstrate that local modulation of pore size grants control over vascularization density in vivo. This provides proof-of-principle that meaningful biological information can be encoded during the 3D printing process, deploying its effect after minimally invasive implantation.

metamaterials. Although typical metamaterials are produced in crystal-like repetitive structures, [3][4][5][6] this is not an absolute requirement, as for instance acoustical negative index materials have been realized as soft metafluids. [7] Here, we develop an injectable metamaterial specifically designed to provide dynamic tissue mechanical matching. Indeed, tissues have strongly non-linear elastic responses, [8] yet it remains a challenge to match more than a given single mechanical parameter. [9] We use here metamaterial design to provide, for the first time, dynamic matching of effective shear modulus over a wide range of deformation amplitudes in a biocompatible injectable. Our aim here is to apply the metamaterial development to soft tissue reconstruction in nearly arbitrary shapes, yet naturally following local tissue movement and mechanics.Disease, trauma, surgery, and aging can indeed result in loss of soft tissue, producing major medical demand for tissue reconstruction. [10,11] Reconstructive procedures should be minimally invasive to decrease patient burden and surgical complications. [12] Ideally, this is addressed by injectability through thin needles. [10] To match patient-specific defect geometries, surgeons desire in situ shapeability, [13] and most importantly, shape-and volume-stability following the procedure. Therefore, an ideal material-based A novel type of injectable biomaterial with an elastic softening transition is described. The material enables in vivo shaping, followed by induction of 3D stable vascularized tissue. The synthesis of the injectable meta-biomaterial is instructed by extensive numerical simulation as a suspension of irregularly fragmented, highly porous sponge-like microgels. The irregular particle shape dramatically enhances yield strain for in vivo stability against deformation. Porosity of the particles, along with friction between internal surfaces, provides the elastic softening transition. This emergent metamaterial property enables the material to reversibly change stiffness during deformation, allowing native tissue properties to be matched over a wide range of deformation amplitudes. After subcutaneous injection in mice, predetermined shapes can be sculpted manually. The 3D shape is maintained during excellent host tissue integration, with induction of vascular connective tissue that persists to the end of one-year follow-up. The geometrical design is compatible with many hydrogel materials, including cell-adhesion motives for cell transplantation. The injectable meta-biomaterial therefore provides new perspectives in soft tissue engineering and regenerative medicine.

Islet transplantation within mechanically stable microcapsules offers the promise of long‐term diabetes reversal without chronic immunosuppression. Reinforcing the ionically gelled network of alginate (ALG) hydrogels with covalently linked polyethylene glycol (PEG) may create hybrid structures with desirable mechanical properties. This report describes the fabrication of hybrid PEG‐ALG interpenetrating polymer networks and the investigation of microcapsule swelling, surface modulus, rheology, compression, and permeability. It is demonstrated that hybrid networks are more resistant to bulk swelling and compressive deformation and display improved shape recovery and long‐term resilience. Interestingly, it is shown that PEG‐ALG networks behave like ALG during microscale surface deformation and small amplitude shear while exhibiting similar permeability properties. The results from this report's in vitro characterization are interpreted according to viscoelastic polymer theory and provide new insight into hybrid hydrogel mechanical behavior. This new understanding of PEG‐ALG mechanical performance is then linked to previous work that demonstrated the success of hybrid polymer immunoisolation devices in vivo.

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