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Patent Application Titled "Biodegradable Nanocomposites with Enhanced Mechanical Properties for Soft Tissue Engineering" Published Online

June 5, 2014

By a News Reporter-Staff News Editor at Gene Therapy Weekly -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Ameer, Guillermo (Chicago, IL); Webb, Antonio R. (Chicago, IL), filed on November 18, 2013, was made available online on May 22, 2014 (see also Patents).

No assignee for this patent application has been made.

Reporters obtained the following quote from the background information supplied by the inventors: "The need for biodegradable polymers in emerging technologies such as tissue engineering, drug delivery, and gene therapy has been fueling a quest for novel biodegradable polymers [13-16]. In particular, biodegradable polymers with elastomeric properties have recently received attention for their potential use in the engineering of soft tissues such as blood vessel, heart valves, cartilage, tendon, and bladder, which exhibit elastic properties. Due to their long history of use in clinical applications, poly(hydroxyortho esters) such as polyglycolic acid (PGA), poly lactic acid (PLA) and copolymers thereof are often used to fabricate three-dimensional porous scaffolds to support cell attachment, proliferation, migration, and extracellular matrix synthesis. The development of a novel family of biodegradable elastomeric polymers referred to as poly(diol citrates) has been reported [1].

"Tissues such as blood vessels, cartilage, ligament, and tendon have specific biomechanical requirements for successful functional tissue engineering. These tissues are often subjected to relatively large tensile or compressive forces, so it is important that synthetic scaffolds or implants intended to model such tissues have the necessary tensile strength, elasticity, and compressive modulus to withstand such forces. Ideally, the mechanical properties of the scaffold or implant would approximate those of the natural tissue it is designed to mimic. The reported tensile strength of human cartilage and ligament are 3.7-10.5 MPa and 24-112 MPa, respectively. The reported Young's modulus of cartilage and ligament are 0.7-15.3 MPa and 65-541 MPa, respectively. The reported tensile strength of human coronary arteries is 1.4-11.14 MPa.

"It is well known in the art that the mechanical properties of elastomers can be enhanced by the fabrication of composites in which a second component or phase is added to the elastomeric phase. One method by which elastomers can be strengthened and stiffened is by incorporating nanoparticles into the elastomeric matrix [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8; Okada, M., Chemical syntheses of biodegradable polymers. Prog Polym Sci, 2002. 27: p. 87-133; Griffith., Polymeric Biomaterials. Acta Mater, 2000. 48: p. 263-277; MacDonald, J. Biomed. Mater. Res. A, 2005, 74, 489-496]. This is the case in the rubber industry where carbon black nanoparticles can be added to greatly increase the mechanical properties [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8]. The nanoparticles act as additional crosslink points to reinforce the network chains and in general, the increase in mechanical properties is inversely proportional to the nanoparticle diameter [Lavik, E. and R. Langer, Tissue engineering: current state and perspectives. Appl Microbiol Biotechnol, 2004. 65: p. 1-8]. Although this method has been used for industrial applications, there have been no reports involving the use of biocompatible, biodegradable nanoparticles to strengthen matrices intended for in vivo use.

"Poly(hydroxyortho esters) or other polymers have been mixed with ceramics, glass microparticles, glass nanoparticles, glass nanofibers, or carbon nanotubes to strengthen scaffolds for bone tissue engineering applications and, to a lesser extent, for soft tissue regeneration. However, most of these approaches introduce inorganic and non-biodegradable components into the polymer composite. A non-degradable second phase may interfere with the body's natural remodeling mechanisms as the continuous presence of a foreign material may induce long-term inflammatory responses. Furthermore, the resulting composite does not exhibit the elasticity and flexibility that is important for soft tissue engineering.

"Chun et al (U.S. patent application Ser. No. 10/383,369) and Melican et al (U.S. patent application Ser. No. 09/747,489) disclose tissue implants comprising a biodegradable mesh reinforcement component and a biodegradable elastomeric foam component. Ma et al (U.S. Pat. No. 6,146,892) disclose three-dimensional biodegradable matrices comprised of nanofibers. However, Chun et al, Melican et al, and Ma et al do not disclose composites having mechanical properties approaching those of natural soft tissue.

"Analogous to rubber which is a three dimensional network of crosslinked polymer chains, poly(diol citrates) are composed of three-dimensional polyester networks formed by reacting citric acid with various aliphatic diols. The mechanical properties could be varied depending on the selection of diols and the applied post-polymerization conditions. In general, longer chain diols have a lower tensile strength and modulus, while increasing polymerization time and/or temperature increase the tensile strength and modulus. Preliminary in vitro cell culture evaluation of poly(diol citrates) showed their great potential as 'cell-friendly' materials, as both smooth muscle and endothelial cells attach and proliferate on the surface. Methods of preparation of poly(diol) citrates are described in detail in U.S. patent application Ser. No. 10/945,354 (incorporated herein by reference and also shown in the Examples below). In vivo biocompatibility results show a thin vascularized collagenous capsule after 4 months of implantation with no inflammation. The thickness of this capsule was smaller than that reported for poly(L-lactide-co-glycolide) (PLGA) [17]. A thin vascularized capsule is considered to be beneficial for mass transfer between a cell-based implant and surrounding tissues.

"Although the mechanical properties of synthetic polymers, in particular poly(diol citrates), can be varied to meet specific applications, it can be desirable to further increase the strength and stiffness while maintaining the ability to be elongated to many times their original length before rupture. The present invention is directed to optimizing the strength and elasticity of biocompatible scaffolds by preparing a composite comprising an elastomeric polymer strengthened by the presence of a biodegradable polymeric nanostructure."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "The present invention describes a composition comprising a biodegradable elastomeric polymeric component and a biodegradable polymeric nano-structure. The present invention describes a composition comprising a composite of a citric acid polyester having the generic formula (A-B--C)n, wherein A is a linear aliphatic dihydroxy monomer; B is citric acid, C is a linear aliphatic dihydroxy monomer, and n is an integer greater than 1; and a biodegradable polymer used for implantable tissue devices. Preferably, the biodegradable polymer is fabricated into a nanostructure such as a nanofiber, a nanoparticle, or the like.

"In specific embodiments, A is a linear diol comprising between about 2 and about 20 carbons. In other embodiments, C is independently a linear diol comprising between about 2 and about 20 carbons. While in certain embodiments, both A and C may be the same linear diol, other embodiments contemplate that A and C are different linear diols. A particularly preferred linear diol is 1,8, octanediol. In other embodiments, one or both of A and C may be 1,10-decanediol. The diol also may be an unsaturated diol, e.g., tetradeca-2,12-diene-1,14-diol, or other diols including macromonomer diols such as polyethylene oxide, and N-methyldiethanoamine (MDEA). This family of elastomers is named as poly(diol citrate). In particularly preferred embodiments, the composition of the invention is dihydroxy poly 1,8-octanediol co-citric acid. Poly(diol citrate) can also form hybrids with other materials like hydroxyapatite to form elastomeric composites.

"In some embodiments the nano-structure of the invention is fabricated from a polymer. Preferably the polymer is a biodegradable polymer selected from the group consisting of poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate), and polyester amide. In more preferred embodiments, the polymer is poly(L)-lactic acid, poly(lactic-co-glycolic acid) (PLGA) or a combination of the two.

"In specific embodiments, the composition further comprises a drug.

"Another aspect of the invention contemplates a substrate that may be formulated for tissue culture and/or tissue engineering wherein the substrate is made of a composition as described herein above. In preferred embodiments, the substrate may further comprise a surface modification that allows cellular attachment. Preferably, the polymer of the invention employed as cell/tissue culture substrate is biodegradable. Preferably, the polymer also is biocompatible. The term 'biocompatible' is intended to encompass a polymer that may be implanted in vivo or alternatively may be used for the growth of cells that may be implanted in vivo without producing an adverse reaction, such as an immunological response or otherwise altering the morphology of the cells grown thereon to render the cells incompatible with being implanted in vivo or used to model an in vivo organ.

"Also contemplated herein is a method of producing engineered tissue, comprising providing a biodegradable composition of the present invention as a scaffold for the growth of cells and culturing cells of said tissue on the scaffold. In preferred methods, the polymer is composite of a poly 1,8-octanediol-co-citric acid, or a derivative thereof; or a poly 1,10-decanediol-co-citric acid or derivative thereof in combination with a biodegradable polymer such as PGLA or PLLA. In specific embodiments, the cells are selected from the group consisting of connective tissue cells, organ cells, muscle cells, nerve cells, and any combination thereof. In more specific embodiments, the cells are selected from the group consisting of tenocytes, fibroblasts, ligament cells, endothelial cells, lung cells, epithelial cells, smooth muscle cells, cardiac muscle cells, skeletal muscle cells, islet cells, nerve cells, hepatocytes, kidney cells, bladder cells, urothelial cells, chondrocytes, and bone-forming cells. In other preferred embodiments, the tissue engineering method comprises growing the cells on the scaffold in a bioreactor.

"In further embodiments, the compositions of the invention may be used as bandages, patches or sutures for implantation during surgery. In still other embodiments, the compositions of the present invention may be used to form a drug delivery device comprising a drug interspersed in the polymer composition of the invention.

"Other features and advantages of the invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, because various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.


"The following drawings form part of the present specification and are included to further illustrate aspects of the present invention. The invention may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.

"FIG. 1: Poly(diol citrate) reaction scheme.

"FIG. 2: PLGA Nanoparticle Formation.

"FIG. 3: SEM micrographs of PLLA nanoscaffolds before and after penetrating the pores with PDC. (Scale bars=1 .mu.m).

"FIG. 4A-C: (A) Tensile strength, (B) Young's modulus, (C) Elongation at break of PLLA-PDC nanoscaffold composites and PDC control that were polymerized at C. for 1 day with vacuum (n=4). (* p

"FIG. 5A-C: SEM micrographs of (A) PLGA nanoparticles (Scale Bar=1 .mu.m), (B) 5% PLGA-PDC nanocomposite (Scale Bar=2 .mu.m), (C) 10% PLGA-PDC nanocomposite (Scale Bar=2 .mu.m).

"FIG. 6A-C: (A) Tensile strength, (B) Young's modulus, (C) Elongation at break of PLLA-PDC nanoscaffold composites and PDC control that were polymerized at C. for 3 days without vacuum (n=4). (* p

"FIG. 7A-D--(A) Tensile strength, (B) Young's modulus, (C) Elongation at break of PLLA-PDC nanocomposites and controls that were polymerized at C. for 3 day without vacuum (n=4). (d) Representative stress-strain curves. PLLA controls were not shown for clarity. (* p

"FIG. 8A-C--(A) Tensile strength, (B) Young's modulus, (C) Elongation at break of PLLA-PDC composites and controls that were polymerized at C. for 3 day without vacuum or C. for 1 day without vacuum then C. for 1 day with vacuum (n=4). (* p

"FIG. 9A-C--(A) Tensile strength, (B) Young's modulus, (C) Elongation at break of PLLA-PDC and PLLA-POC composites and controls that were polymerized at C. for 3 day without vacuum (n=4) (* p

"FIG. 10--Compressive modulus of PDC-PLLA nanofibrous scaffold composites. (* p

For more information, see this patent application: Ameer, Guillermo; Webb, Antonio R. Biodegradable Nanocomposites with Enhanced Mechanical Properties for Soft Tissue Engineering. Filed November 18, 2013 and posted May 22, 2014. Patent URL:

Keywords for this news article include: Biotechnology, Patents, Citrates, Lactates, Citric Acid, Lactic Acid, Gene Therapy, Muscle Cells, Nanoparticle, Bioengineering, Nanotechnology, Carboxylic Acids, Organic Chemicals, Drug Delivery Systems, Emerging Technologies, Biodegradable Polymers.

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Source: Gene Therapy Weekly

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