J Korean Assoc Oral Maxillofac Surg.  2019 Jun;45(3):123-128. 10.5125/jkaoms.2019.45.3.123.

Postulated release profile of recombinant human bone morphogenetic protein-2 (rhBMP-2) from demineralized dentin matrix

• Um IW
• Ku JK
• Lee BK
• Yun PY
• Lee JK
• Nam JH

• KMID: 2451318
• DOI: http://doi.org/10.5125/jkaoms.2019.45.3.123

Abstract

Demineralized dentin matrix (DDM) has been used as a recombinant human bone morphogenetic protein-2 (rhBMP-2) carrier in many clinical trials. To optimize the clinical safety and efficacy of rhBMP-2 with DDM, efforts have been made to improve the delivery of rhBMP-2 by 1) lowering the administered dose, 2) localizing the protein, and 3) prolonging its retention time at the action site as well as the bone forming capacity of the carrier itself. The release profile of rhBMP-2 that is associated with endogenous BMP in dentin has been postulated according to the type of incorporation, which is attributed to the loosened interfibrillar space and nanoporous dentinal tubule pores. Physically adsorbed and modified, physically entrapped rhBMP-2 is sequentially released from the DDM surface during the early stage of implantation. As DDM degradation progresses, the loosened interfibrillar space and enlarged dentinal tubules release the entrapped rhBMP-2. Finally, the endogenous BMP in dentin is released with osteoclastic dentin resorption. According to the postulated release profile, DDM can therefore be used in a controlled manner as a sequential delivery scaffold for rhBMP-2, thus sustaining the rhBMP-2 concentration for a prolonged period due to localization. In addition, we attempted to determine how to lower the rhBMP-2 concentration to 0.2 mg/mL, which is lower than the approved 1.5 mg/mL.

Keyword

Collagen; Bone morphogenetic proteins; Demineralized dentin matrix

MeSH Terms

Bone Morphogenetic Proteins
Collagen
Dentin*
Humans*
Osteoclasts
Bone Morphogenetic Proteins
Collagen

Figure

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  Fig. 1 Surface of demineralized dentin matrix (DDM) powder26. A. The surface of the DDM is stained gray due to the dentinal tubules, while the mineralized core is stained violet (H&E). B. Scanning electron micrography of DDM. The dentinal tubules are enlarged (dentinal tubule pores), and there is loosened surface collagen26. C. Scanning electron micrography of DDM. The dense interfibrillar spaces are loosened (interfibrillar space pores)26.

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  Fig. 2 Illustration of the types of recombinant human bone morphogenetic protein-2 (rhBMP-2) incorporation with demineralized dentin matrix (DDM) (DDM/rhBMP-2). rhBMP-2 at a concentration of 0.2 mg/mL was mixed with 0.3 g of DDM powder, and the mixture was lyophilized1731. Gray: the demineralized surface of the dentin matrix, Purple: the mineralized core of the dentin matrix, Red (physical adsorption): rhBMP-2 incorporated on the surface of loosened interfibrillar space pores of the dentin collagen, Green (modified physical entrapment): rhBMP-2 incorporated into the enlarged dentinal tubule pores, Yellow (endogenous BMPs in the dental matrix): matrix- and hydroxyapatite-binding BMPs in the DDM matrix.

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  Fig. 3 An illustrative diagram of the postulated release kinetics of recombinant human bone morphogenetic protein-2 (rhBMP-2) from demineralized dentin matrix (DDM). Data from the article of Kim et al. (J Hard Tissue Biol 2014;23:415–22)16. Based on the release kinetics of rhBMP-2 from DDM, which showed a sustained release over five weeks (blue line), the postulated release profile of exogenous and endogenous proteins is displayed below the original curve (the blue line is the sum of the red, green, and black lines). The physically adsorbed rhBMP-2 on the interfibrillar space pore is released during the early stage of implantation (red line). In a subsequent stage, the modified, physically entrapped rhBMP-2 is released from the dentin matrix, which is degraded by collagenolytic or osteoclastic resorption (green line). Finally, endogenous BMPs are released with osteoclastic resorption of the remodeling process at the later stage (black line).

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