Recent Progress in Developing Injectable Matrices for Enhancing Cell Delivery and Tissue Regeneration

Abstract

Biomaterials are key factors in regenerative medicine. Matrices used for cell delivery are especially important, as they provide support to transplanted cells that is essential for promoting cell survival, retention, and desirable phenotypes. Injectable matrices have become promising and attractive due to their minimum invasiveness and ease of use. Conventional injectable matrices mostly use hydrogel precursor solutions that form solid, cell-laden hydrogel scaffolds in situ. However, these materials are associated with challenges in biocompatibility, shear-induced cell death, lack of control over cellular phenotype, lack of macroporosity and remodeling, and relatively weak mechanical strength. This Progress Report provides a brief overview of recent progress in developing injectable matrices to overcome the limitations of conventional in situ hydrogels. Biocompatible chemistry and shear-thinning hydrogels have been introduced to promote cell survival and retention. Emerging investigations of the effects of matrix properties on cellular function in 3D provide important guidelines for promoting desirable cellular phenotypes. Moreover, several novel approaches are combining injectability with macroporosity to achieve macroporous, injectable matrices for cell delivery.

Non‐Newtonian Polymer–Nanoparticle Hydrogels Enhance Cell Viability during Injection

“…Administrating cells through high‐gauge needles is becoming more common due to the development of cell therapies and 3D bioprinting technologies; however, previous studies have shown that injecting cells through clinically relevant needles often results in cell death and poor cell viability . Targeted cell delivery is often desired for medical application, but the therapeutic effect of the treatment is decreased because many of the cells injected in saline solutions (i.e., phosphate‐buffered saline [PBS]) are regurgitated due to the pressure in the tissue and fluid flow away from the injection site . Technology development is needed to enhance the delivery, protection, and encapsulation of cells to increase the viability and local retention of cells when injected.…”

“…Technology development is needed to enhance the delivery, protection, and encapsulation of cells to increase the viability and local retention of cells when injected. Previous works have shown that hydrogels are promising alternatives to PBS for administration of cell therapies, as they enhance local retention and improve the viability of cells during injection when compared to injections performed in PBS . It has been proposed that hydrogel “plug flow,” a phenomena caused by the rheology of these materials, protects the cells from the shear and extensional forces during injection from a syringe and needle .…”

“…Therefore, the material is required to be liquid‐like when administering through a needle yet solid‐like after injection. To date, researchers have fit this seemingly contradictory and complex design envelope for cell delivery by developing i) covalently bound static materials such as hydrogels injected as low viscosity precursors that gel in situ to form a localized cell environment; and ii) dynamic supramolecular systems such as hydrogels comprising host–guest moieties, peptide‐functionalized polymers, and peptide amphiphiles that employ shear‐thinning to flow through needle. Supramolecular hydrogels are promising because they shear‐thin and do not require in situ polymerizations …”

“…In the field of drug delivery, hydrogels provide sustained and temporally controlled delivery of drugs in localized regions, reducing off-target toxicity and increasing clinical efficacy. [4,[6][7][8][9] Administrating cells through highgauge needles is becoming more common due to the development of cell therapies [10] and 3D bioprinting technologies [3] ; however, previous studies have shown that injecting cells through clinically relevant needles often results in cell death and poor cell viability. [11] Targeted cell delivery is often desired for medical application, but the therapeutic effect of the treatment is decreased because many of the cells injected in saline solutions (i.e., phosphate-buffered saline [PBS]) are regurgitated due to the pressure in the tissue and fluid flow away from the injection site.…”

Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds

“…Specifically, the biomaterial should provide suitable biophysical and biochemical microenvironmental cues for enhanced control of cell function in vivo . However, current injectable biomaterials suffer from ineffective modulation or lack of porosity for mass transport, cell motility, proliferation, cell–cell adhesion, or new tissue formation …”