Hydrogel Injection Molding to Generate Complex Cell Encapsulation Geometries

Abstract

Biofabrication methods capable of generating complex, three-dimensional, cell-laden hydrogel geometries are often challenging technologies to implement in the clinic and scaled manufacturing processes. Hydrogel injection molding capitalizes on the reproducibility, efficiency, and scalability of the injection molding process, and we adapt this technique to biofabrication using a library of natural and synthetic hydrogels with varied crosslinking chemistries and kinetics. We use computational modeling to evaluate hydrogel library fluid dynamics within the injection molds in order to predict molding feasibility and cytocompatibility. We evaluate the reproducibility of hydrogel construct molding and extraction and establish criteria for the selection of hydrogels suitable for injection molding. We demonstrate that hydrogel injection molding is capable of generating complex three-dimensional cell-laden construct geometries using diverse hydrogel materials and that this platform is compatible with primary human islet encapsulation. These results highlight the versatility and feasibility of hydrogel injection molding as a biofabrication technique with potential applications in the clinic and biomanufacturing.

Tissue engineering modalities in skeletal muscles: focus on angiogenesis and immunomodulation properties

“…The C terminus of IGF-1 (IGF-1C) with functional bioactivity can be linked to the scaffold structure for the regulation of angiogenic properties of encapsulated cells [ 270 ]. An artificial matrix including chitosan and hyaluronic acid modified by IGF-1C peptide was used to regulate the therapeutic neovascularization of AD-MSCs in ischemic limbs [ 271 ]. The transplantation of AD-MSC-load hydrogel enriched with IGF-1C led to improved blood perfusion and myogenesis via the secretion of pro-angiogenic factor angiopoietin-1 and regulation of immune cell infiltrate.…”

“…The transplantation of AD-MSC-load hydrogel enriched with IGF-1C led to improved blood perfusion and myogenesis via the secretion of pro-angiogenic factor angiopoietin-1 and regulation of immune cell infiltrate. Along with these changes, excessive collagen fiber deposition was reduced after the transplantation of hydrogel to the target sites [ 271 ]. In a study (phase I–IIa), gelatin microspheres were transplanted as a therapeutic angiogenesis system to 10 patients with CLI [ 272 ].…”

Engineering synthetic poly(ethylene) glycol‐based hydrogels compatible with injection molding biofabrication

“…1,2 Hydrogel injection molding is a promising alternative biofabrication method, useful for rapid and facile generation of complex cell-laden hydrogel geometries at the patient bedside, and more amenable to high-throughput manufacturing than existing biofabrication methods. 3 With the advancement and development of manufactured cell products, a means to integrate hydrogel encapsulation into the manufacturing process is desirable to scale combination products, 4 such as in the application of macroencapsulated insulin secreting cell therapies for the treatment of type 1 diabetes. 5 Macroencapsulated cell therapies must balance the delivery of a large number of cells within a single device with oxygen availability to preserve encapsulated cell viability and function, often necessitating complex geometries to achieve this balance.…”

“…5 Macroencapsulated cell therapies must balance the delivery of a large number of cells within a single device with oxygen availability to preserve encapsulated cell viability and function, often necessitating complex geometries to achieve this balance. 3,6 We have previously demonstrated the feasibility of hydrogel injection molding complex geometries with natural materials such as alginate and agarose, but synthetic polyethylene glycol (PEG) hydrogels functionalized with the well-characterized and cytocompatible maleimide-thiol Michael-type addition (MTA) chemistry crosslinked too rapidly for successful injection molding. 3 While natural matrices like alginate, agarose, and decellularized extracellular matrices (ECM) provide inherent biocompatibility and native bioactivity, features such as mechanical properties and porosity can be challenging to control or modify, and natural matrices can have high batch-to-batch variability.…”

“…3,6 We have previously demonstrated the feasibility of hydrogel injection molding complex geometries with natural materials such as alginate and agarose, but synthetic polyethylene glycol (PEG) hydrogels functionalized with the well-characterized and cytocompatible maleimide-thiol Michael-type addition (MTA) chemistry crosslinked too rapidly for successful injection molding. 3 While natural matrices like alginate, agarose, and decellularized extracellular matrices (ECM) provide inherent biocompatibility and native bioactivity, features such as mechanical properties and porosity can be challenging to control or modify, and natural matrices can have high batch-to-batch variability. [7][8][9] Identification of synthetic PEG-based hydrogel crosslinking strategies compatible with injection molding is desirable as synthetic materials allow superior control over matrix structure and porosity, precision functionalization with bioactive factors, and improved homogeneity in batch-to-batch manufacturing relative to naturally derived matrices, and would facilitate translation of injection molded tissue engineered products.…”