Status: sutures approved in U.S.

Organizations involved:

Tepha, Inc. –Manuf.; R&D; Tech.; World mark

Metabolix, Inc. –R&D; Tech.

Massachusetts Inst. of Technology –R&D; Tech.

Description: TephaFLEX is suture material (monofilament thread) composed of a biocompatible, resorbable polyhydroxyalkanoate (PHA) polester-type polymer, poly-4-hydroxybutyrate (P4HB; PHA4400), expressed by transformed Escherichia coli (E. coli) K12 bacteria, currently used for sutures. PHA is formed enzymatically (polymerized) in vivo from hydroxyalkanoates, e.g., hydroxybutyrate. TephaFLEX and PHAs are simple, straight-chain aliphatic polyester polymers. Enyzmes in the transformed E. coli genome involved in metabolism/polymarization of P4HB monomers/precursor and polymerization are succinic semialdehyde dehydrogenase, 4-hydroxydehydrogenase, diol oxidoreductase, aldehyde dehydrogenase, coenzyme A transferase, and PHA synthetase. P4HB is sterilized using ethylene oxide.

The structure of P4HB largely resembles that of chemically-Manufactured polyesters. Unlike other biopolymers, such as collagen, hyaluronate and most proteins, TephaFLEX/ P4HB is thermoplastic, i.e., can be melted and fabricated into virtually any shape or form – including fibers, films, tubes, foams, textiles, microspheres, and molded constructs – using a wide range of conventional melt and solvent processing techniques. This allows highly-purified, recombinant-expressed P4HB to be melted and extruded as a single cohesive monofilament for use as sature material.

Sutures are used to hold (sew) together soft tissue while it heals from a deep cut or surgical wound. TephaFLEX Absorbable Suture is engineered to be one of the strongest absorbable fibers, offering up to 50% greater tensile strength than currently marketed monofilament absorbable sutures. P4HB has an elongation-to-break ratio of about 1,000, i.e., it can be stretched to 10-times its length before breaking. TephaFLEX sutures are stronger than typical polypropylene sutures and as comparable in strength to Macon sutures. Compared to synthetic polymers such as polylactic acid (PLA) and polyglycolic acid (PGA), TephaFLEX material is tougher and more flexible with an absorption rate and degradation profile that are compatible with human tissue repair and replacement applications.

P4HB is fully biocompatible and biodegradable/resorbable. After the repair process, the biopolymers degrade in the body to natural metabolites in a biocompatible, cell-friendly manner. TephaFLEX offers surgeons improved flexibility, good knot security, and prolonged strength retention when implanted.

Tepha is also developing TephELAST (PHA 3444), a more elastic and flexible PHA product.

Biological.: Some bacteria have evolved to use stored PHA, including P4HB, polymers as an energy source, much like many (micro)organisms/cells store fats and/or carbohydrates. These polymers are synthesized in nature by numerous microorganisms, and have been recently recognized as the fifth class of naturally occurring biopolymers (along with the polyamino acids, polynucleic acids, polysaccharides, and polyisoprenoids).

Poly(3-hydroxyalkanoates) (PHAs) are structurally simple high molecular weight polyester macromolecules/polymers synthesized by many gram-positive and gram-negative bacteria. PHAs accumulate in these cells as discrete granules to levels as high as 90% of the cell dry weight, and are generally believed to play a role as a sink for carbon and reducing equivalents. When nutrient supplies are imbalanced, it is advantageous for bacteria to store excess nutrients intracellularly. By polymerizing soluble intermediates into insoluble molecules, the cell does not undergo alterations of its osmotic state and leakage of these valuable compounds out of the cell is prevented. PHAs extracted from the bacterial cell show material properties that are similar to some common plastics, such as polypropylene. The bacterial origin of the PHAs make these polyesters a natural material, and many microorganisms have evolved the ability to degrade these macromolecules.

PHAs are generally composed of (R)-hydroxy fatty acids, where the pendant group (R) varies from methyl (C1) to tridecyl (C13), e.g., C4 or butyl. The best-known PHAs are P(3HB) (R=methyl), P(3HB-3HV) (R=methyl or ethyl), and P(3HO-3HH) (R=pentyl or propyl).

The monomeric component of poly(4HB), 4-hydroxybutanoic acid (4HB), is widely distributed in the mammalian body, present in the brain, kidney, heart, liver, lung, and muscle. 4HB (monomer) has been used for over 35 years as an intravenous injection for the induction of anesthesia and for long-term sedation. The half-life of this simple 4-carbon chain-based acid is short (35 min), and relatively high doses (several grams) are required to obtain any hypnotic effect in humans. Leaching and release of 4HB from P4HB is at such a low rate that implants of poly(4HB) cannot induce general sedation or have any other physiological effects.

Companies.: Recombinant PHA technology was originally developed by researchers at the Massachusetts Institute of Technology (MIT) and Metabolix, Inc., a company founded by key MIT researchers. MIT filed its first patents concerning recombinant PHAs and these were exclusively licensed by Metabolix in 1993.

Tepha, Inc. was spun-off from Metabolix in 1998, founded by one of the original founders (Dr. S. Williiam) of Metabolix. Tepha remains privately held, while Metabolix is now publicly traded and is focused on alternatives to petrochemicals. Tepha’s institutional investors include The Vertical Group, a New Jersey based venture capital firm specializing in medical devices and biotechnology; Integra Ventures, a life science venture capital firm located in Seattle, WA; The Novartis Venture Fund, the venture capital arm of Novartis AG; and Westfield Life Sciences Fund, a fund specializing in health care companies.

Tepha reports, “The development of the TephaFLEX Absorbable Suture was supported by grants from the National Institutes of Health (NIH), and the US Department of Commerce’s National Institute of Standards and Technology Advanced Technology Program.”

Manufacture: E. coli K12 was selected as the host organism for manufacture of P4HB due to its widespread industrial use and inherent lack of synthesis of polyester polymers, eliminating a potential source for contamination. Properties, e.g., molecular weight, of P4HB can be controlled by modification of enzymes inserted into the E. coli. Nearly 85% of transformed bacteria hosts’ biomass can be in the form of PHA.

Metabolix has demonstrated recombinant PHA (industrial grade) manufacture at the 60,000 Liter scale using conventional fermentation techniques and materials. PHAs can now be manufactured in bulk for as low $0.50/pound, and Metabolix is working towards $0.30/pound, making PHA competitive with polystyrene and polycarbonate for industrial uses. The company reports that it typically obtains yield of 50 grams or more of P4HB per Liter in less than 48 hours.

FDA class: Medical device PMA

Approvals: Date = 20070402; 510k (equivalent to one or more existing, approved products)

Status: In May 2002, Tepha field a Device Master File (DMF) with FDA for PHA4400. This was approved, allowing initiation of trials and commercial development.

TephaFLEX was approved by FDA as a class II (moderate risk) medical device in April 2007. TephaFLEX is the first recombinant protein or genetically engineered suture material.

Medical: The device is contraindicated in patients allergic to the cells or the growth media used to produce the absorbable polymeric material.

Tech. transfer: Tepha has an intellectual property portfolio that currently comprises over 30 issued U.S. patents, some owned directly by Tepha, and some with the Company as an exclusive licensee. Patent assigned or licensed to Tepha include U.S. 6,913,911, “Transgenic microbial polyhydroxyalkanoate producers,” assigned to Metabolix, concerning transformed bacterial strains for manufacture of polyhydroxyalkanoate (PHA) polymers; 7,109,007 and 6,881,560, “Polyhydroxybutyrate polymerase,” assigned to Massachusetts Institute of Technology, with claims including genes encoding the enzymes in the PHB and PHA synthetic pathway (beta-ketothiolase, acetoacetyl-CoA reductase and PHB polymerise or PHA polymerase) from Zooloea ramigera strain I-16-M; Alcaligenes eutrophus; Nocardia salmonicolur; and Psuedomnas olevarans expressed in a non-PHB producing organism, E. coli; 6,867,248, “Polyhydroxyalkanoate compositions having controlled degradation rates,” assigned to Metabolix; 7,179,883 and 6,867,247, “Medical devices and applications of polyhydroxyalkanoate polymers,” assigned to Metabolix, concerning a number of medical devices, including sutures; and 7,229,804; 7,,081,357 and 6,689,589, “Biological systems for manufacture of polyhydroxyalkanoate polymers containing 4-hydroxyacids,” assigned to Metabolix, concerning 4-hydroxybutyryl-CoA transferase isolated from bacteria and integrated into the genome of bacteria also expressing a polyhydroxyalkanoate synthase, to yield an improved production process for 4-hydroxybutyrate-containing polyhydroxyalkanoates using transformed organisms, including both bacteria and plants.

Tepha has an exclusive license from Metabolix’s for its technology for transgenic bacterial and other organisms, e.g., plants, manufacture of PHA biomaterials for use in medical applications.

Market: The 2007 Average Wholesale Price (AWP) is not available (not in the Red Book).

Ongoing: Tepha’s corporate partners are pursuing a wide array of products including TephaFLEX-based sutures, surgical meshes for orthopedic and hernia repair, anti-adhesion films, hemostats, intra-cardiac devices, absorbable stents, ligament and tendon repair and replacement devices, embolization agents, and drug delivery systems. Tepha’s current partners include Aesculap AG, HemCon Medical Technologies, LifeCell Corporation, NMT Medical and Tornier, Inc.