ABSORB GREEN BACKGROUND 640 X 480
Bioresorbable polymers, also referred to as bioresorbable or degradable polymers, are polymer materials which can be safely absorbed by the body so that the materials from which a construction is made disappear over time.
The following report examines bioresorbables from the following perpectives—compounding, mechanical properties and degradation times; moulding and extrusion; degradation testing; additive manufacturing of resorbable tissue engineering scaffolds; Absorb—the first ever resorbable stent; Purac glass fibre composites; supercritical CO2 sterilisation; and coloration.
The most common bioresorbable polymer is polylactic acid (PLA), also known as polylactide, and is made from a lactide monomer. Generally speaking, PLA is the main building block for bioresorbable polymer materials. Common derivatives of PLA are poly-L-lactide (PLLA), poly-D-lactide (PDLA) and poly-DL-lactide (PDLLA). When in the body, PLA degrades into lactic acid, a non-toxic chemical which occurs naturally in the body.
Polyglycolic acid (PGA), or polyglycolide (PG), is another type of bioresorbable polymer usually used for bioresorbable sutures. The material can be copolymerised with lactic acid to form to form poly(lactic-co-glycolic acid), or PLGA, with e-caprolactone to form poly(glycolide-co-caprolactone), or PGCL, and with trimethylene carbonate to form poly(glycolide-co-trimethylene carbonate), or (PGA-co-TMC). PGA degrades to form glycolic acid.
Compounding, Mechanical Properties and Degradation Times
The mechanical properties and degradation time of a bioresorbable device can be tailored to a specific application by adjusting the molecular weight, crystallinity and hydrophilicity of the polymer. This is achieved by varying the percentage of polylactide D or L forms, and polyglycolide. Tony Listro, managing director of specialist US medical polymer compounder Foster Delivery Science explains: “Compositions with higher hydrophilic and amorphous structures and a lower molecular weight resorb faster, yet often sacrifice mechanical strength. Conversely, higher crystallinity and molecular weight improve mechanical properties and decrease resorption rates.”
Bone growth additives, such as tricalcium phosphate (TCP) or hydroxyapetite acid (HA) can be melt blended into these polymers to enhance bone growth during degradation. Additionally, the low melt temperatures of many bioresorbable polymers allows for melt blending active pharmaceutical ingredients (APIs) for controlled-release drug delivery during degradation. However, higher molecular weight polymers often require higher melt temperatures and thus limit melt blending of some APIs with low degradation temperatures.
Twin screw extruders optimise bioresorbable polymer blending, including distribution and dispersion of additives. Due to the high cost of bioresorbable polymers, which can often exceed US$1,000 per lb (US$2,200 per kg) and the relatively small nature of the implantable applications, small scale twin screw extruders—between 16 mm and 27 mm—are ideal. Since these polymers begin degradation when exposed to moisture, desiccant and vacuum driers are required prior to melt blending. Unlike non-resorbable polymers that are often water cooled upon exiting the extruder in strand form, bioresorbable compounds must be air cooled. Pelletised strands destined for finished device processing must be thoroughly dried and properly packaged to prevent exposure to air moisture that can cause premature degradation.
Moulding and Extrusion Considerations
The processing of bioresorbable polymers must be handled with care. The materials themselves are highly hydrophilic, which is to say that they love water and will absorb any moisture with which they come into contact. Unless properly dry, the materials will not melt and recrystallise as expected, making moulding and extrusion difficult. At the same time, bioresorbable polymers are sensitive to heat, and molecular structures can be damaged through exposure to excessive temperatures during drying.
With this in mind, careful and thorough drying at low temperatures is needed, while the humidity of the processing environment must be considered.
Knowing the melt and recrystallisation behaviour of bioresorbable materials is important, as is understanding the melt flow viscosity. Often materials will have a low melt temperature, a high crystallisation temperature and generally be extremely viscous—like hot honey—except at a small temperature range between the two. This means that there is a very small temperature range at which materials can be processed—that is to say, the range at which the material is molten, at which the viscosity is at the right level for injection moulding or extrusion, and at which the material won’t crystallise prematurely.
Due to their delicate molecular structures, bioresorbable polymers are limited in terms of the amount of time they can remain molten, so cycle times must be kept within this range, which is often not very long.
Degradation Testing of Bioresorbable Medical Devices
On November 28, 2012, the FDA held a public workshop on the testing of bioresorbable medical devices at its White Oak campus in Silver Spring, Maryland, USA.
The workshop, entitled Workshop on Absorbable Medical Devices: Lessons Learned From Correlations of Bench Testing and Clinical Performance, was co-sponsored by ASTM (American Society for Testing and Materials) International, a US organisation responsible for the development and delivery of international voluntary consensus standards for engineered products, including medical devices.
The purpose of the workshop was to provide a forum for highlighting and discussing the use of bioresorbable materials in medical devices across a broad range of indications with the aim of defining successful and unsuccessful methods to predict clinical performance.
The main topics discussed included identification of test methods for establishing correlations between in vitro and in vivo degradation of absorbable implantable devices, and the interaction of mechanical loading and mechanical performance with degradation. While there was an emphasis on cardiovascular indications as part of a panel session, characterisation techniques and experiences from both cardiovascular as well as non-cardiovascular devices were discussed and encouraged.
Additive Manufacturing of Resorbable Tissue Engineering Scaffolds
Additive manufacturing is being used to produce scaffolds for tissue engineering from bioresorbable polymers. A number of years back, researchers from A Star, a leading Singaporean research institution, successfully developed a technology for fabricating resorbable polymeric tissue scaffolds with high strength and porosity using additive manufacturing. Dr Margam Chandrasekaran (Chandra), now CEO and chief scientist at Singapore-based tissue engineering scaffold manufacturer Bioscaffold International, was one of the lead inventors of the technology. Along with a team of clinicians at the National University of Singapore, at A Star Chandra developed an application of the technology to produce a commerical product for high strength resorbable dental scaffolds using additive manufacturing.
Chandra explains: “We used a combination of PLGA with PVA and changed the binder used in the 3D printing process to produce parts in a desired shape and then used a post processing technique similar to particulate leaching to strengthen the structure. In fact, besides PLGA, we did work on PCL, PLA and PGA. A paper was published in 2007 in the Journal of Materials Processing and Technology.”
Today, Chandra’s company manufactures implantable tissue engineering scaffolds for dentists made from PLGA. The scaffolds are used by dentists to preserve tooth sockets following removal of a tooth. The implant encourages bone growth, thereby preserving the socket while the gums heal. This means that any further restorative procedures, such as dentures or implantable false tooth fittings, are vastly improved.
Another resorbable scaffold application, manufactured in the USA by tissue engineering device pioneer 3D Biotek, is a three dimensional PLGA-based degradable porous cell culture device for medical research processes. The device is special because its three dimensional nature allows cells to grow in three dimensions. Its 100% porous nature allows cells to be seeded very easily. Because PLGA is biocompatible, the scaffolds, with or without cells, can be implanted into animals. Degradation time is approximately 4-5 months.
Germany-headquartered 3D printer supplier EnvisionTec’s 3D-Bioplotter is an all-purpose direct manufacturing tissue engineering machine for the production of hard and soft scaffolds from biomaterials, cells as well as synthetic materials. It is specially designed to process a large range of materials, from hard polymers, through ceramic pastes to soft hydrogels.
According to EnvisionTec, the 3D-Bioplotter is specially designed for work in sterile environments in a laminar flow box, a requirement of biofabrication, for example when using alginate cell suspensions for the construction of cell-laden scaffolds. Additionally, the 3D-Bioplotter can use up to five different tools per job. This means that scaffolds fabricated using the 3D-Bioplotter can have up to five different materials, or five different types of cells in specific positions.
In contrast to other rapid prototyping techniques the 3D-Bioplotter, EnvisionTec says, uses a very simple and straightforward technology, invented in 1999 at the Freiburg Materials Research Centre in Germany. The manufacturing process works by air pressure being applied to a liquid and liquefied material, which solidifies upon dispensing.
The 3D-Bioplotter is delivered together with a PC workstation which operates and monitors the system. After transferring the 3D CAD data to the PC it is processed by the Bioplotter’s software package. The preprocessed data is then transferred to the 3D-Bioplotter using a network connection. The Bioplotter software monitors the working process until it is completed.
Abbot Launches First Ever Bioresorbable Vascular Scaffold
USA-headquartered Abbott, one of the world's leading medical device OEMs with 91,000 employees, has launched Absorb (pictured), the first fully resorbable drug eluting vascular scaffold.
Absorb is available for use by clinicians in treating coronary artery disease (CAD) across Europe, Asia Pacific and Latin America. It works by restoring blood flow to the heart—similar to a metallic stent—but instead of being permanent it dissolves into the body. After dissolution it leaves behind a treated vessel that may resume more natural function and movement because it is free of a permanent metallic stent.
In order to create the backbone of the device, PLLA resin is extruded into a tube, then radially and axially expanded in a process that resembles stretch blow moulding. The scaffold pattern is then cut with a laser, and the finished product is coated with a drug and polymer mixture and crimped onto a catheter before being packaged and sterilised.
According to Abbott, PLLA has an intrinsic degradation rate that is influenced in vivo by very few factors. Device performance over its degradation lifecycle is tuned to match physiological requirements for vessel support. The polylactide molecular weight in the finished product and the degradation rate govern this performance.
The potential long term benefits of a scaffold that dissolves are significant. The vessel may expand and contract as needed to increase the flow of blood to the heart in response to normal activities such as exercising. Treatment and diagnostic options are broadened. The need for long-term treatment with anti-clotting medications may be reduced. And future interventions would be unobstructed by a permanent implant.
“This innovation represents a true paradigm shift in how we treat coronary artery disease,” said Patrick W Serruys, a medical doctor and professor of interventional cardiology at the Thoraxcentre, Erasmus University Hospital, Rotterdam, the Netherlands. He added: “With the launch of Absorb, a scaffold that disappears after doing its job is no longer a dream, but a reality.”
Absorb is now available in a broad size matrix to support the needs of physicians treating patients with CAD. There are 7 sizes available—varying in length from 12 mm to 28 mm and in diameter from 2.5 mm to 3.5 mm. The strut thickness and width are approximately 150 µm and 180 µm respectively.
At the time of going to press, Absorb is neither approved nor authorised for sale and currently is in development with no regulatory status in the United States.
Bioresorbable Glass Fibre Composites for Load Bearing
In August 2012, Netherlands-based bioresorbable polymer manufacturer and owner of the Purasorb brand of medical resorbable polymers Purac acquired FiberLive, an advanced resorbable glass fibre composite technology. The acquisition included the intellectual property of the FiberLive technology and its key personnel.
According to Purac, FiberLive is a unique patented composite consisting of a matrix of resorbable silica-based glass fibres and resorbable polymers, forming an exceptionally strong resorbable composite material—up to six times stronger than cortical bone. This unique composite material widens possibilities to use resorbable materials into the fields of bone fixation, where in the past it has been impossible due to a lack of load-bearing properties of conventional biopolymers. The material can be used in different kinds of orthopaedic treatments, including craniomaxillofacial (skull and jaw), sports medicine, trauma and spinal procedures.
When commenting on the acquisition, Menno Lammers, managing director Purac Biomaterials, said: “This technology will be a game changer in the orthopaedic resorbable market, where load bearing properties are needed. The FiberLive technology is the strongest fully resorbable material available for human implants, with strength up to six times higher than cortical bone, comparable to metal. For decades Purac Biomaterial has been the leading company in the field of medical resorbable polymer materials having strong commitment and enthusiasm towards innovation and development in the field. With the acquisition of this innovative resorbable composite material we are able to further widen our capabilities to serve our customers according to their requirements.”
The Purasorb brand of resorbable polymers covers a broad range of grades, including polymers—poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-DL-lactide (PDLLA), polyglycolide (PG), polycaprolactone (PCL)—and copolymers L-lactide/DL-lactide (PLDL), L-lactide/D-lactide (PLD), L-lactide/glycolide (PLG), L-lactide/captrolactone (PLC) and DL-lactide/glycolide (PDLG). The company also offers custom synthesis of bioresorbable polymers.
Supercritical CO2 Sterilisation of Bioabsorbable Polymer Devices>br> A team of researchers at NovaSterilis, a supplier of supercritical carbon dioxide (scCO2) sterilisation technologies and equipment based in the state of New York, working with Dr Chih-Chang Chu, a professor from Cornell University (Ithaca, NY), have developed a novel process for sterilising devices made from bioresorbable polymers using scCO2. The technology is being distributed in Europe by European Medical Contract Manufacturer (EMCM) based in Nijmegen, The Netherlands.
According to a poster presentation from the team displayed at the Ninth World Biomaterials Congress in China in June 2012, which reported the feasibility of NovaSterilis’s scCO2 sterilisation method for an absorbable suture, scCO2 is preferable to ethylene oxide when sterilising bioresorbable devices for a number of reasons, as follows.
Devices can be processed at low pressure and temperature, which reduces costs and energy requirements. Low temperature processing makes it ideal for specialist bioresorbable devices due to their highly sensitive molecular structure (as explained earlier). Furthermore, the CO2 molecule has a low surface tension which also reduces the likelihood of damaging delicate molecular structures commonly found in bioresorbable materials.
The fact that scCO2 sterilisation can be used to sterilise in between the pores of a material—it is said to penetrate deeply into a substance—plays perfectly into the hands of bioresorbable polymer devices as by their very nature they are very porous. The poster points to the fact that spores can live in the pores of the material and the method can get right between the microscopic holes to ensure they are completely sterile. Furthermore, reinforcing the delicate nature of the method, the scCO2 can penetrate inside the spore and oxidise it to render it inactive, which means that when the spore is killed, there is little or no effect on the delicate surrounding material.
Sterilisation can be done inhouse as there are low capital expenditures required, meaning that device manufacturers can retain full control and sight of their products during sterilisation. Furthermore, the time taken for this method is much shorter than traditional ethylene oxide—according to NovaSterilis president and CEO David C Burns, “you are talking minutes to hours rather than hours to days”.
Residual chemicals are non existent or negligible following sterilisation. Any that do remain are non-toxic as confirmed by toxicity testing.
ScCO2 sterilisation is a new technology. The first 510k submission is expected within the next 12 months. Four companies are currently using the technology to sterilise allograft tissue because of its gentle effect on collagen (biopolymer)—three in the USA and one in Australia.
According to David C Burns, president and CEO NovaSterilis: “Today’s highly technical products require very specialised handling, including sterilisation in smaller batches. Moreover, the desire to maintain custody of product is more important to many of our customers.”
The NovaSterilis scCO2 process is said to be safe for many polymers, allograft tissues, plastics, and surgical metals. NovaSterilis manufactures 20-litre and 80-litre fully automated, computerised, and network capable sterilisation units. Designed with a small footprint, these units are ideal for biomedical material companies that require high value and flexibility. NovaSterilis provides supportive technical services, assisting customers to determine if this process is appropriate for specific products, establishing cycle times and developing validation and regulatory plans.
In 2007 NovaSterilis won the Presidential Green Chemistry Challenge Award Presented by the US Environmental Protection Agency.
Profile of a Bioresorbable Expert: Degradable Solutions, Switzerland
Degradable Solutions (DS), based in Switzerland, manufactures a number of bioresorbable products. The company is a spin-off from the Swiss Federal Institute of Technology Zurich (Eidgenössische Technische Hochschule Zürich—ETH) and was taken over in November 2011 by Swiss oral care device manufacturer Sunstar Group. It is a technological leader in its field and has extensive experience of working with bioresorbable polymers. Two areas of interest are bone graft substitutes and tissue fixation devices.
Bone graft substitutes are sold under the brand name easy-graft and are the company’s most important product. Easy-graft consists of resorbable granules of calcium phosphate which have been coated with polylactic acid. The granules are injected into parts of the body where bone needs to grow, particularly broken bones and teeth. An activator liquid is added to the granules just before injection. The activator causes the polylactic acid coatings to form a sticky putty which allows the granules to be applied directly through a syringe.
When in contact with blood, the biomaterial solidifies and forms a defect-analogue, mechanically stable mass of material which is porous and will be replaced by bone tissue over time.
This occurs thanks to the fact that the calcium phosphate degrades over time, allowing bone cells to grow in and around the calcium phosphate granules as they degrade. DS is also talking about incorporating active pharmaceutical ingredients into the material, such as doxycycline antibiotics and cell growth substances.
The process whereby these granules are made is an inhouse developed proprietary process of DS. The materials start out as soft porous granules of tricalcium phosphate (TCP). Then using a sintering process, the granules are hardened and coated with PLA before being packaged into easy-to-use kits ready for orthopaedic surgeons.
Tissue fixation implants are injection moulded degradable PLA-based components for fixing tissue in place during surgery. Processed by closely controlling cycle times and temperatures, DS manufactures a range of devices, including cages for spinal applications, knee interference screws, small pins for foot surgery, implants for cranioplasty and suture anchors for shoulders. In this area, the company offers full device development and manufacturing services, including design and development, manufacturing, packaging, sterilisation, registration as well as development and manufacture of the instruments required for application.
Visibility of small transparent implantable devices can be difficult intra operatively. Coloured devices can support precision and quality control of the surgeon. Bioresorbable colours are another product offering of DS. The company is an expert at integrating FDA approved implantable colours into bioresorbable devices. The issue with pigments in implantable devices is that there are very few suppliers of biocompatible colours. DS has secured the supply of compliant pigments.