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1.  Binding of pro-migratory serum factors to electrospun PLLA nanofibers 
Journal of biomaterials science. Polymer edition  2013;24(17):10.1080/09205063.2013.818915.
Architecture of the poly(l-lactic acid) (PLLA) scaffolds is known to affect protein affinity and binding strength. Here, we demonstrate that nano-fibrous electrospun PLLA scaffolds reversibly absorb thepro-migratory serum factors that stimulate migration of vascular smooth muscle via an NFkB-dependent mechanism. Further, we demonstrate that mesenchymal stem cells seeded on the PLLA scaffolds do not enhance muscle migration but may maintain the ability of induced cells to migrate in an NFkB-independent manner. These findings further support the promising application of PLLA scaffolds for therapeutic angiogenesis and vascular graft engineering.
doi:10.1080/09205063.2013.818915
PMCID: PMC3809951  PMID: 23905695
Vascular smooth muscle cell; Mesenchymal stem cell; Poly L-lactic acid; Scaffold; Migration; Vascular bioengineering
2.  Effect of Temporally Patterned TNF-α Delivery on In Vitro Osteogenic Differentiation of Mesenchymal Stem Cells Cultured on Biodegradable Polymer Scaffolds 
Recent insight into the critical role of pro-inflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), in bone regeneration has heralded a new direction in the design of bone tissue engineering constructs. Previous studies have demonstrated that continuous delivery of 50 ng/ml TNF-α to mesenchymal stem cells (MSCs) cultured on three-dimensional (3D) biodegradable electrospun poly(ε-caprolactone) (PCL) microfiber meshes stimulates mineralized matrix deposition, a marker of osteogenic differentiation. Since TNF-α exhibits a biphasic pattern of expression following bone fracture in vivo, the goal of this study was to investigate the effects of temporal patterns of TNF-α delivery on in vitro osteogenic differentiation of MSCs cultured on 3D electrospun PCL scaffolds. MSCs were cultured for 16 days and exposed to continuous, early, intermediate, or late TNF-α delivery. To further elucidate the effects of TNF-α on osteogenic differentiation, the study design included MSCs pre-cultured both in the presence and absence of the typically required osteogenic supplement dexamethasone. Mineralized matrix deposition was not observed in constructs with dexamethasone-naïve MSCs, suggesting that TNF-α is not sufficient to trigger in vitro osteogenic differentiation of MSCs. For MSCs precultured with dexamethasone, TNF-α suppressed ALP activity, an early marker of osteogenic differentiation, and stimulated mineralized matrix deposition, a late stage marker of MSC osteogenic differentiation. By elucidating the impact of temporal variations in TNF-α delivery on MSC osteogenic differentiation, our results offer insight into the regenerative mechanism of TNF-α and provide the necessary design parameters for a novel tissue engineering strategy that rationally controls TNF-α signaling to stimulate bone regeneration.
doi:10.1080/09205063.2013.803455
PMCID: PMC3773264  PMID: 23746285
mesenchymal stem cells; bone tissue engineering; inflammation; scaffold; tumor necrosis factor-alpha
3.  Hemocompatibility of Polymeric Nanostructured Surfaces 
Tissue integration is an important property when inducing transplant tolerance, however, the hemocompatibility of the biomaterial surface also plays an important role in the ultimate success of the implant. Therefore, in order to induce transplant tolerance, it is critical to understand the interaction of blood components with the material surfaces. In this study, we have investigated the adsorption of key blood serum proteins, in vitro adhesion and activation of platelets and clotting kinetics of whole blood on flat polycaprolactone (PCL) surfaces, nanowire (NW) surfaces and nanofiber (NF) surfaces. Previous studies have shown that polymeric nanostructured surfaces improve cell adhesion, proliferation and viability; however it is unclear how these polymeric nanostructured surfaces interact with the blood and its components. Protein adsorption results indicate that while there were no significant differences in total albumin adsorption on PCL, NW and NF surfaces, NW surfaces had higher total fibrinogen and immunoglobulin-G adsorption compared to NF and PCL surfaces. In contrast, NF surfaces had higher surface FIB and IgG adsorption compared to PCL and NW surfaces. Platelet adhesion and viability studies show more adhesion and clustering of platelets on the NF surfaces as compared to PCL and NW surfaces. Platelet activation studies reveal that NW surfaces have the highest percentage of unactivated platelets, whereas NF surfaces have the highest percentage of fully activated platelets. Whole blood clotting results indicate that NW surfaces maintain an increased amount of free hemoglobin during the clotting process compared to PCL and NF surface, indicating less clotting and slower rate of clotting on their surfaces.
doi:10.1080/09205063.2013.777228
PMCID: PMC3713522  PMID: 23848447
Hemocompatibility; nanowire surfaces; nanofiber surfaces; platelets
4.  pH-Responsive hydrogels containing PMMA nanoparticles: an analysis of controlled release of a chemotherapeutic conjugate and transport properties 
Biopolymers composed of a pH-responsive, hydrophilic poly(methacrylic acid – grafted – ethylene glycol) (P(MAA-g-EG)) network polymerized in the presence of PMMA nanoparticles were designed for the oral delivery of chemotherapeutics for the treatment of colon cancer. An inulin-doxorubicin conjugate, designed to target the colon and improve doxorubicin efficacy, was loaded into these polymer carriers at an efficiency of 54%. Release studies indicated these polymer carriers minimized conjugate release in low pH conditions and released the conjugate at neutral pH conditions using a two – step pH experiment modeling the stomach and the small intestine. At lower concentration levels, the presence of the polymer carriers did not disrupt tight junctions as determined by transepithelial electrical resistance studies using Caco-2 and HT29-MTX cell lines which are an accurate model of the GI tract epithelia. Permeability values of unmodified doxorubicin and the inulin-doxorubicin conjugate in the presence of the polymer carriers were also determined using the same cell models and ranged from 1.87 – 3.80 × 10−6 cm/s.
doi:10.1080/09205063.2012.731376
PMCID: PMC3662499  PMID: 23683036
Chemotherapeutics; oral delivery; permeability; hydrogels; nanoparticles; controlled release
5.  Dense chitosan surgical membranes produced by a coincident compression-dehydration process 
High density chitosan membranes were produced via a novel manufacturing process for use as implantable resorbable surgical membranes. The innovative method utilizes the following three sequential steps: (1) casting an acidic chitosan solution within a silicon mold, followed by freezing; (2) neutralizing the frozen acidic chitosan solution in alkaline solution to facilitate polymerization; and (3) applying coincident compression-dehydration under a vacuum. Resulting membranes of 0.2 – 0.5 mm thickness have densities as high as 1.6 g/cm3. Inclusion of glycerol prior to the compression-dehydration step provides additional physical and clinical handling benefits. The biomaterials exhibit tensile strength with a maximum load as high as 10.9 N at ~ 2.5 mm width and clinically-relevant resistance to suture pull-out with a maximum load as high as 2.2 N. These physical properties were superior to those of a commercial reconstituted collagen membrane. The dense chitosan membranes have excellent clinical handling characteristics, such as pliability and “memory” when wet. They are semi-permeable to small molecules, biodegradable in vitro in lysozyme solution, and the rates of degradation are inversely correlated to the degree of deacetylation. Furthermore, the dense chitosan membranes are biocompatible and resorbable in vivo as demonstrated in a rat oral wound healing model. The unique combination of physical, in vitro, in vivo, and clinical handling properties demonstrate the high utility of dense chitosan membranes produced by this new method. The materials may be useful as surgical barrier membranes, scaffolds for tissue engineering, wound dressings, and as delivery devices for active ingredients.
doi:10.1080/09205063.2012.701549
PMCID: PMC3623014  PMID: 23565872
chitosan; membrane; wound healing; biodegradation; resorbable; mechanical properties; suture
6.  Modeling the Proton Sponge Hypothesis: Examining Proton Sponge Effectiveness for Enhancing Intracellular Gene Delivery through Multiscale Modeling 
Dendrimers have been proposed as therapeutic gene delivery platforms. Their superior transfection efficiency is attributed to their ability to buffer the acidification of the endosome and attach to the nucleic acids. For effective transfection the strategy is to synthesize novel dendrimers that optimize both of these traits, but the prediction of the buffering behavior in the endosome remains elusive. It is suggested that buffering dendrimers induce an osmotic pressure sufficient to rupture the endosome and release nucleic acids, which forms to sequestrate most internalized exogenous materials. Presented here are the results of a computational study modeling osmotically-driven endosome burst, or the “proton sponge effect.” The approach builds on previous cellular simulation efforts by linking the previous model with a sponge protonation model then observing the impact on endosomal swelling and acidification. Calibrated and validated using reported experimental data, the simulations offer insights into defining the properties of suitable dendrimers for enhancing gene delivery as a function of polymer structure.
doi:10.1080/09205063.2012.690282
PMCID: PMC3623018  PMID: 23565683
dendrimer; modeling; drug delivery; gene therapy; proton sponge
7.  Enhanced Mucoadhesive Capacity of Novel Co-polymers for Oral Protein Delivery 
Graft co-polymer networks have shown promise as devices for oral delivery of proteins. By increasing adhesion of these networks at the delivery site of the upper small intestine by utilizing small covalent chemical linkages caused by the addition of an aldehyde functional group we can make them more viable. These aldehydes bind covalently by way of a condensation reaction with the amines of the amino acids found in the glycoprotein network of the mucus layer of the small intestine to form imines. To investigate the effectiveness of this linkage the co-polymers are prepared in three different percentages of poly(ethylene glycol) (PEG) and aldehyde-modified PEG, and characterized through swelling, release and adhesion testing. The percentages of aldehyde-modified PEG used are 0.06, 0.6 and 3.3%. The swelling results indicate that the formulations with the aldehyde-modified PEG maintained the same pH sensitivity and transition around a pH of 5.8 as those formulations without the aldehyde moiety. Release results indicate that the release of insulin of the most promising 3.3% aldehyde formulation was successful with a release of about 80% after 3 h, which compares favorably with the similar release of the controls done in previous work. Adhesion testing was carried out through the use of a mechanical testing apparatus. Data have been gathered and plotted to give a detachment force (N) versus displacement (m) curve, of which the work of adhesion (μJ) was found by taking the area underneath the curve. Adhesion results indicate an increase to the already present adhesion of the co-polymers due to increased percentages of the aldehyde-modified PEG tethers where the 3.3% formulation showed an increase of 10–30 μJ over both control formulations.
doi:10.1163/092050610X533619
PMCID: PMC3934346  PMID: 21375804
Drug delivery; adhesion; hydrogel; in vitro; aldehyde
8.  Time Controlled Release of Arabinofuranosylcytosine (Ara-C) from Agarose Hydrogels using Layer-by-Layer Assembly: An In Vitro Study 
Journal of biomaterials science. Polymer edition  2011;23(0):10.1163/092050610X552221.
Experimentally induced axonal regeneration is compromised by glial scar formation arising from leptomeningeal fibroblasts cells in and around the hydrogel scaffold implanted for nerve repair. Strategies are needed to prevent such fibroblastic reactive cell layer formation for enhanced axonal regeneration. Here, we implement the technique of layer-by-layer assembled degradable, hydrogen bonded multilayers on agarose hydrogels to incorporate an anti-mitotic drug (1-β-D-arabinofuranosylcytosine (Ara-C)) within the agarose hydrogels. We show controlled release of Ara-C under physiological conditions over a period of days. The concentrations of Ara-C released from agarose at the different time points were sufficient to inhibit fibroblast growth in vitro, while not adversely affecting the viability of the neuronal cells.
doi:10.1163/092050610X552221
PMCID: PMC3873741  PMID: 21294967
Time controlled release; agarose; Ara-C; layer-by-layer assembly; reactive cell layer; nerve repair
9.  Application of MS-Based Proteomics to Study Serum Protein Adsorption/Absorption and Complement C3 Activation on Poly(ethylene glycol) Hydrogels 
Journal of biomaterials science. Polymer edition  2010;10.1163/092050610X508400.
Although the interaction between cells and poly(ethylene glycol) (PEG) hydrogels is well documented, there lacks a thorough investigation into the adsorption of blood proteins on these surfaces which dictates the observed cellular and in vivo host response. Thus, a clear understanding of how surface-bound proteins mediate the unique biological property of PEG hydrogels is fundamentally important. The information obtained will also provide insights into future biomaterial design. In this study, several mass-spectrometry-based proteomic tools coupled with complementary immunoassays were employed to survey the complex surface-bound serum proteome. The adsorption of vitronectin, thrombin, fibrinogen and complement component C3 was significantly lower on PEG hydrogels than on tissue culture polystyrene (TCPS). Although PEG hydrogels mediated lower C3 adsorption than TCPS, the extent of C3 activation between the two surfaces was comparable. Adherent monocyte density was also significantly lower on PEG hydrogels as compared to TCPS. Taken together, these results support the critical role of the complement C3 in mediating monocyte adhesion on biomaterials. Thus we conclude that the biocompatibility of PEG hydrogels both in vitro and in vivo can be partly contributed to their limited C3 interaction and monocyte activity.
doi:10.1163/092050610X508400
PMCID: PMC3855078  PMID: 20594411
Poly(ethylene glycol) hydrogel; mass spectrometry; vitronectin; thrombin; fibrinogen; complement C3
10.  Effect of the Addition of a Labile Gelatin Component on the Degradation and Solute Release Kinetics of a Stable PEG Hydrogel 
Journal of biomaterials science. Polymer edition  2011;10.1163/092050611X587547.
Characterization of the degradation mechanisms and resulting products of biodegradable materials is critical in understanding the behavior of the material including solute transport and biological response. Previous mathematical analyses of a semi-interpenetrating network (sIPN) containing both labile gelatin and a stable cross-linked poly(ethylene glycol) (PEG) network found that diffusion-based models alone were unable to explain the release kinetics of solutes from the system. In this study, degradation of the sIPN and its effect on solute release and swelling kinetics were investigated. The kinetics of the primary mode of degradation, gelatin dissolution, was dependent on temperature, preparation methods, PEGdA and gelatin concentration, and the weight ratio between the gelatin and PEG. The gelatin dissolution rate positively correlated with both matrix swelling and the release kinetics of high-molecular-weight model compound, FITC-dextran. Coupled with previous in vitro studies, the kinetics of sIPN degradation provided insights into the time-dependent changes in cellular response including adhesion and protein expression. These results provide a facile guide in material formulation to control the delivery of high-molecular-weight compounds with concomitant modulation of cellular behavior.
doi:10.1163/092050611X587547
PMCID: PMC3849202  PMID: 21801489
Degradation; delivery vehicle; gelatin; hydrogel; poly(ethylene glycol); semi-interpenetrating polymer network (sIPN)
11.  Modulation of the Keratinocyte–Fibroblast Paracrine Relationship with Gelatin-Based Semi-interpenetrating Networks Containing Bioactive Factors for Wound Repair 
Gelatin-based semi-interpenetrating networks (sIPNs) containing soluble and covalently-linked bioactive factors have been shown to aid in wound healing; however, the biological responses elicited by the introduction of sIPN biomaterials remain unclear. In the current study, modulation of the re-epithelialization phase of wound healing by sIPNs grafted with PEGylated fibronectin-derived peptides and utilized as platforms for the delivery of exogenous keratinocyte growth factor (KGF) was evaluated. Following wounding, keratinocyte migration, proliferation and protein secretion is largely controlled by diffusible factors, such as KGF, released by the underlying fibroblasts. The impact of sIPNs and exogenous KGF upon the latter keratinocyte–fibroblast paracrine relationship and keratinocyte behavior was explored by monitoring keratinocyte adhesion and cytokine (IL-1α, IL-1β, IL-6, KGF, GM-CSF and TGF-α) release. Results were generally similar for keratinocyte monoculture and keratinocyte–fibroblast co-culture systems. Although keratinocyte adhesion increased over time for positive control surfaces, adhesion to the sIPNs remained low throughout the course of the study. Release of IL-1α and GM-CSF was increased by exogenous KGF. The effects were more noticeable on the positive control surfaces relative to the sIPN surfaces. Regulation of the release of TGF-α was surface dependent, while IL-6 release was dependent upon surface type, the inclusion of exogenous KGF and the presence of fibroblasts. The findings indicate that during re-epithelialization, sIPNs containing soluble bioactive factors aid in wound healing primarily by serving as conduits for KGF, which induces the release of other key cytokines involved in tissue repair.
doi:10.1163/156856209X444402
PMCID: PMC3757500  PMID: 19454166
Keratinocyte; paracrine; co-culture; semi-interpenetrating network; KGF
12.  Gelatinized Copper–Capillary Alginate Gel Functions as an Injectable Tissue Scaffolding System for Stem Cell Transplants 
In severe hypoxic–ischemic brain injury, cellular components such as neurons and astrocytes are injured or destroyed along with the supporting extracellular matrix. This presents a challenge to the field of regenerative medicine since the lack of extracellular matrix and supporting structures makes the transplant milieu inhospitable to the transplanted cells. A potential solution to this problem is the use of a biomaterial to provide the extracellular components needed to keep cells localized in cystic brain regions, allowing the cells to form connections and repair lost brain tissue. Ideally, this biomaterial would be combined with stem cells, which have been proven to have therapeutic potentials, and could be delivered via an injection. To study this approach, we derived a hydrogel biomaterial tissue scaffold from oligomeric gelatin and copper–capillary alginate gel (GCCAG). We then demonstrated that our multipotent astrocytic stem cells (MASCs) could be maintained in GCCAG scaffolds for up to 2 weeks in vitro and that the cells retained their multipotency. We next performed a pilot transplant study in which GCCAG was mixed with MASCs and injected into the brain of a neonatal rat pup. After a week in vivo, our results showed that: the GCCAG biomaterial did not cause a significant reactive gliosis; viable cells were retained within the injected scaffolds; and some delivered cells migrated into the surrounding brain tissue. Therefore, GCCAG tissue scaffolds are a promising, novel injectable system for transplantation of stem cells to the brain.
doi:10.1163/092050610X519453
PMCID: PMC3753783  PMID: 20699061
Anisotropy; ionotropy; capillary; alginate; gelatin; tissue scaffold; biomaterial; stem cell; tissue engineering
13.  [No title available] 
PMCID: PMC3406182  PMID: 21294971
14.  Crosslinking Characteristics and Mechanical Properties of an Injectable Biomaterial Composed of Polypropylene fumarate and Polycaprolactone Copolymer 
In this work, a series of copolymers of polypropylene fumarate-co-polycaprolactone (PPF-co-PCL) were synthesized via a three-step polycondensation reaction of oligomeric polypropylene fumarate (PPF) with polycaprolactone (PCL). The effects of PPF precursor molecular weight, PCL precursor molecular weight, and PCL fraction in the copolymer (PCL feed ratio) on the maximum crosslinking temperature, gelation time, and mechanical properties of the crosslinked copolymers were investigated. The maximum crosslinking temperature fell between 38.2±0.3 and 47.2±0.4 °C, which increased with increasing PCL precursor molecular weight. The gelation time was between 4.2±0.2 and 8.5±0.7 min, and decreased with increasing PCL precursor molecular weight. The compressive moduli ranged from 44±1.8 to 142±7.4 MPa, with enhanced moduli at higher PPF precursor molecular weight and lower PCL feed ratio. The compressive toughness was in the range of 4.1±0.3 and 17.1±1.3 KJ/m3. Our data suggest that the crosslinking and mechanical properties of PPF-co-PCL can be modulated by varying the composition. Therefore the PPF-co-PCL copolymers may offer increased versatility as an injectable, in situ polymerizable biomaterial than the individual polymers of PPF and PCL.
doi:10.1163/092050610X487765
PMCID: PMC3062160  PMID: 20566042
Polypropylene fumarate; polycaprolactone; injectable biomaterials; in situ polymerizable
15.  Amphiphilic block copolyesters bearing pendant cyclic ketal groups as nanocarriers for controlled release of camptothecin 
Journal of biomaterials science. Polymer edition  2010;10.1163/092050610X504260.
Amphiphilic block copolymers consisting of hydrophilic poly(ethylene glycol) and hydrophobic polyester bearing pendent cyclic ketals were synthesized by ring-opening copolymerization of ε-caprolactone (CL) and 1,4,8-trioxaspiro-[4,6]-9-undecanone (TSU) using α-hydroxyl, ω-methoxy, polyethylene glycol as the initiator and stannous octoate as the catalyst. Compositional analyses indicate that TSU was randomly distributed in the hydrophobic blocks. When the TSU content in the copolymers increased, the polymer crystallinity decreased progressively and the glass transition temperature increased accordingly. Hydrophobic, anticancer drug, camptothecin (CPT), was successfully encapsulated in the block copolymer nanoparticles. The CPT encapsulation efficiency and release kinetics were strongly dependent on the copolymer composition and crystallinity. CPT release from nanoparticles constructed from copolymers containing 0, 39 and 100 mol% TSU in the hydrophobic block followed the same trend, with an initial burst of ~40% within one day followed by a moderate and slow release lasting up to 7 days. At a TSU content of 14 mol%, CPT was released in a continuous and controlled fashion with a reduced initial burst and a 73% cumulative release by day 7. In vitro cytoxicity assay showed that the blank nanoparticles were not toxic to the cultured bone metastatic prostate cancer cells (C4-2B). Compared to the free drug, the encapsulated CPT was more effective in inducing apoptotic responses in C4-2B cells. Modulating the physical characteristics of the amphiphilic copolymers via copolymerization offers a facile method for controlling the bioavailability of anticancer drugs ultimately increasing effectiveness and minimizing toxicity.
doi:10.1163/092050610X504260
PMCID: PMC2974953  PMID: 20594408
Amphiphilic block copolymer; cyclic ketal; crystallinity; nanoparticles; controlled release; camptothecin
16.  Molecular Aspects of Mucoadhesive Carrier Development for Drug Delivery and Improved Absorption 
Although the oral route remains the most favored route of drug administration, major scientific obstacles prevent the effective and efficient delivery of low-molecular-mass drugs, peptides and proteins that exhibit poor solubility and permeability. Mucoadhesive dosage forms and the associated drug carriers have the ability to interact at a molecular level with the mucus gel layer that lines the epithelial surfaces of the major absorptive regions of the body. This interaction provides an increased residence time of the therapeutic formulation while localizing the drug at the site of administration. Such local, non-specific targeting leads to an increase in both oral absorption and bioavailability. Fundamental understanding of the biological processes encountered along the gastrointestinal tract can provide a sufficient engineer of carriers that are capable to provide this increase in residence time. Here we discuss the theoretical framework for achieving mucoadhesive systems as related to biomaterials science and the structure of the biomaterials used.
doi:10.1163/156856208X393464
PMCID: PMC3043381  PMID: 19105897
Hydrogels; mucoadhesives; bioadhesives; diffusion; interpenetration
17.  Nanostructured materials for applications in drug delivery and tissue engineering* 
Research in the areas of drug delivery and tissue engineering has witnessed tremendous progress in recent years due to their unlimited potential to improve human health. Meanwhile, the development of nanotechnology provides opportunities to characterize, manipulate and organize matter systematically at the nanometer scale. Biomaterials with nano-scale organizations have been used as controlled release reservoirs for drug delivery and artificial matrices for tissue engineering. Drug-delivery systems can be synthesized with controlled composition, shape, size and morphology. Their surface properties can be manipulated to increase solubility, immunocompatibility and cellular uptake. The limitations of current drug delivery systems include suboptimal bioavailability, limited effective targeting and potential cytotoxicity. Promising and versatile nano-scale drug-delivery systems include nanoparticles, nanocapsules, nanotubes, nanogels and dendrimers. They can be used to deliver both small-molecule drugs and various classes of biomacromolecules, such as peptides, proteins, plasmid DNA and synthetic oligodeoxynucleotides. Whereas traditional tissue-engineering scaffolds were based on hydrolytically degradable macroporous materials, current approaches emphasize the control over cell behaviors and tissue formation by nano-scale topography that closely mimics the natural extracellular matrix (ECM). The understanding that the natural ECM is a multifunctional nanocomposite motivated researchers to develop nanofibrous scaffolds through electrospinning or self-assembly. Nanocomposites containing nanocrystals have been shown to elicit active bone growth. Drug delivery and tissue engineering are closely related fields. In fact, tissue engineering can be viewed as a special case of drug delivery where the goal is to accomplish controlled delivery of mammalian cells. Controlled release of therapeutic factors in turn will enhance the efficacy of tissue engineering. From a materials point of view, both the drug-delivery vehicles and tissue-engineering scaffolds need to be biocompatible and biodegradable. The biological functions of encapsulated drugs and cells can be dramatically enhanced by designing biomaterials with controlled organizations at the nanometer scale. This review summarizes the most recent development in utilizing nanostructured materials for applications in drug delivery and tissue engineering.
PMCID: PMC3017754  PMID: 17471764
Nanomaterials; biomaterials; drug delivery; tissue engineering; nanoparticles; nanocapsules; nanotubes; nanogels; dendrimers; nanofibril; network; hydrogel; electrospinning; self-assembly; nanocomposites
18.  Fabrication and characterization of poly(DL-lactic-co-glycolic acid)/zirconia-hybridized amorphous calcium phosphate composites 
Several minerals, such as hydroxyapatite and β-tricalcium phosphate, have been incorporated into bioresorbable polyester bone scaffolds to increase the osteoconductivity both in vitro and in vivo. More soluble forms of calcium phosphate that release calcium and phosphate ions have been postulated as factors that increase osteoblast differentiation and mineralization. Recently, a zirconia-hybridized pyrophosphate-stabilized amorphous calcium phosphate (Zr-ACP) has been synthesized allowing controlled release of calcium and phosphate ions. When incorporated into bioresorbable scaffolds, Zr-ACP has the potential to induce osteoconductivity. In this study, 80–90% (w/v) porous poly(DL-LActic-co-glycolic acid) (PLGA) scaffolds were formed by thermal phase separation from dioxane while incorporating Zr-ACP. Scanning electron microscopy revealed a highly porous structure with a pore size ranging from a few μm to about 100 μm, smaller than we had hoped for. Zr-ACP particles were evenly dispersed in the composite structure and incorporated into the pore walls. The amorphous structure of the Zr-ACP was maintained during composite fabrication, as found by X-ray diffraction. Composite scaffolds had larger compressive yield strengths and moduli compared to pure polymer scaffolds. These initial efforts demonstrate that PLGA/Zr-ACP composites can be formed in ways that ultimately serve as promising bone scaffolds in tissue engineering.
PMCID: PMC2962981  PMID: 16768292
Bone tissue engineering; amorphous calcium phosphates; PLGA; osteoblast; phase inversion
19.  Growth and Electrophysiological Properties of Rat Embryonic Cardiomyocytes on Hydroxyl- and Carboxyl-Modified Surfaces 
Biodegradable scaffolds such as poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA) or poly(glycolic acid) (PGA) are commonly used materials in tissue engineering. The chemical composition of these scaffolds changes during degradation which provides a changing environment for the seeded cells. In this study we have developed a simple and relatively high-throughput method in order to test the physiological effects of this varying chemical environment on rat embryonic cardiac myocytes. In order to model the different degradation stages of the scaffold, glass coverslips were functionalized with 11-mercaptoundecanoic acid (MUA) and 11-mercapto-1-undecanol (MUL) as carboxyl- and hydroxyl-group presenting surfaces and also with trimethoxysilylpropyldiethylenetriamine (DETA) and (3-aminopropyl)triethoxysilane (APTES) as controls. Embryonic cardiac myocytes formed beating islands on all tested surfaces but the number of attached cells and beating patches was significantly lower on MUL compared to any of the other functionalized surfaces. Moreover, whole cell patch clamp experiments showed that the average length of action potentials generated by the beating cardiac myocytes were significantly longer on MUL compared to the other surfaces. Our results, using our simple test system, are in agreement with earlier observations that utilized the complex 3D biodegradable scaffold. Thus, surface functionalization with self-assembled monolayers combined with histological/physiological testing could be a relatively high throughput method for biocompatibility studies and for the optimization of the material/tissue interface in tissue engineering.
doi:10.1163/156856208786052399
PMCID: PMC2956168  PMID: 18854125
Cardiomyocytes; cell culture; electrophysiology; cardiac tissue engineering; serum-free; SAM; Hydroxyl; Carboxyl; scaffolds; PLA; PLGA
20.  Citric-Acid-Derived Photo-cross-Linked Biodegradable Elastomers 
Citric-acid-derived thermally cross-linked biodegradable elastomers (CABEs) have recently received significant attention in various biomedical applications, including tissue-engineering orthopedic devices, bioimaging and implant coatings. However, citric-acid-derived photo-cross-linked biodegradable elastomers are rarely reported. Herein, we report a novel photo-cross-linked biodegradable elastomer, referred to as poly(octamethylene maleate citrate) (POMC), which preserves pendant hydroxyl and carboxylic functionalities after cross-linking for the potential conjugation of biologically active molecules. POMC is a low-molecular-mass pre-polymer with a molecular mass average between 701 and 1291 Da. POMC networks are soft and elastic with an initial modulus of 0.07 to 1.3 MPa and an elongation at break between 38 and 382%. FT-IR–ATR results confirmed the successful surface immobilization of type-I collagen onto POMC films, which enhanced in vitro cellular attachment and proliferation. Photo-polymerized POMC films implanted subcutaneously into Sprague–Dawley rats demonstrated minimal in vivo inflammatory responses. The development of POMC enriches the family of citric-acid-derived biodegradable elastomers and expands the available biodegradable polymers for versatile needs in biomedical applications.
doi:10.1163/092050609X12567178204169
PMCID: PMC2943534  PMID: 20557687
Elastomer; photo-cross-linking; biodegradable; tissue engineering; wound dressing; citric acid
21.  Hybrid nanofibrous scaffolds from electrospinning of a synthetic biodegradable elastomer and urinary bladder matrix 
Synthetic materials can be electrospun into submicron or nanofibrous scaffolds to mimic extracellular matrix (ECM) scale and architecture with reproducible composition and adaptable mechanical properties. However, these materials lack the bioactivity present in natural ECM. ECM-derived scaffolds contain bioactive molecules that exert in vivo mimicking effects as applied for soft tissue engineering, yet do not possess the same flexibility in mechanical property control as some synthetics. The objective of the present study was to combine the controllable properties of a synthetic, biodegradable elastomer with the inherent bioactivity of an ECM derived scaffold. A hybrid electrospun scaffold composed of a biodegradable poly(ester-urethane)urea (PEUU) and a porcine ECM scaffold (urinary bladder matrix, UBM) was fabricated and characterized for its bioactive and physical properties both in vitro and in vivo. Increasing amounts of PEUU led to linear increases in both tensile strength and breaking strain while UBM incorporation led to increased in vitro smooth muscle cell adhesion and proliferation and in vitro mass loss. Subcutaneous implantation of the hybrid scaffolds resulted in increased scaffold degradation and a large cellular infiltrate when compared with electrospun PEUU alone. Electrospun UBM/PEUU combined the attractive bioactivity and mechanical features of its individual components to result in scaffolds with considerable potential for soft tissue engineering applications.
doi:10.1163/156856208784089599
PMCID: PMC2860790  PMID: 18419942
Biodegradable; elastomer; electrospinning; polyurethane; scaffold; urinary bladder matrix
22.  Biomimetic Fluorocarbon Surfactant Polymers Reduce Platelet Adhesion on PTFE/ePTFE Surfaces 
We describe a series of fluorocarbon surfactant polymers designed as surface-modifying agents for improving the thrombogenicity of ePTFE vascular graft materials by the reduction of platelet adhesion. The surfactant polymers consist of a poly(vinyl amine) backbone with pendent dextran and perfluoroundecanoyl branches. Surface modification is accomplished by a simple dip-coating process in which surfactant polymers undergo spontaneous surface-induced adsorption and assembly on PTFE/ePTFE surface. The adhesion stability of the surfactant polymer on PTFE was examined under dynamic shear conditions in PBS and human whole blood with a rotating disk system. Fluorocarbon surfactant polymer coatings with three different dextran to perfluorocarbon ratios (1:0.5, 1:1 and 1:2) were compared in the context of platelet adhesion on PTFE/ePTFE surface under dynamic flow conditions. Suppression of platelet adhesion was achieved for all three coated surfaces over the shear-stress range of 0–75 dyn/cm2 in platelet-rich plasma (PRP) or human whole blood. The effectiveness depended on the surfactant polymer composition such that platelet adhesion on coated surfaces decreased significantly with increasing fluorocarbon branch density at 0 dyn/cm2. Our results suggest that fluorocarbon surfactant polymers can effectively suppress platelet adhesion and demonstrate the potential application of the fluorocarbon surfactant polymers as non-thrombogenic coatings for ePTFE vascular grafts.
doi:10.1163/156856209X426439
PMCID: PMC2852637  PMID: 19323880
Platelet adhesion; polytetrafluoroethylene; expanded polytetrafluoroethylene; dextran; fluorocarbon surfactant polymers
23.  Fabrication of a Layered Microstructured Polycaprolactone Construct for 3-D Tissue Engineering 
Successful artificial tissue scaffolds support regeneration by promoting cellular organization as well as appropriate mechanical and biological functionality. We have previously shown in vitro that 2-D substrates with micron-scale grooves (5 μm deep, 18 μm wide, with 12 μm spacing) can induce cell orientation and ECM alignment. Here, we have transferred this microtopography onto biodegradable polycaprolactone (PCL) thin films. We further developed a technique to layer these cellularized microtextured scaffolds into a 3-D tissue construct. A surface modification technique was used to attach photoreactive acrylate groups on the PCL scaffold surface onto which polyethylene glycol (PEG-DA) -diacrylate gel could be photopolymerized. PEG-DA serves as an adhesive layer between PCL scaffolds, resulting in a VSMC-seeded layered 3-D composite structure that is highly organized and structurally stable. The PCL surface modification chemistry was confirmed via XPS, and the maintenance of cell number and orientation on the modified PCL scaffolds was demonstrated using colorometric and imaging techniques. Cell number and orientation were also investigated after cells were cultured in the layered 3-D configuration. Such 3-D tissue mimics fabricated with precise cellular organization will enable the systematic testing of the effects of cellular orientation on the functional and mechanical properties of tissue engineered blood vessels.
doi:10.1163/156856208786052371
PMCID: PMC2737474  PMID: 18854127
micropatterning; vascular smooth muscle cell orientation; scaffold engineering
24.  2D and 3D collagen and fibrin biopolymers promote specific ECM and integrin gene expression by vascular smooth muscle cells 
Collagen Type I and fibrin are polymeric proteins commonly used in the field of regenerative medicine as the foundational matrix of engineered tissues. We examined the response of vascular smooth muscle cells (VSMC) to both two-dimensional (2D) substrates as well as three-dimensional (3D) matrices of these biopolymers. Pure collagen Type I, pure fibrin and composite matrices consisting of 1:1 mixtures of collagen and fibrin were studied. Relative gene expression of three ECM molecules (collagen Type I and III, and tropoelastin) and three integrin subunits (integrins α1, β1 and β3) was determined over 7 days in culture using quantitative RT-PCR. Expression of all of these marker genes was up-regulated in 3D matrices, relative to 2D substrates. Tropoelastin, integrin α1 and integrin β1 were highest in collagen matrices, while collagen III and integrin β3 expression were highest in pure fibrin, and collagen I expression was highest in the collagen-fibrin composite materials. Both the compositional and temporal expression patterns of these specific ECM-related genes were suggestive of a wound healing response. These results illuminate the short-term responses of VSMC to 2D and 3D biopolymer matrices, and have relevance to tissue engineering and cardiovascular biology.
doi:10.1163/156856208786052380
PMCID: PMC2731795  PMID: 18854122
Biopolymers; collagen; fibrin; smooth muscle cells; extracellular matrix; wound healing
25.  A Permanent Change In Protein Mechanical Responses Can Be Produced By Thermally Induced Microdomain Mixing 
Electrospinning was employed to fabricate three dimensional fiber networks from a recombinant amphiphilic elastin-mimetic triblock protein polymer and the effects of moderate thermal conditioning (60°C, 4h) on network mechanical responses investigated. Significantly, while cryo-high resolution scanning electron microscopy (cryo-HRSEM) revealed that macroscopic and microscopic morphology of the network structure was unchanged, solid-state 1H NMR spectroscopy demonstrated enhanced interphase mixing of hydrophobic and hydrophilic blocks. Significantly, thermal annealing triggered permanent changes in network swelling behavior (28.75 ± 2.80 non-annealed vs. 13.55 ± 1.39 annealed; p < 0.05) and uniaxial mechanical responses, including Young’s modulus (0.170 ± 0.010 MPa non-annealed vs. 0.366 ± 0.05 MPa annealed; p < 0.05) and ultimate tensile strength (0.079 ± 0.008 MPa vs 0.119 ± 0.015 MPa; p < 0.05). To our knowledge, these investigations are the first to note that mechanical responses of protein polymers can be permanently altered through a temperature-induced change in microphase mixing.
doi:10.1163/156856208X386228
PMCID: PMC2724671  PMID: 19619402
Protein polymers; thermal annealing; microphase separation; biomechanics; fiber network

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