Polymer chemistry and material selection[ edit ] When investigating the selection of the polymer for biomedical applications, important criteria to consider are; The mechanical properties must match the application and remain sufficiently strong until the surrounding tissue has healed. The degradation time must match the time required. It does not invoke a toxic response. It is metabolized in the body after fulfilling its purpose. It is easily processable in the final product form with an acceptable shelf life and easily sterilized. Mechanical performance of a biodegradable polymer depends on various factors which include monomer selection, initiator selection, process conditions and the presence of additives.

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Langer, Howard Rosen, Robert J. Linhardt, and Kam Leong, which is a continuation of U. Langer, Edith Mathiowitz, Abraham J. Domb, and Cato T. Laurencin, which is a continuation-in-part of U. Laurencin, Paul A. Lucas, Glenn T. Syftestad, Abraham J. Domb, Julia Glowacki, and Robert S. Claims: 1. A method for delivering a bioactive molecule to bone comprising making a polymeric composition including as structural and functional components a polyanhydride, and bioactive molecules, and.

The method of claim 1 wherein the bioactive molecules are selected from the group consisting of antibiotics, chemotherapeutic agents, bone morphogenic factors, angiogenesis inhibitors, and bone growth factors. The method of claim 1 wherein the polyanhydride is selected to degrade over a period of less than approximately a year. The method of claim 1 further comprising mixing bioactive molecules with the polyanhydride and implanting the material in bone. The method of claim 1 further comprising mixing filler materials with polyanhydride to increase the structural strength of the polyanhydride.

The method of claim 1 for treatment of tumors comprising removing tumor material and implanting the polyanhydride-bioactive molecules in place thereof. The method of claim 1 further comprising mixing the polyanhydride and bioactive material with structural and adhesive materials to form a bond cement. A method for delivering a bioactive molecule to bone comprising making a polyanhydride composition including as structural and functional components: a polyanhydride and bioactive molecules, in a bone cement.

Description: This relates to a method and polymeric compositions for treatment of infection in bone. Osteomyelitis, both in its acute and chronic forms, remains a difficult disease entity to treat.

In acute osteomyelitis, a rapidly progressing infection of bone takes place, with involvement of the medullary space, cortex, or periosteum.

The chronic form of osteomyelitis consists of a more longstanding type of bone infection characterized by low-grade inflammation, sequestra areas of dead bone , involucra shells of cortical bone resulting from periosteal elevation due to an inflammatory focus , fistula and bone sclerosis.

Three basic mechanisms by which osteomyelitis occurs have been identified: hematogenous spread, spread from a contiguous focus such as sinuses and teeth , and direct bacterial seeding as a result of trauma, or operative procedure. The microorganism most often responsible for clinical infections is Staphylococcus aureus.

Antibiotics have continued to be the mainstay of treatment for osteomyelitis. Moreover, in most cases, chronic osteomyelitis can only be treated using surgical debridement in combination with antibiotic therapy. Even with surgery, eradication of the disease is not assured. The drawbacks in conventional antibiotic therapy to bone are manifold. Accordingly, the systemic levels of antibiotics used to treat infections can result in serious toxicity to various organ systems.

Further, in conventional therapy, antibiotics must be administered for many weeks in order to effect a cure. Costs to the health care system and to society for close monitoring of intravenous antibiotic therapy in the hospital or outpatient setting, for expensive antibiotics which are excreted before reaching the diseased bone, and for morbidity and mortality due to failure of eradication of disease are considerable.

Controlled local release from implanted carriers has been advocated as a technique for achieving high local antibiotic concentrations while maintaining low systemic levels. Polymethylmethacrylate PMKA bone cement loaded with antibiotics has been used clinically since , principally for fixation of hip replacement components to bone.

Numerous in vitro, animal, and human studies have measured effective local release of antibiotics by PMMA. See, for example, Bayston, et al. Bone Joint Surg.

When used prophylactically, such as in hip arthroplasty patients, PMMA mixed with antibiotics is injected in moldable form and allowed to harden in vivo. The risk of a persistent infection is low, and the prosthetic components require the cement for stabilization.

However, because PMMA is inert and acts as a foreign body, a second surgical procedure is required for its removal in established infections. Thus, for treatment of osteomyelitis, PMMA is first formed into beads to facilitate subsequent removal several weeks after implantation, as described by Majid, et al.

The size and fixed shape of the beads keeps them from penetrating into the smaller interstices of the wound cavity, and thus undesirably lengthens the diffusion path that antibiotics must travel in order to reach the infected tissue. In order to avoid the drawbacks inherent with PMMA when treating established infections, biodegradable materials such as plaster of paris and bone graft have been proposed for use as carrier materials for antibiotics Mackey, et al.

Paul, Minn. These would require no second procedure for removal, and could permit more intimate and complete filling of the wound cavity. Gerhart, et al. This cement is initially moldable and polymerizes in vivo, and could potentially supply some structural support prior to degrading.

However, there is the problem of residual toxic methacrylate monomer being released as the bone cement degrades. It is therefore an object of the present invention to provide biodegradable compositions, and methods for use thereof, for controlled administration of bioactive materials to bone. It is a further object of the present invention to provide biodegradable compositions which completely degrade in vivo over a physiologically useful period of time into completely non-toxic residues.

It is another object of the present invention to provide compositions which show greater clinical efficacy in the treatment of bone disease, as compared to conventional localized treatment. SUMMARY OF THE INVENTION Bioerodible polymers which degrade completely into nontoxic residues over a clinically useful period of time, including polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, and copolymers thereof, are used for the delivery of bioactive agents, including antibiotics, chemotherapeutic agents, inhibitors of angiogenesis, and simulators of bone growth, directly into bone.

The preferred polymers are polyanhydrides. In one example, polyanhydride copolymers were used for the treatment of clinical infections in long bones. Rats were quantitatively infected with a virulent strain of Staphylococcus aureus. After 10 weeks, rats were sacrificed and remaining bacteria were measured.

The bioerodible polyanhydride delivery system effectively treated the osteomyelitis with results showing significantly greater levels of bacteria reduction in tibia than conventional systems of gentamicin delivery in bone using polymethylmethacrylate or polypropylene fumarate-methylmethacrylate bone cements.

A variety of polymers can be used to form the implant for purposes of delivering bioactive molecules to bone. The polymers must be biocompatible. As used herein, biocompatible means that the polymer is non-toxic, non-mutagenic, elicits minimal to moderate inflammatory reaction, and completely degrades in a controlled manner into non-toxic residues. In the preferred embodiment, surface erodible polymers such as polyanhydrides or polyorthoesters are used.

Alternatively, other polymers such as polylactic acid and polyglycolic acid can also be used. The composition of the polymer, as well as the molecular weight and physical properties, can be varied according to the application.

For example, more hydrophobic polyanhydrides can be used where it is desirable to increase the time of degradation. Compounds can be mixed into or polymerized with the polymer as required for additional strength or other desirable physical properties, using materials known to those skilled in the art from studies involving bone cements.

For example, tricalicum phosphate or other ceramic type materials that provide increased physical strength can be added to the composition. In general, for repair of bone breaks, the polymer should release material over a period of approximately four to twelve weeks generally twelve weeks in a human for sufficient repair to occur for the bone to become weight bearing.

The polymer should also degrade completely over a period no longer than about sixteen to twenty weeks. Release and degradation times for treatment of bone tumors and infections have to be determined on an individual basis. The time will depend in part upon what materials are to be released from the polymer. Many polymers are biodegradable if left in vivo for a sufficiently long period of time.

Others have such a long period for degradation that they are not generally termed "biodegradable". Polymethylmethacrylate PMMA is not biodegradable. Further, neither polymer effects controlled release. Ethylene vinyl acetate is also of limited value since it degrades over a period of as long as four years for a relatively thin disk. The polymers can be mixed with or used to encapsulate the bioactive molecules using methods known to those skilled in the art, including mixing polymer particles and compressing, solvent casting, and microencapsulation within polymer in combination with a matrix for delivery.

Examples of useful bioactive molecules include antibiotics such as gentamicin and vancomycin, bone morphogenic factors, bone growth factors such as IGF1, and compounds for treatment of bone tumors, such as angiogenesis inhibitors and chemotherapeutic agents. The polymers such as the polyanhydrides are particularly well adapted for delivery of molecules such as the water soluble molecules described in co-pending U.

The polymeric delivery devices have many advantages over the prior art bone cements, PMMA-drug implants, and systemic administration of antibiotics or chemotherapeutic agents. The release is much more site-specific. Release occurs in a controlled manner over a predetermined period of time. Compounds can be delivered in combination, even using different types of polymers having staggered degradation times to effect release of the compounds in a particular sequence.

The devices completely degrade over relatively short times, ranging from days to a few weeks or months, into non-toxic residues. Fillers and modifications of chemical composition can be used to enhance the strength of the polymer and therefore facilitate restoration of weight bearing capacity. Polymer can be used to fill space and encourage bone growth while inhibiting vascularization or reoccurrence of a tumor.

The present invention is further described with reference to the following non-limiting examples. Osteomyelitis cannot be reliably created in experimental animals unless foreign or necrotic material is present.

Investigators have used sodium morrhuate to create a necrotic focus to potentiate bone infections in rabbits and rats. Others have placed foreign bodies such as stainless steel pins in rabbit, or acrylic cement in rat or dog tibias respectively, to establish an infection. A preferred method uses a modification of an animal model described by Elson, et al.

High speed drilling of the tibia is used to create a small region of necrosis at an inoculation site. PMMA implants are placed into the drilled holes to act as foreign bodies for three weeks, at which time they are removed. Staphylococcal infection is reliably produced in all animals, as indicated clinically by abscesses and draining sinuses. Osteomyelitis was established by inoculating S. The infections were serially evaluated by clinical and radiographic examination, and by quantitative culture for colony forming units CFU , at time of sacrifice.

For treatment, cements containing antibiotic were implanted for 3 weeks. The CFU geometric mean for sites treated with biodegradable cement containing antibiotics 1. Prophylactically treated sites developed no clinically apparent infections 0.

The three week treatment period may have been too short to realize the full theoretical advantages of a biodegradable carrier for controlled antibiotic release. Materials and Methods Osteomyelitis Model.


US8501216B2 - Bioerodible polymers for injection - Google Patents



Synthetic biodegradable polymer


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