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Delivery Systems for the BMPs   |    
Biodegradable Poly-d,l-Lactic Acid-Polyethylene Glycol Block Copolymers as a BMP Delivery System for Inducing Bone
Naoto Saito, MD, PhD; Takao Okada, MS; Hiroshi Horiuchi, MD; Narumichi Murakami, MD; Jun Takahashi, MD; Masashi Nawata, MD; Hiroshi Ota, MD; Shimpei Miyamoto, MD, PhD; Kazutoshi Nozaki, PhD; Kunio Takaoka, MD, PhD
View Disclosures and Other Information
Investigation performed at the Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan
Naoto Saito, MD, PhD
Hiroshi Horiuchi, MD
Narumichi Murakami, MD
Jun Takahashi, MD
Masashi Nawata, MD
Hiroshi Ota, MD
Kunio Takaoka, MD, PhD
Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621, Japan. E-mail address for N. Saito: saitoko@hsp.md.shinshu-u.ac.jp

Takao Okada, MS
Research Institute, Taki Chemical Co., Ltd., 64-1 Nishiwaki, Befucho, Kakogawa, Hyogo 675-0125, Japan

Shimpei Miyamoto, MD, PhD
Department of Orthopaedic Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Kazutoshi Nozaki, PhD
Applied Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouch Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan, a Grant from Japan Rheumatism Foundation, and a Grant from Hip Joint Foundation of Japan. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

J Bone Joint Surg Am, 2001 Apr 01;83(1 suppl 2):S92-S98
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Abstract

Background: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-d,l-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems.

Methods: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA).

Results: All of the PLA6,500-PEG3,000 implants with 10 or 20 g of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values).

Conclusions: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects.

Clinical Relevance:

New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.

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    References

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Benjamin W. Kenny
    Posted on February 22, 2009
    Novel Bone Methodologies: The Biomimetic Implant
    Redcliffe Hospital

    To the Editor:

    Today’s social demographic is changing, with the proportion of people older than 65 years in Australia projected to increase from 12% to 21% by 2031 (1). As a result, it is predicted that the number of fractures suffered annually by Australians will also increase (2). It has been established that 15% of fractures result in non-union and require surgical intervention. The treatment of fracture non-unions is therefore clearly set to become an increasingly important issue from both a public health and an individual perspective. For this reason, there has recently been increasing focus on bone implants and the development of improved methodologies.

    Recent articles have discussed/examined the possibility of using a biodegradable implant in a load bearing application (3,4). However the principles behind the development of these implants need to be addressed because without in-depth focus and analysis on potential vascularisation of these implants, regardless of their possible osteoinductive properties, these novel/biomimetic scaffolds are bound to fail. As such, the ideal implant has remained an elusive entity.

    Wintermantel and Mayer (5) developed criteria to describe the ideal implant, which include biocompatibility, bioactivity, native bone growth and angiogenesis., Biocompatibility is the chemical, biological and physical suitability of an implant to the host tissue, and is enhanced when it resembles the tissue it is replacing (6,7). Bioactivity occurs when healthy progenitor cells can ultimately replace lost or damaged tissue, thus allowing cell and vessel in-growth (8,9,10). Native bone growth is required in order for an implant to be considered as a suitable alternative to current grafting techniques and angiogenesis is necessary for bone metabolism, nutrient delivery and therefore bone regeneration.

    Biomimetic scaffolding holds promise for the future as an ideal implant material. It has been suggested that composite materials offer greater potential of surface biocompatibility than the homogenous monolithic materials (11). However, to date, no graft alternative has been found to combine all of the aforementioned aspects.

    There are currently many composite materials at the forefront of bone implant options for load bearing applications. Many of which fulfill components of the criteria set out by Wintermantel and Mayer (5). Some are true homogenous nano-scaffolds that resembles Hodge Petruska’s model of bone (12) while others are composites made at certain percentage ratios with calcium phosphate crystals.

    For load bearing applicability and eventual use as an arthroplasty device, vessel in-growth is essential. For an implant to be replaced by native tissue and consequently fail due to avascular necrosis is pointless. As stated above, if an implant prevents vascularisation or angiogenesis from taking place, bone regeneration will consequently fail.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References

    1. Williamson OD. Measuring the success of joint replacement surgery. Med J Aust. 1999;179;229-30.

    2. Sanders KM, Nicholson GC, Ugoni AM, Pasco JA, Seeman E, Kotowicz MA. Health burden of hip and other fractures in Australia beyond 2000. Projections based on the Geelong Osteoporosis Study. Med J Aust. 1999;170;467-70.

    3. Cool SM, Kenny B, Wu A, Nurcombe V, Trau M, Cassady AI, Grøndahl L. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) composite biomaterials for bone tissue regeneration: in vitro performance assessed by osteoblast proliferation, osteoclast adhesion and resorption, and macrophage proinflammatory response. J Biomed Mater Res A. 2007;82;599-610.

    4. Bostman OM. Absorbable implants for the fixation of fractures. J Bone Joint Surg Am. 1991;73:148-153.

    5. Wintermantel E, Mayer J. Anisotropic biomaterials strategies and developments for bone implantation. In: Wise DL, editor. Encyclopedic Handbook of Biomaterials and Bioengineering. New York: CRC; 1995. p 3-42.

    6. Wintermantel E, Ha SW. Biokompatible Werkstoffe und Bauweisen: Implantate fur Medizen und Umwelt. Berlin: Springer; 1998. p 1-36.

    7. Hellman KB, Picciolo GL, Fox CF. Prospects for application of biotechnology-derived biomaterials. J Cell Biochem. 1994;56;210-24.

    8. Shea LD, Wang D, Franceschi RT, Mooney DJ. Engineered bone development from a pre-osteoblast cell line on three-dimensional scaffolds. Tissue Eng. 2000;6;605-17.

    9. Ishaug-Riley SL, Crane-Kruger GM, Yaszemski MJ, Mikos AG. Three-dimensional culture of rat calvarial osteoblasts in porous biodegradable polymers. Biomaterials. 1998;19:1405-12.

    10. Lutton C, Read J, Trau M. Nanostructured biomaterials: a novel approach to artificial bone implants. Aust J Chem. 2001;54:621-23.

    11. Peter SJ, Kim P, Yasko AW, Yaszemski MJ, Mikos AG. Crosslinking characteristics of an injectable poly(propylene fumarate)/beta-tricalcium phosphate paste and mechanical properties of the crosslinked composite for use as a biodegradable bone cement. J Biomed Mater Res. 1999;44:314-21.

    12. Rho JY, Kuhn-Spearin L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20:92-102.

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