Engineering the matrix microenvironment for cell delivery and engraftment for tissue repair

Abstract

Cell-based therapies represent promising strategies for tissue repair, particularly in cases in which host cells, due to disease, age, or excessive trauma, are unable to repair the defect or deficiency alone, even with additional delivered therapeutics. Current cell therapies fail to address long-term engraftment or delivery timing and location and result in modest improvements with long term engraftment rates of less than 1%. In many cell therapy applications, an appropriate carrier must be used to deliver transplanted cells and promote cell engraftment and function for a successful outcome by providing the appropriate microenvironment for the interactions between transplanted and host cells. This review highlights important considerations for engineering the microenvironment for cell delivery and engraftment in tissue repair.

Figure 1

Schematic of cell delivery vehicle performance in vivo over time. A) Overview of integration of vehicle and transplanted cells into host tissue. B) Transplanted cells interact with host cells in many ways. Transplanted cells may release trophic or chemotactic factors that activate host cells and host cells in the injury site may release factors that drive differentiation or behavior of the transplanted cells as well as remodel the delivery vehicle and implant site. As cells degrade the matrix by releasing proteases, growth factors and other therapeutic molecules are released on demand. C) In response to specific adhesive ligands, growth factors, and/or soluble cues from the tissue environment, transplanted cells in the matrix undergo proliferation, cell-cell communication, migration and differentiation as the cells degrade the matrix. D) In response to pro-angiogenic growth factors (delivered or cell-secreted) and facilitated by adhesive ligands and matrix degradability, host vasculature infiltrates the matrix delivering nutrients to the transplanted cells and/or facilitates cell recruitment and trophic factor transport.

Figure 2

Schematic of functionalized hydrogel preparation. A) Multi-arm polymer precursors are functionalized with adhesive ligands, growth factor tethering peptides (affinity-based or proteolytically labile-covalent cross-links), and growth factors. The addition of protease degradable cross-linkers creates a 3D hydrogel network. B) Alternatively, polymer chain precursors may also be functionalized with adhesive ligands and mixed with soluble growth factors or therapeutics to deliver untethered, but encapsulated molecules. Addition of cross-linkers creates a 3D hydrogel network. C) Cross-linking density or polymer weight percent may be tuned independently of functionalization. Increasing cross-link density or polymer weight percentage increases stiffness, but decreases diffusivity, pore size, swelling, and degradation rate.