Technology Development to Form Tailor-Made Artificial Bone for Graft Surgery
(March 9, 2006)
NEDO has successfully developed artificial bone that can be optimized for grafting to a patient. This research was jointly carried out with the following institutes and company: Division of Tissue Engineering, The University of Tokyo Hospital; Veterinary Hospital, Graduate School of Agricultural and Life Sciences, The University of Tokyo; Advanced Development and Supporting Center, The Institute of Physical and Chemical Research (RIKEN); and New X-national Technology.
The newly developed artificial bone is formed using computed tomography (CT) imaging, and based on the results of implantation tests with animals, verification tests to demonstrate its effectiveness and safety of are now being conducted. After receiving approval by the ethics committee of The University of Tokyo Hospital, clinical research will be started in the areas of oral surgery, plastic surgery, orthopedic surgery, etc.
In July 2005, surgery was performed at Veterinary Hospital of The University of Tokyo on a Welsh corgi suffering from a skull tumor. During the operation, bone that was damaged due to the tumor was removed, and artificial bone was grafted in place of the bone that was removed. During the first step of the procedure, the inconsistency between the normal shape of the bone and the damaged part of the bone was determined through CT imaging. Following this, data for artificial bone having a favorable internal structure for bone regeneration was developed using computer modeling. Based on the resulting data, the artificial bone needed for the corgi was formed using a 3D computer model.
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| Grafted Artificial Bone |
Corgi after Surgery |
On the basis of blood tests and CT scan results, the post-surgery condition of the corgi showed a very steady recovery. Since the shape of the artificial bone exactly matched that of the damaged bone, the surgery was not very difficult and the implantation procedure was completed in a short amount time. Minimizing the amount of time needed for surgery helped to reduce the physical burden of the corgi. According to examination data, active osteoclastic cell activity was observed in the continuous canals leading to the bone marrow tissue of the artificial bone. Thus, the new artificial bone can be expected to be replaced by regenerated bone more quickly than ever before. The progress of bone formation will be quantitatively measured using X-ray CT.
Background
Three methods are currently used to perform a bone transplant: an autogenous bone graft in which healthy bone is taken from a patient so that it can be grafted with a damaged bone of the patient, an allograft bone graft where bone obtained from a bone bank or donor is used for a graft, and a graft using artificial bone.
The autogenous bone graft is currently considered to be the most effective treatment option. However, the following are issues when using this method: healthy bone is always damaged during the grafting procedure, post-surgery appearance may be important, and only a limited amount of healthy bone can be taken from a patient. In the case of an allograft bone graft, locating suitable bone may be difficult and recently there have been concerns regarding safety. Therefore, allograft bone grafts are not performed very often.
Bone graft surgery using various forms of artificial bone material such as hydroxyapatite or calcium phosphate is also being performed. However, there are both advantages and disadvantages regarding this method of bone grafting. Although bone alternative material has a high strength, three issues need to be considered: artificial bone must be capable of being consistently formed to exactly match the damaged part of a bone, the resorption and substitutability capability of artificial bone must be acceptable, and artificial bone strength must be appropriate.
At present, sintered materials are commonly used to make sintered filling for artificial bone. Although a sintered filling has high strength, it is difficult to form artificial bone that matches the damaged part of a patient’s bone prior to surgery. As a result, the artificial bone needs to be precisely shaped to match the form of the damaged bone at the same time surgery is being performed. In addition, artificial bone with a sintered filling can require a long period of time for resorption or it can fail to be resorbed and replaced by regenerated bone.
Contents of the R&D
In this research, new forming technology for artificial bone was developed utilizing 3D build-up technology and an ink-jet system. Through this technology, it has become possible to form tailor-made artificial bone for graft surgery and graft treatment. The following is an outline of the features of this new technology.
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Based on an X-ray CT image of the affected area of a bone, artificial bone that has an optimized form for a patient is developed. With a superior internal structure, it can be easily resorbed by the original bone or used as a substitute for the bone. |
| (2) |
Powder material such as alpha-TCP, which has guaranteed safety, resorption and substitutability, is then used to form the artificial bone. |
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The internal structure of the bone can be designed to allow osseous conduction and insertion of blood vessels inside. In addition, high assimilability to a living body and sufficient bone strength can be realized as well. |
From 2004 to the present, graft surgery using tailor-made artificial bone developed in this research has been performed on 13 beagle dogs in order to confirm safety. Following surgery, the medical condition of each animal was checked and blood testing was conducted together with diagnosis using X-ray CT images. As a result, no adverse reaction was observed in either the graft area or any other area of the body. To determine the effectiveness of the surgical technique, a conventional artificial bone (high-porous hydroxyapatite) was also grafted to each animal together with the newly developed artificial bone. After the grafting procedure, CT image data was measured for a period of 24 weeks. The post-surgery CT data for the continuous canals of the new artificial bone showed remarkable growth compared to the conventional artificial bone. The tissue of each beagle dog was also observed through HE staining, MT staining and TRAP staining after decalcification. The observation showed the presence of bone cells leading to the continuous canals of the artificial bone. In addition, erythroblasts and megakaryocytes were observed in bone marrow tissue. Thus, the new artificial bone is expected to be replaced by healthy bone tissue over time.
Framework of the Joint Research
In this research, each phase from fundamental research to clinical research has been fully integrated based on the strong linkage between each of the participants. The following describes the role played by each party.
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New X-national Technology
New X-national Technology developed the elemental technology for the artificial bone and performed translational research. (Translational research in this project was utilized to promote smooth interaction between the medical area and the engineering area, which has conventionally been considered to be difficult to achieve.) By playing the role of a translational research framework coordinator, New X-national Technology enhanced the level of communication among all of the involved participants and made it possible to initiate smooth and realistic commercialization. |
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The Institute of Physical and Chemical Research (RIKEN)
The Institute of Physical and Chemical Research (RIKEN) developed the fundamental technology to form three-dimensional bone. |
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Veterinary Hospital, Graduate School of Agricultural and Life Sciences, The University of Tokyo Hospital
Veterinary Hospital investigated the effectiveness of the artificial bone and conducted animal tests. |
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Division of Tissue Engineering, The University of Tokyo Hospital
Together with related divisions within The University of Tokyo Hospital, the Division of Tissue Engineering conducted clinical tests and provided guidance regarding developmental issues during the commercialization phase. |
Future Prospects of the R&D
Through animal testing, the safety and effectiveness of the artificial bone were confirmed. Prior to this research, it was considered that bone regeneration could not be realized with artificial bone. However, the results of this research made it possible to design the internal structure of artificial bone so that bone regeneration could take place. After grafting the artificial bone, not only bone tissue but also bone marrow was observed to be formed inside. Documents required for clinical research have been submitted to the ethics committee of The University of Tokyo Hospital, and clinical research is expected to begin in early 2006. Full-scale clinical research including both RIKEN and University of Tokyo researchers will commence in April 2006.
In addition to the above, the artificial bone will be strengthened and efforts will be made to apply it to not only nonloading bones but also loading bones. The scope of applying the artificial bone will also be expanded, and it will soon be subjected to clinical applications.
Market Demand
The target patients for this new tailor-made artificial bone are those who suffer from cleft lip/palate and bone tumors. There are a substantial number of patients with cleft lip/palate. The rate of neonatal incidence per race is 2.1/1000 in Asians, 1/1000 in whites, and 0.41/1000 in blacks.*1 As for bone tumors, there are 4,200 target patients in Japan.*2 In 2008, global market demand for artificial bone filling material for use in bone graft surgery is expected to amount to 1.9 billion yen per year if patients suffering from bone disease due to aging are included together with bone tumor patients. By increasing the strength of the artificial bone, it will also be applicable to patients suffering from bone disease due to aging.
References
(*1) Source: e-Medicine
http://www.emedicine.com/plastic/topic168.htm
(*2) Source: Ministry of Health, Labour and Welfare (Survey in 1996)
http://www.mhlw.go.jp/toukei/index.html
NEDO Contacts:
Biotechnology and Medical Technology Development Department
Noriyuki Nakamura, Noriko Kimura, Masazumi Matsui
Tel: +81-44-520-5231
Fax: +81-44-520-5233
Note: This information is based on a project introduction announcement presented at a press conference held on December 14, 2005 at The University of Tokyo Hospital.
http://www.nedo.go.jp/informations/press/kaiken/171214/press.pdf
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