Chih-Chang Chu

Amino acid-based bioanalogous polymers. Synthesis, and study of regular poly(ester amide)s based on bis(α-amino acid) α,ω-alkylene diesters, and aliphatic dicarboxylic acids

The purpose of this research was to synthesize new regular poly(ester amide)s (PEAs) consisting of nontoxic building blocks like hydrophobic α-amino acids, α,ω-diols, and aliphatic dicarboxylic acids, and to examine the effects of the structure of these building block components on some physico-chemical and biochemical properties of the polymers. PEAs were prepared by solution polycondensation of di-p-toluenesulfonic acid salts of bis-(α-amino acid) α,ω-alkylene diesters and di-p-nitrophenyl esters of diacids. Optimal conditions of this reaction have been studied. High molecular weight PEAs (Mw = 24,000–167,000) with narrow polydispersity (Mw/Mn = 1.20–1.81) were prepared under the optimal reaction conditions and exhibited excellent film-forming properties. PEAs obtained are mostly amorphous materials with Tg from 11 to 59°C. α-Chymotrypsin catalyzed in vitro hydrolysis of these new PEA substrates was studied to assess the effect of the building blocks of these new polymers on their biodegradation properties.

Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release.

A new type of redox/pH dual stimuli-responsive poly(methacrylic acid) (PMAA)-based nanohydrogels was prepared from methacrylic acid and N,N-bis(acryloyl)cystamine crosslinker via distillation-precipitation polymerization. The nanohydrogels could be easily degraded into individual linear short chains (M(n) ≈ 1200, M(w)/M(n) < 1.1) in the presence of 10 mM dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX) as a model anti-cancer drug was high efficiently loaded into the nanohydrogels (up to 42.3 wt%) due to the strong electrostatic interactions between the amine group in doxorubicin (DOX) and the carboxyl groups in the nanohydrogels at a physiological pH. The cumulative release profile of the DOX-loaded nanohydrogels showed a low level of drug release (less than 15 wt% in 24 h) at pH 7.4, and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt% in 5 h), exhibiting an obvious pH/redox dual-responsive controlled drug release capability. The drug release behavior of the DOX-loaded nanohydrogels in the presence of GSH was very different from the DTT as the loaded DOX could be quickly released in the presence of GSH, but not in DTT. The possible reason is the synergic effect of reduction and charge exchange of GSH at a low pH. The dose-dependent cytotoxicity of the DOX-loaded nanohydrogels was studied by the CCK-8 assay; the DOX-loaded nanohydrogels could be taken up quickly by human glioma (U251MG cells) via endocytosis, and then biodegraded to release the loaded drugs, which exhibited a comparably anti-tumor efficacy. These nanohydrogels possess many favorable traits, such as excellent biocompatibility and biodegradability, adequate drug loading capacity, minimal drug release under an extracellular condition (non-reductive), and rapid drug release in response to the intracellular level of pH and reducing potential, which endow them as a promise candidate for delivering anti-cancer drugs.

Effects of physical configuration and chemical structure of suture materials on bacterial adhesion: A possible link to wound infection☆

The purpose of this study was to examine the effects of physical configuration and the chemical nature of suture materials on the preferential adherence of bacteria. Ten suture materials of 2-0 (chromic catgut, Dexon, Vicryl, PDS, Mersilene, Tycron, Ethibond, Surgilon, Ethilon, and Prolene) were used. The bacterial strains tested were Staph. aureus and E. coli. The level of bacterial adherence was determined quantitatively by radiolabelled cells and qualitatively by scanning electron microscopy. It was found that the amount of adhered bacteria depended on the type of suture material, the type of bacteria, and the duration of contact. In the group of absorbable sutures, the new PDS sutures exhibited the smallest affinity toward the adherence of both E. coli and Staph. aureus. Dexon sutures had the highest affinity toward these two bacteria. With nonabsorbable sutures, the physical configuration of the sutures contributed more to their ability to attract bacteria than the surface finish. The bacterial adherence on suture materials was also time dependent. Scanning electron microscope morphologic observation also indicated that Staph. aureus adhered on the suture surface in clusters whereas E. coli tended to adhere individually.

Synthesis and characterization of dextran–methacrylate hydrogels and structural study by SEM

The objectives of this study were to develop a simple and reproducible method for the preparation of the hydrogel precursor dextran-methacrylate and to conduct a visual observation of the interior structure of the swollen dextran-methacrylate hydrogel with minimum artifacts. A dextran-methacrylate hydrogel precursor was synthesized by reacting dextran with methacrylic anhydride in the presence of triethylamine as a catalyst. The effects of reaction time, temperature, concentration, and catalyst amount were studied to obtain a wide range of degree of substitution (DS) in dextran by methacrylate. The dextran-methacrylate synthesized showed an enhanced solubility in water and common organic solvents. UV irradiation of dextran-methacrylate by a long-wave UV lamp (365 nm) generated a photocrosslinked hydrogel. This dextran-methacrylate hydrogel showed a range of swelling ratio from 67 to 227% and exhibited an increase in swelling ratio with a decrease in methacrylate substitution. The pH of the swelling media did not affect the swelling behavior of the dextran-methacrylate hydrogels at all the degrees of substitution used. Special cryofixation and cryofracturing techniques were used to prepare aqueous swollen dextran-methacrylate hydrogel samples for SEM observation of their surface and interior structures. A unique three-dimensional porous structure was observed in the swollen hydrogel but was absent in the unswollen hydrogel. Different pore sizes and morphologies between the surface and the interior of swollen hydrogels also were observed.

Wound closure biomaterials and devices

Introduction, C.C. Chu Wound Healing and Inflammatory Response to Biomaterials, P.H. Lin, M.K. Hirko, J.A. von Fraunhofer, and H.P. Greisler Introduction Biological Tissues Inflammation and Wound Healing Foreign-Body Reactions Fibrosis and Fibrous Encapsulation Growth Factors Affecting Wound Healing Summary Surgical Needles, J.A. von Fraunhofer and C.C. Chu Introduction Needle Dimensions Needle-Suture Attachment The Needle Body Needle Points Needle Acuity Needle Biomechanics Needle Holders Summary Classification and General Characteristics of Suture Materials, C.C. Chu Absorbable vs. Nonabsorbable Suture Size Multifilament vs. Monofilament Coating Materials Four General Characteristics Summary Chemical Structure and Manufacturing Processes, C.C. Chu Absorbable Sutures Non-Absorbable Sutures Mechanical Properties, J.A. von Fraunhofer and C.C. Chu Tensile Properties Stiffness and Flexibility Viscoelastic Properties Knot Strength and Security Summary Biodegradation Properties, C.C. Chu General Biodegradation Phenomena Natural Absorbable Sutures Synthetic Absorbable Sutures Nonabsorbable Suture Materials Biological Properties of Suture Materials, M.K. Hirko, P.H. Lin, H.P. Greisler, and C.C. Chu General Tissue Reactions and Cellular Response Granuloma Formation Wound Infection Thrombogenicity Formation of Urinary Calculi Carcinogenicity Summary Suture Techniques and Selection, H.P. Greisler Surgical Principles (W. Irvin) Cardiovascular System (S.S. Kang and H.P. Greisler) Abdominal System (S.S. Kang and H.P. Greisler) Bronchial, Tracheal, and Chest System (S.S. Kang and H.P. Greisler) Obstetrics and Gynecologic System (W. Irvin) Orthopaedic System (J.R. Perez-Sanz) Ligating Clips and Staplers, J.A. von Fraunhofer Introduction Metallic Ligating Clips Polymeric Ligating Clips Other Ligating Clips Surgical Staples Staples and Clips vs. Sutures? Summary Tissue Adhesives, Y. Ikada Design Principles of Tissue Adhesives Natural Tissue Adhesion SystemoFibrin Glue Synthetic Tissue Adhesion SystemoPoly(2-Cyanoacrylate)s Hybridized Tissue Adhesive SystemoGRF New Tissue Adhesive Systems New Emerging Materials for Wound Closures, C.C. Chu Antimicrobial Sutures Materials That Could Accelerate Wound Healing Materials for Better Mechanical and Biocompatible Properties New Tissue Adhesives

Biodegradable arginine-based poly(ester-amide)s as non-viral gene delivery reagents

A novel family of synthetic biodegradable poly(ester-amide)s (Arg-PEAs) was evaluated for their biosafety and capability to transfect rat vascular smooth muscle cells, a major cell type participating in vascular diseases. Arg-PEAs showed high binding capacity toward plasmid DNA, and the binding activity was inversely correlated to the number of methylene groups in the diol segment of Arg-PEAs. All Arg-PEAs transfected smooth muscle cells with an efficiency that was comparable to the commercial transfection reagent Superfect. However, unlike Superfect, Arg-PEAs, over a wide range of dosages, had minimal adverse effects on cell morphology, viability or apoptosis. Using rhodamine-labeled plasmid DNA, we demonstrated that Arg-PEAs were able to deliver DNA into nearly 100% of cells under optimal polymer-to-DNA weight ratios, and that such a high level of delivery was achieved through an active endocytosis mechanism. A large portion of DNA delivered, however, was trapped in acidic endocytotic compartments, and subsequently was not expressed. These results suggest that with further modification to enhance their endosome escape, Arg-PEAs can be attractive candidates for non-viral gene carriers owning to their high cellular uptake nature and reliable cellular biocompatibility.

Synthesis and characterization of dextran-maleic acid based hydrogel.

A new class of hydrogel precursor, dextran-maleic acid (Dex-MA), was synthesized by the reaction of dextran with maleic anhydride in the presence of the catalyst triethylamine. The effects of temperature, time, catalyst amount, and reactant concentration on the degree of substitution (DS) by MA was studied to establish an optimum reaction condition. The new hydrogel precursor had excellent solubility in various common organic solvents. The hydrogels based on Dex-MA precursor were made by the irradiation of Dex-MA with a long wave UV lamp. The Dex-MA hydrogels showed a very high swelling ratio in water, and the magnitude of swelling depended on the pH of the medium and the DS by MA. The Dex-MA hydrogels exhibited the highest swelling ratio in neutral pH, followed by acidic (pH 3) and alkaline pH (10). The most distinctive characteristic of Dex-MA hydrogels was that a carboxylic acid group was generated by the reaction of dextran with maleic anhydride. As a result, the swelling ratio increased with an increase of the DS of the MA segment (ionizable moiety that affects swelling ratio) in the Dex-MA hydrogel.

Degradation phenomena of two linear aliphatic polyester fibres used in medicine and surgery

Abstract The changes of pH levels and tensile breaking strength of two synthetic biodegradable polymers, polyglycolic acid and poly(glycolide-lactide) were examined as a function of time of immersion and γ irradiation in in vitro conditions. It was found that (1) the pH of the solution containing the polymers would decrease with time as degradation proceeded; (2) all of the pH-time curves exhibited sigmoidal shape and consisted of three distinctive regions - early, accelerated, and later stages; (3) the lengths of these three regions were a function of γ irradiation and increasing the radiation dosage shortened the time required for the accelerated region to occur; and (4) the appearance of the drastic pH changes coincided with loss of tensile breaking strength. It was suggested that the destruction of the tie-chain segments in the first stage of degradation and the subsequent relaxation of crystal blocks were related to the drastic decrease in pH levels and loss of tensile breaking strength.

Synthesis and characterization of dextran-based hydrogel prepared by photocrosslinking

Abstract A polysaccharide-based hydrogel was prepared by photocrosslinking of modified dextran. Dextran was first bromoacetylated by bromoacetyl bromide and was subsequently reacted with sodium acrylate for incorporating a vinyl group. The acrylated dextran was then irradiated by a long-wave UV lamp for photocrosslinking. Reaction products (bromoacetyl dextran, acrylated dextran, and hydrogel) were characterized by elemental analysis, FT-IR, 1H-NMR, and 13C-NMR. The prepared dextran hydrogels showed a wide range of swelling behavior in different pH media, depending on the degree of substitution in bromoacetyl dextrans.

Synthesis, characterization and biodegradation of functionalized amino acid-based poly(ester amide)s

A series of biodegradable functional amino acid-based poly(ester amide)s (PEA-AG) were designed and synthesized by the solution co-polycondensation of amino acid (L-phenylalanine and DL-2-allylglycine) based monomers and dicarboxylic acid based monomers. Pendant carbon-carbon double bonds located in the DL-2-allylglycine were incorporated into these PEA-AGs, and the double bond contents could be adjusted by tuning the feed ratio of L-phenylalanine to DL-2-allylglycine monomers. Chemical structures of this new functional PEA-AG family were confirmed by FTIR and NMR spectra. The thermal properties of these polymers were investigated; increasing the methylene chain in both the amino acid and dicarboxlic acid segments resulted in a reduction in the polymer glass-transition temperature. The short-term in vitro biodegradation properties of PEA-AGs were investigated as a function of PEA-AG chemical structures and enzymes. Based on the weight loss data, PEA-AGs biodegraded much faster in an enzyme solution than in a PBS buffer solution. The utility of the pendant functional carbon-carbon double bonds in PEA-AG was demonstrated by synthesizing additional functional PEA derivatives. The incorporation of the functional pendant carbon-carbon double bonds along the PEA-AG chains could significantly expand the biomedical applications of these functional PEA-AGs via either their capability to conjugate bioactive agents or prepare additional useful functional derivatives.