MICROFLUIDIC FORMATION OF CELL-LADEN HYDROGEL MODULES FOR TISSUE ENGINEERING - Micro and Nanotechnologies in Engineering Stem Cells and Tissues - page 192

hydrogel modules for transplantation and implantable applications are reviewed in
this section.

8.4.1 Cell-Laden Hydrogel Modules for Transplantation

The approach for the immunoisolation of encapsulated cells uses a semipermeable
membrane made from hydrogels. The membrane forms a mechanical barrier
separating encapsulated cells from the host antibodies ( 150 kDa) and immune

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cells but allows the diffusion of small molecules ( 10 kDa) such as glucose, insulin,

nutrients, and cell waste products. 43 Cells encapsulated into hydrogel beads are
commonly used for implantation. Their spherical shape enables sufficient diffusion
of nutrients and cell products because the bead shape have a better surface-volume
ratio than materials of any other shape. Additionally, hydrogel beads cannot be easily
disrupted, are mechanically stable, are reproducible by microfluidics methods, and
can be implanted into the patient by a simple injection procedure.
Hydrogels for use in transplantation need to be immunoisolated and capable of
diffusing nutrients and cell products. Alginate, agarose, and chitosan as natural
polymers, and poly(hydroxyethyl methacrylate-methyl methacrylate) (HEMA-
MMA), acrylonitrile, and PEG as synthetic polymers have reported uses for cell
encapsulation in hydrogels. 44,45 Alginate-based beads are mainly preferred because
alginate does not interfere with cellular functions and can keep arbitrary shapes. 46
The fabrication process of alginate beads can be broadly classified into two
categories: external gelation and internal gelation. 15 In the external gelation method,
Na-alginate droplets are gelated by the external addition of divalent cations. For
example, in the production of Ca-alginate beads, Na-alginate droplets are transferred
into a calcium chloride (CaCl 2 ) solution. The rapid gelling behavior of alginate in the
external gelation method makes it difficult to produce well-defined, homogeneous,
and monodisperse alginate hydrogel beads. On the other hand, the internal gelation
method involves dispersing an insoluble (or slowly soluble) complex in the Na-
alginate solution. 47 Because of pH reduction, divalent cations are released from the
complex, cross-linking the alginate to form homogeneous and monodisperse hydro-
gel beads.
The type of divalent cations cross-linking the alginate also contributes to the
morphology of the alginate gel and the viability of the encapsulated cells. Ca ions are
suited for the production of perfectly spherical and stable alginate beads. However,
Ca ions have toxic effects, and encapsulated cells are damaged when they are
exposed to Ca ions for a prolonged time. Ba ions react with alginate in a stronger way
compared with Ca ions. Although Ba ions have high biocompatibility and cells
encapsulated in Ba-alginate beads show high viability, Ba-alginate beads are easily
deformable. 48

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8.4.2 Implantable Applications of Cell-Laden Hydrogel Modules

Hydrogel beads are used in cell transplantation (Fig. 8.4a): various types of cells
(e.g., islet and Sertoli cells) encapsulated in alginate beads are transplanted into