A cell delivery vehicle is a matrix (made from natural or synthetic materials or a combination of the two) that can be combined with cells to be transplanted into a human or animal host.
A wide variety of cells at different stages of differentiation from a range of adult and embryonic sources is being investigated for therapeutic use in the human body. However, transplanted cells face a harsh environment and in general, most cells die shortly after implantation.1-5,7 This can be attributed to ischemia due to absence of vascularization, the absence of cell attachment sites resulting in cell death (anoikis), the host immune response,6,7 and low cell density.8 In the end, few cells engraft and many may veer down undesired differentiation pathways.9
Cell delivery vehicles are designed to provide cell attachment sites to overcome anoikis,7 protect from host immune cells, and localize the cells to maintain appropriate cell densities. The vehicle must also be non-immunogenic, biodegrade at appropriate rates, and have a physiological pH and temperature to avoid pH shock and hypothermia.10-12 Ideally, it is desirable for its formulation to be customizable so that appropriate signals can be added (e.g., growth factors, extracellular matrix proteins) to provide boundaries against continued cellular differentiation. With the growing recognition of the benefits of minimally invasive surgical procedures, injectability of the vehicle also becomes an increasingly important attribute.
Several hydrogels are currently used as vehicles in some cases for both preclinical and clinical research. They are differentiated by their origin (natural, synthetic, and semi-synthetic), microstructure (fibrous network), stiffness, degradation time, and potential toxicities. The table below lists some of the more commonly used vehicles.*
(*Although a basement membrane preparation from EHS mouse sarcoma is used widely for in vivo animal research, its rodent origin presents large challenges for obtaining FDA approval for human implantation. It will not be considered in this discussion.)
Comparison of the vehicles listed here is shown below. The primary differentiation occurs in their microstructure (i.e., self-organization into a fibrous network), stiffness (i.e., elastic, tensile, or shear modulus measured in kPa), gelation time (from initial preparation as a liquid to final gel), and the pH, temperature, and salt content when the matrix is still a liquid.
Hyaluronate (HA) is a key component of the cell extracellular matrix and has been used for a variety of medical applications.13 HyStem® hydrogel is thiol-modified HA which is chemically crosslinked in the presence of PEGDA (HyStem® hydrogel). Thiol-modified gelatin can aso be included for providing cellular attachment sites (HyStem®-C hydrogel) as can thiol-modified heparin for providing slow growth factor release (HyStem®-HP hydrogel).
In general, HyStem® hydrogel differentiates itself from its competitors in its user-friendly customizability and gentleness to cells when mixed in liquid form. HyStem® hydrogel allows the user to adjust not only its stiffness but also gelation time by varying concentrations of crosslinker and HA. HyStem® hydrogel is at physiological pH and temperature in its liquid form and hence provides a gentle microenvironment for encapsulated cells during transplantation.In contrast, Collagen I and Puramatrix are pH 2 in liquid form whereas fibrin and alginate gel only in the presence of calcium which may adversely affect neuronal cell signal transduction.15 PEGDA requires UV light for crosslinking in the presence of free radical photocrosslinkers.19 UV light is a known genotoxic agent can have deleterious effects on the cell cycle.23
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