Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Method or apparatus for preparing biological material – Bone
Reexamination Certificate
2000-06-15
2003-08-05
Isabella, David J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Method or apparatus for preparing biological material
Bone
C623S023490, C623S016110
Reexamination Certificate
active
06602296
ABSTRACT:
The present invention provides bone and bone tissue supplemented with at least a therapeutically useful compound and in particular relates to a method for supplementing bone and or bone tissue with said compound(s).
Major allograft surgery has provided a solution to many reconstructive problems in musculoskeletal and maxillofacial surgery. The use of such surgery remains however, retarded by the frequency of infections that are often a disabling complication of such surgery. While the use of small frozen allografts has a very low rate of infection, major allografts have infection rates between 5 and 13%. This susceptibility to infection is probably multifactorial, with avascularity and antigenicity of the implanted graft contributing as well as the frequent extensive soft tissue excision, and potential for wound breakdown.
The use of allograft bone in orthopaedic practice is now well established both as morsellised and site specific structural grafts. The risk of infection, however remains a major complicating factor with such surgery. Like other forms of allograft surgery, the frequency of infection with allograft bone varies between 5 and 13.3%. The outcome in patients who develop infection is poor and often requires either two stage revision or amputation.
Infections typically arise early after allograft surgery with 75% of cases presenting within 4 months. Perioperative introduction of organisms is the presumptive mode of infection in the majority of these cases. The most common organisms isolated are gram positive (54%) followed by gram negative (36%) and mixed (10%).
Numerous attempts have been made to lessen the rate of infection in allograft surgery, particularly in the field of maxillofacial surgery. Perioperative antibiotic regimes are often employed, involving prolonged administration of antibiotics for up to 3 months, although no controlled studies have been performed to show the efficacy of these regimes. The theoretical problem of systemic antibiotic administration in allograft surgery, particularly when using allograft bone is that the allografts are initially avascular and the antibiotics do not reach their target.
Attempts have been made to load allograft bone with antibiotics. In one such study morsellised graft was mixed with antibiotic solutions. More recently antibiotic supplemented bone allograft has been developed and used in the area of avulsive defects of the oral and maxillofacial skeleton. This technique employs demineralised particulate allograft bone and mixes it with purified gelatine powder and cephalothin and tobramycin. A canine model to test this preparation has shown a probable protection from post-operative infection when compared with conventional allografts.
Although these methods have been shown to display a decreased complication rate, the problem of infection in major allograft bone surgery is still a major concern. Furthermore, present methods of preparing allograft bone against infection require a large amount of preparatory work, are typically unsuitable where large bone grafts are required and depending on the methods used may not result in a product that has the same structural integrity as allograft bone. Thus, the problem of infection in major allograft bone surgery is largely unsolved and has severe consequences to patients who develop complications.
The present invention seeks to provide an improved bone and or bone tissue supplemented with at least a therapeutically useful compound. Moreover, the invention seeks to provide a simple and effective procedure for supplementing bone and or bone tissue with at least a therapeutically effective compound.
Throughout the specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
For the purposes of the present invention the phrase “bone and bone tissue” encompasses bone substitutes which comprise any biological or synthetic material used to substitute for bone during reconstruction including material processed from xenograft sources and chemicals manufactured for bone substitute purposes such as calcium phosphate and hydroxyappatite.
The present invention consists in a bone or bone tissue supplemented with at least a therapeutically useful compound, wherein said compound is concentrated within the bone matrix.
Unlike prior art products the present invention does not rely upon the use of binders, protective agents, gelatinisation agents or the like to associate therapeutic compounds with allograft bone or tissue. Rather, therapeutically effective compounds are delivered to and concentrated with the bone matrix by a process of iontophoresis. Preferably the concentration of the therapeutically effective compound within the bone is greater than the amount of therapeutically effective compound that might be absorbed into bone as a result of simple diffusion. It will be appreciated that the relative amount of therapeutic compound which might be loaded into any particular piece of bone will depend on (a) the safe in situ usage limits for that therapeutic compound, (b) the characteristics of the bone or bone tissue, (c) the biochemical characteristics of the particular compound selected and (d) the particular purpose for which the bone or bone tissue is being used.
Therapeutically effective compounds that might be employed in the invention include, but are not limited to: antibiotics, antifungal compounds and chemotherapeutic compounds, tissue growth factors (for example bone morphogenic protein), non-steroidal anti-inflammatory agents, such as indomethacin, neuromuscular agents affecting calcium and bone metabolism (such as calcitonin), anti-viral agents, anti-tuberculosis agents (such as rifampicin), anthelmintic agents (such as mebendazole), antiseptic agents, vitamins and minerals. Most preferably, the compounds that are loaded into the bone are compounds that form a salt in solution and ionise to a single positive or negative ion. Those of ordinary skill in the art will know such compounds.
If, for example, antibiotics are to be loaded into the bone or bone tissue the antibiotic compound is preferably selected from the following: flucloxacillin, gentamicin, cephalothin, ticarcillin, ciprofloxacin, nenzl-peniccillin, cefoperazone, cefuroxime, cephazolin and tobramycin. Most preferably the antibiotic is either flucloxacillin or gentamicin. When loaded into bone these compounds are preferably present at a concentration of between the minimum inhibitory concentration of the antibiotic and the concentration that would provide a total amount of antibiotic equal to the safe maximum single dose for systemic administration. For example, the maximum dose of gentamicin that might be loaded into allograft bone is about 200 mg/kg while the maximum dose of flucloxacillin is about 80 mg/kg.
If the therapeutically effective compound is an antifungal compound, the antifungal compound is preferably selected from the following: miconazole, and ketaconazole. When loaded into bone, these compounds are preferably present at a concentration of between the minimum inhibitory concentration of the antifungal and the concentration that would provide a total amount of antifungal equal to the safe maximum single dose for systemic administration.
If the therapeutically effective compound is a chemotherapeutic compound the chemotherapeutic is preferably selected from the following: 5-fluoro-uracil and vinblastin. Most preferably the chemotherapeutic is 5-fluoro-uracil.
In an alternative form, the present invention consists of a method for supplementing bone or bone tissue with a therapeutically effective compound, wherein said method employs the steps of:
(i) Exposing bone or bone tissue to a therapeutically effective compound; and
(ii) Applying a potential difference across said bone or bone tissue such that the therapeutically effective compound is concentrated within the bone or bone tissue.
Preferably, t
Day Robert Edward
Megson Stephen Manfred
Wood David John
Chattopadhyay Urmi
Frommer & Lawrence & Haug LLP
Isabella David J.
Kowalski, Esq. Thomas J.
The University of Western Australia
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