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Improving targeting efficacy has been a central focus of the studies on nanoparticle (NP)-based drug delivery nanocarriers over the past decades. As cells actively sense and respond to the local physical environments, not only the NP design (e.g., size, shape, ligand density, etc.) but also the cell mechanics (e.g., stiffness, spreading, expressed receptors, etc.) affect the cellular uptake efficiency. While much work has been done to elucidate the roles of NP design for cells seeded on a flat tissue culture surface, how the local physical environments of cells mediate uptake of NPs remains unexplored, despite the widely known effect of local physical environments on cellular responses in vitro and disease states in vivo. Here, we report the active responses of human osteosarcoma cells to fibrous substrate topographies and the subsequent changes in the cellular uptake of NPs. Our experiments demonstrate that surface topography modulates cellular uptake efficacy by mediating cell spreading and membrane mechanics. The findings provide a concrete example of the regulative role of the physical environments of cells on cellular uptake of NPs, therefore advancing the rational design of NPs for enhanced drug delivery in targeted cancer therapy., (© 2015 Wiley Periodicals, Inc.)

Polymeric nanoparticles (NPs) are one of the most studied organic strategies for nanomedicine. Intense interest lies in the potential of polymeric NPs to revolutionize modern medicine. To determine the ideal nanosystem for more effective and distinctly targeted delivery of therapeutic applications, particle size, morphology, material choice, and processing techniques are all research areas of interest. Utilizations of polymeric NPs include drug delivery techniques such as conjugation and entrapment of drugs, prodrugs, stimuli-responsive systems, imaging modalities, and theranostics. Cancer, neurodegenerative disorders, and cardiovascular diseases are fields impacted by NP technologies that push scientific boundaries to the leading edge of transformative advances for nanomedicine., (© 2015 Wiley Periodicals, Inc.)

Natural bone apatite crystals, which mediate the development and regulate the load-bearing function of bone, have recently been associated with strongly bound citrate molecules. However, such understanding has not been translated into bone biomaterial design and osteoblast cell culture. In this work, we have developed a new class of biodegradable, mechanically strong, and biocompatible citrate-based polymer blends (CBPBs), which offer enhanced hydroxyapatite binding to produce more biomimetic composites (CBPBHAs) for orthopedic applications. CBPBHAs consist of the newly developed osteoconductive citrate-presenting biodegradable polymers, crosslinked urethane-doped polyester and poly (octanediol citrate), which can be composited with up to 65 wt % hydroxyapatite. CBPBHA networks produced materials with a compressive strength of 116.23 ± 5.37 MPa comparable to human cortical bone (100-230 MPa), and increased C2C12 osterix gene and alkaline phosphatase gene expression in vitro. The promising results above prompted an investigation on the role of citrate supplementation in culture medium for osteoblast culture, which showed that exogenous citrate supplemented into media accelerated the in vitro phenotype progression of MG-63 osteoblasts. After 6 weeks of implantation in a rabbit lateral femoral condyle defect model, CBPBHA composites elicited minimal fibrous tissue encapsulation and were well integrated with the surrounding bone tissues. The development of citrate-presenting CBPBHA biomaterials and preliminary studies revealing the effects of free exogenous citrate on osteoblast culture shows the potential of citrate biomaterials to bridge the gap in orthopedic biomaterial design and osteoblast cell culture in that the role of citrate molecules has previously been overlooked., (© 2013 Wiley Periodicals, Inc.)

The major challenge for bone tissue engineering lies in the fabrication of scaffolds that can mimic the extracellular matrix and promote osteogenesis. Electrospun fibers are being widely researched for this application due to high porosity, interconnectivity, and mechanical strength of the fibrous scaffolds. Electrospun poly methyl methacrylate (PMMA, 2.416 ± 0.100 μm) fibers were fabricated and etched using a 60% propylene glycol methyl ether acetate (PGMEA)/limonene (vol/vol) solution to obtain fiber diameters ranging from 2.5 to 0.5 μm in a time-dependent manner. The morphology of the fibrous scaffolds was evaluated using scanning electron microscopy and cellular compatibility with etchant-treated scaffold was assessed using immunoflurescence. Mitogen-activated protein kinases (MAPK) activation in response to different fiber diameter was evaluated with western blot as well as quantitative in-cell western. We report that electrospun micro-fibers can be etched to 0.552 ± 0.047 μm diameter without producing beads. Osteoblasts adhered to the fibers and a change in fiber diameter played a major role in modulating the activation of extracellular signal-regulated kinase (ERK) and p38 kinases with 0.882 ± 0.091 μm diameter fibers producing an inverse effect on ERK and p38 phosphorylation. These results indicate that nanofibers produced by wet etching can be effectively utilized to produce diameters that can differentially modulate MAPK activation patterns., (Copyright © 2012 Wiley Periodicals, Inc.)

Tissue engineering often benefits from the use of composites to produce an ideal scaffold. We present the focused development of a novel structure that combines the biomimetic properties of nanofibers with the robust mechanical aspects of the sintered microsphere scaffold to produce a composite scaffold that demonstrates an ability to mimic the mechanical environment of trabecular bone while also promoting the phenotype progression of osteoblast progenitor cells. These composite nanofiber/microsphere scaffolds exhibited a mechanical modulus and compressive strength similar to trabecular bone and exhibited degradation resulting in a mass loss of 30% after 24 weeks. The nanofiber portion of these scaffolds was sufficiently porous to allow cell migration throughout the fibrous portion of the scaffold and promoted phenotype progression through focal adhesion kinase-mediated activation of the transcription factor Runx2, control scaffolds not containing nanofibers did not demonstrate extensive cell migration or phenotype progression. Ultimately, the focal adhesion kinase activity on the composite nanofiber/microsphere scaffolds demonstrated causality over the production of the mature osteoblast marker, osteocalcin, and the development of a calcified matrix., (Copyright © 2010 Wiley Periodicals, Inc.)

The long-term goal of this work is to develop biomimetic polymer-based systems for bone regeneration that both allow for neutral pH degradation products and have the ability to nucleate bonelike apatite. In this study, the etheric biodegradable polyphosphazene, poly[(50%ethyl glycinato)(50%methoxyethoxyethoxy)phosphazene] (PNEG(50)MEEP(50)) was blended with poly(lactide-co-glycolide) PLAGA and studied their ability to produce high-strength degradable biomaterials with bioactivity. Accordingly, two blends with weight ratios of PNEG(50)MEEP(50) to PLAGA 25:75 (BLEND25) and 50:50 (BLEND50) were fabricated using a mutual solvent approach. Increases in PNEG(50)MEEP(50) content in the blend system resulted in decreased elastic modulus of 779 MPa when compared with 1684 MPa (PLAGA) as well as tensile strength 7.9 MPa when compared with 25.7 MPa (PLAGA). However, the higher PNEG(50)MEEP(50) content in the blend system resulted in higher Ca/P atomic ratio of the apatite layer 1.35 (BLEND50) when compared with 0.69 (BLEND25) indicating improved biomimicry. Furthermore, these blends supported primary rat osteoblast adhesion and proliferation with an enhanced phenotypic expression when compared with PLAGA. These findings establish the suitability of PNEG(50)MEEP(50)-PLAGA biodegradable blends as promising bioactive materials for orthopedic applications.

Solvent/non-solvent sintering creates porous polymeric microsphere scaffolds suitable for tissue engineering purposes with control over the resulting porosity, average pore diameter, and mechanical properties. Five different biodegradable biocompatible polyphosphazenes exhibiting glass transition temperatures from -8 to 41 degrees C and poly (lactide-co-glycolide), (PLAGA) a degradable polymer used in a number of biomedical settings, were examined to study the versatility of the process and benchmark the process to heat sintering. Parameters such as: solvent/non-solvent sintering solution composition and submersion time effect the sintering process. PLAGA microsphere scaffolds fabricated with solvent/non-solvent sintering exhibited an interconnected porosity and pore size of 31.9% and 179.1 mum, respectively which was analogous to that of conventional heat sintered PLAGA microsphere scaffolds. Biodegradable polyphosphazene microsphere scaffolds exhibited a maximum interconnected porosity of 37.6% and a maximum compressive modulus of 94.3 MPa. Solvent/non-solvent sintering is an effective strategy for sintering polymeric microspheres, with a broad spectrum of glass transition temperatures, under ambient conditions making it an excellent fabrication route for developing tissue engineering scaffolds and drug delivery vehicles., ((c) 2007 Wiley Periodicals, Inc.)