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

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.

Histological Review of Demineralized Dentin Matrix as a Carrier of rhBMP-2

“…12,17 DDM/rhBMP-2 incorporation is achieved by two methods. 22 First, for physical adsorption to the DDM surface, a simple approach in which the DDM scaffold is dipped into the protein solution and left to dry can be used when there is no specific affinity between the protein and carrier molecules. Alternatively, modified physical entrapment of the protein within nanoporous dentinal tubules can be achieved by freeze-drying.…”

“…In a study of the release of endogenous BMP-7 from DDM (ED-BMP-7), Pietrzak et al 38 proposed a twocompartment model: early release of BMP-7 from the loose compartment and storage of BMP-7 in the tight compartment, resulting in long-term retention. According to their proposal, Um et al 22 also proposed a three-compartment model for DDM. First, early release of physically adsorbed rhBMP-2 occurred from the loosened interfibrillar space pores, whereas modified physically entrapped rhBMP-2 present in the deep dentinal tubules was released during the middle stage.…”

“…43 Thus, if the surface topography of the underlying substrate has the potential to directly guide the resorption behavior of osteoclasts (as reflected by the size and number of resorption lacunae and the resorbed area), the enlarged dentinal tubules and the loosened interfibrillar space pore of the dentin after DDM generation may promote osteoclastic resorption influenced by rhBMP-2. 22,43 This osteoclast-mediated release of ED-BMPs is a type of dual delivery system. 44 After the release of adsorbed rhBMP-2, dentin degradation and the release of ED-BMPs partially follow the principles of natural bone remodeling proposed by Howard et al as a local ''coupling factor'' pathway linking bone resorption to subsequent bone 29 Enlarged dentinal tubules (ED) were observed.…”

“…21 This biodegradability of the dentin matrix in physiologic conditions presents enlarged microporous dentinal tubules and loosened surface interfibrillar space that facilitate the release of HD-GFs and ED-BMPs. 21,22 In 2019, the release profile of rhBMP-2 incorporated with DDM (DDM/rhBMP-2) was postulated according to the type of incorporation method. 22 After the release of adsorbed rhBMP-2, dentin degradation and release of ED-BMPs occur according to the principles of natural bone remodeling.…”

“…21,22 In 2019, the release profile of rhBMP-2 incorporated with DDM (DDM/rhBMP-2) was postulated according to the type of incorporation method. 22 After the release of adsorbed rhBMP-2, dentin degradation and release of ED-BMPs occur according to the principles of natural bone remodeling. 22,23 Although few studies have been carried out, the potential applications of DDM as a potential carrier of rhBMP-2 can be evaluated based on available evidence.…”