Multifunctional Hydrogels that Promote Osteogenic Human Mesenchymal Stem Cell Differentiation Through Stimulation and Sequestering of Bone Morphogenic Protein 2

Abstract

The extracellular environment controls many cellular activities thereby linking external material cues to internal cell function. By better understanding these processes, synthetic extracellular material niches can be tailored to present cells with highly regulated physical and/or chemical cues that promote or suppress selected cell functions. Here, poly(ethylene glycol) (PEG) hydrogels were functionalized with fluvastatin-releasing grafts and growth factor binding heparin domains to enable the dynamic exchange of information between the material and cells from the outside-in and inside-out (i.e., bidirectional signaling). By incorporating a fluvastatin-releasing graft and carefully controlling the dose and temporal release, materials were designed to promote bone morphogenic protein (BMP2) and alkaline phosphatase (ALP) production by human mesenchymal stem cells (hMSCs). When the release of fluvastatin was controlled to occur over 2 weeks, BMP2 and ALP production was increased 2.2-fold and 1.7-fold, respectively, at day 28 compared to hMSCs cultured in the absence of fluvastatin. By introducing a heparin functionality into the gel to sequester and localize the hMSC-produced BMP2, the osteogenic differentiation of hMSCs was further augmented over fluvastatin delivery alone. Osteopontin and core binding factor α1 gene expression was 6-fold and 4-fold greater for hMSCs exposed to fluvastatin in the presence of the heparin functionalities, respectively. These results demonstrate how multifunctional gels that interact with cells in a bidirectional manner can efficiently promote selected cell functions, such as the osteogenic differentiation of hMSCs.

Emerging Ideas: Engineering the Periosteum: Revitalizing Allografts by Mimicking Autograft Healing

“…Thus, we can promote specific cell-material interactions-eg, through particular integrins [1,3]. Other cell functions such as differentiation can be modulated by incorporating releasable drug delivery mechanisms in PEG hydrogels [3,6] to further promote specific cellular effects we posit to be important toward allograft revitalization.…”

“…Based on careful design and thorough in vitro established cohort of degradable hydrogels capable of controlling numerous MSC functions, we expect our newly developed periosteum-mimetics to enhance the healing of allograft tissue in vivo [1][2][3][4][5][6][7]. Loss of osteocytes during allograft devitalization may contribute to an overall decrease in graft resorption and remodeling as compared with autograft controls [45].…”

“…In addition, hydrogel degradation profiles and cell encapsulation densities can be altered, and hierarchical network architectures can be readily achieved [43]. PEG hydrogels also can be modified to controllably release small molecule drugs [3,6,24], or incorporate matrix cues to direct cell function via specific cell-material interactions [1,2] (Fig. 2).…”

“…We believe this stems from limited understanding of critical requirements of the periosteum, and subsequently, the failure to emulate those characteristics. Unlike native periosteum [16,19,36,40], scaffold materials used (eg, Gelfoam 1 (Pfizer Inc, New York, NY) [48], acellular matrices [34,45], poly(lactide-co-glycolide) [22]) have mismatched scaffold properties, lacking three-dimensional hierarchical tissue structure, hydration, and flexibility to incorporate biophysical and biochemical cues to promote specific host or transplanted cell functions [1][2][3][4][5][6][7]. These suboptimal qualities limit cell survival and graft localization [8,10,34,45,48].…”

Intervertebral Disc Regeneration

“…Hydrogel constructs functionalized with heparin and fluvastin have also been proposed for bone repair. Benoit (Benoit et al, 2007) showed that the developed scaffolds were able to promote osteogenic differentiation of human MSCs. Similarly, Edlund et al (2008) reported that BMP-2 loaded in heparin functionalized polymers improved adhesion and proliferation of murine MSCs.…”