Biomaterials with advanced, nano-scale organizations are of great interest for both drug delivery and tissue engineering applications. Current approaches in tissue engineering emphasize the control over cell behaviors and tissue formation by nano-scale topography that closely mimics the natural extracellular matrix (ECM). With the understanding that the natural ECM is a multifunctional, dynamic architecture, this research focused on understanding how osteoprogenitor cells receive information from their external environment (e.g., scaffolds). We utilized a synthetic poly(ethylene glycol) (PEG) platform that provides a highly regulated microenvironment that is permissive (i.e., permits cell survivability), and can be systematically altered biochemically to affect cell signaling pathways. Specifically, how cell-matrix interactions, local presentation of cell-internalized signals, and temporal changes in the scaffold microenvironment regulate functions, such as differentiation, proliferation, and extracellular matrix (ECM) production were investigated.

Further, macromolecular drug delivery systems can be synthesized with controlled composition, shape, size and morphology. siRNA, similar to other macromolecular drugs, once endocytosed, is predominantly trafficked to the lysosome and degraded enzymatically. In addition, serum proteases are capable of rapid siRNA degradation. Therefore, an optimal therapeutic siRNA delivery approach would combine serum-stability, long circulation times, and tissue-specific targeting, with efficient endosomal uptake and escape prior to lysosomal trafficking. We have developed advanced polymer architectures based on reversible addition fragmentation chain transfer (RAFT) polymerizations that enable siRNA-complexation and stabilization and pH-dependent endosomal-disruption. These carriers have been further functionalized with moieties to provide tissue-specific targeting that result in increased efficacy and decreased dosing in vitro and in vivo. Clearly, designing biomaterials with controlled organizations at the nanometer scale can dramatically enhance the biological functions of encapsulated drugs and cells and this approach allows the design of appropriate materials for cell delivery in applications such as tissue engineering and targeted therapeutic delivery.

Applicable peer-reviewed publications:

D.S.W. Benoit, A.J. Convertine, C.L. Duvall, A.S. Hoffman, and P.S. Stayton. Development of a novel endosomolytic diblock copolymer for siRNA delivery. Submitted.

D.S.W. Benoit, M.P. Schwartz, A.R. Durney, and K.S. Anseth. Small molecule functional groups for controlled differentiation of human mesenchymal stem cells encapsulated in poly(ethylene glycol) hydrogels. Submitted.

A.R. Rydholm, N.L. Held, D.S.W. Benoit, C.N. Bowman, and K.S. Anseth. Modifying network chemistry in thiol-acrylate photopolymers through post-polymerization functionalization to control cell-material interactions. Journal of Biomedical Materials Research, Part A, In press.

D.S.W. Benoit and K.S. Anseth. 2007. Multifunctional hydrogels that promote osteogenic hMSC differentiation through stimulation and sequestering of BMP2. Advanced Functional Materials, 17(13):2085-2093.

D.S.W. Benoit, M.C. Tripodi, J.O. Blanchette, S.J. Langer, L.L. Leinwand, and K.S. Anseth. 2007. Integrin-linked kinase production prevents anoikis in human mesenchymal stem cells. Journal of Biomedical Materials Research, Part A, 81A(2):259-268.

D.S.W. Benoit, A.R. Durney, K.S. Anseth. 2007. The effect of heparin-functionalized PEG hydrogels on three-dimensional human mesenchymal stem cell osteogenic differentiation. Biomaterials, 28(1):66-77.

V. Khire, D.S.W. Benoit, K.S. Anseth, and C.N. Bowman. 2006. Ultrathin gradient films using thiol-ene polymerizations. Journal of Polymer Science Part A: Polymer Chemistry, 44(24):7027-7039.

D.S.W. Benoit, C.R. Nuttelman, S.D. Collins, and K.S. Anseth. 2006. Synthesis and characterization of a fluvastatin-releasing to modulate hMSC differentiation and function for bone regeneration. Biomaterials, 27(36): 6102-6110.

D.S.W. Benoit, A.R. Durney, and K.S. Anseth. 2006. Manipulations in hydrogel degradation behavior enhance osteoblast function and mineralized tissue formation. Tissue Engineering, 12(6): 1-11.

C.R. Nuttelman, D.S.W. Benoit, M.C. Tripodi, and K.S. Anseth. 2006. The effect of ethylene glycol methacrylate phosphate in PEG hydrogels on mineralization and viability of encapsulated hMSCs. Biomaterials, 27(8): 1377-1386.

D.S.W. Benoit and K.S. Anseth. 2005. Heparin functionalized PEG gels that modulate protein adsorption for hMSC adhesion and differentiation. Acta Biomaterialia, 1(4): 461-470.

D.S.W. Benoit and K.S. Anseth. 2005. The effect on osteoblast function of colocalized RGD and PHSRN epitopes on PEG surfaces. Biomaterials, 26(25): 5209-5220.

D.S. Wentworth, D. Skonberg, D.W. Donahue, and A. Ghanem. 2004. Application of chitosan entrapped β-galactosidase in a packed bed reactor system. Journal of Applied Polymer Science, 91(2): 1294-1299.