Gradient versus End-Capped Degradable Polymer Sequence Variations Result in Stiff to Elastic Photochemically 3D-Printed Substrates

Additive manufacturing affords the construction of complex scaffolds for tissue engineering, yet the limitation in material choice remains a barrier to clinical translation. Herein, a series of poly­(propylene fumarate-co-propylene succinate) were synthesized using both one-pot and sequential ring-opening copolymerization reactions. Continuous liquid interface production-based photochemical 3D printing utilizing thiol-ene chemistry was used to fabricate precise structures with improved build time over the traditional poly­(propylene fumarate)/diethyl fumarate 3D printing processes. Significantly, the materials do not exhibit a yield point under tension and Young’s modulus of the 3D printed products can be tuned by more than 2 orders of magnitude (0.6–110 MPa) using polymer composition and the degree of polymerization. Printed constructs degrade fully under hydrolytic conditions and degradation rates can be tailored using polymer composition, polymer sequence, and resin formulation

Branched Amino Acid Based Poly(ester urea)s with Tunable Thermal and Water Uptake Properties

A series of amino-acid based poly­(ester urea)­s (PEU) with controlled amounts of branching was synthesized and characterized. The mechanical properties, thermal characteristics and water absorptions varied widely with the extent of branch unit incorporation. Herein, the details of the synthesis of a linear bis­(l-phenylalanine)-hexane 1,6-diester monomer, a branch tri-<i>O</i>-benzyl-l-tyrosine-1,1,1-trimethylethane triester monomer and a series of copolymers are described. The extent of branching was varied by adjusting the molar ratio of linear to branched monomer during the interfacial polymerization. The elastic moduli span a range of values (1.0–3.1 GPa) that overlaps with several clinically available degradable polymers. Increasing the amount of branching monomers reduces the molecular entanglement, which results in a decrease in elastic modulus values and an increase in values of elongation at break. The l<i>-</i>phenylalanine-based poly­(ester urea)­s also exhibited a branch density dependent water uptake ability that varied between 2 and 3% after 24 h of immersion in water. Nanofibers incorporating 8% branching were able to maintain their morphology at elevated temperature, in hydrated conditions, and during ethylene oxide sterilization which are critical to efforts to translate these materials to clinical soft tissue applications

Clustering and Solvation in Poly(acrylic acid) Polyelectrolyte Solutions

Clustering and Solvation in Poly(acrylic acid) Polyelectrolyte Solution

Stereochemistry-Controlled Mechanical Properties and Degradation in 3D-Printable Photosets

Stereochemistry provides an appealing handle by which to control the properties of small molecules and polymers. While it is established that stereochemistry in linear polymers affects their bulk mechanical properties, the application of this concept to photocurable networks could allow for resins that can accommodate the increasing demand for mechanically diverse materials without the need to significantly change their formulation. Herein, we exploit cis and trans stereochemistry in pre-resin oligomers to create photoset materials with mechanical properties and degradation rates that are controlled by their stereochemistry and molecular weight. Both the synthesis of stereopure (cis or trans) acrylate-terminated pre-polymers and the subsequent UV-triggered cross-linking occurred with a retention of stereochemistry, close to 100%. The stereochemistry of a 4 kDa oligomer within the resin enabled the tuning of the formulation to either a fast eroding, soft cis elastomer or a stiff trans plastic that is more resistant to degradation. These results demonstrate that stereochemistry is a powerful tool to modify the stiffness, toughness, and degradability of high-resolution, three-dimensional printed scaffolds from the same formulated ratio of components

Poly(ester urea)-Based Adhesives: Improved Deployment and Adhesion by Incorporation of Poly(propylene glycol) Segments

The adhesive nature of mussels arises from the catechol moiety in the 3,4-dihydroxyphenylalanine (DOPA) amino acid, one of the many proteins that contribute to the unique adhesion properties of mussels. Inspired by these properties, many biomimetic adhesives have been developed over the past few years in an attempt to replace adhesives such as fibrin, cyanoacrylate, and epoxy glues. In the present work, we synthesized ethanol soluble but water insoluble catechol functionalized poly­(ester urea) random copolymers that help facilitate delivery and adhesion in wet environments. Poly­(propylene glycol) units incorporated into the polymer backbone impart ethanol solubility to these polymers, making them clinically relevant. A catechol to cross-linker ratio of 10:1 with a curing time of 4 h exceeded the performance of commercial fibrin glue (4.8 ± 1.4 kPa) with adhesion strength of 10.6 ± 2.1 kPa. These adhesion strengths are significant with the consideration that the adhesion studies were performed under wet conditions

Peptide-Derivatized Shell-Cross-Linked Nanoparticles. 2. Biocompatibility Evaluation

The conjugation of the protein transduction domain (PTD) from the HIV-1 Tat protein to shell cross-linked (SCK) nanoparticles is a method to facilitate cell surface binding and transduction. In the previous report, the preparation, derivatization, and characterization of peptide-functionalized SCK nanoparticles were reported in detail. Following assembly, the constructs were evaluated in vitro and in vivo to obtain a preliminary biocompatibility assessment. The effects of SCK exposure on cell viability were evaluated using a metabolic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and a fluorescent apoptosis assay. Furthermore, stages of apoptosis were quantified by flow cytometry. Although higher levels of peptide functionalization resulted in decreased metabolic function as measured by MTT assay, significant apoptosis was not observed below 500 mg/L for all the samples. To evaluate the potential immunogenic response of the peptide-derivatized constructs, a real-time polymerase chain reaction (RT-PCR) system that allows for the in vitro analysis and quantification of the cellular inflammatory responses tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL1-β) was utilized. The inflammatory response to the peptide-functionalized SCK nanoparticles as measured by RT-PCR show statistically significant increases in the levels of both TNF-α and IL1-β relative to tissue culture polystyrene (TCPS). However, the measured cytokine levels did not preclude the further testing of SCKs in an in vivo mouse immunization protocol. In this limited assay, measured increases in immunoglobulin G (IgG) concentration in the sera were minimal with no specific interactions being isolated, and more importantly, none of the mice (>50) subjected to the three 100 μg immunization protocol have died. Additionally, no gross morphological changes were observed in postmortem organ histology examinations

α‑Amino Acid-Based Poly(Ester urea)s as Multishape Memory Polymers for Biomedical Applications

The thermal shape memory behavior of a series of α-amino acid-based poly­(ester urea)­s has been explored. We demonstrate that these materials exhibit excellent shape memory performance in dual- and triple-shape thermomechanical testing. Significant activation of chain mobility above the <i>T</i>_g as well as a hydrogen bonding network provide the basis for shape transformations and recovery. Additionally, we tuned the shape memory properties of these materials with polymer blending, enabling the demonstration of quadruple-shape memory cycles

Postfabrication Tethering of Molecular Gradients on Aligned Nanofibers of Functional Poly(ε-caprolactone)s

Substrates with combinations of topographical and biochemical cues are highly useful for a number of fundamental biological investigations. Tethered molecular concentration gradients in particular are highly desired for a number of biomedical applications including cell migration. Herein, we report a versatile method for the fabrication of aligned nanofiber substrates with a tunable concentration gradient along the fiber direction. 4-Dibenzocyclooctynol (DIBO) was used as an initiator for the ring-opening copolymerization of ε-caprolactone (εCL) and allyl-functionalized ε-caprolactone (AεPCL), which yielded a well-defined polymer with orthogonal functional handles. These materials were fabricated into aligned nanofiber substrates via touch-spinning. Fibers were modified post-spinning with a concentration gradient of fluorescently labeled dye via a light activated thiol–ene reaction through a photomask. As a demonstration, the cell adhesive peptide RGD was chemically tethered to the fiber surface at a second functionalization site via strain-promoted azide–alkyne cycloaddition (SPAAC). This novel approach affords fabrication of dual functional nanofiber substrates

Versatile Ring-Opening Copolymerization and Postprinting Functionalization of Lactone and Poly(propylene fumarate) Block Copolymers: Resorbable Building Blocks for Additive Manufacturing

Additive manufacturing has the potential to change medicine, but clinical applications are limited by a lack of resorbable, printable materials. Herein, we report the first synthesis of polylactone and poly­(propylene fumarate) (PPF) block copolymers with well-defined molecular masses and molecular mass distributions using sequential, ring-opening polymerization and ring-opening copolymerization methods. These new copolymers represent a diverse platform of resorbable printable materials. Furthermore, these polymers open a previously unexplored range of accessible properties among stereolithographically printable materials, which we demonstrate by printing a polymer with a molecular mass nearly 4 times that of the largest PPF homopolymer previously printed. To further demonstrate the potential of these materials in regenerative medicine, we report the postprinting “click” functionalization of the material using a copper-mediated azide–alkyne cycloaddition

l‑Leucine-Based Poly(ester urea)s for Vascular Tissue Engineering

Poly­(ester urea)­s (PEUs) derived from α-amino acids are promising for vascular tissue engineering applications. The objective of this work was to synthesize and characterize l-leucine-based PEUs and evaluate their suitability for vascular tissue engineering. Four different PEUs were prepared from di-<i>p</i>-toluenesulfonic acid salts of bis-l-leucine esters and triphosgene using interfacial condensation polymerizations. Mechanical testing indicated that the elastic moduli of the respective polymers were strongly dependent on the chain length of diols in the monomers. Three of the resulting PEUs showed elastic moduli that fall within the range of native blood vessels (0.16 to 12 MPa). The in vitro degradation assays over 6 months indicated that the polymers are surface eroding and no significant pH drop was observed during the degradation process. Human umbilical vein endothelial cells (HUVECs) and A-10 smooth muscle cells (A-10 SMCs) were cultured on PEU thin films. Protein adsorption studies showed the PEUs did not led to significant platelet adsorption in platelet rich plasma (PRP) after pretreatment with fibrinogen. Taken together, our data suggest that the l-leucine-based PEUs are viable candidate materials for use in vascular tissue engineering applications