Concise review: tailoring bioengineered scaffolds for stem cell applications in tissue engineering and regenerative medicine

Abstract

The potential for the clinical application of stem cells in tissue regeneration is clearly significant. However, this potential has remained largely unrealized owing to the persistent challenges in reproducibly, with tight quality criteria, and expanding and controlling the fate of stem cells in vitro and in vivo. Tissue engineering approaches that rely on reformatting traditional Food and Drug Administration-approved biomedical polymers from fixation devices to porous scaffolds have been shown to lack the complexity required for in vitro stem cell culture models or translation to in vivo applications with high efficacy. This realization has spurred the development of advanced mimetic biomaterials and scaffolds to increasingly enhance our ability to control the cellular microenvironment and, consequently, stem cell fate. New insights into the biology of stem cells are expected to eventuate from these advances in material science, in particular, from synthetic hydrogels that display physicochemical properties reminiscent of the natural cell microenvironment and that can be engineered to display or encode essential biological cues. Merging these advanced biomaterials with high-throughput methods to systematically, and in an unbiased manner, probe the role of scaffold biophysical and biochemical elements on stem cell fate will permit the identification of novel key stem cell behavioral effectors, allow improved in vitro replication of requisite in vivo niche functions, and, ultimately, have a profound impact on our understanding of stem cell biology and unlock their clinical potential in tissue engineering and regenerative medicine.

Keywords: Bioengineering; Hydrogel; Niche; Scaffold; Stem cell; Tissue engineering.

Figure 1.

Schematic representation of the stem cell niche and underlying regulatory mechanisms. A large variety of factors (left) present in the stem cell niche are known to tightly regulate stem cell behavior and fate choice. In vivo stem cells reside in anatomically defined location, the stem cell niche (center). The niche is a multifaceted entity (right).

Figure 2.

Schematic representation of synthetic hydrogel engineering to emulate the stem cell niche. (A): Cross-linking chemistries. Hydrogel scaffolds are generated from prepolymer solutions, and various cross-linking schemes can be used, such as chemical, enzymatic, or photo-reactions. (B): Tailoring biomechanical properties. Synthetic hydrogels can be tuned to generate hydrogel scaffolds with defined physicochemical properties. Increasing the polymer concentration typically results in hydrogels with increased mechanical properties, including stiffness. Hydrogels formed from macromers of varying architecture (i.e., linear, branched, or multiarm) display different mechanical properties. (C): Tailoring degradability. Depending on the cross-linking reaction, hydrogel networks can display degradable or nondegradable behavior (via hydrolysis). For example, the integration of an MMP-sensitive peptide sequence in the polymer network renders the hydrogel susceptible to cell-mediated degradation via the action of cell-secreted MMP enzymes. Light-triggered reactions have been developed to modify hydrogel scaffolds (photo-patterning of bioactive molecules or local degradation of the polymer networks), enabling alteration of the hydrogel properties at any given point during the course of the cell culture, permitting temporal cues to the stem cells. (D): Tailoring bioactivity. Bioactive compounds, such as adhesion ligands or growth factors, can be covalently tethered to the hydrogel network by consuming reactive groups of the macromer (these will thus not contribute to the network formation). This simple scheme can be readily used to bind single factors or any combination of factors. The introduction of orthogonal chemistries can provide enhanced temporal control over functionalization and cross-linking. (E): 3D cell culture. Hydrogels can be cross-linked in the presence of cells, thus, presenting more appropriate 3D culture models, in terms of mimicking in vivo microenvironments. Abbreviations: 3D, three-dimensional; MMP, matrix metalloproteinase.

Figure 3.

Examples of applications of hydrogel to stem cell biology and translational medicine. (A): Injectable enzymatically (horseradish peroxidase) cross-linked hydrogel for in vitro and in vivo encapsulation of mesenchymal stem cells (MSCs). Adapted from [15]. (B): High-throughput generation of miniaturized and combinatorial cell-laden microgel arrays. This method was demonstrated to enable the screen of various biomaterials in combination with selected soluble factors, to a total of 96 independent conditions in a single assay, for their MSC osteogenic-inductive potential. Adapted from [16] with permission. (C): Synthetic methacrylate-based hydrogel encapsulating MSC implants to bridge acute spinal cord injury. Adapted from [17] with permission. (D): Enhanced stem cell (MSCs) intracoronary infusion in alginate shells for treatment of acute myocardial infarct. Adapted from [18].