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Charles R Nuttelman

Publications and source records attributed to Charles R Nuttelman.

7 recordsLinked to original sources
PubMed2006

Synthesis and characterization of a fluvastatin-releasing hydrogel delivery system to modulate hMSC differentiation and function for bone regeneration.

Increases in bone formation have been demonstrated in mice and rats treated with statins, a group of molecules that increase the production of bone morphogenetic proteins-2 (BMP2) by stimulating its promoter. However, clinical use of statins (e.g., fluvastatin) is limited by the lack of a suitable delivery system to localize and sustain release. To harness the therapeutic effect of statins in orthopedic applications, a fluvastatin-releasing macromer was synthesized. When copolymerized with a dimethacrylated poly(ethylene glycol) solution, this fluvastatin-containing molecule was covalently incorporated into hydrogel networks, and hydrolysis of lactic acid ester bonds resulted in the release of the pendantly tethered fluvastatin from the hydrogel into the surrounding solution. The rate of fluvastatin release was controlled by the length of lactic acid spacer (2-6 repeats), and the dose was controlled by the initial comonomer composition (5-500 microg fluvastatin/gel). Released fluvastatin increased human mesenchymal stem cell (hMSC) gene expression of CBFA1, ALP, and COL I by 34-fold, 2.6-fold, and 1.8-fold, respectively, after 14 days of in vitro culture. In addition, treating hMSCs with the released fluvastatin resulted in an average of 2.0- and 1.5-fold greater BMP2 production whereas mineralization increased an average of 3.0-fold and 2.5-fold for 0.01 and 0.1 microM fluvastatin, respectively, over the 2 week culture period. Therefore, fluvastatin-releasing hydrogels may be useful in bone tissue engineering applications, not only for triggering osteogenic differentiation of hMSCs, but also by modulating their function.

Biocompatible Materials↗
PubMed2006

Dexamethasone-functionalized gels induce osteogenic differentiation of encapsulated hMSCs.

Synthetic hydrogels represent highly controlled environments for three-dimensional culture of human mesenchymal stem cells (hMSCs). Encapsulated hMSCs are presented with a "blank" environment, and this environment can be closely controlled in order to elicit an osteogenic response. In vitro, dexamethasone is an efficient and reliable factor that leads to the osteogenic differentiation of human mesenchymal stem cells (hMSCs). The aim of this work was to develop a dexamethasone-releasing poly(ethylene glycol) (PEG)-based hydrogel scaffold to deliver dexamethasone to encapsulated cells in a sustained manner. To accomplish this goal, dexamethasone was covalently linked to a photoreactive mono-acrylated PEG molecule through a degradable lactide bond, and this molecule was covalently incorporated into the PEG hydrogel during photopolymerization. Over time, hydrolysis of the ester bonds resulted in dexamethasone release from the gel. The biological activity of the released dexamethasone was verified in monolayer cell culture and in three-dimensional culture (i.e., in the gel) by the ability of hMSCs to express osteogenic genes, including alkaline phosphatase, osteopontin, and core binding factor alpha 1, as measured using real-time reverse transcription polymerase chain reaction (RT-PCR). These studies indicate that encapsulated hMSCs are capable of osteogenic differentiation in response to released dexamethasone.

Alkaline Phosphatase↗
PubMed2005

The effect of ethylene glycol methacrylate phosphate in PEG hydrogels on mineralization and viability of encapsulated hMSCs.

Owing to their resistance to protein adsorption, poly(ethylene glycol) (PEG) hydrogels are unable to support the adhesion of human mesenchymal stem cells (hMSCs). Human MSCs attach to various substrates through cell adhesion proteins, and osteopontin is an important cell adhesion protein for both MSCs and osteoblasts found in bone. As such, we hypothesized that cell adhesion to a PEG hydrogel could be dramatically improved by actively promoting the formation of a mineral phase throughout the hydrogel. This was accomplished using the photoreactive, phosphate-containing molecule ethylene glycol methacrylate phosphate (EGMP). When EGMP was incorporated into the PEG hydrogel, it resulted in the formation of a bone-like mineral phase, as verified using compositional analysis and X-ray diffraction. Furthermore, cell viability of gel-encapsulated hMSCs was increased in the presence of EGMP from 15% in the absence of EGMP to 97% in the presence of 50 mm EGMP. This improvement in cell viability was thought to be due to the ability of mineralized hydrogels to sequester cell-secreted osteopontin. It was found that EGMP-containing PEGDA hydrogels are able to sequester the important cell adhesion protein osteopontin, and these hydrogels promoted hMSC adhesion and spreading.

Calcium Phosphates↗
PubMed2005

Synthetic hydrogel niches that promote hMSC viability.

Photopolymerized poly(ethylene glycol) (PEG) hydrogels were used as a base platform for the encapsulation and culture of human mesenchymal stem cells (hMSCs). The base PEG formulation presents an environment completely devoid of cell-matrix interactions. As such, viability of hMSCs in unmodified PEG hydrogels is very low. This formulation was modified to contain pendant phosphate groups to facilitate the sequestering of osteopontin within the gel, as well as pendant cell-adhesive RGD peptide sequences, which are found in osteopontin and other cell adhesion proteins. The survivability of hMSCs was examined with culture time and as a function of the gel chemistry to examine the role of cell-matrix interactions in promoting long-term viability. In the absence of any adhesive ligands, hMSC viability drops to 15% after 1 week in culture. However, by incorporating the RGD sequence or pendant phosphate groups this low viability was rescued to 75% and 97%, respectively. It is believed that the phosphate groups promote mineralization of the hydrogel network, and this mineral phase sequesters cell-secreted osteopontin, resulting in enhanced cell-matrix interactions and improved cell viability.

Absorption↗
PubMed2004

In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels.

Much research has focused on the differentiation of human mesenchymal stem cells (hMSCs) in monolayer culture; however, little is known about their differentiation potential in three-dimensional culture conditions. In this research, hMSCs were encapsulated in a photocrosslinkable, injectable scaffolding system based on poly(ethylene glycol) (PEG) hydrogels. To demonstrate the ability of hMSCs to differentiate in PEG hydrogels, cell/polymer constructs were cultured in osteogenic differentiation media to elicit an osteoblastic response. First, viability of encapsulated hMSCs up to 4 weeks in culture was investigated using a membrane integrity assay. Second, gene expression of encapsulated cells was determined with reverse transcription polymerase chain reaction (RT-PCR) as a function of media composition. After 1 week in osteogenic differentiation media, encapsulated hMSCs expressed osteonectin, osteopontin, and alkaline phosphatase, which are all characteristic of osteoblasts. Finally, von Kossa staining was used to evaluate mineralization of the PEG gels. Results support the hypothesis that hMSCs photoencapsulated in PEG hydrogels and cultured in the presence of osteogenic differentiation media are able to differentiate to osteoblasts inside the gel and mineralize the matrix. These experiments demonstrate the feasibility of using a PEG-based, photocrosslinkable system to culture and deliver human mesenchymal stem cells for bone tissue regeneration and repair.

Bone Substitutes↗
PubMed2002

Synthesis and characterization of photocrosslinkable, degradable poly(vinyl alcohol)-based tissue engineering scaffolds.

Hydrogels have many advantages that make them prime candidates for tissue engineering applications: high water content, tissue-like elasticity, and relative biocompatibility. We aim to tissue engineer heart valves using a hydrogel scaffold based on poly(vinyl alcohol) (PVA), and the design parameters for a suitable tissue engineering scaffold are quite stringent. In this research, we develop degradable and photocrosslinkable poly(lactic acid)-g-PVA multifunctional macromers that can be reacted in solution to form degradable networks. The mass loss profiles and bulk properties of the resulting scaffolds are easily tailored by modifying the structure of the starting macromers. Specifically, altering the number of lactide repeat units per crosslinking side chain, percent substitution, molecular weight of PVA backbone, and macromer solution concentration, the rate of mass loss from these degradable networks is controlled. In addition, by increasing the network's hydrophobicity, valve interstitial cell adhesion is improved.

Animals↗