WO2007046109A2

WO2007046109A2 - System and method for bone repair and/or bone augmentation

Info

Publication number: WO2007046109A2
Application number: PCT/IL2006/001213
Authority: WO
Inventors: Ronen Cohen; Amos Yahav
Original assignee: Ronen Cohen; Amos Yahav
Priority date: 2005-10-21
Filing date: 2006-10-22
Publication date: 2007-04-26
Also published as: WO2007046109A3

Abstract

A novel composition-of-matter for repairing a bone defect, being a flake, or a plurality of such flakes, which includes two or more agents that have different pre-determined resorbability rates under physiological conditions, and optionally further containing other particles, is disclosed. Further disclosed are systems containing these flakes, processes for preparing these flakes, methods of repairing bone defects using these flakes and kits for preparing and/or using these flakes for repairing bone defects.

Description

SYSTEM AND METHOD FOR BONE REPAIR AND/OR BONE

AUGMENTATION

FIELD AND BACKGROUND OF THE INVENTION The present invention relates to novel compositions-of-matter, systems and methods for repairing bone defects and, more particularly, to compositions-of-matter and systems that are characterized by controlled, pre-determined resorbability rates and hence can be beneficially utilized for repairing, for example, relatively large bone defects. Owing to the rapid development of surgery, it is nowadays possible to carry out operations to bones and joints which were still inconceivable a little while ago. For example, in orthopedics or maxillofacial surgery, it is now possible to carry out surgical removal of cysts, foci of suppuration in bone and malignant tumors from bones. This results in defects, voids or gaps in the bone. - Other examples of bone defects include those resulting, for example, from compression fractures, high-energy trauma, peri-articular fractures, cranial-maxillo facial fractures, osteoporotic reinforcement (i.e. screw augmentation) and periodontal reconstruction.

Dentistry is an important field in which repairing bone defects is necessary and is used in addition to dental implants, for replacing missing teeth. When a person experiences a loss of teeth due to trauma or other circumstances, or suffers from periodontal disease, there is often a loss of interproximal crestal alveolar bone. This bone loss may further result in the loss of a person's interproximal or papillary oral tissue between the corresponding teeth and may cause a bone defect that is very unappealing aesthetically, as well as difficult to restore. Without the proper regeneration of this bone defect, any replacement tooth is likely to be mal-positioned, out of proportion, shape and form, and lack interproximal tissue for a natural appearance.

Depending on the cause and/or location of the various possible bone defects within the body, the volume of the defect can vary, but may, in some cases, reach 6 cm³ and larger.

Since natural bone healing is very slow and is limited to small cavities, large bone defects often need to be filled by bone replacement materials which act as temporary fillers, offering a lattice or scaffold upon which natural bone is slowly built. These materials may be liquid, pasty or solid, and are mostly classified by their source: natural or artificial, a feature which invariably will influence the biocompatibility of these materials. Natural bone replacement materials, known as transplants or grafts, include endogenous or exogenous bone fragments, hi endogenous bone grafting (autograft), the graft is harvested from a "donor site" in the patient's own body. Autografts are generally the best grafting technique and usually result in the greatest regeneration of missing bone, since the bone is 100 % compatible with the patient's body. Although endogenous bone material is irreplaceable due to its osteogenic (bone forming), osteoconductive (providing an inert scaffold on which osseous tissue can regenerate bone), and osteoinductive (stimulating cells to undergo phenotypic conversion to osteoprogenitor cell types capable of formation of bone) properties, it is only available in very limited amounts, and thus ^"several surgical procedures are usually necessary to obtain the necessary bone mass from several donor sites. These repetitive surgical procedures pose severe disadvantages to this otherwise beneficial technique.

Exogenous bone graft may be derived from either a human donor (allograft), after undergoing rigorous tests and sterilization, or from an animal source (xenograft), most commonly bovine, after being specially processed to make it biocompatible and sterile. In both cases the exogenous bone acts as a "filler" until the patient's body replaces it with natural bone. Unfortunately, exogenous grafts have low or no osteogenicity, increased immunogenicity and a much faster resorbtion compared to autogenous bone. In clinical practice, fresh allografts are rarely used because of immune response and the risk of transmission of disease. The frozen and freeze-dried types are osteoconductive but are considered, at best, to be only weakly osteoinductive. Freeze-drying diminishes the structural strength of the exogenous graft and renders it unsuitable for use in situations in which structural support is required. In practice, exogenous bone transplant is often not successful. Some of the most significant advances in biomaterial research over the last 30 years have been in the field of bone graft substitutes, also termed synthetic grafts or alloplastic grafts, which use inert, man-made synthetic materials to mimic natural bone. Examples of synthetic bone implant and/or bone filler materials include, but are not limited to, metals (for example, special steels, noble metals or titanium, often used in the replacement of joints) ceramic materials (for example, alumina, glass- ceramics or hydroxyapatite ceramics), calcium phosphate, calcium sulfate and more. While natural bone grafts are preferable in terms of biocompatibility, they are less practical, especially in the treatment of large cavities, and using synthetic grafts may in fact avoid the additional surgical operations needed to obtain enough natural bone mass.

The type of the synthetic bone replacement material of choice is often dictated by the size, type and location of the bone cavity.

Resorbable bone replacement materials (otherwise termed biodegradable, bioerodable, or bioabsorbable) include materials that are broken down and gradually absorbed or eliminated by various processes in the body. These materials are used as temporary support media or as osteoconductive bone grafts, temporarily filling bone cavities and allowing the body itself to compensate, in the course of time, the defect with living bone material. The exact degree of resorbability is preferably selected such that the rate of resorbtion at the recipient bone site will match the rate of natural bone growth.

Non-resorbable bone replacement materials are used in bone implantation or "bone augmentation" when the bone cavity is too large to be ever replaced naturally, for example following surgical operations, or when replacing lost teeth. These bone implants must themselves be secured to a supporting bone. Occasionally, the use of non-resorbable bone replacement materials has to be supplemented by the use of resorbable bone replacement materials. For example, in dentistry, when the loss of teeth or periodontal disease results in the loss of the root bone, the potential dental implant site in the upper or lower jaw does not offer enough bone volume or quantity to support the dental implant. Hence, before the placement of bridges or, more commonly, dental implants, supporting bone and/or tissue must be re-grown. This procedure, known as Guided Bone Regeneration (GBR), is accomplished using bone grafts and biocompatible membranes that prevent tissue growth on or around the implant. A bone graft normally takes at least four to six months to heal, before a dental implant can be placed thereon or therein. One of the most common substances utilized in repairing bone defects in general, and in dental applications, in particular, is hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂. Hydroxyapatite is a mineral component found in bones and teeth, and is therefore characterized by the required biocompatibility. Hydroxyapatite, however, often causes irritation of the surrounding bone material.

Calcium sulfate compositions are also widely used in bone treatment, and in GDR procedures. Gypsum, for example, is a very soft mineral composed of calcium sulfate dihydrate, CaSO₄-IH₂O. This form is referred to in the art as calcium sulfate. Heating gypsum at above approximately 150 °C partially dehydrates it to obtain calcium sulfate hemihydrate, CaSO₄-VaH₂O (commonly known as "calcined gypsum" or "plaster of Paris"). When calcium hemihydrate is mixed with water at ambient temperatures, it crystallizes into a strong gypsum crystal lattice in an exothermic reaction. Gypsum also has an anhydrous form, termed anhydrous calcium sulfate or calcium sulfate anhydrate, CaSO₄, which is produced by further heating of the calcium sulfate hemihydrate to above approximately 180 °C. Anhydrous calcium sulfate reacts slowly with water to return to the dihydrated state.

In a pure water system, the solubility of these different types of calcium sulfate ranges from about 1.0 x 10^"2 M to about 4.0 x 10^"2 M (at 25° C). The anhydrate form, however, is a very hard crystal (hardness rating of 3.5, according to the Mohs Hardness Scale, and a relative density of about 3.0, compared to water at 1) and has an extremely low dissolution rate in water, even when finely ground, rendering it impractical for use in in vivo applications. In practice, the anhydrate form is mainly used as a desiccant,

The strong crystal structure obtained upon a reaction of the calcium sulfate hemihydrate with water renders it highly suitable for casting into sheets, sticks and molds. This feature attributes to its wide spread use in various applications such as setting broken bones (see, for example, U.S. Patent No. 3,746,680), in dental GBR for filling small volume cavities (see, for example, U.S. Patent No. 6,224,635) or in the preparation of dental molds (see, for example, U.S. Patent No. 4,526,619). Combined with natural or synthetic polymers, calcium sulfate hemihydrate is used for the controlled release of medicaments or pesticides (see, for example, U.S. Patent No. 6,030,636) or as an implant having a controlled resorbtion rate in vivo for stimulating bone growth (see, for example, U.S. Patent Application No. 2004/0254259, and U.S. Patent Nos. 4,192,021 and 4,381,947).

Interestingly, U.S. Patent No. 6,224,635 teaches that when calcium sulfate hemihydrate dissolves in vivo it elevates the local calcium ion concentration in the surrounding tissue. Then, the newly formed calcium ions react with body fluids to cause local precipitation of calcium phosphate bone mineral in the new soft granulation tissue that is formed around the calcium sulfate as it dissolves and recedes. Since the calcium phosphate is stable in vivo, it provides a matrix for the formation of new in-growing bone tissue, although this process is quite unpredictable. Unfortunately, the calcium sulfate hemihydrate form is not suitable for the treatment of large cavities due to its expansion properties during setting, which cause pain to the patients. Furthermore, it is characterized by a high dissolution rate and inherently by a fast resorbtion by the human bone, usually within two to seven weeks, depending upon the particular surgical site. Such a fast absorption renders the calcium sulfate hemihydrate impractical for use in the treatment of large bone cavities, since it cannot be retained at the bone site for long periods of time and is resorbed faster than it can be replaced by new bone, thereby reducing its value to both patient and practitioners in fields such as orthopedics or maxiofacial surgery [Arun K. Garg, D. M. D in Bones biology, Harvesting, Grafting for dental implant. Quintessence publication Ed-I ] .

The calcium sulfate dihydrate form has acceptable expansion properties. However, its use in repairing bone defects is limited since it has no cementious properties. Thus, while calcium sulfate dihydrate is often used as surgical cement, additional components are often required so as to achieve the desired cementious effect. U.S. Patent No. 5,281,265, for example, teaches that a calcium ion can react with a citrate ion to form a less soluble calcium citrate salt, thus forming cement. Hence, while dihydrated calcium sulfate can theoretically fill large bone cavities, the obtained structures are not stable and invariably break. In fact, there is only limited practical healing success when using dihydrated calcium sulfate in the treatment of large bone defects.

Clearly, the use of the currently available biocompatible synthetic compositions for filling large bone cavities suffer severe disadvantages, such as irritation of the surrounding bone material, poor resorbability, low stability and high expansion, which result in pain and discomfort to the patient and a possible leaking out of the filling material or even a loss of the implant.

There is thus a widely recognized need for, and it would be highly advantageous to have, compositions that are suitable for use in repairing bone defects, particularly bone defects associated with large cavities, devoid of the above limitations.

SUMMARY QF THE INVENTION The present inventors have now designed and successfully practiced novel compositions-of-matter, which are based on flakes that exhibit various, predetermined resorbability rates. These flakes are characterized by both stability (resulting from a portion that exhibits slow resorbability rate) that provides a support for bone growth and cementability (resulting from a portion that exhibits fast resorbability rate) that enables fast integration of the composition. Such compositions-of-matter can be beneficially utilized for repairing bone defects, particularly large bone defects, either per se or as a part of a system that comprises additional components.

As is demonstrated in the Examples section that follows, these compositions- of-matter are superior to the presently known compositions utilized for repairing bone defects, since the various resorbability rates of the agents forming the compositions, as well as the unique shape thereof, result in compositions and system for repairing bone defects that serve as highly efficient cavity filling and/or bone augmentation material, which is devoid of limitations such as irritation, high expansion, poor stability and/or poor cementability.

According to one aspect of the present invention there is provided a composition-of-matter comprising a flake, which comprises a first agent having a first pre-determined resorbability rate under physiological conditions and a second agent having a second pre-determined resorbability rate under physiological conditions, the second resorbability rate being different than the first resorbability rate.

According to further features of preferred embodiments of the invention described below, the flake further comprises a third agent, the third agent having a third pre-determined restorability rate under physiological conditions that is different than the first and the second resorbability rates.

According to still further features in the described preferred embodiments the flake is characterized by an average resorbability rate that does not exceed a bone generation rate at a selected bone defect.

According to still further features in the described preferred embodiments the average resorbability rate ranges from about 5 weeks to about 10 weeks.

According to still further features in the described preferred embodiments the average resorbability rate ranges from about 6 weeks to about 10 weeks. According to still further features in the described preferred embodiments each of the first agent and the second agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

According to still further features in the described preferred embodiments each of the first agent, the second agent and the third agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

According to still further features in the described preferred embodiments the calcium sulfate hemihydrate is selected from the group consisting of alpha-calcium sulfate hemihydrate, beta-calcium sulfate hemihydrate or a combination thereof.

According to still further features in the described preferred embodiments an amount of the calcium sulfate dihydrate ranges from about 10 weight percentages to about 50 weight percentages of the total weight of the flake.

According to still further features in the described preferred embodiments an amount of the calcium sulfate dihydrate ranges from about 40 weight percentages to about 45 weight percentages of the total weight of the flake.

According to still further features in the described preferred embodiments an amount of the calcium sulfate hemihydrate ranges from about 30 weight percentages to about 60 weight percentages of the total weight of the flake. According to still further features in the described preferred embodiments an amount of the calcium sulfate hemihydrate ranges from about 40 weight percentages to about 45 weight percentages of the total weight of the flake. δ

According to still further features in the described preferred embodiments an amount of the calcium sulfate anhydrate ranges from about 5 weight percentages to about 20 weight percentages of the total weight of the flake.

According to still further features in the described preferred embodiments an amount of the calcium sulfate anhydrate ranges from about 10 weight percentages to about 15 weight percentages of the total weight of the flake.

According to still further features in the described preferred embodiments a weight ratio of the calcium sulfate dihydrate, the calcium sulfate hemihydrate and the calcium sulfate anhydrate is about 45:45:10. According to still further features in the described preferred embodiments the flake has a rounded shape.

According to still further features in the described preferred embodiments a length of the flake is smaller from about 5 mm.

According to still further features in the described preferred embodiments the length ranges from about 0.5 mm to about 3 mm.

According to still further features in the described preferred embodiments the flake is characterized by a powder X-ray diffraction pattern exhibiting peaks at diffraction angles of about 12, 21, 29 and about 29.5 °2Θ.

According to still further features in the described preferred embodiments the flake is further characterized by a powder X-ray diffraction pattern exhibiting peaks at diffraction angles of about 15, 25.5 and 32 °2Θ.

According to further features of preferred embodiments of the invention described below, the composition-of-matter described herein comprises a plurality of the flakes. According to still further features in the described preferred embodiments the composition-of-matter further comprising a plurality of particles, each containing a fourth agent that has a fourth pre-determined resorbability rate under physiological conditions.

According to still further features in the described preferred embodiments the fourth resorbability rate is faster than an average resorbability rate of the flakes.

According to still further features in the described preferred embodiments the plurality of particles form a powder. According to still further features in the described preferred embodiments an average size of the particles is smaller than 300 micron.

According to still further features in the described preferred embodiments the average size is smaller than 100 micron. According to still further features in the described preferred embodiments the plurality of particles further comprises a carrier.

According to still further features in the described preferred embodiments the plurality of particles and the carrier form a paste.

According to still further features in the described preferred embodiments the fourth agent is selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrate and any combination thereof.

According to still further features in the described preferred embodiments the fourth agent is calcium sulfate hemihydrate.

According to still further features in the described preferred embodiments a weight ratio of the plurality of flakes and the plurality of particles ranges from about 1:5 to about 5:1.

According to still further features in the described preferred embodiments the ratio is about 1:1.

According to another aspect of the present invention there is provided a system comprising the composition-of-matter described herein and a fifth agent, the fifth agent being capable of protecting the composition-of-matter such that the predetermined resorbability rates are substantially maintained under physiological conditions.

According to further features of preferred embodiments of the invention described below, the fifth agent has a fifth pre-determined resorbability rate under physiological conditions.

According to still further features in the described preferred embodiments the fifth resorbability rate is faster than an average resorbability rate of the flake.

According to still further features in the described preferred embodiments the fifth agent is selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrate and any combination thereof. According to still further features in the described preferred embodiments the fifth agent is calcium sulfate hemihydrate.

According to yet another aspect of the present invention there is provided a process of preparing the composition-of-matter described herein, the process comprising: subjecting the first agent having the first pre-determined resorbability rate to a first reaction condition at which at least a portion of the first agent is converted into the second agent having the second pre-determined resorbability rate, to thereby obtain a mixture of the first agent and the second agent; and subjecting the mixture to a second reaction conditions, to thereby obtain a flake which comprises the first agent and the second agent, thereby obtaining the composition-of-matter.

According to further features of preferred embodiments of the invention described below, the second reaction condition is performed prior to, concomitant with or subsequent to the first reaction condition.

According to still further features in the described preferred embodiments the first reaction condition comprises contacting the first agent with an aqueous solution.

According to still further features in the described preferred embodiments the first reaction condition comprises contacting the first agent with an accelerator.

According to still further features in the described preferred embodiments the first reaction condition further comprises heating the first agent. According to still further features in the described preferred embodiments the second reaction condition comprises grinding the mixture.

According to still further features in the described preferred embodiments the flake further comprises a third agent having a third pre-determined resorbability rate under physiological conditions, the process further comprising: subjecting the first agent having the first pre-determined resorbability rate and/or the mixture of the first agent and second agent to a third reaction condition at which at least a portion of the first agent and/or second agent is converted into the third agent, to thereby obtain a mixture of the first agent, the second agent and the third agent.

According to still further features in the described preferred embodiments the first agent is selected from the group consisting of calcium sulfate hemihydrate and calcium sulfate dihydrate. According to still further features in the described preferred embodiments the first reaction condition comprises contacting the calcium sulfate hemihydrate or the calcium sulfate dehydrate with an aqueous solution, to thereby obtain an aqueous solution of the calcium sulfate hemihydrate or the calcium sulfate dehydrate. According to still further features in the described preferred embodiments the first reaction condition further comprises drying the aqueous solution, to thereby obtain calcium sulfate particles.

According to still further features in the described preferred embodiments the first reaction condition further comprises heating the calcium sulfate particles. According to still further features in the described preferred embodiments the composition-of-matter comprises a flake which comprises at least two agents selected from the group consisting of calcium sulfate hemihydrate, calcium sulfate dehydrate and calcium sulfate anhydrate.

According to still further features in the described preferred embodiments the composition-of-matter comprises a flake which comprises a mixture of calcium sulfate hemihydrate, calcium sulfate dehydrate and calcium sulfate anhydrate.

According to an additional aspect of the present invention there is provided a method of repairing a bone defect, the method comprising contacting the bone defect with the composition-of-matter or the system described herein. According to further features of preferred embodiments of the invention described below, repairing the bone defect comprises filling a cavity in the bone defect and/or augmenting a bone in the bone defect.

According to still further features in the described preferred embodiments the contacting comprises applying the composition-of-matter to the bone defect and applying the agent capable of protecting the composition-of-matter to the bone defect having the composition-of-matter applied thereto.

According to still further features in the described preferred embodiments the contacting is effected by injection.

According to still further features in the described preferred embodiments the bone defect is selected from the group consisting of a bone void and/or bone gap. According to still further features in the described preferred embodiments the bone defect is selected from the group comprising of a defect resulting from a bone loss, a fracture, a bone cyst, a bone disease, trauma, and surgical procedures.

According to still further features in the described preferred embodiments the bone defect is a dental bone defect.

According to still further features in the described preferred embodiments repairing the bone defect further comprises incorporating an implant within the bone defect prior to, concomitant with or subsequent to the contacting.

According to still further features in the described preferred embodiments the implant is a synthetic implant.

According to still further features in the described preferred embodiments the synthetic implant is selected from the group consisting of a metal implant, a ceramic implant and a polymeric implant

According to still further features in the described preferred embodiments the^" implant is a dental implant.

According to yet an additional aspect of the present invention there is provided a use of the composition-of-matter or the system described hereinabove in the manufacture of a medicament for repairing a bone defect.

According to a further aspect of the present invention there is provided a kit for repairing a bone defect, the kit comprising: a plurality of flakes, each of the flakes comprises a first agent having a first pre-determined resorbability rate under physiological conditions, and a second agent having a second pre-determined resorbability rate under physiological conditions, the second resorbability rate being different than the first resorbability rate a; and a packaging material, the kit being identified in print, in or on the packaging material, for use in repairing a bone defect.

According to further features of preferred embodiments of the invention described below, each of the flakes further comprises a third agent having a third predetermined restorability rate under physiological conditions that is different than the first and the second resorbability rates. According to further features of preferred embodiments of the invention described below, an average resorbability rate of the flakes does not exceed a bone generation rate at the bone defect. According to still further features in the described preferred embodiments the first and the second agent are each independently selected from the group c consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate. According to still further features in the described preferred embodiments each of the first agent, the second agent and the third agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

According to still further features in the described preferred embodiments the kit further comprising a plurality of particles, each containing a fourth agent that has a fourth pre-determined resorbability rate under physiological conditions, wherein the plurality of flakes and the plurality of particles are each being individually packaged within the kit.

According to still further features in the described preferred embodiments the kit further comprising a fifth agent having a fifth pre-determined resorbability rate under physiological conditions, and further being capable of protecting the flakes such that the pre-determined resorbability rates are substantially maintained under physiological conditions, wherein the plurality of flakes and the plurality of particles and/or the fifth agent are each being individually packaged within the kit. According to still further features in the described preferred embodiments the kit further comprises a solvent.

According to still further features in the described preferred embodiments the solvent is individually packaged within the kit.

According to still further features in the described preferred embodiments the solvent is mixed with the plurality of particles.

According to still further features in the described preferred embodiments the solvent is mixed with the fifth agent.

According to still further features in the described preferred embodiments the kit further comprises an implant. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts. The term "comprising" means that other steps and ingredients that do not affect the final result can be added. This term encompasses the terms "consisting of and "consisting essentially of.

The phrase "consisting essentially of means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.

As used herein, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. As used herein the term "about" means ± 10 %.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. In the drawings:

FIG. 1 presents an XRD spectrum of an exemplary calcium sulfate flakes composition, according to preferred embodiments of the present invention;

FIG. 2 presents comparative plots obtained for four exemplary compositions- of-matter according to the present embodiments, each containing a 1:1 mixture of calcium sulfate flakes composition and calcium sulfate hemihydrate powder, demonstrating the reproducible narrow PSD obtained;

FIG. 3 is an image of a large cavity in a dental bone, before treatment; FIG. 4 is an image showing a calcium sulfate flakes composition, according to preferred embodiments of the present invention, being placed in the bone cavity presented in Figure 3;

FIG. 5 is an image showing the setting of the calcium sulfate flakes composition presented in Figure 4, 3 minutes after being placed in the cavity;

FIG. 6 is an image showing a calcium sulfate paste composition, according to preferred embodiments of the present invention, being placed on top of the set flakes presented in Figure 5;

FIG. 7 is an image showing the setting of the paste presented in Figure 6, 15 minutes after being placed on top of the bone cavity;

FIG. 8 is an image showing the treated bone defect presented in Figures 3-7, 7 weeks post treatment;

FIGs. 9 a-d are images presenting X-ray analysis of the bone repair process shown in Figures 3-8,^" wherein Figure 9a shows the large cavity before treatment, Figure 9b shows the defected area upon placing the calcium sulfate flakes and powder system in the cavity, Figure 9c shows the beginning of bone generation at the defected site, and Figure 9d shows a complete bone recovery;

FIGs. 10a-b are images of a bone augmentation procedure effected 12-13 weeks after treating the bone defect with calcium sulfate flakes and powder, as presented in Figures 3-7;

FIG. 11 is an image of a large cavity in a dental bone fitted with a metal implant, being treated with a calcium sulfate composition according to preferred embodiments of the present invention, which comprises a 1:1 flakes :powder calcium sulfate composition; and FIGs. 12 a-c are images presenting X-ray analysis of the bone augmentation process shown in Figure 11, wherein Figure 12a shows an implant being placed in a large cavity, Figure 12b shows a calcium sulfate system according to preferred embodiments of the present invention, being placed in the cavity, and Figure 12c shows the treated bone defect presented in Figures 12a and 12b, 7 weeks post treatment. DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of novel compositions-of-matter, which comprise flakes that are composed of two or more agents, each being characterized by a different pre-determined resorbability rate under physiological conditions. These flakes provide a matrix that enables to control and adjust the resorbability rate of the composition-of-matter such that, for example, at least a portion thereof is resorbed relatively slow and hence serves as a stable filling matrix for supporting new bone growth and at least another portion thereof is resorbed relatively fast and hence serves as a cementious matrix. These flakes are preferably designed so as to exhibit an average resorbability rate that does not exceed a bone generation rate at a selected bone defect and hence can be beneficially utilized for repairing bone defects and particularly large bone defects. The present invention is further of systems comprising the composition-of-matter, of processes of preparing same, of methods utilizing same for treating bone defects and of kits for preparing same and/or for utilizing same in repairing bone defects.

The principles and operation of the compositions-of-matter, systems, processes, methods and kits according to the present invention may be better understood with reference to the accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. As detailed in the Background section hereinabove, bone defects include bone voids and/or gaps resulting, for example, from compression fractures, high-energy trauma, peri-articular fractures, cranial-maxillo facial fractures, osteoporotic reinforcement (i.e. screw augmentation) and periodontal reconstruction.

Bone defects are classified as either cavitary bone defects, namely defects which are contained and have an intact rim of cortical bone surrounding the deficient area, or uncontained, namely defects which are more peripherally located and lack a bony cortical rim. Bone defects are further classified by the size of the bone cavity or bone deficiency. A small cavity is defined herein as having a volume of up to 2 cm³, a medium sized cavity is defined herein as having a volume in the range between 2 cm³ and 6 cm³, and a large bone cavity is defined herein as having a volume larger than 6 cm³]. A critical bone defect is defined as a defect wherein the cavity or deficiency is of a size or shape in which healing would not naturally occur without intervention.

As used herein, the term "bone" refers to a calcified (mineralized) connective tissue primarily comprising a composite of deposited calcium and phosphate in the form of hydroxyapatite collagen and bone cells, such as osteoblasts, osteocytes and osteoclasts, as well as to the bone marrow tissue which forms in the interior of true endochondral bone. Examples of bones include, but are not limited to, joints (e.g. ball and socket joints such as the hip and shoulder, hinge joints such as the knee and elbow) the skull, jaw, spine, ribs, collarbone, shoulder blade, humerus, radius, ulna, teeth, finger and hand bones, breast bone, femur, tibia and fibula. Repairing bone defects is often necessary following fractures, bone disease, trauma or surgery, and is particularly important in dentistry as a support for dental implants.

As is further discussed in the Background section hereinabove, natural bone healing is a very slow process. Therefore, bone repair often involves the use of natural and/or artificial bone replacement materials which act either as temporary fillers until the bone heals and grows, or, in cases where the defect is too large or complicated, as a permanent replacement of parts of, or all of the bone.

Various artificial (synthetic) bone replacement materials, such as metals, ceramic materials and various inorganic salts, have been developed over the years. However, as discussed hereinabove, the use of these materials has often been limited due to, for example, insufficient biocompatibility, irritation and/or inadequate cementability and/or stability.

Novel compositions which would be suitable for use in repairing bone defects, and particularly large bone defects are therefore highly desirable. In a search for such novel compositions, the present inventors have designed and successfully prepared and practiced flake compositions, in which each flake is composed of two or more agents that exhibit different pre-determined resorbability rates under physiological conditions. Compositions comprising a plurality of these flakes, either alone or in combination with other components, were found highly beneficial in treating large bone defects while circumventing the limitations and overcoming the disadvantages associated with the presently known bone replacement compositions described hereinabove.

As shown in the Examples section below, exemplary flakes comprising a mixture of calcium sulfate hemihydrate, dihydrate and anhydrate forms were designed, prepared and successfully used in repairing bone defects such as dental bone cavities. These flakes were found to exhibit both a desired biostability and simultaneously a desired cementability, which can be finely controlled so as to suit the desired stability and cementability parameters at a certain defect. These flakes were therefore designed so as to exhibit a controllable average resorbability rate, which can be adjusted to suit the specific bone site and size of defect, so as to match the rate of natural bone growth, thus optimizing bone healing. Hence, according to one aspect of the invention, there is provided a composition-of-matter which comprises a flake, whereas the flake comprises a first agent that has a first pre-determined resorbability rate under physiological conditions and a second agent that has a second pre-determined resorbability rate under physiological conditions, whereby the first and the second resorbability rates are different from one another.

As used herein and is well known in the art, the term "flake" describes a particle that is formed by grinding a hard substance. Flakes are typically relatively thin and shallow particles having non-spherical and often non-uniform, non-defined shape, depending on the grinding process used for their formation and the substance from which they are formed. The shallow, non-spherical nature of the flakes attributes to a relatively large contact area thereof when compacted and is hence beneficial in the context of the present invention, as is detailed hereinbelow.

The size of a flake also depends on the substance and the process involved in their formation and can range from about few micrometers to few centimeters. Preferred flakes, according to the present embodiments, have a rounded shape.

More preferred flakes have a length which is smaller than 5 mm, preferably smaller than 4 mm, more preferably smaller than 3 mm. More preferably, the flakes have a rounded shape and length that ranges from about 0.5 mm to about 3 mm. The term "length" as used herein refers to average height of the flake. As detailed in the experimental section below, the size distribution of the flakes was determined via laser diffraction. The purpose of this experiment was to check if there was a linear slope correlation between the size of the particle and the accumulated weight percentage of the flakes, such that a maximum compacting factor could be achieved for the cementious reaction. Thus flakes were chosen to represent a good compacting factor and a pre-determined composition. The term "agent", as used herein, describes any compound or substance that exhibits at least some resorbability, of at least a portion thereof, under physiological conditions. A resorbability of a substance can result from, for example, dissolution in a physiological environment and/or any other physical and/or chemical decomposition in a physiological environment. Preferred agents, according to the present embodiments, include substances that can serve as bone replacement materials, such that upon resorbtion thereof, minerals that are used for bone generation are formed. Hence, preferred agents are also referred to herein as bone replacement agents.

The bone replacement agents may be either natural (namely, obtained from a natural source) or synthetic (namely, derived from a natural source and subjected to synthetic processes, or synthetically prepared) and are preferably synthetic. Representative examples include, but are not limited to, ceramic materials (for example, alumina, glass-ceramics or hydroxyapatite ceramics), phosphorylated minerals (e.g., calcium phosphate), sulfurylated minerals (e.g., calcium sulfate) and polymeric materials (for example, polyglycolic acid, poly-L-lactic acid polyhydroxybutyrate and polyanhydrides).

As used herein the term "ceramic material" refers to a polycrystalline inorganic, non-metallic material that is typically produced by the fusion of mineral substances in a kiln. The term "mineral" as used herein describes a naturally occurring, inorganic, crystalline substance that is made up of elements, typically of one or more metallic elements with one or more other elements. Examples include, without limitation, Chalcopyrite (CuFeS₂), galena (PbS)₅ sphalerite (ZnS), chalcocite (Cu₂S), pyrite (FeS₂), silica (SiO₂), alumina (Al₂O₃), magnesia (MgO), lime (CaO), hematite (Fe₂O₃), magnetite (Fe₃θ₄), wustite (FeO) and the like. Additional elements that typically compose minerals include, but are not limited to, calcium, chromium and selenium, oxides and sulfides thereof and halide, phosphate and sulfate salts thereof.

The term "resorbtion", as used herein, describes a loss of a substance through physiologic or pathologic means. Typically, this term is used herein and in the art to describe such a process which involves decomposition of a substance (by, e.g., chemical or physical break-down such as hydrolysis and/or dissolution), followed by absorption of the break down products by the body (via, for example, metabolism). The term resorbtion is therefore often referred to herein and in the art as "bioresorbtion".

Thus, as used herein, the term "resorbability" describes a feature of a substance that leads to its loss, or leads to loss of a portion thereof, under physiological conditions, whereby the loss is typically effected via chemical and/or physical breakdown of the substance under physiological conditions. The term "resorbable" therefore describes the capability of a substance to undergo at least partial decomposition or disintegration under physiological conditions.

Herein throughout, agents are referred to as resorbable if at least 20 weight percentages thereof, preferably at least 40 weight percentages, more preferably 60 weight percentages, more preferably 80 weight percentages thereof and most preferably 100 weight percentages thereof undergo decomposition under physical conditions.

The phrase "resorbability rate" describes the rate at which resorbtion of a substance is effected under physiological conditions. Typically, for bone replacement materials or agents, resorbability rate can range from a few days to a few months. However, as discussed hereinabove, it is desired that the resorbability rate of compositions that are intended for use in repairing bone defects will not exceed the bone generation rate, so as to exert the desired effect at the defected site, as is detailed hereinbelow.

The phrase "resorbability rate under physiological conditions" describes the resorbability rate of an agent, as described herein, under physiological conditions, namely, when the agent is in contact with a physiological system (namely, acts in vivo) or when an agent is exposed to conditions that mimic a physiological system. This phrase is also referred to herein interchangeably as "bioresorbability rate".

The resorbability rate, as referred to herein throughout, describes the rate at which at least 20 weight percentages thereof, preferably at least 40 weight percentages, more preferably 60 weight percentages, more preferably 80 weight percentages thereof and most preferably 100 weight percentages of the agent are lost upon decomposition under physiological conditions.

The flakes described herein comprise at least two agents, each having a different, pre-determined bioresorbability rate. This feature is highly advantageous in terms of using these flakes for repairing bone defects since it allows to control, already in manufacturing stage, both the average bioresorbability rate of the flakes and the differences in the resorbability rates of the agents. The differences in the resorbability rates allow adjusting the nature of the flakes to the desired application and to design flakes in which one portion of a flake has, for example, a relatively fast resorbability rate, whereby another portion of the flake has a relatively slow resorbability rate. Such flakes simultaneously exhibit stability, in terms of a slow- resorbable support for bone growth, and cementability, in terms of forming an adhered layer at the treated site. Thus, according to preferred embodiments of the present invention, each of the flakes comprised in the composition-of-matter described herein comprises at least one slowly resorbing agent, namely, an agent that has a relatively slow resorbability rate, and at least one fast resorbing agent, which has a relatively fast resorbability rate. Thus, the flake provides, on one hand, a stable, almost "inert", scaffold on which natural bone growth can occur, and on the other hand provides an agent which quickly reacts with the body fluids or under physiological conditions, and thereby acts as a cement. The terms "relatively fast" and "relatively slow" with regard to resorbability rates preferably refer to the respective bone generation rate at a defected bone site. Slow rate refers to a resorbability rate slower than the bone generation rate and is typically 7 weeks and higher whereby fast rate refers to resorbability rate faster than the bone generation rate and is typically less than 7 weeks, often measured in days. Since, in practice, the resorbability rate of the flake preferably reflects a combination of a fast resorbability rate and a slow resorbability rate, this rate will be faster than the slow resorbability rate of one agent, and slower than the resorbability rate of the other agent. Although the exact resorbability of each agent in the flake may not necessarily be identifiable by a person using this flake, the flake itself can be characterized by a certain resorbability rate, termed herein "an average resorbability rate", which is a practical rather than a theoretical value reflecting the flake's actual resorbability rate. The average resorbability rate is determined by the resorbability rates of each of its components, by the weight ratio therebetween, and by the geometrical shape and final structure of the flake. This value may further vary depending on the specific physiological conditions at the bone defect site.

The flake's average resorbability rate can be pre-determined based on the factors listed above, and therefore can be controlled so as to suit any selected bone defect. As detailed in the Background section hereinabove, bone healing is a slow process, measured in weeks and even months. For example, in a dental bone, a bone generation rate typically ranges from about 5 weeks to about 10 weeks. Thus, in most cases, for a medium-sized or larger bone defect, a bone replacement material is used as temporary filler, offering a lattice or scaffold upon which natural bone is built over time. This property is especially important in repairing large bone cavities, since the larger the cavity, the longer time during which the support will be necessary.

It is therefore preferable that an average resorbability rate of the flakes described herein does not exceed the bone generation rate of the selected bone defect. If the flake's average resorbability rate exceeds the rate of bone generation, it may cause a collapse of the support/filler before enough natural bone has grown, thus leading to a loss of a bone replacement material and/or an implant inserted into the bone defect, and eventually resulting in a failure of the repair procedure, and obvious discomfort and extra time and cost to both patient and practitioner.

Thus, according to preferred embodiments of the present invention, a flake is characterized by an average resorbability rate that does not exceed a bone generation rate at a selected bone defect. An average resorbability rate of the flakes described herein is therefore preferably equal to or slower than a bone generation rate at the desired treated site. In one embodiment of the present inventions, the flakes described herein have a core-shell structure, wherein an internal part thereof comprises mainly the slow- resorbable agent and the external part comprises mainly the fast-resorbable agent.

Thus, the core serves as a stable scaffold for bone generation and the shell serves for forming a cementious matrix.

The flakes described herein may be designed so as to exhibit additional desirable properties, particularly when the flakes are intended for use in bone repair. These include, for example, a suitable compacting factor, a suitable dissolution rate, a suitable expansion factor and biocompatibility. These properties can be pre- determined by selecting the appropriate agents, the appropriate ratio therebetween within the flake and the appropriate route for preparing the flakes. Thus, for example, a good compacting ensures that when filling large cavities, the cementious reaction between the flakes and body fluids creates a structure which is stable and yet does not cause an elevated reaction heat at the defected site. Relatively slow dissolution rate guarantees that the bone has enough time to grow while being supported on the scaffold. This feature is especially important in repairing large bone cavities. A suitable expansion factor assures that over expansion, which may cause pain and discomfort, is avoided.

The term "biocompatibility" as used herein and is well known in the art refers to a property of a material that renders it biocompatible, namely, which does not provoke an adverse response (such as an immunological response) in a living subject and which is non-toxic to the living subject.

The flakes described herein may further comprise more than two agents, characterized by other pre-determined resorbabilities. Thus, according to a preferred embodiment of the present invention, a flake may further comprise a third agent having a third pre-determined resorbability rate under physiological conditions that is different from the first and second resorbability rates. Similarly, a flake can comprise four, five and even six different agents, each having a distinct resorbability rate compared to the other agents in each flake. According to particularly preferred embodiments of the present invention, the flakes described herein comprise at least two agents selected from calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate. Such flakes are also referred to herein, interchangeably, as calcium sulfate flakes, whereas a composition-of-matter that comprises such flakes is also referred to herein interchangeably as calcium sulfate flakes composition.

According to the presently most preferred embodiments of the present invention, each flake comprises a mixture of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

As detailed in the Background section above, calcium sulfate hemihydrate is an acceptable bone replacement material, which, due to its high dissolution in water and high expansion during setting, is typically used for repairing small bone defects, and is not considered suitable for repairing large bone defects.

Calcium sulfate dihydrate is not suitable in itself as a bone replacement material, since it is not cementious and does not adhere to the defected area. This form of calcium sulfate is characterized by a relatively slow resorbability rate, and can only be used in repairing bone defects when combined with additional cementious materials, for example polymeric materials.

Calcium sulfate anhydrate is the least resorbing form of calcium sulfate, having virtually no solubility in water.

Thus, in flakes comprising a mixture of these different forms of calcium sulfate, the calcium sulfate hemihydrate typically serves as an agent that has fast resorbability rate and hence acts as a cementious matrix; the calcium sulfate dihydrate serves as an agent that has a moderate to slow resorbability rate and hence acts as a filling matrix and/or stable structure for bone growth, while further balancing the high expansion of the calcium sulfate hemihydrate and avoiding possible pain to the patient upon setting of the calcium sulfate hemihydrate; and the calcium sulfate anhydrate serves as an almost "inert" agent in terms of reaction with body fluids, and hence provides a stable support for bone growth.

Hence, while the calcium sulfate hemihydrate agent undergoes a cementious reaction with the body fluids, the calcium sulfate dihydrate and calcium sulfate anhydrate remain relatively stable, and provide support the growing bone. Further, while the hydration reaction of the calcium sulfate hemihydrate, when used per se, is very exothermic and results in a painful expansion of the setting material, when utilized within the flakes, the proximity of the other calcium sulfate particles effectively dissipates the heat and avoids the undesirable expansion.

The amount of calcium sulfate dihydrate in each of the preferred flakes described herein preferably ranges from about 10 weight percentages to about 90 weight percentages of the total weight of the flake, more preferably, from about 10 weight percentages to about 80 weight percentages of the total weight of the flake, more preferably from about 10 weight percentages to about 70 weight percentages of the total weight of the flake, more preferably from about 10 weight percentages to about 60 weight percentages of the total weight of the flake, and more preferably from about 10 weight percentages to about 50 weight percentages of the total weight of the flake. More preferably, the amount of calcium sulfate dihydrate in each of the flakes described herein preferably ranges from about 20 weight percentages to about 50 weight percentages, more preferably from about 30 weight percentages to about 50 weight percentages, more preferably from about 40 weight percentages to about 50 weight percentages, and most preferably it ranges from about 40 weight percentages to about 45 weight percentages of the total weight of the flake.

Calcium sulfate hemihydrate is the calcium sulfate form responsible for the flake's fast resorbability, and hence for the cementious properties thereof. As is well known in the art, the hemihydrate exists in several crystalline forms. Thus, the calcium sulfate hemihydrate utilized in the context of the present embodiments can be, for example, alpha-calcium sulfate hemihydrate, beta-calcium sulfate hemihydrate or a combination thereof. The amount of calcium sulfate hemihydrate in each of the flakes described herein preferably ranges from about from about 10 weight percentages to about 90 weight percentages of the total weight of the flake, more preferably from about 10 weight percentages to about 80 weight percentages of the total weight of the flake, more preferably from about 10 weight percentages to about 70 weight percentages of the total weight of the flake, more preferably from about 10 weight percentages to about 60 weight percentages of the total weight of the flake, more preferably from about 20 weight percentages to about 60 weight percentages of the total weight of the flake, and more preferably from about 30 weight percentages to about 60 weight percentages of the total weight of the flake. More preferably, the amount of calcium sulfate hemihydrate in each of the flakes described herein preferably ranges from about 35 weight percentages to about 60 weight percentages, more preferably from about 40 weight percentages to about 60 weight percentages, more preferably from about 40 weight percentages to about 55 weight percentages, more preferably from about 40 weight percentages to about 50 weight percentages, and most preferably it ranges from about 40 weight percentages to about 45 weight percentages of the total weight of the flake.

Calcium anhydrate is a hard desiccant-like component, hardly having any solubility in water. The amount of calcium sulfate anhydrate in each of the flakes described herein preferably ranges from about 5 weight percentages to about 50 weight percentages of the total weight of the flake, more preferably from about 5 weight percentages to about 40 weight percentages of the total weight of the flake, more preferably from about 5 weight percentages to about 30 weight percentages of the total weight of the flake, and more preferably from about 5 weight percentages to about 20 weight percentages of the total weight of the flake. More preferably, the amount of calcium sulfate anhydrate in each of the flakes described herein preferably ranges from about 10 weight percentages to about 20 weight percentages, and most preferably it ranges from about 10 weight percentages to about 15 weight percentages of the total weight of said flake.

In a preferred embodiment of the present invention, the weight ratio of the calcium sulfate dihydrate, the calcium sulfate hemihydrate and the calcium sulfate anhydrate is about 45:45:10.

As is described in detail in the Examples section that follows, such flakes are characterized by a powder X-ray diffraction pattern exhibiting peaks at particular diffraction angles. Thus, these flakes exhibited a characteristic X-ray diffraction pattern as depicted in Figure 1, wherein calcium sulfate dihydrate (gypsum), calcium sulfate hemihydrate and calcium sulfate anhydrate each had a set of characteristic peaks (marked as G, H and A, respectively). Specifically, the calcium sulfate flakes according to these embodiments of the present invention exhibited peaks at diffraction angles of about 12, 21, 29 and about 29.5 °2Θ, and were further characterized by peaks at diffraction angles of about 15, 25.5 and 32 °2Θ.

According to the present embodiments, the calcium sulfate flakes can comprise various ratios of the agents included therein. Thus, the relative amount of each of the calcium sulfate dihydrate, the calcium sulfate hemihydrate and the calcium sulfate anhydrate may independently range from about 10 weight percentages to about 90 weight percentages of the total weight of the flake, as long as the sum of weight percentages does not exceed 100 %. The desired ratio between the various agents composing the flakes can be pre-determined.

In addition to exhibiting the above-described features, the calcium sulfate flakes described herein maintain the good characteristics of calcium products, such as, for example, biocompatibility, availability and cost-effectiveness, and therefore afford an exciting alternative to existing bone replacement materials. The composition-of-matter described herein preferably comprises a plurality of the flakes described hereinabove. The flakes in such a composition-of-matter can be the same or different and are preferably the same.

Depending on the desired application thereof, the composition-of-matter can comprise either a plurality of the flakes per se, or, can comprise a mixture of the flakes, as described herein, with an additional agent. Thus, according to a preferred embodiment, a composition-of-matter which comprises the plurality of flakes, further comprises a plurality of particles, each containing a fourth agent that has a fourth predetermined resorbability rate under physiological conditions.

Preferably, the fourth agent is selected such that the fourth resorbability rate is faster than the average resorbability rate of the flakes. Any agent having a relatively fast resorbtion rate is suitable for use in this context of the present embodiments, so as to enhance and/or accelerate the resorbability rate of the composition-of-matter and thus to enhance the cementability of the obtained matrix. Such a mixture of flakes and fastly-resorbing particles is desirable in cases where the composition-of-matter is utilized for repairing a bone defect that is, or is likely to be, exposed to (e.g., inflammation) reactions, which may result in contamination (e.g., infection). The contamination can be caused, for example, by saliva, in cases where the defected site is within the oral cavity, or by other contaminants that can accumulate within the defected site. The fast-resorbable agent is utilized in these cases to form a cementious matrix that serves as a protecting matrix (a sealing layer), protecting the defected site and/or the flakes from possible contamination Optionally and preferably, the plurality of particles in such a composition-of- matter, forms a powder.

The term "powder", as used herein, refers to particulate material consisting of a loose aggregation of very fine solid particles.

Preferably, an average size of the particles forming the powder is smaller than 1 mm, more preferably smaller than 500 microns, more preferably smaller than 300 micron, more preferably smaller than 200 microns and more preferably, smaller than 100 micron.

The powder form provides for a larger contact area of the fourth agent with body fluids, which in turn provides for fast resorbability of the particles.

The powder described herein can further comprise a carrier, which, when mixed with the powder, forms a paste. Such a carrier facilitates the application of the composition-of-matter to the defected site. The carrier is preferably a pharmaceutically acceptable carrier.

As used herein, the phrase "pharmaceutically acceptable carrier" describes a carrier that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered composition. Examples, without limitations, of carriers include, water and saline.

Alternatively, the fourth agent has a resorbability rate that is slower than the average resorbability rate of the flakes.

The weight ratio between^' the plurality of flakes and the plurality of particles is determined according to the desired application of the composition-of-matter. For example, in repairing large bone defects in the oral cavity, there is a high risk of contamination due to exposure to saliva. In such cases, a high powder to flakes ratio is preferred.

Thus, according to preferred embodiments of the present invention, the ratio between the plurality of flakes and the plurality of particles ranges from about 1 :5 to about 5:1 flakes:powder, and can be, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5.

The compositions-of-matter described hereinabove may be utilized in various applications either as is, or as part of a system, which comprises additional components. For example, in some cases, it is desired to protect the flakes and/or particles from possible interactions with the surroundings, so as, for example, avoid contamination and/or maintain the desired, pre-determined resorbability rate of the components. To this end, another agent, which has, for example, sealing or cementing properties, is used in combination with the composition-of-matter, so as to protect it.

Thus, according to another aspect of the present invention, there is provided a system which comprises any of the above-described compositions-of-matter and a fifth agent, which is capable of protecting the composition-of-matter such that its predetermined resorbability rates are substantially maintained under physiological conditions.

The term "protecting" as used herein refers to preventing, minimizing or reducing the exposure of the composition-of-matter to undesired reactions and/or components such as bacteria, fungi, infected tissue, and saliva.

The fifth agent can be an inert substance, which does not react or resorbed under physiological conditions. Optionally and preferably, the fifth agent is a resorbable agent, more preferably a bone replacement agent, which has a fifth predetermined resorbability rate under physiological conditions.

Further preferably, the fifth agent has a resorbability rate that is faster than an average bioresorbability rate of the composition-of-matter. Alternatively, the fifth agent has a resorbability rate that is slower than an average bioresorbability rate of the composition-of-matter.

Various materials can be used as the fifth agent, as long as they are capable of forming a protective layer as described hereinabove. Representative examples, include, without limitation, ceramics, polymeric materials, hydroxyapetite, which exhibit the desired the desired characteristics described hereinabove.

According to preferred embodiments of the present invention, the fifth agent comprises calcium sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrate or a combination thereof. In one preferred embodiment, the fifth agent comprises calcium sulfate hemihydrate, as described herein. As discussed hereinabove, calcium sulfate hemihydrate has cementious properties, exhibits fast resorbability rate, yet its application involves high expansion during setting, which often causes pain to the treated subject. The use of calcium sulfate hemihydrate as the fifth, protecting agent, is substantially devoid of the undesirable expansion, since it does not serve as the main filling mater.

Further according to preferred embodiments, the fifth agent, as described herein (e.g., calcium sulfate hemihydrate), is utilized in a form of a powder, which, optionally and preferably, is mixed with a carrier so as to form a paste, as detailed hereinabove.

Preferably, the weight ratio between the composition-of-matter and the fifth agent in the system described herein ranges from about 1:10 to about 10:1, depending on the intended use of the system. In one preferred embodiment, the weight ratio of the composition-of-matter and the fifth agent is 1:1.

Each of the systems, compositions-of-matter and the various components thereof (e.g., the flakes, fourth and fifth agents described herein) can optionally further comprise an accelerator. The accelerator is used to facilitate the resorbtion reaction. Exemplary accelerators include, but are not limited to, CaSO₄, CaF₂, NaOH and CaCO₃. The amount of the accelerator can range from about 0.1 weight percentages to about 10 weight percentages of the total weight of the system, composition-of-matter or other component that includes the accelerator.

As discussed in detail hereinabove, the compositions-of-matter and systems presented herein are highly suitable for use in repairing bone defects. Thus, according to another aspect of the present invention, there is provided a method of repairing a bone defect. The method, according to this aspect of the present invention, is effected by contacting the bone defect with any of the above- described compositions-of-matter, agents or systems.

As used herein, the term "contacting" describes bringing the composition and/or the system described herein to the area or site of the bone defect.

Further, the contacting is performed so as to place the compositions/systems on and/or within the bone defect.

The contacting route and means are selected suitable for the treated bone defect, its site and size and is further selected applicable for the selected composition, agent and/or system.

Thus, for example, if a composition-of-matter or an agent has a low viscosity, it may be injected into a bone cavity. On the other hand, if it possesses a high viscosity, a manual placing thereof, with or without the aid of a mechanical tool, may be used.

Contacting the bone defect with the compositions-of-matter, agents and/or systems can be effected by, for example, injection, manual placement, and/or using mechanical tools, preferably by injection.

Placing the compositions-of-matter and/or agents described herein by injection is desired particularly in cases where the defected bone is contaminated or is exposed to possible contamination, since it avoids further contamination by hand- or a mechanical tool-contact. The compositions-of-matter, flakes and/or agents described herein are therefore preferably designed suitable for use in injectable preparations.

It should be noted in this respect that using the flakes-containing composition- of-matter described herein conveniently allows to practice an injectable preparation.

In cases where a system, as described herein, is utilized for repairing a bone defect, the method is preferably effected by first contacting the bone defect with the composition-of-matter and subsequently contacting the bone defect having the composition-of-matter applied therein or thereon, with the fifth (protecting) agent.

Thus, for example, in a preferred embodiment, the bone defect is first filled with the composition-of-matter and then, preferably upon setting of the composition, the fifth agent is added on top of the composition-of-matter. Alternatively, the fifth, protecting agent is first applied and the composition-of-matter is thereafter added thereto.

Repairing the bone defect according to this aspect of the present invention can comprise filling a cavity in the bone defect and/or augmenting a bone in the bone defect, depending on the nature of the bone defect and the desired repair procedure.

The method described herein is suitable for repairing any bone defect, as defined hereinabove, including bone void and/or bone gaps resulting, for example, from a bone loss, a fracture, a bone cyst, a bone disease, trauma, and/or surgical procedures.

The method described herein is particularly advantageous is repairing large bone defects, due to the beneficial properties of compositions-of-matter described hereinabove. Large bone defect typically has a volume of 6 cm³ and up.

The method described herein is further particularly advantageous is repairing dental bone defects and can therefore be utilized in applications such as GBR. As detailed in the Background section hereinabove, in some cases the bone defect is too large or complicated to be repair with resorbable bone replacement materials, and the use of more permanent supports or implants, is required.

Thus, according to preferred embodiments of this aspect of the present invention, the method is further effected by incorporating an implant within the bone defect prior to, concomitant with or subsequent to contacting the bone defect with the compositions-of-matter and/or systems.

The implant can be a natural implant, or, optionally and preferably, a synthetic implant. Exemplary synthetic implants include, without limitation, metal implants, ceramic implants and polymeric implants.

The system and/or compositions of the present invention can thus be used in the manufacture of a medicament for repairing a bone defect.

The compositions-of-matter, agents and/or systems described herein can also be incorporated within a kit for use in repairing a bone defect. Such a kit, according to the present embodiment, comprises a packaging material and a plurality of the flakes described herein and can further comprise a plurality of particles comprising a fourth agent and/or a fifth agent, as described herein, which are packaged in the packaging material. The kit is preferably identified in print, in or on the packaging material, for use in repairing a bone defect. When the kit comprises the flakes described herein and a plurality of particles comprising the fourth agent, as described herein, the flakes and the particles are preferably individually packaged within the kit, and are mixed prior to the application of the formed composition-of-matter. In cases where the particles are utilized as a paste, the kit preferably further comprises an appropriate carrier, as described in detail hereinabove.

The carrier can be either individually packaged within the kit, to be pre-mixed with the powder, before or after mixing it with the flakes, before the application of the composition-of-matter. Alternatively, a mixture of the powder and the carrier can be packaged together within the kit. Similarly, the kit can further comprise a fifth agent, as described herein, for protecting the flakes or the flakes and powder mixture. The fifth agent is preferably individually packaged within the kit. When the fifth agent is a powder which further comprises a carrier, the carrier can be either individually packaged within the kit, to be pre-mixed with the powder before use. Alternatively, a mixture of the powder and the carrier can be packaged together within the kit. The kit may further comprise an individually packaged implant, to be used before, during or following the use of the flakes and/or the other components described hereinabove.

Further according to the present invention there are provided processes of preparing each of the components described herein, namely, a flake, a powder, a paste, and a composition-of-matter.

Thus, according to an additional aspect of the present invention there is provided a process of preparing the composition-of-matter described herein. The process, according to this aspect of the present invention is effected by subjecting the first agent to a first reaction condition at which at least a portion of this first agent is converted into a second agent, as described hereinabove, to thereby obtain a mixture of the first agent and the second agent; and subjecting the obtained mixture to a second reaction condition, to thereby obtain a flake which comprises the first agent and the second agent, or a plurality of such flakes, thereby obtaining the composition- of-matter. The underlying basis of the process described herein lies in the conversion of a portion of a first agent to a second agent, while using reaction conditions that affect the resorbability rate of the first agent when transformed to the second agent. Since one of the factors affecting a resorbability rate of a substance under physiological conditions is its dissolution or hydrolysis rate, it was envisioned that by manipulating the water content in one agent, by means of hydration/dehydration, conversion of at least a portion thereof to another agent, which has a different resorbability rate, would be obtained. Such a methodology allows to use a single agent as a starting material, and hence results is an easy-to-practice and cost-effective process, which further enables to finely control the desired composition of the obtained flakes. Examples of reaction conditions which can be utilized as the first and second reaction conditions include, but are not limited to, temperature, pressure, time, dissolution in a solvent and/or reaction media, and combinations thereof. In one particular, the first reaction condition comprises contacting the first agent with an aqueous solution, to thereby affect a hydration reaction. Such a hydration reaction can result in a different agent characterized by a different amount of water included therein and therefore by different properties, including a different resorbability, and a different resorbability rate.

The first reaction condition may further comprise, in addition to or as an alternative to the contacting with the aqueous agent, heating the first agent. Thus either the agent per se or an aqueous solution thereof is subjected to heating. During the heating, dehydration may be affected. The extent at which the dehydration reaction is effected can be controlled by manipulating the temperature and/or time at which heating is effected.

Thus, the heating can be effected once, at a certain temperature and time, or, can be effected two or more times, while manipulating in each heating procedure the temperature and/or time. Optionally, the first reaction condition may further comprise contacting the first agent with an accelerator, which catalyzes the desired reaction.

The accelerator can be, for example, an inorganic salt such as CaSO₄, CaF₂, NaOH and CaCO₃, and its amount can range from about 0.1 weight percentages to about 10 weight percentages of the weight of the starting material. The conversion of the first agent to the second agent can be effected such that at least a portion of the first agent is converted to the second agent and a mixture of the first and the second agent is preferably obtained. Thus, for example, at least 10 weight percentages, at least 20 weight percentages, at least 30 weight percentages, at least 40 weight percentages, at least 50 weight percentages, at least 60 weight percentages, at least 70 weight percentages, at least 80 weight percentages, and even at least 90 weight percentages of the first agent are converted to the second agent, depending on the selected reaction conditions. Optionally, the entire first agent is converted to the second agent.

The second reaction condition can be performed either prior to, concomitant with or subsequent to the first reaction condition.

The second reaction condition preferably includes grinding the first and/or the second agent, to thereby obtain flakes. The size and shape of the flakes depend on the grinding technique and instrumentation utilized. Any of the common grinding techniques can be applied.

The second reaction condition can further comprise additional heating of the first and/or the second agent, before or after the grinding is effected. The additional heating can be performed under similar or different conditions, compared to the heating effected within the first reaction condition.

In cases where the flake further comprises a third agent having a third predetermined resorbability rate under the physiological conditions, the process further comprises subjecting the first agent and/or the mixture of the first agent and the second agent to a third reaction condition, at which at least a portion of the first agent and/or the second agent is converted into the third agent, to thereby obtain a mixture of the first agent, the second agent and the third agent.

The third reaction condition can involve any of the reaction conditions described hereinabove. The following describes an exemplary process for preparing a preferred composition-of-matter according to the present embodiments, which comprises a mixture of at least two of calcium sulfate dehydrate, calcium sulfate hemihydrate and calcium sulfate anliydrate, as described herein. The process is effected while utilizing a commercially available calcium sulfate hemihydrate powder or a commercially available calcium dehydrate (gypsum) as a starting material (the first agent). Thus, for example, a calcium sulfate hemihydrate powder is mixed with and an aqueous diluent, and the obtained solution is subjected to a first heating. Calcium sulfate particles obtained thereby are thereafter subjected to grinding, to thereby obtain calcium sulfate flakes. Optionally and preferably, the flakes are subjected to another heating, at different temperatures. Preferably, the aqueous diluent is water.

Using such a process, a calcium sulfate hemihydrate, for example, is converted to calcium sulfate dehydrate upon mixing is with an aqueous solution. Heating the aqueous solution results is dehydration, converting a portion of the calcium dihydrate to calcium hemihydrate. Further heating the thus formed mixture of calcium sulfate hemihydrate and calcium sulfate dihydrate results in conversion of a portion of the hemihydrate to calcium sulfate anhydrate. Thus, by controlling the temperature and time of the heating, and the number of heatings effected, a desired, pre-determined ratio of each of the calcium sulfate agents in the final flake is obtained.

According to a preferred embodiment of the present invention, a first heating is conducted at a temperature that ranges from about 30 °C to about 70 ⁰C, preferably from about 40 °C to about 50 °C. Under such conditions, calcium sulfate dihydrate is converted into calcium sulfate hemihydrate. The conversion extent can be controlled by controlling the heating time.

According to another preferred embodiment of the present invention, a second heating is conducted at a temperature that ranges from about 150 °C to about 250 °C, preferably from about 180 °C to about 200 °C. Under such conditions, calcium sulfate dehydrate and/or calcium sulfate hemihydrate is converted into calcium sulfate anhydrate. The conversion extent can be controlled by controlling the heating time.

Grinding the calcium sulfate particles obtained before or after the first and/or second heating, increases the surface area of the particles and hence further allows to control the conversion extent at each heating. Thus, for example, when grinding is effected prior to the second heating, a larger portion of the hemihydrate and/or dihydrate is converted to the calcium sulfate anhydrate form.

Further according to the present invention there is provided a process of preparing a powder, which comprises the fourth or the fifth agents described hereinabove. The process is effected by drying a powder of the selected agent, to thereby obtain a dried coarse powder; and grinding the coarse powder.

In an exemplary procedure, a calcium sulfate hemihydrate powder is prepared by drying a commercially available calcium sulfate dihydrate powder, to thereby obtain a dried coarse calcium sulfate hemihydrate powder; and grinding this coarse powder, to thereby obtain the calcium sulfate hemihydrate powder. The means and time of the grinding are selected so as to obtain desired, pre-determined particles size and shape.

According to a preferred embodiment of the present invention, the drying is conducted at a temperature ranging from about 100 ⁰C to about 200 °C, preferably from about 120 °C to about 150 ⁰C.

Further according to the present invention there is provided a process of preparing a paste, as described herein, composed of a powder and a carrier, as described herein. The process is effected by mixing the powder, preferably obtained as described hereinabove, with the carrier.

In an exemplary process, a calcium sulfate hemihydrate powder is mixed with an aqueous carrier such as water, to thereby obtain a paste. The weight ratio between the powder and the carrier preferably ranges from about 1:2 to about 2:1, more preferably from about 1:0.2 to about 1:0.5. Optionally, an accelerator, as described hereinabove is added to the mixture.

Compositions-of-matter which comprise a mixture of flakes and a powder or a paste can be simply prepared by preparing the flakes, as described hereinabove and mixing the obtained flakes with a powder or a paste, prepared as described herein, preferably at room temperature.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non limiting fashion.

MATERIALS AND EXPERIMENTAL METHODS Calcium sulfate hemihydrate and calcium sulfate dihydrate (98 % - 100 %) analytically pure powder were obtained from Aldrich

Images were captured using an Olympus C5050 camera in a f-1.8 resolution. X-ray images were obtained using an Odontix 65kv.

X-Ray Diffraction (XRD) measurements: The crystalline forms of the calcium sulfate flakes and powder, according to preferred embodiments of the present invention, were characterized by powder X-ray diffraction (XRD), which produces a fingerprint of a particular crystalline form. Measurements of 2Θ values are typically accurate to within ± °2Θ. X-ray diffraction data were acquired using a Thermo ARL XTRA X-ray diffractometer. System description: goniometer type: vertical 0-0, detector: Si-Li, Cu X-ray tube 200 Kw with Retveld analysis.

Scanning Electron Microscopy (SEM): The surface morphologies of the calcium sulfate compositions of the present invention were measured by scanning electron microscopy (SEM) using a JOEL 35 CF emission source at 30 kV accelerating voltage. Samples were washed with methanol and dried at room temperature before subjected to analysis. The samples were vacuum deposited with gold before analysis Laser Diffraction: Laser diffraction was used to determine the particle size distributions (PSD) of the flakes and was performed by a CIS -100, manufactured by Ankersmid. The instrument uses the principle of time of transition (TOT)₃ has an accuracy of ± 0.5 micron, and is set to measure particles in the size range 300microns. A spherical (general) model was used. PSD measurements were used to determine the compacting factor of the flakes.

EXAMPLE 1

Preparation of Calcium Sulfate Flakes

General procedure: Calcium sulfate flakes are prepared by first mixing a calcium sulfate hemihydrate powder with a diluent, such as sterile water. If the calcium sulfate hemihydrate is not 100 % pure, up to 0.20 % of an accelerator, such as calcium sulfate dihydrate is added. The mixed solution is baked in an oven at 45 ⁰C until complete drying is achieved and the resulting particles are thereafter grinded in a sterilized media to obtain round flakes having a length in the range of 0.1- 3 mm. The flakes are then baked again in a sterile oven at about 180 - 200 °C for about 2-3 hours, until a predetermined ratio of calcium sulfate hemihydrate (30 - 60 %), calcium sulfate dihydrate (up to 45 %) and calcium sulfate anhydrate (up to 15 %) is obtained.

The flakes composition is characterized by XRD and SEM measurements.

Alternatively, flakes are prepared by repeating this process while using calcium sulfate dihydrate as the starting material.

In an exemplary procedure, calcium sulfate hemihydrate (99.8 %, 1 kg) was placed in a flask and was mixed with sterile water (400 grams) for 5 minutes, and the solution was thereafter placed in an oven at 45 ⁰C. After hardening, the product was grinded in a coffee grinder for 65 seconds and flakes were baked again at 180 - 200 °C for 1.8 hours. The composition of the obtained flakes was determined by SEM and wet sulfate test according to En-196 (part 2 chemical analysis of SO₃ in cement) measurements and by XRD, as depicted in Figure 1.

Table 1 below presents the data obtained in XRD measurements, and demonstrates that three types of minerals were present in the obtained flakes: calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

Table 1

PSD measurements showed a product having a good compacting factor in the range of 1-300 microns vs. weight percentage.

EXAMPLE 2

Preparation of a calcium sulfate hemihydrate powder General procedure: Calcium sulfate hemihydrate powder is either used as provided by the vendor or alternatively is prepared using the following general procedure:

A calcium sulfate dihydrate powder is baked in an oven at 120 - 150 ⁰C for about 2 hours, until a completely dry calcium sulfate hemihydrate powder is obtained. The dried powder is then grinded in a ceramic ball mill for about 20 minutes to obtain a powder having particles smaller than 100 micron.

Preparation of a calcium sulfate hemihydrate paste

General procedure: A calcium sulfate hemihydrate paste is prepared by mixing a calcium sulfate hemihydrate powder with a diluent. If the calcium sulfate hemihydrate is not 100 % pure, up to 0.20 % of an accelerator such as calcium sulfate dihydrate is added. The paste is used within 10 minutes of its preparation. In an exemplary procedure, a calcium sulfate hemihydrate powder was mixed with sterile water in a 0.4:1 water to powder weight ratio. Alternatively, a paste was prepared by mixing the hemihydrate powder with saline, in the same ratio.

EXAMPLE 3

Preparation of Calcium Sulfate Flakes-Powder Mixture General procedure: Calcium sulfate hemihydrate powder and calcium sulfate flakes are prepared as detailed hereinabove from a calcium sulfate dihydrate powder (98.6 % purity). The flakes and powder are then mixed at room temperature in a predetermined ratio, to obtain a calcium sulfate flakes-powder mixture.

In an exemplary procedure, a mixture was prepared in a 1 : 1 weight ratio. Figure 2 presents the results obtained in PSD measurements for exemplary 1:1 calcium sulfate flakes-powder mixtures, and show a reproducible narrow particles size distribution for all the-tested mixtures.

EXAMPLE 4 Treatment of a dental bone defect Using a Calcium Sulfate Flakes and Powder

System (Bone Augmentation)

Figure 3 presents a large dental bone cavity before treatment. The dental bone cavity was first treated with calcium sulfate flakes, prepared as described in Example

1 hereinabove, which were injected into the bone cavity, as shown in Figure 4. The flakes started setting after 2 minutes as depicted in Figure 5. A calcium sulfate hemihydrate paste, prepared as described in Example 2 hereinabove, was then added on top of the injected flakes to completely cover the cavity, as shown in Figure 6. The paste started setting after about 5 hours, as depicted in Figure 7. After 6 -7 weeks from the beginning of the treatment, complete healing of the filled bone cavity was observed, as is clearly shown in Figure 8. After 6 additional weeks (12-13 weeks from the beginning of the treatment), bone augmentation was performed on the healed cavity, and a metal bone implant was inserted into the newly formed bone, as depicted in Figures 9a and 9b. The augmentation process presented in Figures 9a-b is further shown in X-ray images 10a-d (Figure 10a, which shows a large cavity, Figure 10b, which shows the calcium system that was placed in the cavity, Figure 10c, which shows a young bone starting to grow, and Figure 1Od, which shows a complete bone recovery).

EXAMPLE 5 Treatment of a dental hone defect Using a Calcium Sulfate Flakes and Powder

System (Primary Integration)

A large dental bone cavity was initially fitted with a metal dental implant, as depicted in Figure 11, and a calcium sulfate flakes-powder mixture obtained as described in Example 3 hereinabove was placed within the cavity. The calcium sulfate flakes were topped by the calcium sulfate powder, as described in Example 4 hereinabove. The generation of the new bone material in the primary integration process is shown in X-ray images 12a-c (Figure 12a, which shows a large cavity, Figure 12b, which shows the placing of calcium sulfate system within the cavity, and Figure 12c, which shows the growth of young bone in the repair area around the implant.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A composition-of-matter comprising a flake, said flake comprises a first agent having a first pre-determined resorbability rate under physiological conditions and a second agent having a second pre-determined resorbability rate under physiological conditions, said second resorbability rate being different than said first resorbability rate.

2. The composition-of-matter of claim 1, wherein said flake further comprises a third agent, said third agent having a third pre-determined restorability rate under physiological conditions that is different than said first and said second resorbability rates.

3. The composition-of-matter of any of claims 1 or 2, wherein said flake is characterized by an average resorbability rate that does not exceed a bone generation rate at a selected bone defect.

4. The composition-of-matter of claim 1, wherein each of said first agent and said second agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

5. The composition-of-matter of claim 2, wherein each of said first agent, said second agent and said third agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

6. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate dihydrate ranges from about 10 weight percentages to about 50 weight percentages of the total weight of said flake.

7. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate dihydrate ranges from about 40 weight percentages to about 45 weight percentages of the total weight of said flake.

8. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate hemihydrate ranges from about 30 weight percentages to about 60 weight percentages of the total weight of said flake.

9. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate hemihydrate ranges from about 40 weight percentages to about 45 weight percentages of the total weight of said flake.

10. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate anhydrate ranges from about 5 weight percentages to about 20 weight percentages of the total weight of said flake.

11. The composition-of-matter of claim 5, wherein an amount of said calcium sulfate anhydrate ranges from about 10 weight percentages to about 15 weight percentages of the total weight of said flake.

12. The composition-of-matter of claim 5, wherein a weight ratio of said calcium sulfate dihydrate, said calcium sulfate hemihydrate and said calcium sulfate anhydrate is about 45:45:10.

13. The composition-of-matter of any of claims 1-12, comprising a plurality of said flakes.

14. The composition-of-matter of claim 13, further comprising a plurality of particles, each containing a fourth agent that has a fourth pre-determined resorbability rate under physiological conditions.

15. The composition-of-matter of claim 14, wherein said fourth resorbability rate is faster than an average resorbability rate of said flakes.

16. The composition-of-matter of claim 14, wherein said fourth agent is selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrate and any combination thereof.

17. The composition-of-matter of claim 14, wherein said fourth agent is calcium sulfate hemihydrate.

18. A system comprising the composition-of-matter of any of claims 1-17 and a fifth agent, said fifth agent being capable of protecting said composition-of- matter such that said pre-determined resorbability rates are substantially maintained under physiological conditions.

19. The system of claim 18, wherein said agent has a fifth pre-determined resorbability rate under physiological conditions.

20. The system of claim 19, wherein said fifth resorbability rate is faster than an average resorbability rate of said flake.

21. The system of claim 18, wherein said fifth agent is selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, calcium sulfate anhydrate and any combination thereof.

22. The system of claim 21, wherein said fifth agent is calcium sulfate hemihydrate.

23. A process of preparing the composition-of-matter of claim 1, the process comprising: subjecting said first agent having said first pre-determined resorbability rate to a first reaction condition at which at least a portion of said first agent is converted into said second agent having said second pre-determined resorbability rate, to thereby obtain a mixture of said first agent and said second agent; and subjecting said mixture to a second reaction conditions, to thereby obtain a flake which comprises said first agent and said second agent, thereby obtaining the composition-of-matter.

24. The process of claim 23, wherein said first reaction condition comprises contacting said first agent with an aqueous solution.

25. The process of claim 23, wherein said first reaction condition comprises contacting said first agent with an accelerator.

26. The process of claim 24, wherein said first reaction condition further comprises heating said first agent.

27. The process of claim 23, wherein said second reaction condition comprises grinding said mixture.

28. The process of claim 24, wherein said flake further comprises a third agent having a third pre-determined resorbability rate under physiological conditions, the process further comprising: subjecting said first agent having said first pre-determined resorbability rate and/or said mixture of said first agent and second agent to a third reaction condition at which at least a portion of said first agent and/or second agent is converted into said third agent, to thereby obtain a mixture of said first agent, said second agent and said third agent.

29. The process of claim 23, wherein said first agent is selected from the group consisting of calcium sulfate hemihydrate and calcium sulfate dihydrate.

30. A method of repairing a bone defect, the method comprising contacting the bone defect with the composition-of-matter of any of claims 1-17.

31. A method of repairing a bone defect, the method comprising contacting the bone defect with the system of any of claims 18-22.

32. The method of claim 31, wherein said contacting comprises applying said composition-of-matter to the bone defect and applying said agent capable of protecting said composition-of-matter to said bone defect having said composition-of- matter applied thereto.

33. The method of any of claims 30 and 31, wherein said contacting is effected by injection.

34. The method of any of claims 30 and 31, wherein repairing the bone defect further comprises incorporating an implant within the bone defect prior to, concomitant with or subsequent to said contacting.

35. Use of the composition-of-matter of any of claims 1-17 in the manufacture of a medicament for repairing a bone defect.

36. Use of the system of any of claims 18-22 in the manufacture of a medicament for repairing a bone defect.

37. A kit for repairing a bone defect, the kit comprising: a plurality of flakes, each of said flakes comprises a first agent having a first pre-determined resorbability rate under physiological conditions, and a second agent having a second pre-determined resorbability rate under physiological conditions, said second resorbability rate being different than said first resorbability rate a; and a packaging material, the kit being identified in print, in or on said packaging material, for use in repairing a bone defect.

38. The kit of claim 37, wherein each of said flakes further comprises a third agent having a third pre-determined restorability rate under physiological conditions that is different than said first and said second resorbability rates.

39. The kit of claim 37, wherein said first and said second agent are each independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

40. The kit of claim 38, wherein each of said first agent, said second agent and said third agent is independently selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate and calcium sulfate anhydrate.

41. The kit of claim 37, further comprising a plurality of particles, each containing a fourth agent that has a fourth pre-determined resorbability rate under physiological conditions, wherein said plurality of ftakes and said plurality of particles are each being individually packaged within the kit.

42. The kit of any of claims 37 and 41, further comprising a fifth agent having a fifth pre-determined resorbability rate under physiological conditions, and further being capable of protecting said flakes such that said pre-determined resorbability rates are substantially maintained under physiological conditions, wherein said plurality of flakes and said plurality of particles and/or said fifth agent are each being individually packaged within the kit.

43. The kit of any of claims 37-42, further comprising a carrier.

44. The kit of claim 37, further comprising an implant.