Buffered resorbable internal fixation devices and methods...

Details Buffered resorbable internal fixation devices and methods... Buffered resorbable internal fixation devices and methods...

1998-10-05

2002-07-16

Azpuru, Carlos A. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C514S772100, C514S772300, C514S772400

Reexamination Certificate

active

06419945

ABSTRACT:

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable
BACKGROUND OF THE INVENTION
The trend in internal fixation devices for repair of damaged bone is toward the use of resorbable, tissue compatible biopolymers. Biopolymers such as poly(glycolic acid) (PGA), poly(lactide) (PLA), and copolymers of lactic and glycolic acids, (poly(lactide-co-glycolide) or PLGA) have been used in the production of internal fixation devices, such as screws, pins, and rods to hold bone together following surgery, or to repair broken bones. Other polymers, such as poly(dioxanone) , have also been considered for use in the manufacture of surgical internal fixation devices. However, it has been observed that tissue response to resorbable implants fabricated from these biopolymers is not uniformly acceptable (Bostman, J. Bone and Joint Surg. 73, 148-153 (1991)).
The tissue response to biopolymer-based implants has been well documented. Late sterile inflammatory foreign body response (sterile abscess) has been reported in about 8% of fractures repaired with these polymers (Bostman, supra). In a randomized study of 56 open reduction and internal fixation of malleolar fractures of the ankle with metal ASIF screws and plates or with rods of PLGA, two cases of sterile inflammatory wound sinus were observed 3 to 4 months after the operation in the injuries fixed with the polymer rods (Rokkanen et al., Lancet 1, 1422-1425 (1985); Bostman et al., J. Bone and Joint Surg., 69-B(4), 615-619 (1987)). Other studies have also documented an inflammatory reaction following implantation of PGA or PLGA fixation devices. The fraction of patients suffering from this reaction ranges from 4.6 to 22.5% (Bostman et al., Clin. Orthop. 238, 195-203 (1989); Bostman et al., Internat. Orthop. 14, 1-8 (1990); Hirvensalo et al., Acta Orthop. Scandinavica, Supplementum 227, 78-79 (1988); Hoffman et al., Unfallchirurgie 92, 430-434 (1989); Partio et al., Acta Orthop. Scandinavica, Supplementum 237, 43-44 (1990); Bostman et al., Internat. Orthop. 14, 1-8 (1990)). The inflammatory reaction is not limited to poly(glycolide) polymers. Internal fixation devices made from poly(lactide) have also been observed to exhibit an inflammatory reaction. Eitenmuller et al. reports that 9 of 19 patients (47.7%) who had fractures of the ankle treated with absorbable plates and screws of poly(lactide) had an inflammatory response. (J. Eitenmuller, A. David, A. Pomoner, and G. Muhyr: “Die Versorgung von Sprunggelenlzsfrakturen unter Verwendung von Platten und Schrauben aus resorbserbarem Polymermaterial”, Read at Jahrestagung der Deutschen Gesellschaft fur Unfallheilkunde, Berlin, Nov. 22, 1989).
In vitro studies have been performed to monitor pH changes as well as weight loss and the appearance of lactic acid from screws fabricated from poly(lactide-co-glycolide) with a lactide:glycolide ratio of 85:15. (Vert et al., J. Controlled Release 16, 15-26 (1991)). An induction period of about ten weeks was observed before any significant change in media pH or weight loss occurred. This time period corresponds to the induction periods of seven to twenty weeks noted by clinicians. However, no attempt has been made to alleviate the source of inflammation.
BRIEF SUMMARY OF THE INVENTION
The invention is a bioerodible, or resorbable, implantable material, and devices made therefrom, comprising a bioerodible polymer that produces acidic products or low molecular weight resorbable fragments upon hydrolytic degradation, and a neutralization or buffering compound included in sufficiently high concentration to buffer the acidic products and maintain the local pH within a desired range or to decrease the rate of pH change as the implantable material degrades. The buffer compound incorporated into the material of the invention acts to neutralize the acidic degradation products which cause inflammatory foreign body response upon degradation of the bioerodible polymer. Thus, the invention reduces the sterile abscess condition that occurs in the bioerodible implant materials of the prior art.
Materials made according to the invention may be used for internal fixation devices (IFDs) for, e.g., the repair, replacement or reconstruction of damaged bone in any area of the body. For example, screws, pins and rods according to the invention are useful to hold bones together following surgery or to repair broken bones. An interbody spinal fusion device according to the invention can be used for spine repair. Bone graft devices according to the invention can be used to repair or reconstruct defects caused by surgery, tumors, trauma, implant revisions and infections, and also for joint fusion. Void filler devices according to the invention can be placed in the void created by removal of, e.g., a cyst or infected bone, or from trauma. A space-filling internal fixation device according to the invention can be prepared either ex situ or in situ, e.g., in the form of a space-filling, solidifying foam. Furthermore, IFDs according to the invention are also useful, e.g., as stents to separate or maintain the shape of blood vessels, as sutures or fibrous devices for incision repair, or for any other use that may benefit from the combination of a bioerodible polymer with a neutralization or buffering compound into an implantable internal fixation device.
The bioerodible materials and methods of the invention include a bioerodible polymer that forms acidic products as it degrades. The bioerodible polymer undergoes hydrolysis in the body and generates acidic products that cause irritation, inflammation, and swelling (sterile abscess formation) in the treated area. To counteract this effect, a neutralization compound, or buffer, is included in the bioerodible material to neutralize the acidic degradation products, or control the rate of pH decline, and thereby reduce the sterile abscess reaction. The neutralization compound included in the bioerodible material of the invention maintains the pH surrounding the area of surgery at approximately neutrality (i.e., pH 7), or any other pH chosen by the surgeon. Preferably, the pH is maintained in the range of 6-8, and more preferably in the range of 6.8-7.4. Alternatively, the neutralization compound controls the rate of acid production as the bioerodible material degrades, thereby serving to control the rate of pH decrease.
According to the invention, the bioerodible material includes a bioerodible polymer that undergoes hydrolysis to produce acidic products when exposed to an aqueous medium. In one preferred embodiment, the polymer poly(lactide-co-glycolide) (H[—OCHR—CO—]
n
OH, R═H, CH
3
) (PLGA) is used. The PLGA polymers used according to the invention have a lactide to glycolide ratio in the range of 0:100% to 100:0%, inclusive, i.e., the PLGA polymer can consist of 100% lactide, 100% glycolide, or any combination of lactide and glycolide residues. These polymers have the property of degrading hydrolytically to form lactic and glycolic acids. In another preferred embodiment, the bioerodible polymer is poly(propylene fumarate) (H[—O—CH(CH
3
)—CH
2
—O—CH═CH—CO—]
n
OH), which may be desirably crosslinked using vinyl monomers such as vinyl pyrrolidone (VP). An advantage of VP crosslinking of PPF is that the crosslinks terminate at hydrolytically labile fumarate ester bonds, making the crosslinked network hydrolytically degradable. Furthermore, the hydrolysis products are highly soluble. Other bioerodible polymers useful in the invention include polydioxanone, poly(&egr;-caprolactone); polyanhydrides; poly(ortho esters); copoly(ether-esters); polyamides; polylactones; and combinations thereof.
The neutralization or buffering compound included in the bioerodible material of the invention may be any salt, base, base-containing or base-generating material that is capable of reacting with the acidic products generated upon hydrolysis of the bioerodible polymer. Exemplary buffering materials that may be implemented according to the invention include the salts of inorganic acids, the salts of organic a

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