Simon F. Williams

PHA APPLICATIONS: ADDRESSING THE PRICE PERFORMANCE ISSUE: I. TISSUE ENGINEERING

This paper describes the development of medical applications for polyhydroxyalkanoates (PHAs), a class of natural polymers with a wide range of thermoplastic properties. Methods are described for preparing PHAs with high purity, modifying these materials to change their surface and degradation properties, and methods for fabricating them into different forms, including tissue engineering scaffolds. Preliminary reports characterizing their in vivo behavior are given, as well as methods for using the natural polymers in tissue engineering applications.

Medical applications of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial

Poly-4-hydroxybutyrate (P4HB) is being developed as a new absorbable material for implantable medical applications. P4HB promises to open up new opportunities for the development of medical applications by offering a new set of properties that are not currently available. The absorbable biomaterial is strong yet flexible, and degrades in vivo at least in part by a surface erosion process. While the chemical structure of P4HB is similar to that of current absorbable polyesters used in implantable medical products, P4HB is produced by a fermentation process rather than through a chemical synthesis. P4HB is a thermoplastic material that can be processed using standard plastics processing techniques, such as solution casting or melt extrusion. The strength of P4HB fibers prepared by melt extrusion compare well with that of traditional suturing materials, however, P4HB is typically more flexible. P4HB should find use in a wide variety of medical fields such as cardiovascular, wound healing, orthopedic, drug delivery, and tissue engineering applications. This paper describes some of the basic properties of P4HB and several of its potential applications in medicine.

Poly-4-hydroxybutyrate (P4HB): a new generation of resorbable medical devices for tissue repair and regeneration

Abstract Poly-4-hydroxybutyrate (P4HB) is a thermoplastic, linear polyester, produced by recombinant fermentation, that can be converted into a wide range of resorbable medical devices. P4HB fibers are exceptionally strong, and can be designed to provide prolonged strength retention in vivo. In 2007, the FDA cleared a monofilament suture made from P4HB for general soft tissue approximation and/or ligation. Subsequently, surgical mesh devices for hernia repair, tendon and ligament repair, and plastic and reconstructive surgery have been introduced for clinical use. This review describes the unique properties of P4HB, its clinical applications, and potential uses that are under development.

A biodegradable stent based on poly(L-lactide) and poly(4-hydroxybutyrate) for peripheral vascular application: preliminary experience in the pig.

Purpose: To assess the technical feasibility and biocompatibility of a novel stent based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for peripheral vascular applications. Methods: A polytetrafluoroethylene aortobi-iliac graft was implanted in 5 pigs through a midline abdominal incision. After transverse graft limb incision, 5 PLLA/P4HB stents and 5 metal stents (316L stainless steel) were randomly deployed at both iliac anastomotic sites with 6-mm balloon catheters. Angiography was performed to determine patency prior to sacrifice at 6 weeks. Stented segments were surgically explanted and processed for quantitative histomorphometry. Vascular injury and inflammation scores were assigned to the stented iliac segments. Results: No animals were lost during follow-up. All PLLA/P4HB stents were deployed within 2 minutes by balloon inflation to 8 bars without rupture of the stent struts or anastomotic suture. All stents were patent on postprocedural angiography. Histological analysis showed no signs of excessive recoiling or collapse. PLLA/P4HB stents demonstrated decreased residual lumen area and increased neointimal area after 6 weeks (12.27±0.62 and 8.40±1.03 mm2, respectively) compared to 316L stents (13.54±0.84 and 6.90±1.11 mm2, respectively) as the result of differences in stent areas (PLLA/P4HB: 4.31±0.15 mm2; 316L: 2.73±0.29 mm2). Vascular injury scores showed only mild vascular trauma for all stents (PLLA/P4HB: 0.41±0.59; 316L: 0.32±0.47). Inflammatory reaction was slightly higher around PLLA/P4HB stent struts (1.39±0.52) compared to 316L (1.09±0.50). Conclusion: Rapid balloon expansion of PLLA/P4HB stents is feasible without risk of strut rupture. PLLA/P4HB stents provide adequate mechanical stability after iliac anastomotic stenting in pigs. Smaller residual luminal areas in the PLLA/P4HB stents might have been caused by tissue ingrowth into the larger strut interspaces due to higher strut thickness (stent area) in this group. This limitation needs to be addressed in future work on the stent design.

Characterization of poly-4-hydroxybutyrate mesh for hernia repair applications.

BACKGROUND Phasix mesh is a fully resorbable implant for soft tissue reconstruction made from knitted poly-4-hydroxybutyrate monofilament fibers. The objectives of this study were to characterize the in vitro and in vivo mechanical and resorption properties of Phasix mesh over time, and to assess the functional performance in a porcine model of abdominal hernia repair. MATERIALS AND METHODS We evaluated accelerated in vitro degradation of Phasix mesh in 3 mol/L HCl through 120 h incubation. We also evaluated functional performance after repair of a surgically created abdominal hernia defect in a porcine model through 72 wk. Mechanical and molecular weight (MW) properties were fully characterized in both studies over time. RESULTS Phasix mesh demonstrated a significant reduction in mechanical strength and MW over 120 h in the accelerated degradation in vitro test. In vivo, the Phasix mesh repair demonstrated 80%, 65%, 58%, 37%, and 18% greater strength, compared with native abdominal wall at 8, 16, 32, and 48 wk post-implantation, respectively, and comparable repair strength at 72 wk post-implantation despite a significant reduction in mesh MW over time. CONCLUSIONS Both in vitro and in vivo data suggest that Phasix mesh provides a durable scaffold for mechanical reinforcement of soft tissue. Furthermore, a Phasix mesh surgical defect repair in a large animal model demonstrated successful transfer of load bearing from the mesh to the repaired abdominal wall, thereby successfully returning the mechanical properties of repaired host tissue to its native state over an extended time period.

MonoMax Suture: A New Long-Term Absorbable Monofilament Suture Made from Poly-4-Hydroxybutyrate

A long-term absorbable monofilament suture was developed using poly-4-hydroxybutyrate (P4HB) made from a biosynthetically produced homopolymer of the natural metabolite 4-hydroxybutyrate. The suture, called MonoMax, has prolonged strength retention. At 12 weeks, a size 3-0 MonoMax suture retains approximately 50% of its initial tensile strength in vivo and is substantially degraded in one year with minimal tissue reaction. In contrast, PDS II monofilament suture (Ethicon, Inc., Somerville, NJ) has no residual strength in vivo after 12 weeks. In vivo, the MonoMax suture is hydrolyzed primarily by bulk hydrolysis, and is then degraded via the Krebs cycle. MonoMax is substantially more compliant than other monofilament sutures, and incorporates an element of elasticity. Its tensile modulus of 0.48 GPa is approximately one-third of the value of the PDS II fiber providing an exceptionally flexible and pliable fiber with excellent knot strength and security. These features are further enhanced by the fibers elasticity, which also improves knot security and may help prevent wound dehiscence. Because of its performance advantages, this suture may find clinical utility in applications where prolonged strength retention, and greater flexibility are required, particularly in procedures like abdominal wall closure where wound dehiscence is still a significant post-surgical complication.

Development of a sirolimus-eluting poly (l-lactide)/poly(4-hydroxybutyrate) absorbable stent for peripheral vascular intervention

Abstract Fully absorbable drug-eluting stent platforms are currently entering the clinical arena for the interventional treatment of coronary artery disease. This new technology also holds potential for application in peripheral vascular settings. Our study reports on the development of a sirolimus- (SIR) eluting absorbable polymer stent made from a blend of poly(l-lactide) and poly(4-hydroxybutyrate) (PLLA/P4HB) for peripheral vascular intervention. Stent prototypes were laser-cut from PLLA/P4HB tubes (I.D.=2.2 mm, t=250 µm), spray-coated with different PLLA/P4HB/SIR solutions, and bench-tested to determine expansion properties, fatigue, trackability and in vitro drug release kinetics. The stent prototypes were expanded with a 5.0×20 mm balloon catheter, and exhibited a recoil of 3.6% upon balloon deflation. Stent collapse pressure of 0.4 bar (300 mm Hg) was measured under external pressure load. Sustained scaffolding properties were observed in vitro over 14 weeks of radial fatigue loading (50±25 mm Hg at 1.2 Hz). Trackability was demonstrated in bench tests with an 8 French contralateral introducer sheath. SIR release kinetics were adjusted over a broad range by varying the PLLA/P4HB ratio of the coating matrix. The newly developed absorbable SIR-eluting PLLA/P4HB stent successfully fulfilled the requirements for peripheral vascular intervention under in vitro conditions.

The History of GalaFLEX P4HB Scaffold

The GalaFLEX Scaffold (Galatea Surgical, Inc., Lexington, MA) for plastic and reconstructive surgery belongs to a new generation of products for soft tissue reinforcement made from poly-4-hydroxybutyrate (P4HB). Other members of this new family of products include MonoMax Suture (Aesculap AG, Tuttlingen, Germany) for soft tissue approximation, BioFiber Scaffold (Tornier, Inc., Edina, MN) for tendon repair, and Phasix Mesh (C.R. Bard, Inc., Murray Hill, NJ) for hernia repair. Each of these fully resorbable products provides prolonged strength retention, typically 50% to 70% strength retention at 12 weeks, and facilitates remodeling in vivo to provide a strong, lasting repair. P4HB belongs to a naturally occurring class of biopolymers and fibers made from it are uniquely strong, flexible, and biocompatible. GalaFLEX Scaffold is comprised of high-strength, resorbable P4HB monofilament fibers. It is a knitted macroporous scaffold intended to elevate, reinforce, and repair soft tissue. The scaffold acts as a lattice for new tissue growth, which is rapidly vascularized and becomes fully integrated with adjacent tissue as the fibers resorb. In this review, we describe the development of P4HB, its production, properties, safety, and biocompatibility of devices made from P4HB. Early clinical results and current clinical applications of products made from P4HB are also discussed. The results of post-market clinical studies evaluating the GalaFLEX Scaffold in rhytidectomy and cosmetic breast surgery demonstrate that the scaffold can reinforce lifted soft tissue, resulting in persistent surgical results in the face and neck at one year, and provide lower pole stability after breast lift at one year.

Biocompatibility of biodegradable polymeric stents in an interventional porcine carotid artery model

Biodegradable polymeric stents (PLLA/P4HB) and permanent bare-metal stents (316L) were implanted interventionally into both common carotid arteries (CCA) of 6 female pigs via the left common iliac artery (8F-sheath). The stents were mounted on a balloon catheter (5.0x40 mm), and balloon-expanded with either 8 bar (PLLA/P4HB) or 9 bar (316L). The pigs were administered peroral aspirin (100 mg) and clopidogrel (75 mg) starting 5 days before the procedure until the end of the study. Stented CCA segments were explanted after 4 weeks, and processed for quantitative histomorphometry, and estimation of vascular inflammation and injury scores.