The Effect of Heat-Treated Human Bone Morphogenetic Protein on Clinical Implantation

Izawa, Hiroyuki; Hachiya, Yudo; Kawai, Takeshi; Muramatsu, Koichi; Narita, Yasushi; Ban, Naoki; Yoshizawa, Hidezō

doi:10.1097/00003086-200109000-00029

Cited by 31 publications

(19 citation statements)

References 25 publications

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“…BMP-2 is a fairly heat-tolerant protein and bound to native bone matrix components it is resistant to temperatures of up to 70 o C [8]. Other proteins such as, e.g., insulin are even more heat-tolerant, at least in the absence of water [9].…”

Section: Discussionmentioning

confidence: 99%

Heat‐treated BMP‐2 depots release BMP‐2 in its bioactive form

Winkler

Müller

Wiemann³

2006

Materialwissenschaft Werkst

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Small depots of locally fixed bone morphogenetic protein-2 (BMP-2), which were dried onto biocompatible carriers and afterwards heat-treated, induce a local differentiation of contacting osteoblastic cells. Here we investigate whether such depots may act via a release of bioactive BMP-2. For in vivo experiments we employed a modified gap-healing approach using dump bell-shaped implants made from titanium plasma-sprayed Ti-6Al-4V, which were coated with BMP-2 at only one side. Four weeks after implantation into the cancellous bone of the lateral femur condylus of adult sheep we observed a polar formation of new trabecular bone close to the side where BMP-2 had been immobilized. We also tested whether BMP-2 depots stimulate remote cells under cell culture conditions and found that alkaline phosphatase (ALP) of MC3T3-E1 cells was induced over a distance of several millimetres. Experiments show that BMP-2 at least in part desorbs from air-dried and heat-treated BMP-2 depots in its bioactive form. Local depots of BMP-2 may therefore allow to improve bone formation next to metal implants at predefined sites.Key Words: alkaline phosphatase, bone morphogenetic protein, bone formation, heat-tolerant protein Kleine Depots von lokal fixiertem bone morphogenetic protein-2 (BMP-2), das auf biokompatible Träger aufgetrocknet und anschließend Wärme-behandelt wurde, führen zu einer lokalen Differenzierung aufwachsender Osteoblasten. Wir haben untersucht, ob BMP-2-Depots diese Wirkung u. a. durch eine Freisetzung von bioaktivem BMP-2 entfalten. Für in vivo Experimente haben wir dazu ein modifiziertes Spaltüberbrückungsexperiment durchgeführt, bei dem hantelförmige Implantate aus Titan-Plasma-beschichtetem Ti6Al-4V eingesetzt wurden, deren Schaft nur einseitig mit BMP-2 beschichtet wurde. Vier Wochen nach Implantation der Probenkör-per in den spongiösen Knochen des Femur-Kondylus von erwachsenen Schafen beobachteten wir in der Nähe der lokal fixierten BMP-2-Depots eine polare Neubildung von trabekulärem Knochen. Darüber hinaus haben wir getestet, ob BMP-2-Depots auch unter Zellkulturbedingungen in der Lage sind, entfernt liegende Zellen zur Differenzierung anzuregen. Wir fanden, dass eine Induktion der alkalischen Posphatase bei MC3T3-E1-Zellen in einer Entfernung von einigen Millimetern möglich war. Die Experimente zeigen, dass BMP-2 zumindest teilweise von getrockneten, Hitze-behandelten BMP-2-Depots in bioaktiver Form freigesetzt wird. Lokale BMP-2-Depots eröffnen daher die Möglichkeit, die Knochenneubildung um metallische Implantate an vorherbestimmten Stellen zu verbessern.

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Section: Discussionmentioning

confidence: 99%

Heat‐treated BMP‐2 depots release BMP‐2 in its bioactive form

Winkler

Müller

Wiemann³

2006

Materialwissenschaft Werkst

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“…The rhBMP-2 molecule is a heat-stable protein [57]. For example, biologic activity of rhBMP-2 was unchanged after heating to 60°C for 30 min.…”

Section: Injectable Polymeric Delivery Systems For Rhbmp-2mentioning

confidence: 99%

Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins

Saito

Murakami

Takahashi

et al. 2005

Advanced Drug Delivery Reviews

113

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Bone morphogenetic proteins (BMP) induce bone formation in vivo, and clinical application in repair of bone fractures and defects is expected.However, appropriate systems to deliver BMP for clinical use need to be developed. We synthesized a new synthetic biodegradable polymer, poly-D,L-lactic acid-para-dioxanon-polyethylene glycol block copolymer (PLA-DX-PEG), to serve as a biocompatible, biodegradable polymer for recombinant human (rh) BMP-2 delivery systems. In animal experiments new bone was efficiently formed and a large bone defect was repaired using PLA-DX-PEG/rhBMP-2 composites. In addition, this new polymer could be used as an injectable delivery system for rhBMP-2. The rhBMP-2/PLA-DX-PEG composites also could be combined with other materials such as hydroxyapatite or titanium. This new synthetic polymer might be used for rhBMP-2 delivery in various clinical situations involving repair of bone, leading to great changes in orthopedic treatment.2

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“…Izawa et al (11) demonstrated thermotherapy experiments at 60°C for bone tumors. An induction activity of albumen occurred in terms of bone shape, but there was no change within 10 h. Therefore, in order to treat bone tumors and kill the tumor cells, it was vital to maintain temperatures at 50–65°C for 30 min.…”

Section: Discussionmentioning

confidence: 99%

Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats

et al. 2014

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The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50–55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.

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The Effect of Heat-Treated Human Bone Morphogenetic Protein on Clinical Implantation

Cited by 31 publications

References 25 publications

Heat‐treated BMP‐2 depots release BMP‐2 in its bioactive form

Heat‐treated BMP‐2 depots release BMP‐2 in its bioactive form

Synthetic biodegradable polymers as drug delivery systems for bone morphogenetic proteins

Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats

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