The repair of outsized deficiencies, typically defined as gaps of at least about 2.4 mm in size, in the diaphyseal, craniomaxillofacial and other skeletal bones is a considerable problem in orthopedic surgery.
In 1998, about 300,000 bone-graft procedures were performed in the United States alone. This number increased to approximately 450,000 by the year of 2000, when the number of bone grafting procedures performed worldwide exceeded 2.2 million (Lewandrowski et al, 2000). Of the 300,000 procedures performed in 1998, 90% involved the use of either autologous grafts (i.e. using tissue from another part of the body of the patient), or of allografts (i.e. using tissue from a live human donor or cadaver). Therefore, a phase of tissue harvest from the patient or from a donor is required.
The tissue harvesting is executed by a surgical procedure usually involved collecting tissue from the iliac crest, the distal femur, the proximal tibia, the fibula, or from other small bones. The harvested tissue is restructured and transplanted at the damaged site.
However, the graft-harvesting procedures are associated with considerable morbidity and substantial pain. Tissue harvesting for an autologous grafts or from live donors for an allograft may also result in complications such as inflammation, infection, or even death. Allografts taken from live donors or cadavers also carry risks of disease transmission and although grafts are subjected to protective and sterilization treatments such as tissue freezing, freeze-drying, gamma irradiation, electron beam radiation, and ethylene oxide, this risk is not completely removed. Furthermore, substantial supply problems exist, as the bone tissues harvested are limited.
The limited supply and inherited harvesting complications have inspired the development of alternative strategies for the repair of significant bone defects.
The use of 3-dimensional (3-D) bone substitutes such as bone extract, polymer or mineral scaffolds as implants has been investigated and porous biocompatible scaffolds have been used for the repair and regeneration of bone tissue.
Early attempts at tissue repair have focused mainly on the use of amorphous, biocompatible foam as porous plugs to fill large voids in bone. U.S. Pat. No. 4,186,448 described the use of porous mesh plugs composed of polyhydroxy acid polymers, such as polylactide, for healing bone voids. Several different methods for making other scaffolds were also described (i.e. U.S. Pat. Nos. 5,133,755; 5,514,378; 5,522,895; 5,607,474; 5,677,355; 5,686,091; 5,716,413; 5,755,792; 5,769,899; 5,770,193; 6,333,029; 6,365,149 and 6,534,084).
Bone marrow (BM) has been shown to contain population of cells that possess osteogenic potential. As such, an alternative to the scaffold-osteoinductive approach is to transplant into patients living cells that possess this capacity.
Cytokine-manipulated, naïve autologous and allogeneic BM cells have successfully healed diffracted or resorbed bones in experimental models (Werntz et al, 1996; Lane et al, 1999; Nilsson et al, 1999; Kawaguchi et al, 2004) and human patients (Horwitz et al, 1999; Horwitz et al 2001, 2004).
These techniques were further developed by using enriched mesenchymal cells for transplantation, and were demonstrated to be successful in animal models and human patients (Pereira et al, 1995; Shang et al, 2001; Horwitz et al, 2002). Accordingly, U.S. Pat. Nos. 5,716,616 and 6,200,606 describe experimental therapies for treating bone loss syndromes that are based on the implantation of fresh stromal cells isolated from autologous or syngeneic individuals to recipients (i.e. U.S. Pat. No. 5,716,616). Although this approach is promising in theory, it is difficult in practice to obtain the sufficient quantities of BM having the requisite number of osteoprogenitor cells.
Tissue Induction methods (TI) have been developed, wherein tissue regeneration occurs through in-growth of surrounding cells into 3-D scaffolds. The limitations of the TI procedure include the requirement for scaffolding material that possesses both TI capability and mechanical properties similar to those of autologous bone tissues.
Another approach to bone tissue generation is referred to as “complex cell transplantation”, which combines scaffold technology with cell cultivation techniques. In its simplest form, autologous BM aspirate is passed through a biocompatible, implantable substrate placed intra-peritoneally to provide a composite bone graft (Nade et al, 1983 and U.S. Pat. Nos. 5,824,084; 6,049,026).
Alternatively, progenitor cells of the osteogenic lineage are seeded onto biocompatible (biodegradable or non-biodegradable) scaffolds in the presence or absence of growth promoting factors (U.S. Pat. Nos. 6,541,024; 6,544,290; 6,852,330). Transplantation into affected patients is performed following an ex-vivo expansion phase of the cells on the given scaffold. Using this approach, either primary osteogenic cells or expanded Mesenchymal Stromal Cells (MSC) layered upon ceramic scaffolds was able to regenerate bone tissue (Kadiyala et al, 1997; Bruder et al, 1998a,b; Cinotti et al, 2004).
However, experimental results revealed a number of disadvantages of those complex cell transplantations. Firstly, bone marrow transplantation (BMT) in human patients is associated with a general decrease in the skeletal mineral density (Valimaki et al, 1999). Secondly, it was demonstrated that after BMT, although peripheral mononuclear cells (MNC) in the recipients are of donor origin, the BM stroma cells and MSCs are basically of the recipient origin (Koc et al, 1999; Lee et al, 2002). Finally, during the first year follow-up of bone marrow transplanted patients, a gradual decrease in bone repair was evident and significant loss of donor MSC was observed (Lee et al, 2002).
Living bone is a continuously evolving organ and in the normal course of bone maintenance, a constant remodeling process is being employed. In those procedures, Old bone is being replaced by new bone and the organ responds to its environment changing requirements for strength and elasticity. Therefore, normal remodeling progression requires that the mechanical loading processes of bone resorption and bone formation procedures are tightly coordinated.
In cellular terms, this depends on sequential functioning of osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells). In addition, endothelial cell and endothelial cell precursors (angioblasts) are required to form the new blood vessels in the developed bone tissue. Yet, the various cell types participating in bone formation are of different lineages. It is now known that osteoblasts stalk from mesenchymal stem cells, while osteoclasts (directly originating from Hematopoietic Stem Cells (HSC)) and endothelial cells are descendents of a common blast colony-forming cell (Choi et al, 1998; Hamaguchi et al, 1999). As such, methodologies for ex-vivo production of bone-like material that rely on osteoblasts as the exclusive cellular component suffer from an inherited fault.
It would be highly advantageous to have a material for use in repairing bone lesions that is devoid of at least some of the limitations of the prior art.
External fixation devices for keeping fractured bones stabilized and aligned, and ensuring that the bones remain at an optimal position during the healing process are known and commonly used. Such devices typically comprise a plurality of pins placed proximal and distal to the fracture, fixed in a surrounding external mechanical assembly.
External fixation devices are also used for reconstructive orthopedics, such as treatment of bone losses and defects. In such cases the device can either remain in place until healing occurs and then to be removed, leaving no foreign material inside the bone, or it can totally or partially remain inside the bone.
External fixation devices are further useful in experimental models of bone repair which have been developed for a variety of purposes, including the investigation of factors influencing fracture repair, and development of improved methods of managing fractures in human and animals. Such models make use of long bones of large experimental animals, whose weight is more than 40 gr, such as dogs, sheep, rabbits and rats. The term long bone refers to bones in which the length is greater than the width, such as a femur, a tibia, a humerus and a radius.
US application No. 20030149437 to the same inventors as the present application discloses a method of repairing a long bone having a defect. The method comprising mechanically fixating the long bone or portions thereof and filling the defect with a biodegradable scaffold impregnated with growth factors and/or cells to cause a regeneration of the bone.
USPTO Backgrounds
USPTO Backgrounds