| Project/Area Number |
16109009
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Osaka City University |
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Principal Investigator |
TAKAOKA Kunio Osaka City University, department of Orthopaedic Surgery, Chairman and professor (30112048)
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| Co-Investigator(Kenkyū-buntansha) |
KAZUKI Kennichi Osaka City University, Graduate School of Medicine Orthopaedic Surgery, Associate professor (80254407)
WAKITANI Shigeyuki Osaka City University, Graduate School of Medicine Orthopaedic Surgery, Associate professor (70243243)
小林 章郎 大阪市立大学, 大学院医学研究科, 客員助教授 (70285287)
大橋 弘嗣 済生会中津病院, 整形外科, 部長 (70254406)
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| Project Period (FY) |
2004 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥98,020,000 (Direct Cost: ¥75,400,000、Indirect Cost: ¥22,620,000)
Fiscal Year 2007: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2006: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2005: ¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2004: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000)
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| Keywords | bone / regeneration / BMP / polymer / CAD / biomaterial / 再生医療 / コンピューター支援デザイン / 骨形成 / 骨形成タンパク / 人工関節 / 骨欠損修復 / 薬物伝達系 / ポリマー材料 |
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| Research Abstract |
Currently, recombinant BMP-2 (rhBMP-2) is approved in USA and Europe and practically utilized in limited clinical cases for the treatment of severe open fracture or to achieve spinal fusion with use of the BMP-retaining implant as bone graft substitute. However, further wide use of the BMP-2 to repair damaged bone is not realized mainly due to 2 reasons; too expensive cost of the BMP due to requirement of high dose (mg order) of BMP in humans and inadequate delivery systems of the BMP (bovine-derived type 1 collagen with drawbacks of weak mechanical strength and potential concern for immunogenic reaction and/or prion disease transmission). This study aimed at the solution of the issues to enable wide use of the BMP with improved safety, efficacy and reasonable cost In order to eliminate the use of bovine collagen as carrier material for BMP, we originally developed synthetic biodegradable polymer carrier. In order to minimize BMP dose (consequently reduce the cost of BMP-retaing implan
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t), we screened drugs with capacity to intensify bone inducing capacity of BMP. We also attempted to establish a bone defect repairing system with use the BMP-retaining implant in combination with computer aided design system (CAD) and computer aided surgery system (CAS). We believe that these experimental results will be helpful to establish an innovative clinical technology to regenerate or reconstruct damaged skeletal tissue. More details of the results obtained from this project are described below.
1) Development of new drug delivery system for recombinant BMP-2. We have succeeded to develop new biodegradable synthetic polymer (polylactic acid- polyethylene glycol block co-polymer, PLA-PEG) that work well as carrier material for BMP. Optimized molecular size of a block co-polymer polymer is approximately 10,000 daotons and molar ratio of PLA to PEG is 2 by 1. The polymers presented highly sticky nature and not convenient to handle in intra-operative situation. In order to eliminate the difficulty, we added equal volume of biodegradable β -tricalcium phosphate (TCP) powder to the polymer to make to composite material with dough nature. With use of the dough implant in combination with the recombinant BMP-2(mixture ratio of TCP / polymer BMP-2 is 10000 / 10000 / 1 in weight)large bone defects in femur of rabbits or pelvis of dogs were successfully repaired in 6〜8 weeks. And with use of the BMP retaining implants, postero-lateral lumbar fusion (PLF) was successfully achieved in sheep without use of autogeneic bone grafting which has routinely been done in current spine surgery. No adverse event was seen in the use of the implant. Consequently, the artificial bioactive implant consisted of recombinant BMP, TCP and PLA-PEG polymer would be a useful material to repair large bone defects that are difficult in current orthopaedic technology. With use of the new synthetic BMP delivery materials, bone repairing surgery would be less invasive due to no need of additional surgery to procure graft bone mass from other part of the body.
2) Screening of drugs to intensity bone-inducing activity of recombinant BMP. Intracellurar signaling after binding of BMP to BMP receptors (BMPR1 and BMPR2) locating at the cell surface is mediated by Smad family molecules, R-Smad (Smad 1,5), C-Smad(Smad 4) that regulate transcriptional activity of the BMP responding genes that are essential for differentiation of the cell to osteogenic cells. We previously found that protein A kinase (PKA) / cAMP responsive element binging protein (CREB) signaling pathway potentiates the BMP signaling. Based on this fact, we added drugs that elevate intracellular cAMP levels to the above described BMP-retaining implant to examine the capacity to enhance the bone-inducing activity of BMP both in vitro and in vivo mice models. The examined drugs included phosphodiesterase (PDE) inhibitors (rolipram-a PDE4 specific inhibitors, pentoxifylline-a non-specific PDE inhibitor), a prostaglandin E2-redceptor Ep4 agonist (ONO 4819), and teriparatide (PTH1-34 fragmenta). Each of the drugs consistentry potentiated the bone-inducing capacity of the BMP-2 because approximatery 2 times larger bone mass was ectopically generated in the muscle of mice in 3 weeks after implantation of the constant volume of BMP/TCP/polymer composite pellet implant added by small dose of the respective drug. These results indicated half reduction of BMP dose would be possible with concomitant use of those drugs to the implants and lead to potential cost reduction of the BMP-retaining implant with bone-inducing capacity.
3) New individualizes bone defect repairing system based on 3-dimensional computed tomography (3-D CT) data. Usually size and shape of bone defect to be regenerated varied from case to case. To repair such bone defect, we used 3D-CT image data to estimate the size and shape of the defect by subtracting the defect by subtracting the damaged bone (with bone defect) image from symmetrical mirror image of the normal contralateral bone. The image data were then used to make a porous biomaterial implant compatible to the bone defect by a computer aided designing machine. Then the BMP-retaining dough was pasted on and in the implant to add bone-inducing capacity and implanted into the bone defect, This individualized bone defect repairing system worked well in model and expected to be useful in clinical practice. Less
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