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Polyglycolide (PGA) is a biodegradable polymer with multiple applications in the medical sector. Here the synthesis of high molecular weight polyglycolide by ring-opening polymerization of diglycolide is reported. For the first time stabilizer free supercritical carbon dioxide (scCO(2)) was used as a reaction medium. scCO(2) allowed for a reduction in reaction temperature compared to conventional processes. Together with the lowering of monomer concentration and consequently reduced heat generation compared to bulk reactions thermal decomposition of the product occurring already during polymerization is strongly reduced. The reaction temperatures and pressures were varied between 120 and 150 degrees C and 145 to 1400 bar. Tin(II) ethyl hexanoate and 1-dodecanol were used as catalyst and initiator, respectively. The highest number average molecular weight of 31 200 g mol(-1) was obtained in 5 hours from polymerization at 120 degrees C and 530 bar. In all cases the products were obtained as a dry white powder. Remarkably, independent of molecular weight the melting temperatures were always at (219 +/- 2)degrees C.
Polyglycolide (PGA) is a biodegradable polymer with multiple applications in the medical sector. Here the synthesis of high molecular weight polyglycolide by ring-opening polymerization of diglycolide is reported. For the first time stabilizer free supercritical carbon dioxide (scCO2) was used as a reaction medium. scCO2 allowed for a reduction in reaction temperature compared to conventional processes. Together with the lowering of monomer concentration and consequently reduced heat generation compared to bulk reactions thermal decomposition of the product occurring already during polymerization is strongly reduced. The reaction temperatures and pressures were varied between 120 and 150 °C and 145 to 1400 bar. Tin(II) ethyl hexanoate and 1-dodecanol were used as catalyst and initiator, respectively. The highest number average molecular weight of 31 200 g mol−1 was obtained in 5 hours from polymerization at 120 °C and 530 bar. In all cases the products were obtained as a dry white powder. Remarkably, independent of molecular weight the melting temperatures were always at (219 ± 2) °C.
An atomistic molecular dynamics simulation approach is applied to model the influence of urethane linker units as well as the addition of water molecules on the simulated shape-memory properties of poly[(rac-lactide)-co-glycolide] (PLGA) and PLGA-based copolyester urethanes comprising different urethane linkers. The shape-memory performance of these amorphous packing models is explored in a simulated heating-deformation-cooling-heating procedure. Depending on the type of incorporated urethane linker, the mechanical properties of the dry copolyester urethanes are found to be significantly improved compared with PLGA, which can be attributed to the number of intermolecular hydrogen bonds between the urethane units. Good shape-memory properties are observed for all the modeled systems. In the dry state, the shape fixation is found to be improved by implementation of urethane units. After swelling of the copolymer models with water, which results in a reduction of their glass transition temperatures, the relaxation kinetics during unloading and shape recovery are found to be substantially accelerated.
Polyester networks can be prepared by ultraviolet (UV)-light-induced radical polymerization of methacrylate functionalized oligo(epsilon-caprolactone)s. The properties and functions of the obtained materials depend on defined network structures and may be altered, if crosslinking would occur by side reactions in other positions than the methacrylate endgroups. In order to explore whether and to which extent such side reactions occur, network synthesis as well as related model reactions were performed in the absence of photoinitiator. Hereby precursor structures (linear and four-arm star-shaped) and reaction conditions (in solution and in the melt) were varied. Unspecific side reactions were found only upon extensive UV irradiation for 60min (26 mW cm(-2)) with minor but detectable alterations of physicochemical properties of the networks. The analysis of model reactions suggested minor photolytic cleavage of ester bonds during polymer network synthesis. However, the effect of these side reactions on network properties and functions appeared to be less relevant than an incomplete precursor integration because of a too short UV irradiation for crosslinking. Copyright (c) 2014 John Wiley & Sons, Ltd.
For in vitro studies assessing the interaction of platelets with implant materials, common and standardized protocols for the preparation of platelet rich plasma (PRP) are lacking, which may lead to non-matching results due to the diversity of applied protocols. Particularly, the aging of platelets during prolonged preparation and storage times is discussed to lead to an underestimation of the material thrombogenicity. Here, we study the influence of whole blood-and PRP-storage times on changes in platelet morphology and function.
Whole blood PFA100 closure times increased after stimulation with collagen/ADP and collagen/epinephrine. Twenty four hours after blood collection, both parameters were prolonged pathologically above the upper limit of the reference range. Numbers of circulating platelets, measured in PRP, decreased after four hours, but no longer after twenty four hours. Mean platelet volumes (MPV) and platelet large cell ratios (P-LCR, 12 fL - 40 fL) decreased over time. Immediately after blood collection, no debris or platelet aggregates could be visualized microscopically. After four hours, first debris and very small aggregates occurred. After 24 hours, platelet aggregates and also debris progressively increased. In accordance to this, the CASY system revealed an increase of platelet aggregates (up to 90 mu m diameter)with increasing storage time.
The percentage of CD62P positive platelets and PF4 increased significantly with storage time in resting PRP. When soluble ADP was added to stored PRP samples, the number of activatable platelets decreased significantly over storage time. The present study reveals the importance of a consequent standardization in the preparation of WB and PRP. Platelet morphology and function, particularly platelet reactivity to adherent or soluble agonists in their surrounding milieu, changed rapidly outside the vascular system. This knowledge is of crucial interest, particularly in the field of biomaterial development for cardiovascular applications, and may help to define common standards in the in vitro hemocompatibility testing of biomaterials.
A series of multiblock copolymers (PDLCL) synthesized from oligo(omega-pentadecalactone) diol (OPDL) and oligo(epsilon-caprolactone) diol (OCL), which are linked by 2,2(4), 4-trimethyl-hexamethylene diisocyanate (TMDI), is investigated by the Langmuir monolayer technique at the air-water interface. Brewster angle microscopy (BAM) and spectroscopic ellipsometry are employed to characterize the polymer film morphologies in situ. PDLCL containing >= 40 wt% OCL segments form homogeneous Langmuir monofilms after spreading. The film elasticity modulus decreases with increasing amounts of OPDL segments in the copolymer. In contrast, the OCL-free polyesterurethane OPDL-TMDI cannot be spread to monomolecular films on the water surface properly, and movable slabs are observed by BAM even at low surface pressures. The results of the in situ morphological characterization clearly show that essential information concerning the reliability of Langmuir monolayer degradation (LMD) experiments cannot be obtained from the evaluation of the pi-A isotherms only. Consequently, in situ morphological characterization turns out to be indispensable for characterization of Langmuir layers before LMD experiments.
Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo-and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials.
Hemocompatible materials are needed for internal and extracorporeal biomedical applications, which should be realizable by reducing protein and thrombocyte adhesion to such materials. Polyethers have been demonstrated to be highly efficient in this respect on smooth surfaces. Here, we investigate the grafting of oligo- and polyglycerols to rough poly(ether imide) membranes as a polymer relevant to biomedical applications and show the reduction of protein and thrombocyte adhesion as well as thrombocyte activation. It could be demonstrated that, by performing surface grafting with oligo- and polyglycerols of relatively high polydispersity (>1.5) and several reactive groups for surface anchoring, full surface shielding can be reached, which leads to reduced protein adsorption of albumin and fibrinogen. In addition, adherent thrombocytes were not activated. This could be clearly shown by immunostaining adherent proteins and analyzing the thrombocyte covered area. The presented work provides an important strategy for the development of application relevant hemocompatible 3D structured materials.
Open porous foams with identical foam density but different pore-size distributions (bimodal or monomodal) are prepared from a shape-memory polyetherurethane (PEU) by thermally induced phase separation. The shape-memory effect of the two PEU foams is explored by cyclic thermomechanical compression tests and microstructural analysis. The obtained results reveal that the PEU foam with a bimodal pore-size distribution exhibits an increased shape-recovery under stress-free conditions, both on the macro- (foam level) as well as the microscale (pore level). While bimodal pore-size distributions induce microscale bending during compression, buckling occurs in foams with monomodal pore-size distributions, leading to both a reduced and delayed shape recovery.
Polymers exhibiting cell-selective effects represent an extensive research field with high relevance for biomedical applications e.g. in the cardiovascular field supporting re-endothelialization while suppressing smooth muscle cell overgrowth. Such an endothelial cell-selective effect could be recently demonstrated for a copolyetheresterurethane (PDC) containing biodegradable poly(p-dioxanone) and poly(epsilon-caprolactone) segments, which selectively enhanced the adhesion of human umbilical vein endothelial cells (HUVEC) while suppressing the attachment of smooth muscle cells (SMC).
In this study we investigated the influence of the fibre orientation (random and aligned) and fibre diameter (2 mu m and 500 nm) of electrospun PDC scaffolds on the adhesion, proliferation and apoptosis of HUVEC and SMC.
Adhesion, viability and proliferation of HUVEC was diminished when the fibre diameter was reduced to a submicron scale, while the orientation of the microfibres did only slightly influence the cellular behaviour. In contrast, a submicron fibre diameter improved SMC viability. In conclusion, PDC scaffolds with micron-sized single fibres could be promising candidate materials for cell-selective stent coatings.
The thermally induced shape-memory effect of polymers is typically characterized by cyclic uniaxial thermomechanical tests. Here, a molecular-dynamics (MD) simulation approach of such a cyclic uniaxial thermomechanical test is presented for amorphous switching domains of poly(L-lactide) (PLLA). Uniaxial deformation of the constructed PLLA models is simulated with a Parinello-Rahman scheme, as well as a pragmatic geometrical approach. We are able to describe two subsequent test cycles using the presented simulation approach. The obtained simulated shape-memory properties in both test cycles are similar and independent of the applied deformation protocols. The simulated PLLA shows high shape fixity ratios (Rf 94%), but only a moderate shape recovery ratio is obtained (Rr 30%). Finally, the structural changes during the simulated test are characterized by analysis of the changes in the dihedral angle distributions.
The chain length and end groups of linear PEG grafted on smooth surfaces is known to influence protein adsorption and thrombocyte adhesion. Here, it is explored whether established structure function relationships can be transferred to application relevant, rough surfaces. Functionalization of poly(ether imide) (PEI) membranes by grafting with monoamino PEG of different chain lengths (M-n=1kDa or 10kDa) and end groups (methoxy or hydroxyl) is proven by spectroscopy, changes of surface hydrophilicity, and surface shielding effects. The surface functionalization does lead to reduction of adsorption of BSA, but not of fibrinogen. The thrombocyte adhesion is increased compared to untreated PEI surfaces. Conclusively, rough instead of smooth polymer or gold surfaces should be investigated as relevant models.
Shape-memory polymers (SMPs) are stimuli-sensitive materials capable of performing complex movements on demand, which makes them interesting candidates for various applications, for example, in biomedicine or aerospace. This trend article highlights current approaches in the chemistry of SMPs, such as tailored segment chemistry to integrate additional functions and novel synthetic routes toward permanent and temporary netpoints. Multiphase polymer networks and multimaterial systems illustrate that SMPs can be constructed as a modular system of different building blocks and netpoints. Future developments are aiming at multifunctional and multistimuli-sensitive SMPs.
Purpose: The formation of photoresponsive hydrogels were reported by irradiation of star-shaped poly(ethylene glycol)s with terminal cinnamylidene acetic acid (CAA) groups, which are capable of a photoinduced [2+2] cycloaddition. In this study we explored whether oligo(ethylene glycol) s and oligo(propylene glycol)s of varying molecular architecture (linear or star-shaped) or molecular weights could be functionalized with CAA as terminal groups by esterification or by amide formation.
Methods: Oligo(ethylene glycol) (OEG) and oligo(propylene glycol) (OPG) with varying molecular architecture (linear, star-shaped) and weight average molecular weights between 1000 and 5000 g.mol(-1) were functionalized by means of esterification of hydroxyl or amine endgroups with cinnamylidene acetic acid (CAA) or cinnamylidene acetyl chloride (CAC) as telechelic endgroups. The chemical structure, thermal properties, and molecular weights of the oligoethers obtained were determined by NMR spectroscopy, UV spectroscopy, DSC, and MALDI-TOF.
Results: CAA-functionalized linear and star-shaped OEGs or OPGs could be obtained with a degree of functionalization higher than 90%. In MALDI-TOF measurements an increase in Mw of about 150 g.mol(-1) (for each terminal end) after the functionalization reaction was observed. OEGCAA and OPGCAA showed an increase in glass transition temperature (T-g) from about -70 degrees C to -50 degrees C, compared to the unfunctionalized oligoethers. In addition, the melting temperature (T-m) of OEGCAA decreased from about 55 C to 30 degrees C, which can be accounted for by the hampered crystallization of the precursors because of the bulky CAA end groups as well as by the loss of the hydroxyl telechelic end groups.
Conclusion: The synthesis of photoresponsive oligoethers containing cinnamylidene acetic acid as telechelic endgroup was reported and high degrees of functionalization could be achieved. Such photosensitive oligomers are promising candidates as reactive precursors, for the preparation of biocompatible high molecular weight polymers and polymer networks.
Although the shape-changing capabilities of LCEs hold great potential for applications ranging from micropumps to artificial muscles, customization of the LCE functionality to the applications' requirements is still a challenge. It is studied whether the orientation of NMC-LCPs and NMC-LCEs based on 2-tert-butyl-1,4-bis[4-(4-pentenyloxy)benzoyl]hydroquinone can be enhanced by copolymerization with 2-methyl-1,4-bis[4-(4-pentenyloxy)benzoyl]hydroquinone or 2,6-bis[4-(4-pentenyl-oxy)-benzoyl]anthracene. An increasing content of the comonomers stabilizes the nematic phase, which enables a tailoring of T-NI for the NMC-LCP between 45 and 68 degrees C, while for the NMC-LCE T-NI ranges between 69 and 76 degrees C. In addition, NMC-LCE show an increased actuation performance.
Hybrid magnetic nanoparticles (mgNP) with a magnetite core diameter of 10 +/- 1 nm surface functionalized with oligo(omega-pentadecalactone) (OPDL) oligomers with M-n between 1300 and 3300 g mol(-1) could be successfully prepared having OPDL grafted from 200 mg g(-1) to 2170 mg g(-1). The particles are dispersible in chloroform resulting in stable suspensions. Magnetic response against an external magnetic field proved the superparamagnetic nature of the particles with a low coercivity (B-c) value of 297 mu T. The combination of the advantageous superparamagnetism of the mgNP with the exceptional stability of OPDL makes these novel hybrid mgNP promising candidates as multifunctional building blocks for magnetic nanocomposites with tunable physical properties.
Aim: The hydrolytic degradation behavior of degradable aliphatic polyester-based polymers is strongly influenced by the uptake or transport of water into the polymer matrix and also the hydrolysis rate of ester bonds.
Methods: We examined the volumetric swelling behavior of poly[(rac-lactide)-co-glycolide] (PLGA) and PLGA-based polyurethanes (PLGA-PU) with water contents of 0 wt%, 2 wt% and 7 wt% water at 310 K using a molecular modeling approach. Polymer systems with a number average molecular weight of M-n = 10,126 g.mol(-1) were constructed from PLGA with a lactide content of 67 mol%, whereby PLGA-PU systems were composed of five PLGA segments with M-n = 2052 g.mol(-1), which were connected via urethane linkers originated from 2,2,4-trimethyl hexamethylene-1,6-diisocyanate (TMDI), hexamethyl-1,6-diisocyanate (HDI), or L-lysine-1,6-diisocyanate (LDI).
Results: The calculated densities of the dry PLGA-PU systems were found to be lower than for pure PLGA. The obtained volumetric swelling of the PLGA-PU was depending on the type of urethane linker, whereby all swollen PLGA-PUs contained larger free volume distribution compared to pure PLGA. The mean square displacement curves for dry PLGA and PLGA-PUs showed that urethane linker units reduce the mobility of the polymer chains, while an increase in backbone atoms mobility was found, when water was added to these systems. Consequently, an increased water uptake of PLGA-PU matrices combined with a higher mobility of the chain segments should result in an accelerated hydrolytic chain scission rate in comparison to PLGA.
Conclusions: It can be anticipated that the incorporation of urethane linkers might be a helpful tool to adjust the degradation behavior of polyesters.
Aim: Multifunctional polymer-based biomaterials, which combine degradability with a shape-memory capability and in this way enable the design of actively moving implants such as self-anchoring implants or controlled release systems, have been recently introduced. Of particular interest are approved degradable polymers such as poly(L-lactide) (PLLA), which can be easily functionalized with a shape-memory effect. In the case of semicrystalline PLLA, the glass transition can be utilized as shape-memory switching domain.
Methods: In this work we applied a fully atomistic molecular dynamics simulation to study the shape-memory behavior of PLLA. A heating-deformation-cooling programming procedure was applied to atomistic PLLA packing models followed by a recovery module under stress-free conditions allowing the shape recovery. The recovery was simulated by heating the samples from T-low = 250 K to T-high = 500 K with different heating rates beta of 125, 40 and 4 K.ns(-1).
Results: We could demonstrate that the obtained strain recovery rate (R-r) was strongly influenced by the applied simulation time and heating rate, whereby R-r values in the range from 46% to 63% were achieved. On its own the application of a heating rate of 4 K.ns(-1) enabled us to determine a characteristic switching temperature of T-sw = 473 K for the modeled samples.
Conclusions: We anticipate that the atomistic modeling approach presented should be capable of enabling further study of T-sw with respect to the molecular structure of the investigated SMP and therefore could be applied in the context of design and development of new shape-memory (bio) materials.
Background: Magnetic composites of thermosensitive shape-memory polymers (SMPs) and magnetite nanoparticles (MNPs) allow noncontact actuation of the shape-memory effect in an alternating magnetic field. In this study, we investigated whether the magnetic heating capability of cross-linked poly(epsilon-caprolactone)/MNP composites (cPCLC) could be improved by covalent coating of MNPs with oligo(epsilon-caprolactone) (OCL).
Methods: Two different types of cPCLC containing uncoated and OCL-coated MNP with identical magnetite weight content were prepared by thermally induced polymerization of poly(epsilon-caprolactone) diisocyanatoethyl methacrylate. Both cPCLCs exhibited a melting transition at T-m = 48 degrees C, which could be used as switching transition.
Results: The dispersion of the embedded nanoparticles within the polymer matrix could be substantially improved, when the OCL-coated MNPs were used, as visualized by scanning electron microscopy. We could further demonstrate that in this way the maximal achievable bulk temperature (T-bulk) obtained within the cPCLC test specimen in magnetic heating experiments at a magnetic field strength of H = 30 kA.m(-1) could be increased from T bulk = 48 degrees C to T bulk = 74 degrees C.
Shape-memory properties of polyetherurethane foams prepared by thermally induced phase separation
(2012)
In this study, we report the preparation of two structurally different shape-memory polymer foams by thermally induced phase separation (TIPS) from amorphous polyetherurethanes. Foams with either a homogeneous, monomodal, or with a hierarchically structured, bimodal, pore size distribution are obtained by adoption of the cooling protocol. The shape-memory properties have been investigated for both foam structures by cyclic, thermomechanical experiments, while the morphological changes on the micro scale (pore level) have been compared to the macro scale by an in situ micro compression device experiment. The results show that the hierarchically structured foam achieves higher shape-recovery rates and a higher total recovery as compared to the homogeneous foam, which is due to an increased energy storage capability by micro scale bending of the hierarchically structured foam compared to pure compression of the homogeneous foam.
Degradable polymers with a tailorable degradation rate might be promising candidate materials for biomaterial-based cartilage repair. In view of the poor intrinsic healing capability of cartilage, implantation of autologous chondrocytes seeded on a biocompatible slow degrading polymer might be an encouraging approach to improve cartilage repair in the future. This study was undertaken to test if the fiber orientation (random versus aligned) of two different degradable polymers and a polymer intended for long term applications could influence primary articular chondrocytes growth and ultrastructure.
A degradable copoly(ether) esterurethane (PDC) was synthesized via co-condensation of poly(p-dioxanone) diol and poly(epsilon-caprolactone) diol using an aliphatic diisocyanate as linker. Poly(p-dioxanone) (PPDO) was applied as commercially available degradable polymer, while polyetherimide (PEI) was chosen as biomaterial enabling surface functionalization. The fibrous scaffolds of PDC and PPDO were obtained by electrospinning using 1,1,1,3,3,3 hexafluoro-2-propanol (HFP), while for PEI dimethyl acetamide (DMAc) was applied as solvent. Primary porcine articular chondrocytes were seeded at different cell densities on the fibrous polymer scaffolds and analyzed for viability (fluorescein diacetate/ethidiumbromide staining), for type II collagen synthesis (immunolabelling), ultrastructure and orientation on the fibers (SEM: scanning electron microscopy).
Vital chondrocytes adhered on all electrospun scaffolds irrespective of random and aligned topologies. In addition, the chondrocytes produced the cartilage-specific type II collagen on all tested polymer topologies suggesting their differentiated functions. SEM revealed an almost flattened chondrocytes shape on scaffolds with random fiber orientation: whereby chondrocytes growth remained mainly restricted to the scaffold surface. On aligned fibers the chondrocytes exhibited a more spindle-shaped morphology with rougher cell surfaces but only a minority of the cells aligned according to the fibers. As a next step the reduction of the fiber diameter of electrospun scaffolds should be addressed as an important parameter to mimic cartilage ECM structure.
Purpose: Polymer networks with adjustable properties prepared from endgroup-functionalized oligoesters by UV-crosslinking in melt have evolved into versatile multifunctional biomaterials. In addition to the molecular weight or architecture of precursors, the reaction conditions for crosslinking are pivotal for the polymer network properties. Crosslinking of precursors in solution may facilitate low-temperature processes and are compared here to networks synthesized in melt.
Methods: Oligo(epsilon-caprolactone)-(z) methacrylate (oCL-(z) IEMA) precursors with a linear (z = di) or a four-armed star-shaped (z = tetra) architecture were crosslinked by radical polymerization in melt or in solution with UV irradiation. The thermal, mechanical, and swelling properties of the polymer networks obtained were characterized.
Results: Crosslinking in solution resulted in materials with lower Young's moduli (E), lower maximum stress (sigma(max)), and higher elongation at break (epsilon(B)) as determined at 70 degrees C. Polymer networks from 8 kDa star-shaped precursors exhibited poor elasticity when synthesized in the melt, but can be established as stretchable materials with a semi-crystalline morphology, a high gel-content, and a high elongation at break when prepared in solution.
Conclusions: The crosslinking condition of methacrylate functionalized precursors significantly affected network properties. For some types of precursors such as star-shaped telechelics, synthesis in solution provided semi-crystalline elastic materials that were not accessible from crosslinking in melt.
Background: Triblock copolymers from hydrophilic oligo(ethylene glycol) segment A and oligo(propylene glycol) segment B, providing an ABA structure (OEG-OPG-OEG triblock), are known to be biocompatible and are used as self-solidifying gels in drug depots. A complete removal of these depots would be helpful in cases of undesired side effects of a drug, but this remains a challenge as they liquefy below their transition temperature. Therefore we describe the synthesis of covalently cross-linked hydrogel networks.
Method: Triblock copolymer-based hydrogels were created by irradiating aqueous solutions of the corresponding macro-dimethacrylates with UV light. The degree of swelling, swelling kinetics, mechanical properties and morphology of the networks were investigated.
Results: Depending on precursor concentration, equilibrium degree of swelling of the films ranged between 500% and 880% and was reached in 1 hour. In addition, values for storage and loss moduli of the hydrogel networks were in the 100 Pa to 10 kPa range.
Conclusion: Although OEG-OPG-OEG triblocks are known for their micellization, which could hamper polymer network formation, reactive OEG-OPG-OEG triblock oligomers could be successfully polymerized into hydrogel networks. The degree of swelling of these hydrogels depends on their molecular weight and on the oligomer concentration used for hydrogel preparation. In combination with the temperature sensitivity of the ABA triblock copolymers, it is assumed that such hydrogels might be beneficial for future medical applications -e.g., removable drug release systems.
Materials for biomedical applications are often chosen for their bulk properties. Other requirements such as a hemocompatible surface shall be fulfilled by suitable chemical functionalization. Here we show, that linear, side-chain methylated oligoglycerols (OGMe) are more stable to oxidation than oligo(ethylene glycol) (OEG). Poly(ether imide) (PEI) membranes functionalized with OGMes perform at least as good as, and partially better than, OEG functionalized PEI membranes in view of protein resistance as well as thrombocyte adhesion and activation. Therefore, OGMes are highly potent surface functionalizing molecules for improving the hemocompatibility of polymers.
Purpose: Previous investigations have shown that poly(ether imide) (PEI) membranes can be functionalized with aminated macromolecules. In this study we explored whether the characterization of PEI functionalized with oligo(ethylene glycol) (OEG) or linear, side chain methylated oligoglycerols (OGMe), by angle-dependent X-ray induced photoelectron spectroscopy (XPS) can be used to prove the functionalization, give insight into the reaction mechanism and reveal the spatial distribution of the grafts.
Methods: PEI membranes were functionalized under alkaline conditions using an aqueous solution with 2 wt% of alpha-amino-methoxy oligo(ethylene glycol) (M-n = 1,320 g.mol(-1)) or linear, side chain methylated monoamine oligoglycerols (M-n = 1,120, 1,800 or 2,270 g.mol(-1)), respectively. The functionalized membranes were investigated using XPS measurements at different detector angles to enable comparison between the signals related to the bulk and surface volume and were compared with untreated and alkaline-treated PEI membranes.
Results: While at a perpendicular detector angle the bulk signals of the PEI were prominent, at larger surface volume-related detector angles, the signals for OGMe and OEG were determinable.
Conclusion: The surface functionalization of PEI with OEG and OGMe could be verified by the angle-dependent XPS. The observations proved the functionalization at the PEI surface, as the polyethers were detected at angles providing signals of the surface volume. Furthermore, the chemical functions determined verified a covalent binding via the nucleophilic addition of the amine functionalized OGMe and OEG to the PEI imide function.
Langmuir monolayer degradation (LMD) experiments with polymers possessing outstanding biomedical application potential yield information regarding the kinetics of their hydrolytic or enzymatic chain scission under well-defined and adjustable degradation conditions. A brief review is given of LMD investigations, including the author's own work on 2-dimensional (2D) polymer systems, providing chain scission data, which are not disturbed by simultaneously occurring transport phenomena, such as water penetration into the sample or transport of scission fragments out of the sample.
A knowledge-based approach for the description and simulation of polymer hydrolytic and enzymatic degradation based on a combination of fast LMD experiments and computer simulation of the water penetration is briefly introduced. Finally, the advantages and disadvantages of this approach are discussed.
Influence of tyrosine-derived moieties and drying conditions on the formation of helices in gelatin
(2011)
The single and triple helical organization of protein chains strongly influences the mechanical properties of gelatin-based materials. A chemical method for obtaining different degrees of helical organization in gelatin is covalent functionalization, while a physical method for achieving the same goal is the variation of the drying conditions of gelatin solutions. Here we explored how the introduction of desaminotyrosine (DAT) and desaminotyrosyl tyrosine (DATT) linked to lysine residues of gelatin influenced the kinetics and thermodynamic equilibrium of the helicalization process of single and triple helices following different drying conditions. Drying at a temperature above. the helix-to-coil transition temperature of gelatin (T > T-c, called nu(short)) generally resulted in gelatins with relatively lower triple helical content (X-c,X-t = 1-2%) than lower temperature drying (T < T-c, called nu(long)) (X-c,X-t = 8-10%), where the DAT(T) functional groups generally disrupted helix formation. While different helical contents affected the thermal transition temperatures only slightly, the mechanical properties were strongly affected for swollen hydrogels (E = 4-13 kPa for samples treated by nu(long) and E = 120-700 kPa for samples treated by nu(short)). This study shows that side group functionalization and different drying conditions are viable options to control the helicalization and macroscopic properties of gelatin-based materials.
Biopolymers of the extracellular matrix are attractive starting materials for providing degradable and biocompatible biomaterials. In this study, hyaluronic acid-based hydrogels with tunable mechanical properties were prepared by the use of copper-catalyzed azide-alkyne cycloaddition (known as "click chemistry"). Alkyne-functionalized hyaluronic acid was crosslinked with linkers having two terminal azide functionalities, varying crosslinker density as well as the lengths and rigidity of the linker molecules. By variation of the crosslinker density and crosslinker type, hydrogels with elastic moduli in the range of 0.5-4 kPa were prepared. The washed materials contained a maximum of 6.8 mg copper per kg dry weight and the eluate of the gel crosslinked with diazidostilbene did not show toxic effects on L929 cells. The hyaluronic acid-based hydrogels have potential as biomaterials for cell culture or soft tissue regeneration applications.
Combining gelatins functionalized with the tyrosine-derived groups desaminotyrosine or desaminotyrosyl tyrosine with hydroxyapatite (HAp) led to the formation of composite materials with much lower swelling ratios than those of the pure matrices. Shifts of the infra-red (IR) bands related to the free carboxyl groups could be observed in the presence of HAp, which suggested a direct interaction of matrix and filler that formed additional physical cross-links in the material. In tensile tests and rheological measurements the composites equilibrated in water had increased Young's moduli (from 200 kPa up to 2 MPa) and tensile strengths (from 57 kPa up to 1.1 MPa) compared with the matrix polymers without affecting the elongation at break. Furthermore, an increased thermal stability of the networks from 40 to 85 degrees C could be demonstrated. The differences in the behaviour of the functionalized gelatins compared with pure gelatin as a matrix suggested an additional stabilizing bond between the incorporated aromatic groups and the HAp as supported by the IR results. The composites can potentially be applied as bone fillers.
Biomaterials are used in regenerative medicine for induced autoregeneration and tissue engineering. This is often challenging, however, due to difficulties in tailoring and controlling the respective material properties. Since functionalization is expected to offer better control, in this study gelatin chains were modified with physically interacting groups based on tyrosine with the aim of causing the formation of physical crosslinks. This method permits application-specific properties like swelling and better tailoring of mechanical properties. The design of the crosslink strategy was supported by molecular dynamic (MD) simulations of amorphous bulk models for gelatin and functionalized gelatins at different water contents (0.8 and 25 wt.-%). The results permitted predictions to be formulated about the expected crosslink density and its influence on equilibrium swelling behavior and on elastic material properties. The models of pure gelatin were used to validate the strategy by comparison between simulated and experimental data such as density, backbone conformation angle distribution, and X-ray scattering spectra. A key result of the simulations was the prediction that increasing the number of aromatic functions attached to the gelatin chain leads to an increase in the number of physical netpoints observed in the simulated bulk packing models. By comparison with the Flory-Rehner model, this suggested reduced equilibrium swelling of the functionalized materials in water, a prediction that was subsequently confirmed by our experimental work. The reduction and control of the equilibrium degree of swelling in water is a key criterion for the applicability of functionalized gelatins when used, for example, as matrices for induced autoregeneration of tissues.
Gelatin is a non-immunogenic and degradable biopolymer, which is widely applied in the biomedical field e. g. for drug capsules or as absorbable hemostats. However, gelatin materials present limited and hardly reproducible mechanical properties especially in aqueous systems, particularly caused by the uncontrollable partial renaturation of collagen-like triple helices. Therefore, mechanically demanding applications for gelatin-based materials, such as vascular patches, i.e. hydrogel films that seal large incisions in vessel walls, and for induced autoregeneration, are basically excluded if this challenge is not addressed. Through the synthesis of a defined chemical network of gelatin with hexamethylene diisocyanate (HDI) in DMSO, the self-organization of gelatin chains could be hindered and amorphous gelatin films were successfully prepared having Young's moduli of 60-530 kPa. Transferring the crosslinking reaction with HDI and, alternatively, ethyl lysine diisocyanate (LDI), to water as reaction medium allowed the tailoring of swelling behaviour and mechanical properties by variation of crosslinker content while suppressing the formation of helices. The hydrogels had Young's moduli of 70-740 kPa, compressive moduli of 16-48 kPa, and degrees of swelling of 300-800 vol%. Test reactions investigated by ESI mass spectrometry allowed the identification and quantification of reaction products of the crosslinking reaction. The HDI crosslinked networks were stabilized by direct covalent crosslinks (ca. 10 mol%), supported by grafting (50 mol%) and blending of hydrophobic oligomeric chains. For the LDI- based networks, less crosslinked (3 mol%) and grafted species (5 mol%) and much higher amounts of oligomers were observed. The adjustable hydrogel system enables the application of gelatin-based materials in physiological environments.
The influence of coating polystyrene tissue culture plates with different proteins on murine hybridoma cell growth and antibody production was investigated. Fibronectin, collagen I, bovine serum albumin and laminin were used to coat NUNC and COSTAR cell culture plates. Cell number and antibody concentration in culture fluids were quantified as indicators for cell viability, proliferation and productivity. Adhesive behaviour, morphology, expression of surface receptors of hybridoma cells and the presence of tyrosine-phosphorylated proteins in cell lysates were characterized by cell adhesion experiments, microscopy, flow cytometry and Western Blot analysis. It was shown that coatings with fibronectin (0.2 ;g/ml) lead to a substantial improvement of cell growth by 50-70% and an increase of monoclonal antibody production by 100-120%. Collagen I coatings showed an improvement in cell growth by 30-70% and by 60% for the production of monoclonal antibodies. Coatings with BSA and laminin had minor effects on these parameters. It was found that the hybridoma cell lines used in this study did not express the ;2-chain of the ;2;1-integrin, which is responsible for binding to collagen and laminin. However, the presence of ;1- integrin on the cell surface was shown, which should enable hybridoma cells to bind fibronectin. We propose, therefore, that fibronectin adsorption to cell culture materials may be a promising approach to enhance the production of monoclonal antibodies by cultivated hybridoma cells.
The multiplication and antibody production of murine hybridoma cells cultured on five different polymer membranes were tested and compared with conventional tissue culture polystyrene (TCPS). Membranes were prepared from polyacrylonitrile (PAN) and acrylonitrile copolymerized with N-vinylpyrrolidone (NVP20, NVP30), Na-methallylsulfonate (NaMAS) and N-(3-amino-propyl-methacrylamide-hydrochloride) (APMA). Cell number and antibody concentration were quantified as criteria for viability and productivity. Adhesion of hybridoma cells was characterized by vital and scanning electron microscopy. The results suggest that a strong adhesion of cells, observed on APMA and TCPS, increased cell growth but reduced monoclonal antibody production. In contrast membranes with lowered adhesivity such as NVP20 provided favourable conditions for monoclonal antibody production. In addition it was shown that this membrane also possessed a minor fouling as indicated by the low decrease of water flux across the membrane after protein adsorption. It was concluded that NVP20 could be a suitable material for the development of hollow fibre membranes for bioreactors.
Using standard cell biological and biochemical methods we were able to test the ability of a degradable, thermoplastic block copolymer to support the adhesion, proliferation, and the cellular activity of primary cell cultures of the oral cavity in vitro. The delicate balance between a group of endogenous enzymes, Matrix Metalloproteinases (MMPs), and their inhibitors (Tissue Inhibitor of MMPs, TIMPs) have a decisive function in the remodeling of the extracellular matrix during processes like wound healing or the integration of biomaterials in surrounding tissues after implantation. Recently developed, biodegradable thermoplastic elastomers with shape-memory properties may be the key to develop new therapeutical options in head and neck surgery. Primary cell cultures of the oral cavity of Sprague-Dawley rats were seeded on the surface of a thermoplastic block copolymer and on a polystyrene surface as control. Conditioned media of the primary cells were analyzed for MMPs and TIMPs after different periods of cell growth. The MMP and TIMP expression was analysed by zymography and a radiometric enzyme assay. No statistically significant differences in the appearance and the kinetic of MMP-1, MMP-2, MMP-9 and TIMPs were detected between cells grown on the polymer surface compared to the control. An appropriate understanding of the molecular processes that regulate cellular growth and integration of a biomaterial in surrounding tissue is the requirement for an optimal adaptation of biodegradable, polymeric biomaterials to the physiological, anatomical, and surgical conditions in vivo to develop new therapeutic options in otolaryngology and head and neck surgery
Shape-memory polymers
(2004)