## 6 DDM as a Carrier to Deliver Growth Factors  
Besides serving as a scaffold to support bone regeneration and as a nature reservoir of growth factors, DDM can also serve as a delivery vehicle for additional growth factors. The tubules in DDM provide a high specific surface area and are advantageous to increase the protein retain and reduce protein diffusional loss [60]. Indeed, DDM has been employed as a recombinant human BMP-2 (rhBMP-2) carrier involving in vitro, in vivo and clinical trials [61; 62; 63; 64; 65] In one study, the dentin matrix was demineralized, then DDM was mixed with BMP-2 solutions, and the BMP-2/DDM composite was grafted into the skin over the back region of immunodeficiency mice [62]. The results showed that the volume of induced bone increased at a BMP-2 dose-dependent manner. The time-dependent study of bone induction by the BMP-2 (5.0 \(\upmu\)g) with DDM (70 mg) showed that the BMP-2 and DDM construct increased new bone formation between the DDM particles. The dry weight of the repair tissue, the ALP activity and calcium content in the BMP-2/DDM group were higher when compared with the DDM alone group (Figure 4) [62]. In another study, 5.0 ug of 0.2 mg/mL rhBMP-2 was placed onto 0.03 g of DDM, then the mixture was lyophilized and sterilized [63]. The DDM/rhMP-2 construct was transplanted into rectangular bone defects on the second and third premolars in beagles. DDM with rhBMP-2 showed 48% new bone formation 12 weeks after transplantation. Clinical studies were also launched in patients. The DDM/rhBMP-2 complex was grafted into patients, with surgeries including guided bone regeneration, sinus bone grafting, and ridge augmentation. At an average follow up of 10.5 months, favorable osseointegration was acquired in 35 out of 36 implanted sites [63]. In another case report, the DDM/rhBMP-2 construct was used for socket preservation, and the new bone amount was more in DDM/rhBMP-2 group than in DDM group [64]. In a prospective randomized controlled trial of DDM/rhBMP-2 in ridge preservation, DDM, DDM/rhBMP-2, and deproteinized bovine bone with collagen (DBBC), a conventional xenograft, were transplanted into the extraction pockets immediately after tooth extraction [66]. DDM was as beneficial for ridge preservation as DBBC.  
Figure 3: In vivo pulp-capping effects after pulp exposure. Dentin bridge formation was analyzed by Micro-CT. (From [PERSON] [10] _J. Tissue Eng. Regen. Med._, with permission.)  
The DDM/rhBMP-2 showed appreciable volumetric stability and higher rates new bone formation compared to DDM alone and DBBC [66]. Compared to conventional BMP-2 carriers, the advantage of DDM as the carrier was that DDM was osteoconductive and osteoinductive, and could synergistically combine the properties of the scaffold with the delivered growth factors. However, further studies are needed to investigate the rhBMP-2 concentration and amount, the DDM particle size, the processing method of DDM, the loading method of rhBMP-2 into DDM, and the synergistic effects of rhBMP-2 with the DDM growth factors on tissue regeneration. In addition, besides BMP-2, the delivery of other growth factors via DDM to promote bone and dental tissue regeneration also needs to be investigated.