The University of Akron

Other

Cook Medical Technologies LLC

Covestro LLC

The Ohio State University

Houston Methodist Hospital

Duke University

University of Warwick

Becker, Matthew

Wilson, James

Petersen, Shannon

Tasciotti, Ennio

Weiner, Bradley

Isayev, Avraam

Matthew L Becker

Zachary Kurtiss Zander

Robert A Weiss

Karl W Haider

Don S Wardius

Bruce D Lawrey

James A Wilson

Jiayi Yu

Shannon R Petersen

Michael C Hiles

Sean Chambers

Darrell H Reneker

Avraam I Isayev

Ali Dhinojwala

Howard David Dean

Yaohua Gao

Shan Li

Ennio Tasciotti

Andrew P Dove

Alec Cerchiari

Yusheng Chen

Alex P Kleinfehn

Yanyi Xu

Gaelle Le Fer

Yongjun Shin

Rodger A Dilla

Garrett Fredric Bass

Nathan Z Dreger

Trenton Parsell

Ian A Barker

Willie C McRoy, Jr

Jukuan Zheng

Fei Lin

Bradley Weiner

Vrushali Dinkar Bhagat

Adrian Defante

Jinjun Zhou

Yuanyuan Luo

Wen Tang

Vinh X Truong

Craig A Bell

Richard Lee Murray

Avraam Isayev

In one or more embodiments, the present invention provides a low molecular weight, non-toxic, resorbable poly(ethylene glycol) (PEG)-block-poly(propylene fumarate) (PPF) diblock copolymers and poly(propylene fumarate) (PPF)-block-poly(ethylene glycol) (PEG)-block-poly(propylene fumarate) (PPF) triblock copolymers (and related methods for their making and use) that permits hydration for the formation of such things as hydrogels and has constrained and predictable material properties suitable for 3D printing and drug delivery applications. Using continuous digital light processing (cDLP) hydrogels the diblock and triblock copolymers can be photochemically printed from an aqueous solution into structures having a 10-fold increase in elongation at break compared to traditional diethyl fumarate (DEF) based printing. Furthermore, PPF-PEG-PPF triblock hydrogels have also been found in vitro to be biocompatible across a number of engineered MC3T3, NIH3T3, and primary Schwann cells.

Synthesis and characterization of well defined poly(propylene fumarate) and poly (ethylene glycol) block copolymers

In various embodiments, the present invention is directed to a PPF-based copolymer for 3D printing applications and methods for its making and use. These copolymers have a viscosity in a printable viscosity range and allow light transmittance at curing wavelengths. In various embodiments, a lower viscosity copolymers are obtained by substitution of a portion of maleic anhydride with succinic anhydride and then forming a poly(propylene fumarate-co-succinate) copolymer by the copolymerization of maleic anhydride and succinic anhydride with propylene oxide via Mg(BHT)(THF)catalyzed ring opening copolymerization (ROCOP). Because of their lower viscosities, these copolymers require less, if any, diethyl fumarate (DEF) to prepare the 3D printing resin, while the mechanical properties can still be adjusted as with a PPF polymer prepared without the succinic anhydride.

Poly(propylene fumarate)-based copolymers for 3D printing applications

In various embodiments, the present invention provides well-defined biodegradable poly(lactone-b-propylene fumarate) diblock and triblock polymers formed using a novel one-pot, scalable ring-opening block-order copolymerization (ROBOCOP) technique that utilizes magnesium 2,6-di-tert-butyl-4-methylphenoxide (Mg(BHT)(THF)) to 'switch' from the ROP of cyclic esters to the ROCOP of maleic anhydride (MAn) and propylene oxide (PO) to produce PPF based block copolymers for application in additive manufacturing and patient specific regenerative medicine. These block copolymers are fully resorbable and can be photochemically crosslinked in a number of applications, including 3D printing. By adding the lactone block to the PPF polymer, the viscosity of the resulting block copolymer at working temperatures can be precisely controlled and the quantity of the reactive diluent in printable resins can be reduced or eliminated.

Block copolymers of lactones and poly(propylene fumarate)

In one or more embodiments, the present invention is directed to a novel method for synthesizing Mg(BHT)(THF)catalyst, which has several advantages over previous methods. Dry toluene or pentane are not required for synthesizing the catalyst, and the reaction is done in a bulk solution of BHT and THF. Further, because the Mg(BHT)(THF)is made in a one-step ('one-pot') synthesis, the time required for synthesizing and drying the catalyst is reduced. Using the new method of the present invention, the Mg(BHT)(THF)is pure after removing excess THF, thereby eliminating the need for washes and recrystallization.

Synthesis of Mg(BHT)(THF)

In one or more embodiments, the present invention provides am method of making a poly(propylene fumarate-co-succinate) (PPFS) copolymer containing a random incorporation of succinate groups and targetable reduction profiles without the need for three or more monomer units. To achieve this, a time-dependent sonication-promoted zinc/acetic acid reduction of the PPM unsaturated double bonds has been used to create a random PPMS copolymer which may be isomerized into the PPFS equivalent. By changing the sonication time as well as the ratios of acetic acid, zinc, and PPM unsaturated alkenes, partial reduction of the PPM alkenes has been shown to give PPMS products containing varying compositions of succinic and maleate units, which may then be isomerized to the PPFS product.

Resorbable complex shape memory poly(propylene fumarate) star scaffolds for 4D printing applications

In various aspects, the present invention is directed to novel bioactive peptide loaded poly(propylene fumarate) (PPF) tissue scaffolds and related methods for their making and use. In various embodiments, these bioactive peptide loaded poly(propylene fumarate) tissue scaffolds are formed by forming a PPF structure or matrix using photochemical 3-D printing techniques and then loading that printed PPF structure or matrix with a bioactive peptides or other bioactive compounds that have, or have been functionalized to have, a thiol functional group at or near its terminus. The thiol groups on the bioactive peptides or other compound will react with exposed alkene functional groups on the PPF polymer matrix via a thiol-ene 'click' reaction, thereby binding these bioactive peptides or other compounds to the tissue scaffolds. The bioactive peptide loaded PPF tissue scaffolds of the present invention are particularly useful in repairing bone defects.

Post-3D printing functionalization of polymer scaffolds for enhanced bioactivity

In various embodiments, the present invention is directed to a degradable poly(ester urea) (PEU)-based adhesion barrier, particularly suitable for use in connection with surgical mesh repair in the treatment of hernias and other soft tissue injuries comprising an amino acid based poly(ester urea) backbone and one or more zwitterionic side chains connected to the amino acid based poly(ester urea) backbone through a sulfide bond. In some other embodiments, the present invention is directed to method of making the PEU-based adhesion barriers comprising: preparing an amino acid based PEU polymer or terpolymer having one or more allyl functional groups; preparing a thiol functionalized zwitterionic compound; and reacting the allyl functionalized PEU polymer or terpolymer with the thiol functionalized zwitterionic compound to form a degradable PEU-based adhesion barrier having an amino acid based PEU backbone having zwitterionic side chains.

Poly(ester urea) adhesion barriers for use in the treatment of hernia-mesh repair

In various embodiments, the invention relates to poly(propylene fumarate) (PPF)-based star-shaped copolymers synthesized using a core-first approach that uses a multi-functional alcohols as an initiator, and Mg(BHT)(THF)as catalyst for controlled ring opening copolymerization (ROCOP) of maleic anhydride (MAn) with propylene oxide (PO). In some embodiments, these star-PPF copolymers have lower viscosities than their linear analogs, allowing a decrease in DEF fraction in resin formulation, as well as the use of higher molecular weights. These star-shape PPF can be used to prepare PPF:DEF resins containing as much as 70% by weight of the multi-arm PPF star copolymers, and have a low complex viscosity of highstar PPF resin that affords rapid printing with anearly eight times larger than the largest linear PPF oligomer printed previously.

Star-shaped poly(propylene fumarate) copolymers for 3D printing applications

An end and monomer functionalized poly(propylene fumarate) polymer and methods for preparing this polymer, comprising isomerized residue of a maleic anhydride monomer and a functionalized propylene oxide monomer according to the formula:  where n is an integer from more than 1 to 100; R is the residue of an initiating alcohol having a propargyl, norbornene, ketone or benzyl functional group; and R' is a second functional group selected from the group consisting of propargyl groups, 2-nitrophenyl groups, and combinations thereof are disclosed. The end and monomer functional groups allow for post-polymerization modification with bioactive materials using 'click' chemistries and use of the polymer for a variety of applications in medical fields, including, for example, 3-D printed polymer scaffold.

Functionalized poly (propylene fumarate) polymers made by ring opening polymerization using magnesium catalysts

In one or more embodiments, the present invention provides a novel approach to the addition of plasticizers for softening TPUs, i.e., lowering the durometer and the melt viscosity. This approach involves incorporating bonded sulfonate groups with quaternary ammonium counterions into the TPU. In one or more embodiments of the present invention, the softening of TPU is achieved by incorporating an ionic diol, such as N,N-bis (2-hydroxyethyl)-2-aminoethane-sulfonic acid (BES), coupled with various bulky alkyl ammonium cations, during the chain extension step of the TPU synthesis. It is believed that that steric hindrance of the bulky quaternary ammonium groups weakens the dipole-dipole interactions of the sulfonate groups and/or lowers the crystallinity of the hard block, thereby creating additional free volume that softens the polymer and lowers the melt viscosity.

Softening thermoplastic polyurethanes using ionomer technology

In various embodiments, the present invention provides a functionalized thermoplastic polyurethane (TPU) containing bulk incorporated or surface-grafted quaternary ammonium compounds (QAC)s for contact-killing of a variety of microbes, where the QACs are on the surface of TPU to provide a sterile surface material that prevents bacteria commonly involved in device-associated infections (DAIs) from proliferating. The functionalized TPUs of the present invention can be formed into a wide variety of 3-dimensional shapes, such as catheters, medical tubing, laryngeal or tracheal stents, sutures, prosthetics, wound dressings, and/or a coating for medical devices and contains the residue of either a QAC containing diol monomer or an alkene functional diol monomer, which then allows the TPU to be functionalized with a QAC containing disulfide or free thiol compound, to form a quaternary ammonium functionalized thermoplastic polyurethane compound having antimicrobial properties for use in medical devices.

Contact-killing, QAC functionalized thermoplastic polyurethane for catheter applications

In various aspects, the present invention provides a degradable and resorbable novel phosphate functionalized amino acid-based poly(ester urea) adhesive and related methods for its synthesis and use. These adhesives are formed from phosphate functionalized PEU polymers and copolymers crosslinked using one or more divalent metal crosslinking agents. The phosphate functionalized amino acid-based poly(ester urea) adhesives of various embodiments of the present invention have been found particularly effective in bonding bone to either bone or metal and have demonstrated adhesive strengths on bone samples that were significant and comparable to commercially available poly(methyl methacrylate) bone cement.

Phosphorylated poly (ester-urea) based degradable bone adhesives

In various embodiments, the present invention provides a strong, synthetic elastomer materials (and related methods for making same) with mechanical properties that are controlled by the stereochemically-defined double bonds within their backbone, yet have physical properties that are derived from monomer selection and defined, modifiable, chain end groups. The use of the organocatalyzed, stereospecific addition of thiols to activated alkynes, affords isolated high molar mass materials (&#x3e;100 kDa) via step-growth polymerization with high levels of cis- or trans-double bond content. Furthermore, in various aspects of the present invention, it has been found that changing the monomer composition and chain end groups provides additional control over the materials' physical properties to provide more efficient compounding with polar additives. Using this approach to elastomer synthesis, further end group modification and toughening through various vulcanization strategies are also possible.

Biomimetic synthetic rubber and methods for controlling its physical properties through backbone double bond stereochemistry by monomer selection and end group modification

In various aspects, embodiments of the present invention are directed to a series of multivalent dendrons containing a bioactive peptide domain and surface-binding catechol domains. In some embodiments, these multivalent dendrons were obtained through solid phase synthesis and have a strong binding affinity to metal oxide surfaces such as, TiO, ZrO, CeO, and FeO, SiO2, as well as other inorganic surfaces such as hydroxyapatite, silver, fluorapatite, calcium carbonate and gold. These catechol-bearing dendrons provide a fast and efficient method to functionalize a wide range of inorganic materials with bioactive peptides and have the potential to be used in coating orthopaedic implants and fixation devices.

Composition and methods for tethering bioactive peptides to metal oxide surfaces

Growing community of inventors

Chapel Hill, NC, United States of America

Matthew L Becker