Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-03-03
2003-02-04
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S425000, C424S501000, C424S502000
Reexamination Certificate
active
06514515
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to bioabsorbable, biocompatible polymers and methods for making devices for tissue engineering and tissue regeneration from these materials.
BACKGROUND TO THE INVENTION
During the last 20 to 30 years, several bioabsorbable, biocompatible polymers have been developed for use in medical devices, and approved for use by the U.S. Food and Drug Administration (FDA). These FDA approved materials include polyglycolic acid (PGA), polylactic acid (PLA), Polyglactin 910 (comprising a 9:1 ratio of glycolide per lactide unit, and known also as VICRYL™), polyglyconate (comprising a 9:1 ratio of glycolide per trimethylene carbonate unit, and known also as MAXON™), and polydioxanone (PDS). In general, these materials biodegrade in vivo in a matter of months, although certain more crystalline forms biodegrade more slowly. These materials have been used in orthopedic applications, wound healing applications, and extensively in sutures after processing into fibers. More recently, some of these polymers also have been used in tissue engineering applications.
Tissue engineering has emerged as a multi-disciplinary field combining biology, materials science, and surgical reconstruction, to provide living tissue products that restore, maintain, or improve tissue function. The need for this approach has arisen primarily out of a lack of donor organs and tissues, but also because it offers the promise of being able to dramatically expand the ability to repair tissues and develop improved surgical procedures.
In general, three distinct approaches currently are used to engineer new tissue. These are (1) infusion of isolated cells or cell substitutes, (2) use of tissue inducing materials and/or tissue regeneration scaffolds (sometimes referred to as guided tissue repair), and (3) implantation of cells seeded in scaffolds (either prior to or subsequent to implantation). In the third case, the scaffolds may be configured either in a closed manner to protect the implanted cells from the body's immune system, or in an open manner so that the new cells can be incorporated into the body.
In open scaffold systems and guided tissue repair, tissue engineering devices have normally been fabricated from natural protein polymers such as collagen, or from the synthetic polymers listed above, which in both cases degrade over time and are replaced by new tissue. While some of these materials have proven to be good substrates for cell and tissue growth, and provide good scaffolding to guide and organize the regeneration of certain tissues, they often do not have the specific mechanical requirements that the scaffold needs to provide until the new tissue is developed and able to take over these functions. These materials may also be difficult to process and fabricate into the desired form, handle poorly in the operating room, be difficult to suture, and sometimes fall apart prematurely. For example, it has been reported that tissue engineered heart valve leaflet scaffolds derived from polyglactin and PGA are too stiff and cause severe pulmonary stenosis when implanted in sheep (Shinoka, et al., “New frontiers in tissue engineering: tissue engineered heart valves” in
Synthetic Bioabsorbable Polymer Scaffolds
(Atala & Mooney, eds.) pp.187-98 (Birkhäuser, Boston, 1997)).
FIG. 1
, which plots the tensile strength and elongation to break values for representative FDA approved (compression molded) bioabsorbable biocompatible polymers against these values for different tissue structures, reveals a significant mismatch between the mechanical properties of these polymers and the different tissue structures. In particular, it is apparent that the existing bioabsorbable biocompatible polymers are stiff, inelastic materials, with elongations to break of around 25%, yet many tissues are much more flexible, elastic, and have longer elongation to break values. Accordingly, the biomaterial products currently used in temporary scaffolds for regenerating human tissues do not exhibit the same multi-axial physical and mechanical properties as native tissues, which are hierarchical, three-dimensional structures (see abstract of an award by the Advanced Technology Program to Johnson and Johnson Corporate Biomaterials Center, October 1997).
Attempts have been made to develop new bioabsorbable biocompatible polymers with more flexible, elastomeric properties. One approach has been to incorporate lactide or glycolide and caprolactone joined by a lysine-based diisocyante into a polyurethane (Lamba, et al., “Degradation of polyurethanes” in
Polyurethanes in Biomedical Applications,
pp.199-200 (CRC Press LLC, Boca Raton, Fla., 1998). However, these crosslinked polyurethane networks cannot be processed by standard techniques such as solution casting or melt processing, limiting their usefulness. There is also no evidence that the polyurethane segments are completely biodegraded in vivo. A commercial material, known as TONE™, has also been evaluated as an elastomeric implant material. However, this material degrades in vivo very slowly, and therefore has limited application (Perrin, et al., “Polycaprolactone” in
Handbook of Bioabsorbable Polymers
(Domb, et al., eds.) pp.63-76 (Harwood, Amsterdam, 1997)). Another approach has been to synthesize protein-based polymers, particularly polymers containing elastomeric polypeptide sequences (Wong, et al., “Synthesis and properties of bioabsorbable polymers used as synthetic matrices for tissue engineering” in
Synthetic Bioabsorbable Polymer Scaffolds
(Atala & Mooney, eds.) pp.51-82 (Birkhäuser, Boston, 1997). However, these materials are not reported to biodegrade in vivo, although cells can invade matrices derived from these materials. They also lack the advantages of thermoplastic polymers in fabrication of devices.
U.S. Pat. Nos. 5,468,253 and 5,713,920, both to Bezwada et al., disclose bioabsorbable elastomeric materials which are used to form devices that, based on in vitro data, are alleged to completely bioabsorb within one year or six months. However, deGroot et al., Biomaterials, 18:613-22 (1997) provides in vivo data for these materials and reports that the implanted material fragmented after 56 weeks into white crystalline-like fragments. It is suspected that these fragments are crystalline poly-L-lactide, which is very slow to degrade. Nonetheless, whatever the composition of the fragments, the material is not completely bioabsorbed after one year in vivo. These materials also typically are difficult to process and may have poor shelf stability.
Thus, while the current bioabsorbable biocompatible polymers offer a range of useful properties for certain medical applications, it is desirable to develop methods to prepare bioabsorbable biocompatible polymers that significantly extend the range of properties available. It would thus be desirable to develop methods for preparing bioabsorbable biocompatible polymers with mechanical properties closer to those of tissue, particularly soft tissues. It would also be desirable to develop methods for making bioabsorbable biocompatible materials which can be readily processed, and fabricated into tissue engineering devices that can be easily implanted.
It is therefore an object of this invention to provide methods for preparing bioabsorbable biocompatible polymers with mechanical properties that provide a better match with those of tissue structures.
It is a further object of this invention to provide new compositions with mechanical properties that provide a better match with those of tissue structures.
It is another object of this invention to provide methods for fabricating devices from these compositions.
SUMMARY OF THE INVENTION
Bioabsorbable biocompatible polymers are selected based on their physical and/or mechanical properties to correspond to the physical properties of tissues to be regenerated or constructed. Physical properties include elasticity, strength, flexibility, and processibility. These properties can be measured by determining factors such as tensile strength, elo
Azpuru Carlos
Holland & Knight LLP
Tepha, Inc.
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