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1.  Logical Analysis of Data in Structure-Activity Investigation of Polymeric Gene Deliverya 
To date semi-empirical or surrogate modeling has demonstrated great success in the prediction of the biologically relevant properties of polymeric materials. For the first time, a correlation between the chemical structures of poly(β-amino esters) and their efficiency in transfecting DNA was established using the novel technique of logical analysis of data (LAD). Linear combination and explicit representation models were introduced and compared in the framework of the present study. The most successful regression model yielded satisfactory agreement between the predicted and experimentally measured values of transfection efficiency (Pearson correlation coefficient, 0.77; mean absolute error, 3.83). It was shown that detailed analysis of the rules provided by the LAD algorithm offered practical utility to a polymer chemist in the design of new biomaterials.
PMCID: PMC4316747
combinatorial library; computational modeling; machine-learning algorithms; polymeric gene delivery; prediction of biological response
2.  Enzymatic Surface Erosion of High Tensile Strength Polycarbonates Based on Natural Phenols 
Biomacromolecules  2014;15(3):830-836.
Surface erosion has been recognized as a valuable design tool for resorbable biomaterials within the context of drug delivery devices, surface coatings, and when precise control of strength retention is critical. Here we report on high tensile strength, aromatic–aliphatic polycarbonates based on natural phenols, tyrosol (Ty) and homovanillyl alcohol (Hva), that exhibit enzymatic surface erosion by lipase. The Young’s moduli of the polymers for dry and fully hydrated samples are 1.0 to 1.2 GPa and 0.8 to 1.2 GPa, respectively. Typical characteristics of enzymatic surface erosion were confirmed for poly(tyrosol carbonate) films with concomitant mass-loss and thickness-loss at linear rates of 0.14 ± 0.01 mg cm–2 d–1 and 3.0 ± 0.8 μm d–1, respectively. The molecular weight and the mechanical properties of the residual films remained constant. Changing the ratio of Ty and Hva provided control over the glass transition temperature (Tg) and the enzymatic surface erosion: increasing the Hva content in the polymers resulted in higher Tg and lower enzymatic erosion rate. Polymers with more than 50 mol % Hva were stable at 37 °C in enzyme solution. Analysis on thin films using quartz crystal microbalance with dissipation (QCM-D) demonstrated that the onset temperature of the enzymatic erosion was approximately 20 °C lower than the wet Tg for all tested polymers. This new finding demonstrates that relatively high tensile strength polycarbonates can undergo enzymatic surface erosion. Moreover, it also sheds light on the connection between Tg and enzymatic degradation and explains why few of the high strength polymers follow an enzyme-meditated degradation pathway.
PMCID: PMC3983148  PMID: 24432806
3.  Synthesis and Characterization of Fatty Acid/Amino Acid Self-Assemblies 
In this paper, we discuss the synthesis and self-assembling behavior of new copolymers derived from fatty acid/amino acid components, namely dimers of linoleic acid (DLA) and tyrosine derived diphenols containing alkyl ester pendent chains, designated as “R” (DTR). Specific pendent chains were ethyl (E) and hexyl (H). These poly(aliphatic/aromatic-ester-amide)s were further reacted with poly(ethylene glycol) (PEG) and poly(ethylene glycol methyl ether) of different molecular masses, thus resulting in ABA type (hydrophilic-hydrophobic-hydrophilic) triblock copolymers. We used Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies to evaluate the chemical structure of the final materials. The molecular masses were estimated by gel permeation chromatography (GPC) measurements. The self-organization of these new polymeric systems into micellar/nanospheric structures in aqueous environment was evaluated using ultraviolet/visible (UV-VIS) spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The polymers were found to spontaneously self-assemble into nanoparticles with sizes in the range 196–239 nm and critical micelle concentration (CMC) of 0.125–0.250 mg/mL. The results are quite promising and these materials are capable of self-organizing into well-defined micelles/nanospheres encapsulating bioactive molecules, e.g., vitamins or antibacterial peptides for antibacterial coatings on medical devices.
PMCID: PMC4285403  PMID: 25347356
amphiphilic block copolymers; fatty acid; micelle
4.  Molecular Design and Evaluation of Biodegradable Polymers Using a Statistical Approach 
Journal of materials science. Materials in medicine  2013;24(11):10.1007/s10856-013-5008-0.
The challenging paradigm of bioresorbable polymers, whether in drug delivery or tissue engineering, states that a fine-tuning of the interplay between polymer properties (e.g., thermal, degradation), and the degree of cell/tissue replacement and remodeling is required. In this paper we describe how changes in the molecular architecture of a series of terpolymers allow for the design of polymers with varying glass transition temperatures and degradation rates. The effect of each component in the terpolymers is quantified via design of experiment (DoE) analysis. A linear relationship between terpolymer components and resulting Tg (ranging from 34 to 86 °C) was demonstrated. These findings were further supported with mass-per-flexible-bond (MPFB) analysis. The effect of terpolymer composition on the in vitro degradation of these polymers revealed molecular weight loss ranging from 20 to 60% within the first 24 hours. DoE modeling further illustrated the linear (but reciprocal) relationship between structure elements and degradation for these polymers. Thus, we describe a simple technique to provide insight into the structure property relationship of degradable polymers, specifically applied using a new family of tyrosine-derived polycarbonates, allowing for optimal design of materials for specific applications.
PMCID: PMC3809329  PMID: 23888354
Glass transition; polymer degradation; Design of Experiments; modeling; polycarbonates
5.  Investigating the Release of a Hydrophobic Peptide from Matrices of Biodegradable Polymers: An Integrated Method Approach 
Polymer  2013;54(15):3806-3820.
The objectives of this work were: (1) to select suitable compositions of tyrosine-derived polycarbonates for controlled delivery of voclosporin, a potent drug candidate to treat ocular diseases, (2) to establish a structure-function relationship between key molecular characteristics of biodegradable polymer matrices and drug release kinetics, and (3) to identify factors contributing in the rate of drug release. For the first time, the experimental study of polymeric drug release was accompanied by a hierarchical sequence of three computational methods. First, suitable polymer compositions used in subsequent neural network modeling were determined by means of response surface methodology (RSM). Second, accurate artificial neural network (ANN) models were built to predict drug release profiles for fifteen polymers located outside the initial design space. Finally, thermodynamic properties and hydrogen-bonding patterns of model drug-polymer complexes were studied using molecular dynamics (MD) technique to elucidate a role of specific interactions in drug release mechanism. This research presents further development of methodological approaches to meet challenges in the design of polymeric drug delivery systems.
PMCID: PMC3770487  PMID: 24039300
hydrophobic peptide; polymeric drug release; structure-function relationship; computational modeling; hydrogen bonding
6.  Pro-angiogenic and Anti-inflammatory Regulation by Functional Peptides Loaded in Polymeric Implants for Soft Tissue Regeneration 
Tissue Engineering. Part A  2012;19(3-4):437-447.
Inflammation and angiogenesis are inevitable in vivo responses to biomaterial implants. Continuous progress has been made in biomaterial design to improve tissue interactions with an implant by either reducing inflammation or promoting angiogenesis. However, it has become increasingly clear that the physiological processes of inflammation and angiogenesis are interconnected through various molecular mechanisms. Hence, there is an unmet need for engineering functional tissues by simultaneous activation of pro-angiogenic and anti-inflammatory responses to biomaterial implants. In this work, the modulus and fibrinogen adsorption of porous scaffolds were tuned to meet the requirements (i.e., ∼100 kPa and ∼10 nm, respectively), for soft tissue regeneration by employing tyrosine-derived combinatorial polymers with polyethylene glycol crosslinkers. Two types of functional peptides (i.e., pro-angiogenic laminin-derived C16 and anti-inflammatory thymosin β4-derived Ac-SDKP) were loaded in porous scaffolds through collagen gel embedding so that peptides were released in a controlled fashion, mimicking degradation of the extracellular matrix. The results from (1) in vitro coculture of human umbilical vein endothelial cells and human blood-derived macrophages and (2) in vivo subcutaneous implantation revealed the directly proportional relationship between angiogenic activities (i.e., tubulogenesis and perfusion capacity) and inflammatory activities (i.e., phagocytosis and F4/80 expression) upon treatment with either type of peptide. Interestingly, cotreatment with both types of peptides upregulated the angiogenic responses, while downregulating the inflammatory responses. Also, anti-inflammatory Ac-SDKP peptides reduced production of pro-inflammatory cytokines (i.e., interleukin [IL]-1β, IL-6, IL-8, and tumor necrosis factor alpha) even when treated in combination with pro-angiogenic C16 peptides. In addition to independent regulation of angiogenesis and inflammation, this study suggests a promising approach to improve soft tissue regeneration (e.g., blood vessel and heart muscle) when inflammatory diseases (e.g., ischemic tissue fibrosis and atherosclerosis) limit the regeneration process.
PMCID: PMC3542873  PMID: 22953721
7.  Enhanced Femoral Nerve Regeneration After Tubulization with a Tyrosine-Derived Polycarbonate Terpolymer: Effects of Protein Adsorption and Independence of Conduit Porosity 
Tissue Engineering. Part A  2013;20(3-4):518-528.
Following complete nerve transection, entubulation of the nerve stumps helps guide axons to reconnect distally. In this study, a biodegradable and noncytotoxic tyrosine-derived polycarbonate terpolymer composed of 89.5 mol% desaminotyrosyl tyrosine ethyl ester (DTE), 10 mol% desaminotyrosyl tyrosine (DT), and 0.5 mol% poly(ethylene glycol) (PEG, molecular weight [Mw]=1 kDa) [designated as E10-0.5(1K)] was used to fabricate conduits for peripheral nerve regeneration. These conduits were evaluated against commercially available nonporous polyethylene (PE) tubes. The two materials are characterized in vitro for differences in surface properties, and the conduits are then evaluated in vivo in a critical-sized nerve defect in the mouse femoral nerve model. Conduits were fabricated from E10-0.5(1K) in both porous [P-E10-0.5(1K)] and nonporous [NP-E10-0.5(1K)] configurations. The results illustrate that adsorption of laminin, fibronectin, and collagen type I was enhanced on E10-0.5(1K) compared to PE. In addition, in vivo the E10-0.5(1K) conduits improved functional recovery over PE conduits, producing regenerated nerves with a fivefold increase in the number of axons, and an eightfold increase in the percentage of myelinated axons. These increases were observed for both P-E10-0.5(1K) and NP-E10-0.5(1K) after 15 weeks. When conduits were removed at 7 or 14 days following implantation, an increase in Schwann cell proteins and fibrin matrix formation was observed in E10-0.5(1K) conduits over PE conduits. These results indicate that E10-0.5(1K) is a pro-regenerative material for peripheral nerves and that the porosity of P-E10-0.5(1K) conduits was inconsequential in this model of nerve injury.
PMCID: PMC3926162  PMID: 24011026
8.  Development of paclitaxel-TyroSpheres for topical skin treatment 
A potential topical psoriasis therapy has been developed consisting of tyrosine-derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4,000 times greater than PBS) by effective encapsulation and enable sustained, dose-controlled release over 72 hours under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm2 of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC50 of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape.
PMCID: PMC3462247  PMID: 22732474
psoriasis; topical drug delivery; tyrosine-derived nanospheres; cytotoxicity; skin distribution; viscous formulation
9.  Study of nanoscale structures in hydrated biomaterials using small-angle neutron scattering 
Acta Biomaterialia  2011;8(4):1459-1468.
Distribution of water in three classes of biomedically relevant and degradable polymers was investigated using small-angle neutron scattering. In semicrystalline polymers, such as poly(lactic acid) and poly(glycolic acid), water was found to diffuse preferentially into the noncrystalline regions. In amorphous polymers, such as poly(D,L-lactic acid) and poly(lactic-co-glycolic acid), the scattering after 7-days of incubation was attributed to water in microvoids that form following the hydrolytic degradation of the polymer. In amorphous copolymers containing hydrophobic segments (desaminotyrosyl-tyrosine ethyl ester) and hydrophilic blocks (poly(ethylene glycol) PEG), a sequence of distinct regimes of hydration were observed: homogeneous distribution (~ 10 Å length scales) at <13 wt% PEG (~ 1 water per EG), clusters of hydrated domains (~50 Å radius) separated at 24 wt% PEG (1 to 2 water per EG), uniformly distributed hydrated domains at 41 wt% PEG (~ 4 water per EG), and phase inversion at > 50 wt% PEG ( > 6 water per EG ). Increasing PEG content increased the number of these domains with only a small decrease in distance between the domains. These discrete domains appeared to coalesce to form submicron droplets at ~60 °C, above the melting temperature of crystalline PEG. Significance of such observations on the evolution of μm size channels that form during hydrolytic erosion is discussed.
PMCID: PMC3289755  PMID: 22227373
Hydration; PEG-containing copolymers; hydrated PEG domains; biodegradation; neutron scattering
10.  Multiscale analysis of water uptake and erosion in biodegradable polyarylates 
Polymer degradation and stability  2012;97(3):410-420.
The role of hydration in degradation and erosion of materials, especially biomaterials used in scaffolds and implants, was investigated by studying the distribution of water at length scales from 0.1 nm to 0.1 mm using Raman spectroscopy, small-angle neutron scattering (SANS), Raman confocal imaging, and scanning electron microscopy (SEM). The measurements were demonstrated using L-tyrosine derived polyarylates. Bound- and free- water were characterized using their respective signatures in the Raman spectra. In the presence of deuterium oxide (D2O), H-D exchange occurred at the amide carbonyl but was not detected at the ester carbonyl. Water appeared to be present in the polymer even in regions where there was little evidence for N-H to N-D exchange. SANS showed that water is not uniformly dispersed in the polymer matrix. The distribution of water can be described as mass fractals in polymers with low water content (~5 wt%), and surface fractals in polymers with larger water content (15 to 60 wt%). These fluctuations in the density of water distribution are presumed to be the precursors of the ~ 20 μm water pockets seen by Raman confocal imaging, and also give rise to 10–50 μm porous network seen in SEM. The surfaces of these polymers appeared to resist erosion while the core of the films continued to erode to form a porous structure. This could be due to differences in either the density of the polymer or the solvent environment in the bulk vs. the surface, or a combination of these two factors. There was no correlation between the rate of degradation and the amount of water uptake in these polymers, and this suggests that it is the bound-water and not the total amount of water that contributes to hydrolytic degradation.
PMCID: PMC3285249  PMID: 22368310
multiscale analysis; hydration; degradation; spectroscopy; scattering; confocal imaging; microscopy; polyarylates
11.  Predicting biomaterial property-dendritic cell phenotype relationships from the multivariate analysis of responses to polymethacrylates 
Biomaterials  2011;33(6):1699-1713.
Dendritic cells (DCs) play a critical role in orchestrating the host responses to a wide variety of foreign antigens and are essential in maintaining immune tolerance. Distinct biomaterials have been shown to differentially affect the phenotype of DCs, which suggested that biomaterials may be used to modulate immune response towards the biologic component in combination products. The elucidation of biomaterial property-DC phenotype relationships is expected to inform rational design of immuno-modulatory biomaterials. In this study, DC response to a set of 12 polymethacrylates (pMAs) was assessed in terms of surface marker expression and cytokine profile. Principal component analysis (PCA) determined that surface carbon correlated with enhanced DC maturation, while surface oxygen was associated with an immature DC phenotype. Partial square linear regression, a multivariate modeling approach, was implemented and successfully predicted biomaterial-induced DC phenotype in terms of surface marker expression from biomaterial properties with R2prediction = 0.76. Furthermore, prediction of DC phenotype was effective based on only theoretical chemical composition of the bulk polymers with R2prediction = 0.80. These results demonstrated that immune cell response can be predicted from biomaterial properties, and computational models will expedite future biomaterial design and selection.
PMCID: PMC3399429  PMID: 22136715
dendritic cells; polymethacrylate; combinatorial library; material properties; principal component analysis; partial linear squares regression
12.  Hydration-Induced Phase Separation in Amphiphilic Polymer Matrices and its Influence on Voclosporin Release 
Voclosporin is a highly potent, new cyclosporine-A derivative that is currently in Phase 3 clinical trials in the USA as a potential treatment for inflammatory diseases of the eye. Voclosporin represents a number of very sparingly soluble drugs that are difficult to administer. We therefore selected it as a model drug that is dispersed within amphiphilic polymer matrices, and investigated the changing morphology of the matrices using neutron and x-ray scattering during voclosporin release and polymer resorption. The hydrophobic segments of the amphiphilic polymer chain are comprised of desaminotyrosyl-tyrosine ethyl ester (DTE) and desaminotyrosyl-tyrosine (DT), and the hydrophilic component is poly(ethylene glycol) (PEG). Water uptake in these matrices resulted in the phase separation of hydrophobic and hydrophilic domains that are a few hundred Angstroms apart. These water-driven morphological changes influenced the release profile of voclosporin and facilitated a burst-free release from the polymer. No such morphological reorganization was observed in poly(lactide-co-glycolide) (PLGA), which exhibits an extended lag period, followed by a burst-like release of voclosporin when the polymer was degraded. An understanding of the effect of polymer composition on the hydration behavior is central to understanding and controlling the phase behavior and resorption characteristics of the matrix for achieving long-term controlled release of hydrophobic drugs such as voclosporin.
PMCID: PMC4030927  PMID: 24955746
hydration-induced phase separation; amphiphilic polymer; resorption; voclosporin; small angle scattering
13.  Impact of Polymer-bound Iodine on Fibronectin Adsorption and Osteoblast Cell Morphology Radiopaque Medical Polymers: Tyrosine-derived Polycarbonate Blends as a Model System 
Biomacromolecules  2009;10(9):2418-2426.
Imaging of polymer implants during surgical implantations is challenging in that most materials lack sufficient X-ray contrast. Synthetic derivatization with iodine serves to increase the scattering contrast but results in distinct physico-chemical properties in the material which influence subsequent protein adsorption and cell morphology behavior. Herein we report the impact of increasing iodine inclusion on the cell morphology (cell area and shape) of MC3T3-E1 osteoblasts on a series of homopolymers and discrete blend thin films of poly(desaminotyrosyl tyrosine ethyl ester carbonate), poly(DTE carbonate) and an iodinated analogue poly(I2-DTE carbonate). Cell morphology is correlated to film chemical composition via measuring Fibronectin (FN) adhesion protein adsorption profile on these films. FN exhibits up to 2 fold greater adsorption affinity for poly(I2-DTE carbonate) than (poly(DTE carbonate)). A correlation was established between cell area, roundness and the measured FN adsorption profile on the blend films up to 75 % by mass poly(I2-DTE carbonate). Data suggest that incorporation of iodine within the polymer backbone has a distinct impact on the way FN proteins adsorb to the surface and within the studied blend systems; the effect is composition dependent.
PMCID: PMC3494279  PMID: 19645443
tyrosine-derived polycarbonates; biomaterials; MC3T3-E1; cellular morphology; imaging; Fibronectin; protein adsorption
14.  The fate of ultrafast degrading polymeric implants in the brain 
Biomaterials  2011;32(24):5543-5550.
We have recently reported on an ultra fast degrading tyrosine-derived terpolymer that degrades and resorbs within hours, and is a suitable for use in cortical neural prosthetic applications. Here we further characterize this polymer, and describe a new tyrosine-derived fast degrading terpolymer in which the poly(ethylene glycol) (PEG) is replaced by poly(trimethylene carbonate) (PTMC). This PTMC containing terpolymer showed similar degradation characteristics but its resorption was negligible in the same period. Thus, changes in the polymer chemistry allowed for the development of two ultrafast degrading polymers with distinct difference in resorption properties. The in vivo tissue response to both polymers used as intraparenchymal cortical devices was compared to poly(lactic-co-glycolic acid) (PLGA). Slow resorbing, indwelling implant resulted in continuous glial activation and loss of neural tissue. In contrast, the fast degrading tyrosine-derived terpolymer that is also fast resorbing, significantly reduced both the glial response in the implantation site and the neuronal exclusion zone. Such polymers allow for brain tissue recovery, thus render them suitable for neural interfacing applications.
PMCID: PMC3109174  PMID: 21609850
brain tissue response; biodegradation; bioerosion; ultrafast-degrading polymers; tyrosine-derived terpolymer
15.  Biohybrid Carbon Nanotube/Agarose Fibers for Neural Tissue Engineering 
Advanced functional materials  2011;21(14):2624-2632.
We report a novel approach for producing carbon nanotube fibers (CNF) composed with the polysaccharide agarose. Current attempts to make CNF’s require the use of a polymer or precipitating agent in the coagulating bath that may have negative effects in biomedical applications. We show that by taking advantage of the gelation properties of agarose one can substitute the bath with distilled water or ethanol and hence reduce the complexity associated with alternating the bath components or the use of organic solvents. We also demonstrate that these CNF can be chemically functionalized to express biological moieties through available free hydroxyl groups in agarose. We corroborate that agarose CNF are not only conductive and nontoxic, but their functionalization can facilitate cell attachment and response both in vitro and in vivo. Our findings suggest that agarose/CNT hybrid materials are excellent candidates for applications involving neural tissue engineering and biointerfacing with the nervous system.
PMCID: PMC3163387  PMID: 21887125
Carbon-nanotubes; agarose; fibers; functionalization; neural
16.  Computational modeling of in vitro biological responses on polymethacrylate surfaces 
Polymer  2011;52(12):2650-2660.
The objective of this research was to examine the capabilities of QSPR (Quantitative Structure Property Relationship) modeling to predict specific biological responses (fibrinogen adsorption, cell attachment and cell proliferation index) on thin films of different polymethacrylates. Using 33 commercially available monomers it is theoretically possible to construct a library of over 40,000 distinct polymer compositions. A subset of these polymers were synthesized and solvent cast surfaces were prepared in 96 well plates for the measurement of fibrinogen adsorption. NIH 3T3 cell attachment and proliferation index were measured on spin coated thin films of these polymers. Based on the experimental results of these polymers, separate models were built for homo-, co-, and terpolymers in the library with good correlation between experiment and predicted values. The ability to predict biological responses by simple QSPR models for large numbers of polymers has important implications in designing biomaterials for specific biological or medical applications.
PMCID: PMC3138629  PMID: 21779132
Combinatorial; Polymethacrylates; Quantitative Structure Property Relation (QSPR)
17.  Control of Surface Chemistry, Substrate Stiffness, and Cell Function in a Novel Terpolymer Methacrylate Library 
A focused library of methacrylate terpolymers was synthesized to explore the effects of varying surface chemistry and adhesive peptide ligands on cell function. The chemical diversity of methacrylate monomers enabled construction of a library of polymers in which one can systematically vary the chemical composition to achieve a wide range of contact angle, Young's modulus, and Tg values. Furthermore, the materials were designed to allow surface immobilization of bioactive peptides. We then examined the effects of these material compositions on protein adsorption and cell attachment, proliferation, and differentiation. We observed that chemical composition of the polymers was an important determinant for NIH 3T3 cell attachment and proliferation, as well as human mesenchymal stem cell differentiation, and correlated directly with the ability of the polymers to adsorb proteins that mediate cell adhesion. Importantly, functionalization of the methacrylate terpolymer library with an adhesive GRGDS peptide normalized cellular responses. RGD-functionalized polymers uniformly exhibited robust attachment, proliferation, and differentiation irrespective of the underlying substrate chemistry. These studies provide a library-based approach to rapidly explore the biological functionality of biomaterials with a wide range of compositions, and highlights the importance of cell and protein cell adhesion in predicting their performance.
PMCID: PMC3043143  PMID: 21226505
18.  Gas-Foamed Scaffold Gradients for CombinatorialScreening in 3D 
Current methods for screening cell-material interactions typically utilize a two-dimensional (2D) culture format where cells are cultured on flat surfaces. However, there is a need for combinatorial and high-throughput screening methods to systematically screen cell-biomaterial interactions in three-dimensional (3D) tissue scaffolds for tissue engineering. Previously, we developed a two-syringe pump approach for making 3D scaffold gradients for use in combinatorial screening of salt-leached scaffolds. Herein, we demonstrate that the two-syringe pump approach can also be used to create scaffold gradients using a gas-foaming approach. Macroporous foams prepared by a gas-foaming technique are commonly used for fabrication of tissue engineering scaffolds due to their high interconnectivity and good mechanical properties. Gas-foamed scaffold gradient libraries were fabricated from two biodegradable tyrosine-derived polycarbonates: poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (pDTEc) and poly(desaminotyrosyl-tyrosine octyl ester carbonate) (pDTOc). The composition of the libraries was assessed with Fourier transform infrared spectroscopy (FTIR) and showed that pDTEc/pDTOc gas-foamed scaffold gradients could be repeatably fabricated. Scanning electron microscopy showed that scaffold morphology was similar between the pDTEc-rich ends and the pDTOc-rich ends of the gradient. These results introduce a method for fabricating gas-foamed polymer scaffold gradients that can be used for combinatorial screening of cell-material interactions in 3D.
PMCID: PMC4031022  PMID: 24956523
combinatorial screening; polymer; scaffold; tissue engineering
19.  Thin Film Elastic Modulus of Degradable Tyrosine-Derived Polycarbonate Biomaterials and Their Blends 
Macromolecules  2009;42(4):1212-1218.
The integrity, function, and performance of biomedical devices having thin polymeric coatings are critically dependent on the mechanical properties of the film, including the elastic modulus. In this report, the elastic moduli of several tyrosine-derived polycarbonate thin films, specifically desaminotyrosyl ethyl tyrosine polycarbonates p(DTE carbonate), an iodinated derivative p(I2-DTE carbonate), and several discrete blends are measured using a method based on surface wrinkling. The data shows that the elastic modulus does not vary significantly with the blend composition as the weight percentage of p(I2-DTE carbonate) increases for films of uniform thickness in the range of 67 to 200 nm. As a function of film thickness, the observed elastic moduli of p(DTE carbonate), p(I2-DTE carbonate) and their 50:50 by mass blend show little variation over the range 30 to 200 nm.
PMCID: PMC3092710  PMID: 21572899
20.  A Comparison of Degradable Synthetic Polymer Fibers for Anterior Cruciate Ligament Reconstruction 
We compared mechanical properties, degradation rates, and cellular compatibilities of two synthetic polymer fibers potentially useful as ACL reconstruction scaffolds: poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate)(12,10), p(DTD DD) and poly(L-lactic acid), PLLA. The yield stress of ethylene oxide (ETO) sterilized wet fibers was 150 ± 22 MPa and 87 ± 12 MPa for p(DTD DD) and PLLA, respectively, with moduli of 1.7 ± 0.1 MPa and 4.4 ± 0.43 MPa. Strength and molecular weight retention were determined after incubation under physiological conditions at varying times. After 64 weeks strength decreased to 20 and 37% of the initial sterile fiber values and MW decreased to 41% and 36% of the initial values for p(DTD DD) and PLLA, respectively. ETO sterilization had no significant effect on mechanical properties. Differences in mechanical behavior may be due to the semicrystalline nature of PLLA and the small degree of crystallinity induced by mesogenic ordering in p(DTD DD) suggested by DSC analysis. Fibroblast growth was similar on 50-fiber scaffolds of both polymers through 16 days in vitro. These data suggest that p(DTD DD) fibers, with higher strength, lower stiffness, favorable degradation rate and cellular compatibility, may be a superior alternative to PLLA fibers for development of ACL reconstruction scaffolds.
PMCID: PMC2845725  PMID: 19623532
21.  Interplay of Anionic Charge, Poly(ethylene glycol), and Iodinated Tyrosine Incorporation within Tyrosine-derived Polycarbonates: Effects on Vascular Smooth Muscle Cell Adhesion, Proliferation and Motility 
Regulation of smooth muscle cell adhesion, proliferation, and motility on biomaterials is critical to the performance of blood-contacting implants and vascular tissue engineering scaffolds. The goal of this study was to examine the underlying substrate-smooth muscle cell response relations, using a selection of polymers representative of an expansive library of multifunctional, tyrosine-derived polycarbonates. Three chemical components within the polymer structure were selectively varied through copolymerization: 1) the content of iodinated tyrosine to achieve X-ray visibility; 2) the content of poly(ethylene glycol) (PEG) to decrease protein adsorption and cell adhesivity; and 3) the content of desaminotyrosyl-tyrosine (DT) which regulates the rate of polymer degradation. Using quartz crystal microbalance with dissipation, we quantified differential serum protein adsorption behavior due to the chemical components DT, iodinated tyrosine, and PEG: increased PEG content within the polymer structure progressively decreased protein adsorption but the simultaneous presence of both DT and iodinated tyrosine reversed the effects of PEG. The complex interplay of these components was next tested on the adhesion, proliferation, and motility behavior cultured human aortic smooth muscle cells. The incorporation of PEG into the polymer reduced cell attachment, which was reversed in the presence of iodinated tyrosine. Further, we found that as little as 10% DT content was sufficient to negate the PEG effect in polymers containing iodinated tyrosine while in non-iodinated polymers the PEG effect on cell attachment was reversed. Cross-functional analysis of motility and proliferation revealed divergent substrate chemistry related cell response regimes. For instance, within the series of polymers containing both iodinated tyrosine and 10% of DT, increasing PEG levels lowered smooth muscle cell motility without a change in the rate of cell proliferation. In contrast, for non-iodinated tyrosine and 10% of DT, increasing PEG levels increased cell proliferation significantly while reducing cell motility. Clearly, the polycarbonate polymer library offers a sensitive platform to modulate cell adhesion, proliferation, and motility responses, which, in turn, may have implications for controlling vascular remodeling in vivo. Additionally, our data suggests unique biorelevant properties following the incorporation of iodinated subunits in a polymeric biomaterial as a potential platform for X-ray visible devices.
PMCID: PMC2845728  PMID: 19585568
22.  High-Content Profiling of Cell Responsiveness to Graded Substrates Based on Combinatorially Variant Polymers 
We have developed a novel approach combining high information and high throughput analysis to characterize cell adhesive responses to biomaterial substrates possessing gradients in surface topography. These gradients were fabricated by subjecting thin film blends of tyrosine-derived polycarbonates, i.e. poly(DTE carbonate) and poly(DTO carbonate) to a gradient temperature annealing protocol. Saos-2 cells engineered with a green fluorescent protein (GFP) reporter for farnesylation (GFP-f) were cultured on the gradient substrates to assess the effects of nanoscale surface topology and roughness that arise during the phase separation process on cell attachment and adhesion strength. The high throughput imaging approach allowed us to rapidly identify the “global” and “high content” structure-property relationships between cell adhesion and biomaterial properties such as polymer chemistry and topography. This study found that cell attachment and spreading increased monotonically with DTE content and were significantly elevated at the position with intermediate regions corresponding to the highest “gradient” of surface roughness, while GFP-f farnesylation intensity descriptors were sensitively altered by surface roughness, even in cells with comparable levels of spreading.
PMCID: PMC3061568  PMID: 19531022
23.  X-ray imaging optimization of 3D tissue engineering scaffolds via combinatorial fabrication methods 
Biomaterials  2008;29(12):1901-1911.
We have developed a combinatorial method for determining optimum tissue scaffold composition for several X-ray imaging techniques. X-ray radiography and X-ray microcomputed tomography enable non-invasive imaging of implants in vivo and in vitro. However, highly porous polymeric scaffolds do not always possess sufficient X-ray contrast and are therefore difficult to image with X-ray-based techniques. Incorporation of high radiocontrast atoms, such as iodine, into the polymer structure improves X-ray radiopacity but also affects physicochemical properties and material performance. Thus, we have developed a combinatorial library approach to efficiently determine the minimum amount of contrast agent necessary for X-ray-based imaging. The combinatorial approach is demonstrated in a polymer blend scaffold system where X-ray imaging of poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (pDTEc) scaffolds is improved through a controlled composition variation with an iodinated-pDTEc analog (pI2DTEc). The results show that pDTEc scaffolds must include at least 9%, 16%, 38% or 46% pI2DTEc (by mass) to enable effective imaging by microradiography, dental radiography, dental radiography through 0.75 cm of muscle tissue or micro-computed tomography, respectively. Only two scaffold libraries were required to determine these minimum pI2DTEc percentages required for X-ray imaging, which demonstrates the efficiency of this new combinatorial approach for optimizing scaffold formulations.
PMCID: PMC2996266  PMID: 18242689
Combinatorial library; Polycarbonate; Scaffolds; Radiopacity; X-ray microcomputed tomography; X-ray radiography
24.  Cellular response to phase-separated blends of tyrosine-derived polycarbonates* 
Two-dimensional thin films consisting of homopolymer and discrete compositional blends of tyrosine-derived polycarbonates were prepared and characterized in an effort to elucidate the nature of different cell responses that were measured in vitro. The structurally similar blends were found to phase separate after annealing with domain sizes dependent on the overall composition. The thin polymer films were characterized with the use of atomic force microscopy (AFM), water contact angles, and time-of-flight secondary ion mass spectrometry (TOF-SIMS) and significant changes in roughness were measured following the annealing process. Genetic expression profiles of interleukin-1β and fibronectin in MC3T3-E1 osteoblasts and RAW 264.7 murine macrophages were measured at several time points, demonstrating the time and composition-dependent nature of the cell responses. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) depicted upregulation of the fibronectin gene copy numbers in each of the blends relative to the homopolymers. Moreover, the interleukin-1β expression profile was found to be compositionally dependent. The data suggest strongly that optimal composition and processing conditions can significantly affect the acute inflammatory and extracellular matrix production responses.
PMCID: PMC2996268  PMID: 16278865
biomaterials; fibronectin; tyrosine-derived polycarbonate; phase separation; real-time reverse transcriptase polymerase chain reaction (RT-PCR); interleukin-1β
25.  Simple, Rapid, and Highly Sensitive Detection of Diphosgene and Triphosgene by Spectrophotometric Methods 
Talanta  2009;80(1):231-235.
Methods for the detection and estimation of diphosgene and triphosgene are described. These compounds are widely used phosgene precursors which produce an intensely colored purple pentamethine oxonol dye when reacted with 1,3-dimethylbarbituric acid (DBA) and pyridine (or a pyridine derivative). Two quantitative methods are described, based on either UV absorbance or fluorescence of the oxonol dye. Detection limits are ~ 4 µmol/L by UV and <0.4 µmol/L by fluorescence. The third method is a test strip for the simple and rapid detection and semi-quantitative estimation of diphosgene and triphosgene, using a filter paper embedded with dimethylbarbituric acid and poly(4-vinylpyridine). Addition of a test solution to the paper causes a color change from white to light blue at low concentrations and to pink at higher concentrations of triphosgene. The test strip is useful for quick on-site detection of triphosgene and diphosgene in reaction mixtures. The test strip is easy to perform and provides clear signal readouts indicative of the presence of phosgene precursors. The utility of this method was demonstrated by the qualitative determination of residual triphosgene during the production of poly(Bisphenol A carbonate).
PMCID: PMC2757637  PMID: 19782219
triphosgene; phosgene; spectrophotometry; spectrofluorimetry; test strip; poly(Bisphenol A carbonate)

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