Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1999-03-02
2001-11-27
Saucier, Sandra E. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C514S021800
Reexamination Certificate
active
06322785
ABSTRACT:
FIELD OF INVENTION
The present invention relates to methods and compositions for bone repair and, in particular, an implantable, thrombin-free, autologous platelet gel and matrix that promotes bone augmentation and regeneration.
BACKGROUND OF THE INVENTION
Fibrin glue, also known as fibrin sealant or fibrin gel, is one of many materials developed in response to a recognized need for improved hemostatic agents and sealant (Ref. 1). Platelet-based implantable gels have been used extensively as wound healing and bone regeneration agents in preferred substitution for fibrin glues. Fibrin glues are a two component system comprising, as a first component, concentrated fibrogen, a fibrin stabilizing factor and fibroconectin. The second component includes thrombin, calcium chloride, and an inhibitor of fibrinolysis. The constituents when combined form a fibrin gel or clot. Thrombin and the calcium cleave the fibrogen to fibrin in the coagulation cascade and activate factor XIII which crosslinks fibrin into an organized clot. The gel may be topically applied or in-vitro molded prior to implantation.
The fibrogen content is customarily plasma based. Such plasma may be derived from a variety of sources including random donor or single-donor cryoprecipitate or from autologous plasma. Homologous sourcing presents numerous quality control problems. Procured from donor blood, certain patient risks may be encountered including compatibility problems, disease transmission dangers, clerical and storage errors. While an autologous cryoprecipitate overcomes some of the above, the donor blood must be procured substantially in advance of surgery, 3 to 5 days or more.
Autologous platelet gel was developed in further response to the above. Therein, whole blood is obtained from the patient in the preoperative period and processed in the operating area. Through differential centrifugation, a fraction representing the platelet strata is separated. This strata or platelet-rich-plasma (PRP) is combined with thrombin and calcium chloride representatively using the technique set forth in Whitman et. al, Ref. 1 above. It has also been proposed that such resultant clots be supplemented with calcium phosphate minerals and other osseoparticulates including autologous bone and marrow material for use in oral and maxillofacial surgery.
Autologous platelet gel differs from fibrin glue in the presence of a high concentration of platelets and a high concentration of native fibrogen. The platelets, activated by the thrombin, release factors and form scaffolding for the development of a clot. Two of the growth factors, platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-B) are known to promote wound healing. PDGF is an activator of collangenase during wound healing allowing reshaping of collagen for wound strength. It also is known to be chemotactic for monocytes and macrophages. TGF-B is known to activate fibroblasts to form procollagen resulting in collagen deposition within the wound.
Autologous platelets gels have gained acceptance in the area of reconstructive oral surgery in connection with ablative surgery of the maxillofacial region, mandibular reconstruction, surgical repair of alveolar clefts and associated oral-antral/oral-nasal fistulas, and adjunctive procedures related to the placement of osteointegrated implants. Such platelet gels have also been used in combination with particulate cancellous bone and marrow grafts (PCBM) (Ref. 1, Ref. 2). It is reported that such platelet gels with the graft material evidenced substantially greater maturation rates and bone density than such implants without the platelet-rich-plasma. The PDGF and TGF growth factors were amplified in this approach and the probable primary initiators of the results.
The action of the thrombin in such autologous platelet gels has been recognized as the primary biological release mechanism of these growth factors as discussed in U.S. Pat. No. 5,165,938 to Knighton. While other biological release agents such as collagen, ADP, and srotonin have been suggested for activating, the performance of thrombin was preferred and appears to have been adopted in the art as the agent of choice. The thrombin customarily used in both platelet gels and fibrin systems has been a bovine derivative. To reduce potential xenographic effects, the bovine thrombin has been used in highly purified form.
Notwithstanding the improved results reported with the thrombin-based fibrin and platelet systems, there are numerous reports detailing adverse clinical effects that have been linked potentially to the bovine thrombin. Sosolik et. al. reported a prolongation of thrombin time was associated with the presence of anti-bovine thrombin antibodies following surgical procedures when fibrin glues or bovine thrombin preparations were applied topically and it was suggested that such exposure could lead to serious bleeding complications during surgery or the postoperative period (Ref. 3). Spero concluded that bovine-induced coagulopathy may occur following surgical exposure to topical bovine thrombin and may result in both postoperative morbidity and mortality in a subset of patients resulting from topical-induced antibodies to clotting factor V following neurolosurgical procedures (Ref. 4). Cmolik et. al. reports coagulopathy occasioned by bovine thrombin-induced factor V deficiency after exposure to bovine thrombin in topical hemostatic agents during cardiovascular or vascular operation (Ref. 5). Muntean et. al. reported inhibitors to factor V following exposure to fibrin sealant during cardiac surgery and concluded that exposure to topical thrombin preparations may lead to the development of inhibitors in the postoperative period that may cause bleeding complications (Ref. 6). Based on the foregoing and other reports, Landsberg et. al. cautioned against use of bovine topical thrombin-based platelet gels in oral and maxilofacial procedures and expressed the need for alternative methods of activating PRP in the oral surgery area (Ref. 7).
BRIEF SUMMARY OF THE INVENTION
The present invention provides an autologous platelet gel and bone graft matrix that is thrombin-free and promotes osteoconduction, osteoinduction and osteogenesis at a bone augmentation site, and initiates and augments the bone replacement process. The implant compositions of the present invention comprise an admixture of platelet-rich-plasma, osseoparticulates, a gelling initiator, and a osseoinductive carrier comprising a suspension of terminally defribillated fibrillar collagen. The admixture is in-vitro cured to form a gelled composition that is formable for implantation into bone deficient sites. Osseoparticluates in a variety of forms can be utilized as the osseocondutive medium including autologous bone and marrow, allographic bone particulate, xenographic particulate bone substitutes and other calcium phosphate minerals. The collagen suspension is a microfibrillar Type I collagen processed to undergo partial unwinding of the collagen strands at the ends thereof sufficient to maintain suspension in a physiological medium and effective to act as a carrier for the scaffolding and as an osseogenetic promoter.
REFERENCES. The publications set forth above are hereby incorporated by reference.
1. “Platelet Gel: An autologous Alternative to Fibrin Glue with Applications in Oral and Maxilofacial Surgery”, Whitman, D H et al., J. Oral Maxilofacial Surgery, 1294-1299 (1997).
2. “Platelet-rich plasma: Growth factor enhancement for bone grafts”, Mars, R E et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod, Vol. 85, 638-646, (1998).
3. “Anti-Bovine Thrombin Antibody”, Sosolik, R C et al., Laboratory Medicine, Vol. 27, No. 10, 651-653 (1998).
4. “Bovine thrombin-induced inhibitor of factor V and bleeding risk in postoperative neurosurgical patients”, Spero J A, J Neurosurg, Vol 78, 817-820 (1993).
5. “Redo cardiac surgery: Late bleeding complications from topical thrombin-induced factor V deficiency”, Cmolik, B L, J Thorac Cardiovasc Surg, Vol 105, 222-228 (1993).
6. “Inhibitor to f
Gainey Glenn Morris
Landesberg Regina
Hopkins Susanne M
Natrex Technologies
Saucier Sandra E.
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