Chitosan based bioadhesives for biomedical applications: A review.

Due to the promising properties of chitosan for biomedical engineering applications like biodegradability, biocompatibility, and non-toxicity, it is one of the most interesting biopolymers in this field. Therefore, Chitosan and its derivatives have attracted great attention in vast variety of biomedical applications. In the current paper, different types of chitosan-based bioadhesives including passive and active and their different types of external stimuli response structure such as thermo, pH and Light responsive systems are discussed. Different bioadhesives mechanisms with chitosan as an adhesive agent or main polymer component and some examples were also presented. Chitosan based bioadhesives and their potential biomedical applications in drug delivery systems, suture less surgery, wound dressing and hemostatic are also discussed. The results confirmed wound healing, hemostatic and bioadhesion capabilities of the chitosan bioadhesives and its great potential for biomedical applications.

Delivery of pharmaceuticals and other active ingredients with their crystalline cyclodextrin inclusion compounds.

In honor of Prof. Thorsteinn Loftsson's 70th birthday, we offer this personal review of our work using cyclodextrins (CDs) complexed with a variety of active ingredients, including pharmaceuticals, for the purpose of improving their delivery to polymer materials, e.g., fibers, films, hydrogels, etc. Using the affinity of CDs to host and form non-covalent inclusion complexes (ICs) with guest molecules, including a variety of high molecular weight polymers, it is possible to readily deliver these guest molecules into polymer materials via either melt or solution processing of their crystalline or soluble guest molecule-CD-ICs or -rotaxanes. This provides the following advantages: i. CDs are non-toxic, implantable, and biodegradable and have earned the GRAS rating from the FDA. ii. Guest molecules, even those that are neat liquids, can form solid crystalline CD-ICs that are thermally stable to ~ 200 °C and above. This approach permits facile melt-processing into polymer materials for delivery without migration, loss, or degradation of the active guest ingredient. iii. For guests harmful and toxic to their users and the environment, delivery in the form of crystalline CD-ICs can limit any contact with and release of the included toxic guests before they function and are used. iv. It has been demonstrated that, by simple precipitation methods, neat as-received CDs that adopt cage crystal structures can be readily transformed to their columnar crystal structures containing only water in their channels, which can be easily displaced by small molecule, as well as polymer guests. v. Guest-CD-rotaxanes are water soluble, they protect the threaded guest from sources of degradation, and the CD hydroxyl groups may be modified to direct the guest-CD-rotaxane to specific substrates. For these reasons, here we summarize our contributions to the study of CD inclusion and delivery of a variety of guest molecules, including antibacterials, spermicides, insecticides, flame retardants, and dyes, that can more usefully functionalize polymer materials.

Physical Characterization of Inclusion Complexes of Triphenyl Phosphate and Cyclodextrins in Solution.

The goal of this work is to provide physical insights into the formation and stability of inclusion complexes (ICs) in aqueous solution between cyclodextrins (CDs) and a common flame retardant, triphenyl phosphate (TPP). Quantum chemistry calculations reveal the possible energetically favorable geometries of TPP in their 1:1 IC form with α-, ß-, and γ-CDs as well as their associated complexation, conformational, and interaction energies. High-resolution mass spectrometry (MS) and tandem MS were used with electrospray ionization to study the soluble ICs formed between TPP and CDs. Successful formation of TPP ICs with both ß- and γ-CD in solution was detected in the ratio of 1:1 using high-resolution MS in the positive ion mode. Collision-induced dissociation confirmed the formation of TPP ICs with ß- and γ-CDs by generating two product ions, TPP and ß- or γ-CD, in both cases. Although quantum chemistry calculations suggest that IC formation with α-CD is energetically possible, an IC with α-CD is not observed in aqueous solution using MS, which aligns with what we also previously observed in the solid state. Since TPP forms stable ICs with ß- and γ-CDs both in the solid state and in solution suggests that complexation could be a safer alternative than applying TPP directly to a substrate. In addition, complexation with CDs in solution also opens up new processing methods to create flame-retardant fabrics and foams with TPP.

Nanoscale Restructuring of Polymer Materials to Produce Single Polymer Composites and Miscible Blends.

I summarize work conducted in our laboratories over the past 30 years using small host molecules to restructure polymer materials at the nanometer level. Certain small molecules, such as the cyclic starches cyclodextrins (CDs) and urea (U) can form non-covalent crystalline inclusion compounds (ICs) with a range of guest molecules, including many polymers. In polymer-CD- and -U-ICs, guest polymer chains reside in narrow channels created by the host molecule crystals, where they are separated and highly extended. When the host crystalline lattice is carefully removed, the guest polymer chains coalesce into a bulk sample with an organization that is distinct from that normally produced from its melt or from solution. Amorphous regions of such coalesced polymer samples have a greater density, likely with less chain entanglement and more chain alignment. As a consequence, after cooling from their melts, coalesced amorphous polymers show glass-transition temperatures (Tgs) that are elevated above those of samples prepared from their solutions or melts. Upon cooling from their melts, coalesced samples of crystallizable polymers show dramatically-increased abilities to crystallize more rapidly and much closer to their melting temperatures (Tms). These unique behaviors of polymers coalesced from their CD- and U-ICs are unexpectedly resistant to extended annealing above their Tgs and Tms. Taking advantage of this behavior permits us to create polymer materials with unique and improved properties. Among these are amorphous polymers with elevated Tgs and semi-crystalline polymers with finer more uniform morphologies. Improved mechanical properties can be achieved through self-nucleation with small amounts of the same polymer made rapidly crystallizable through coalescence from its CD- or U-IC. This can lead to single polymer composites with as-received polymer matrices and self-nucleated reinforcements. Through simultaneous formation and subsequent coalescence from their common CD-ICs, stable well-mixed blends can be achieved between any two or more polymers, despite their inherent immiscibilities. Such coalesced and well-mixed blends are also resistant to phase segregation when heated for extensive periods well above their Tgs and Tms.

Polymers Containing Non-Covalently Bound Cyclodextrins.

We summarize and review the formation, characterization, behaviors, and possible uses of polymers that are threaded through, but only partially covered by cyclodextrins (CDs), which we call non-stoichiometric polymer⁻CD inclusion compounds (ICs) or non-stoichiometric (n-s) polymer⁻CD ICs. Emphasis is placed on comparison of the behaviors of unthreaded neat polymers with those that are threaded through and partially covered by CDs. These comparisons lead to several suggested uses for (n-s) polymer⁻CD ICs.

Chitosan based hydrogels and their applications for drug delivery in wound dressings: A review.

Advanced development of chitosan hydrogels has led to new drug delivery systems that can release their active ingredients in response to environmental stimuli. This review considers more recent investigation of chitosan hydrogel preparations and the application of these preparations for drug delivery in wound dressings. Applications and structural characteristics of different types of active ingredients, such as growth factors, nanoparticles, nanostructures, and drug loaded chitosan hydrogels are summarized.

Aliphatic Polyester Nanofibers Functionalized with Cyclodextrins and Cyclodextrin-Guest Inclusion Complexes.

The fabrication of nanofibers by electrospinning has gained popularity in the past two decades; however, only in this decade, have polymeric nanofibers been functionalized using cyclodextrins (CDs) or their inclusion complexes (ICs). By combining electrospinning of polymers with free CDs, nanofibers can be fabricated that are capable of capturing small molecules, such as wound odors or environmental toxins in water and air. Likewise, combining polymers with cyclodextrin-inclusion complexes (CD-ICs), has shown promise in enhancing or controlling the delivery of small molecule guests, by minor tweaking in the technique utilized in fabricating these nanofibers, for example, by forming core⁻shell or multilayered structures and conventional electrospinning, for controlled and rapid delivery, respectively. In addition to small molecule delivery, the thermomechanical properties of the polymers can be significantly improved, as our group has shown recently, by adding non-stoichiometric inclusion complexes to the polymeric nanofibers. We recently reported and thoroughly characterized the fabrication of polypseudorotaxane (PpR) nanofibers without a polymeric carrier. These PpR nanofibers show unusual rheological and thermomechanical properties, even when the coverage of those polymer chains is relatively sparse (~3%). A key advantage of these PpR nanofibers is the presence of relatively stable hydroxyl groups on the outer surface of the nanofibers, which can subsequently be taken advantage of for bioconjugation, making them suitable for biomedical applications. Although the number of studies in this area is limited, initial results suggest significant potential for bone tissue engineering, and with additional bioconjugation in other areas of tissue engineering. In addition, the behaviors and uses of aliphatic polyester nanofibers functionalized with CDs and CD-ICs are briefly described and summarized. Based on these observations, we attempt to draw conclusions for each of these combinations, and the relationships that exist between their presence and the functional behaviors of their nanofibers.

Nanoscale considerations responsible for diverse macroscopic phase behavior in monosubstituted isobutyl-POSS/poly(ethylene oxide) blends.

Nanocomposites prepared by incorporating functionalized polyhedral oligomeric silsesquioxane (POSS) into polymer matrices afford a wide range of versatile hybrid materials for use in technologies ranging from cosmetics and pharmaceuticals to sensors and batteries. Here, we investigate the phase behavior of nanocomposites composed of poly(ethylene oxide) (PEO) and monosubstituted isobutyl POSS (iPOSS) modified with different functional moieties. Microscopic analyses of blends containing these iPOSS variants reveal the existence of different macroscopic morphologies and surface topologies. In the presence of octa-iPOSS, a POSS-rich surface cell motif reminiscent of breath patterns develops, whereas addition of allyl-iPOSS promotes the formation of surface plates. While aminopropyl-iPOSS forms dispersed aggregates, maleamic acid-iPOSS disperses in PEO with little effect on PEO crystal morphology. We perform rotational isomeric state Monte Carlo simulations to discern the effect of monosubstitution on the interaction energy between iPOSS and PEO, and establish the molecular-level origin for these observed differences in phase behavior.

Reorganizing Polymer Chains with Cyclodextrins.

During the past several years, we have been utilizing cyclodextrins (CDs) to nanostructure polymers into bulk samples whose chain organizations, properties, and behaviors are quite distinct from neat bulk samples obtained from their solutions and melts. We first form non-covalently bonded inclusion complexes (ICs) between CD hosts and guest polymers, where the guest chains are highly extended and separately occupy the narrow channels (~0.5⁻1.0 nm in diameter) formed by the columnar arrangement of CDs in the IC crystals. Careful removal of the host crystalline CD lattice from the polymer-CD-IC crystals leads to coalescence of the guest polymer chains into bulk samples, which we have repeatedly observed to behave distinctly from those produced from their solutions or melts. While amorphous polymers coalesced from their CD-ICs evidence significantly higher glass-transition temperatures, Tgs, polymers that crystallize generally show higher melting and crystallization temperatures (Tms, Tcs), and some-times different crystalline polymorphs, when they are coalesced from their CD-ICs. Formation of CD-ICs containing two or more guest homopolymers or with block copolymers can result in coalesced samples which exhibit intimate mixing between their common homopolymer chains or between the blocks of the copolymer. On a more practically relevant level, the distinct organizations and behaviors observed for polymer samples coalesced from their CD-ICs are found to be stable to extended annealing at temperatures above their Tgs and Tms. We believe this is a consequence of the structural organization of the crystalline polymer-CD-ICs, where the guest polymer chains included in host-IC crystals are separated and confined to occupy the narrow channels formed by the host CDs during IC crystallization. Substantial degrees of the extended and un-entangled natures of the IC-included chains are apparently retained upon coalescence, and are resistant to high temperature annealing. Following the careful removal of the host CD lattice from each randomly oriented IC crystal, the guest polymer chains now occupying a much-reduced volume may be somewhat "nematically" oriented, resulting in a collection of randomly oriented "nematic" regions of largely extended and un-entangled coalesced guest chains. The suggested randomly oriented nematic domain organization of guest polymers might explain why even at high temperatures their transformation to randomly-coiling, interpenetrated, and entangled melts might be difficult. In addition, the behaviors and uses of polymers coalesced from their CD-ICs are briefly described and summarized here, and we attempted to draw conclusions from and relationships between their behaviors and the unique chain organizations and conformations achieved upon coalescence.

Fabrication and Characterization of Poly(ε-caprolactone)/α-Cyclodextrin Pseudorotaxane Nanofibers.

Multifunctional scaffolds comprising neat poly(ε-caprolactone) (PCL) and α-cyclodextrin pseudorotaxanated in α-cyclodextrin form have been fabricated using a conventional electrospinning process. Thorough in-depth characterizations were performed on the pseudorotaxane nanofibers prepared from chloroform (CFM) and CFM/dimethylformamide (DMF) utilizing scanning electron microscopy (SEM), transmission electron microscopy (TEM), rheology, differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), wide-angle X-ray diffraction (WAXD), and Instron tensile testing. The results indicate the nanofibers obtained from chloroform retain the rotaxanated structure; while those obtained from CFM/DMF had significantly dethreaded during electrospinning. As a consequence, the nanowebs obtained from CFM showed higher moduli and lower elongations at break compared to neat PCL nanowebs and PCL/α-CD nanowebs electrospun from CFM/DMF.

Coalesced poly(ε-caprolactone) fibers are stronger.

Melt-spun fibers were made from poly(ε-caprolactone) (PCL) coalesced from stoichiometric inclusion complex crystals formed with host urea. Melting and crystallization behaviors, mechanical properties, and the birefringence of undrawn and cold-drawn fibers were investigated. Undrawn coalesced PCL fibers were observed to have 500-600% higher moduli than undrawn as-received (asr) PCL fibers and a modulus comparable to drawn asr PCL fibers. Drawn coalesced PCL fibers have the highest crystallinity, orientation, and 65% higher moduli than drawn asr PCL fibers. Drawn coalesced PCL fibers have only a 5% higher crystallinity than drawn asr PCL fibers, yet they have 65% higher moduli and lower elongation at break values. Clearly, the intrinsic alignment of the coalesced polymers is the reason for their higher moduli and lower elongation, as confirmed by the birefringence observed in drawn coalesced and asr-PCL fibers. The improved mechanical properties of coalesced PCL fibers make them a better candidate for use in tissue engineering as scaffolds.

Estimation of the poly (ε-caprolactone) [PCL] and α-cyclodextrin [α-CD] stoichiometric ratios in their inclusion complexes [ICs], and evaluation of porosity and fiber alignment in PCL nanofibers containing these ICs.

This paper describes the utilization of Proton-Nuclear Magnetic Resonance spectroscopy ((1)H NMR) to quantify the stoichiometric ratios between poly (ε-caprolactone) [PCL] and α-cyclodextrin (α-CD) present in their non-stoichiometric inclusion complexes [(n-s)-ICs]. This paper further describes the porosity and fiber alignment of PCL nanofibers nucleated by the [(n-s)-ICs] during electrospinning. (1)H NMR indicated that the two non-stoichiometric inclusion complexes utilized in this study had differing stoichiometric ratios that were closely similar to those of the starting ratios used to make them. Studies on porosity and fiber alignments were conducted on the scanning electron microscope images using ImageJ. The data indicates that both fiber alignment as well as porosity values remain almost the same over all the samples. Thus we can conclude the improvement in mechanical properties was due only to the loading of the ICs, and their subsequent interaction with bulk unthreaded PCL.

Poly(ε-caprolactone) nanowebs functionalized with α- and γ-cyclodextrins.

The effects of alpha- and gamma-cyclodextrins (α- and γ-CDs) on the thermal and crystal nucleation behavior of electrospun poly(ε-caprolactone) (PCL) nanofibers have been investigated. PCL/CD composite nanofibers were obtained for the first time by electrospinning the mixture from chloroform/N,N-dimethylformamide (60:40). Scanning electron microscopy analyses indicated that neat PCL nanofibers have an average diameter of 400 nm, which increases with the addition of CDs. The presence of CDs on or in the electrospun PCL fibers in the electrospun mats was investigated using Fourier transform infrared spectroscopy, thermogravimetric analysis, and wide-angle X-ray diffraction analysis. Differential scanning calorimetry showed that the PCL/CD composite fibers exhibit higher crystallization temperatures and sharper crystallization exotherms with increased CD loading, indicating the ability of CDs to nucleate PCL crystallization. Water contact angle (WCA) measurements indicate an inverse relationship between WCA and α- or γ-CD concentration up to 30% loading. Phenolphthalein absorption tests were performed to study the kinetics of their inclusion complex (IC) formation with CDs. Unexpectedly, γ-CD-functionalized nanowebs performed better than α-CD. This might be because at elevated loadings some α-CDs may have threaded over PCL chains and formed ICs, whereas γ-CD did not. With their encapsulation capabilities and their lowered hydrophobicity, PCL/CD composite fibers might have potential uses in medical applications, in particular as wound odor absorbants in dressings, because it is well known that CDs can form ICs with these odorants, thereby effectively removing them.

Restructuring polymers via nanoconfinement and subsequent release.

During the past several years my students and I have been utilizing certain small-molecule hosts to create nanostructured polymers. This is accomplished by first forming noncovalently bonded inclusion complexes (ICs) between these small-molecule hosts and guest polymers, followed by the careful removal of the host crystalline lattice to obtain a coalesced bulk polymer. We have repeatedly observed that such coalesced polymer samples behave distinctly from those produced from their solutions or melts. Coalesced amorphous homopolymers exhibit higher glass-transition temperatures, while crystallizable homopolymers coalesced from their ICs display higher melting and crystallization temperatures, and sometimes different crystalline polymorphs. When ICs are formed with block copolymers or with two or more different homopolymers, the resulting coalesced samples can exhibit intimate mixing between the copolymer blocks, or between entire homopolymer chains. Each of the distinct behaviors observed for polymers coalesced from their ICs is a consequence of the structural organization of the polymer-host-ICs. Polymer chains in host-IC crystals are confined to occupy narrow channels (diameter ~0.5-1.0 nm) formed by the small-molecule hosts around the included guest polymers during IC crystallization. This results in the separation and high extension of the included guest polymer chains, which leads, following the careful removal of the host molecule lattice, to unique behaviors for the bulk coalesced polymer samples. Apparently, substantial degrees of the extended and unentangled natures of the IC-included chains are retained upon coalescence. In this review we summarize the behaviors and uses of coalesced polymers, and attempt to draw conclusions on the relationship between their behavior and the organization/structures/conformations of the constituent polymer chains achieved upon coalescence from their ICs.

Effect of guest hydrophobicity on water sorption behavior of oligomer/alpha-cyclodextrin inclusion complexes.

Cyclomaltohexaose (alpha-cyclodextrin, alpha-CD) can form inclusion complexes (ICs) with polymer molecules in the columnar crystal structure in which alpha-CD molecules stack to form a molecular tube. Complementary water vapor sorption and wide-angle X-ray diffractomery (WAXD) were performed on oligomer/alpha-CD ICs to determine their structures and stabilities. To discern the effect of guest molecule hydrophobicity on water adsorption isotherms, polyethylene glycol (PEG, MW = 600 g/mol) and hexatriacontane (HTC) guests were used. Sorption isotherms for PEG/alpha-CD IC are similar to those obtained for pure alpha-CD and PEG, suggesting the presence of dethreaded PEG in the sample. WAXD collected before and after water vapor sorption of PEG/alpha-CD IC indicated a partial conversion from columnar to cage crystal structure, the thermodynamically preferred structure for pure alpha-CD, due to dethreading of PEG. This behavior does not occur for HTC/alpha-CD IC. Sorption isotherms collected at 20, 30, 40, and 50 degrees C allowed the calculation of the isosteric heats of adsorption and the integral entropies of adsorbed water which are characterized by minima that indicate the monolayer concentration of water in the ICs.

Structural study of irregular amino acid sequences in the heavy chain of Bombyx mori silk fibroin.

Recently, genetic studies have revealed the entire amino acid sequence of Bombyx mori silk fibroin. It is known from X-ray diffraction studies that the beta-sheet crystalline structure (silk II) of fibroin is composed of hexaamino acid sequences of GAGAGS. However, in the heavy chain of B. mori silk fibroin, there are also present 11 irregular sequences, with about 31 amino acid residues (irregular GT approximately GT sequences). The structure and role of these irregular sequences have remained unknown. One of the most frequently appearing irregular sequences was synthesized and its 3-D solution structure was studied by high-resolution 2-D NMR techniques. The 3-D structure determined for this peptide shows that it makes a loop structure (distorted omega shape), which implies that the preceding backbone direction is changed by 180 degrees, i.e., reversed, by this sequence. This may facilitate the beta-sheet formation between the crystal-forming building blocks, GAGAGS/GY approximately GY sequences, in the fibroin heavy chain.

Structure and stability of columnar cyclomaltooctaose (gamma-cyclodextrin) hydrate.

Rapid recrystallization of cyclomaltooctaose (gamma-cyclodextrin, gamma-CD) from aqueous solution resulted in formation of a columnar structure with only water as the guest molecule. Upon vacuum drying at 90 degrees C for 15 h, gamma-CD, which was initially in the columnar structure, became amorphous. Complementary water vapor sorption and wide-angle X-ray diffractometry experiments were performed on columnar gamma-CD in its vacuum dried and as-precipitated states to elucidate its stability in humid environments and the crystal structure present at varying sorption levels. These experiments show that both types of gamma-CD transform to the cage crystal structure upon exposure to water vapor at 40 degrees C and with an activity of 1.0. Sorption equilibrium is reached long before the crystal structure transformation is complete, indicating that a significant amount of molecular mobility exists in the various hydrated gamma-CD crystal structures.

Structural studies of Bombyx mori silk fibroin during regeneration from solutions and wet fiber spinning.

Regenerated silk fibroin materials show properties dependent on the methods used to process them. The molecular structures of B. mori silk fibroin both in solution and in solid states were studied and compared using X-ray diffraction, FTIR, and (13)C NMR spectroscopy. Some portion of fibroin protein molecules dissolved in formic acid already have a beta-sheet structure, whereas those dissolved in TFA have some helical conformation. Moreover, fibroin molecules were spontaneously assembled into an ordered structure as the acidic solvents were removed from the fibroin-acidic solvent systems. This may be responsible for the improved physical properties of regenerated fibroin materials from acidic solvents. Regenerated fibroin materials have shown poor mechanical properties and brittleness compared to their original form. These problems were technically solved by improving the fiber forming process according to a method reported here. The regenerated fibroin fibers showed much better mechanical properties compared to the native silk fiber and their physical and chemical properties were characterized by X-ray diffraction, solid state (13)C NMR spectroscopy, SinTech tensile testing, and SEM.

Structure and stability of columnar cyclomaltohexaose (alpha-cyclodextrin) hydrate.

Rapid recrystallization of cyclomaltohexaose (alpha-cyclodextrin, alpha-CD) from aqueous solution resulted in formation of the columnar crystal structure of alpha-CD containing only water as the guest molecule. Complementary water vapor sorption and wide-angle X-ray diffractometry (WAXD) experiments were performed on the alpha-CD columnar structure to elucidate the crystal structure present at varying sorption levels. Equilibrium isothermal water vapor sorption experiments at 40 degrees C revealed that the alpha-CD columnar structure is unstable above a water activity of approximately 0.67. This was confirmed by WAXD diffractograms collected over time, which further revealed that alpha-CD columnar structure undergoes a phase transformation to the cage structure after approximately 0.25 h at 40 degrees C and a water activity of 1.0.