Demography of DDM/rhBMP-2 application.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"471",leadTitle:null,fullTitle:"The Economic Geography of Globalization",title:"The Economic Geography of Globalization",subtitle:null,reviewType:"peer-reviewed",abstract:'Very often the process of globalization is referred the word economy evolution. 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DDM is fabricated from the tooth that is traditionally discarded after extraction as medical waste product. Based on the historical work of Dr. Urist since 1965 [1], DDM itself can be defined as acid insoluble, microporous, type I collagenous scaffold that has several non-collagenous growth factors such as BMPs, PDGF and FGF2 in addition to a mineral phase [2, 3, 4]. DDM is mainly processed by dehydration, defatting, and partial demineralization. Demineralization with 0.6 N HCl results in the elimination of the major part of the mineral phase and immunogenic components, while retaining a very low fraction of minerals (5–10 wt.%), the majority of Type I collagen, and non-collagenous proteins (NCPs), providing an osteoconductive and osteoinductive scaffold [5, 6].
We developed two types of DDM (AutoBT®): one is powder, the other is block. The clinical efficacy and safety of DDM powder and block have been approved as new health technology assessment (nHTA) in Korea 2015 based on the several experimental and clinical evidences [7, 8, 9, 10, 11].
DDM powder, which is proved to be osteoinductive and osteoconductive, is 300–800μm size with enlarged dentinal tubules and loosened collagen matrix that serve as channels for releasing essential growth factors from the dentin matrix. The indications of powder are socket preservation, alveolar bone augmentation, guided bone regeneration and sinus augmentation [12].
DDM block, which is osteoconductive and osteoinductive, is root form shaped and has several 200–300 μm-sized macropores from surface to pulp chamber and canal to provide a space for vascular invasion from the host tissues when implanted in the alveolar bone. The indication of block are socket preservation, alveolar wall repair and replacement of conventional membranes [11].
The rhBMP-2 was well known cytokines that has great potential of stimulation, proliferation, and differentiation of stem cells into osteoblastic cells to deposit newly formed osteoid. It has been shown that rhBMP-2 requires suitable carrier to achieve clinical efficacy. Suitable carriers should meet some requirements such as adequate porosity to allow cell and blood vessel infiltration, appropriate mechanical stability against compression and tension, biocompatibility, biodegradability, amenability to sterilization, adhesiveness to adjacent bone, affinity for BMPs, and should provide retention of the protein for a sufficient period of time to affect the repair [13].
Type I collagen (absorbable collagen sponge, ACS) is the most preferred and commonly used BMP carrier. In 2007, the FDA granted approval of rhBMP-2/ACS (INFUSE Bone Graft®, Medtronics, Memphis, TN) as an alternative to autogenous bone grafts for sinus augmentations, and for localized alveolar ridge augmentation of defects associated with extraction sockets. Dose dependent clinical studies have determined 1.5mg/cc as a safe and predictable dose for bone formation. However, the only approved carrier for rhBMP-2 by the US FDA at this time has many drawbacks such as poor mechanical properties, squeezing tendency of rhBMP-2 resulting in burst release and overdose complication, and less osteoconductivities. So that ideal rhBMP-2 carrier has not been established yet in field of clinical implant dentistry [14, 15, 16].
DDM has been considered as one of the potential candidate of the rhBMP-2 carrier in perspectives of the main role that is to retain the factor at the site for a prolonged period of time [17]. Regarding to DDM as rhBMP-2 carrier, Ike et al. reported that exogenous rhBMP-2 adsorbed into pulverized root partially demineralized dentin matrix (PDM) proved to be as osteoinductive as autogenous bone graft [18]. Murata et al. also showed that human DDM particles are osteoinductive, insoluble collagenous matrices, and DDMs might be effective as an rhBMP-2 carrier for bone engineering [19].
Based on the previous report of Ike and Murata, Kim et al. [20] and Um et al. [21] have reported and confirmed
Jeon et al. reported the evaluation of soft tissue volume change after socket preservation using DDM/rhBMP-2 compared with Bio-Oss collagen (Geistlich, Wolhusen, Switzerland) that the volume decreases of DDM/rhBMP-2 is not inferior to Bio-Oss [23].
Another clinical study of a total of 23 patients who received DDM/rhBMP-2 with implant placements (36 implants; maxilla: 14, mandible: 22) showed favorable osseointegration in terms of the implant stability, marginal bone loss, and clinical outcomes [24].
Recently, the author reported a clinical study of DDM/rhBMP-2 application on extraction socket preservation that DDM may be potential carrier of rhBMP-2 with reduced concentration of rhBMP-2 [25]. This chapter will introduce the surgical technique, clinical outcome, long term results of DDM/rhBMP-2 graft in implant dentistry.
DDM powder was produced using human teeth that were soaked in 70% ethyl alcohol. After dividing the teeth into the crown and root, the root portion was crushed to a powder. The size of the particles was between 300 and 800 μm diameter. The crushed particles were soaked in distilled water and a hydrogen dioxide solution, and the remaining foreign substances were removed by using an ultrasonic cleaner. The cleaned particles were dehydrated with ethyl alcohol and went through defatting using ethyl ether solutions. The particles were then demineralized for 30 min in 0.6 N HCl. The demineralized particles were lyophilized and sterilized with ethylene oxide gas (Figure 1a).
Types of DDM. (a) DDM powder; (b) DDM block with the through and through holes, 200–300μm diameter; (c) sheet like structure fabricated from block; (d) wettability with the blood via macropores.
DDM block also was fabricated after crowns were severed at the cementoenamel junctions. Only root dentin part was processed for the block fabrication (European Patent No. 2462899) for its intended use as described in other report. [11] Additional holes sized in 0.2–0.3 mm were made from surface of the root to the canal area to create through and through macropores for promoting vascular invasion and bone formation. The block went through the same fabrication process with the powder form, but the only difference was not being crushed into particles so that the block maintains the original tooth root form and shape (Figure 1b).
DDM block can be transformed into various shapes according to its indication such as sheet like structure to be membrane substitute, ring structure for vertical augmentation (Figure 1c). Figure 1d shows the characteristic wettability with patient’s own blood via macropores of DDM block (Figure 1d).
The rhBMP-2 was loaded on the DDM powder and block by placing 5.0 μg of 0.2 mg/mL rhBMP-2 (Cowellmedi, Busan, Korea) and 0.3 g of DDM powder into individual 15-mL conical tubes. The mixtures were frozen in a deep freeze at −70°C for 60 min, slotted into a lyophilization glass bottle, and then fixed in a lyophilizer (ILShin Lab, Seoul, Korea). After sterilization with ethylene oxide, the DDM powder loaded with rhBMP-2 was packed and transported to the hospital where the implant surgery would be performed [22].
Because DDM/rhBMP-2 powder and block were manufactured in laboratory with maintaining its form and shape clinician can use this material simple and easy as usual.
Demographic information of patients, sites, procedure, materials and follow-up periods are summarized in Table 1.
Demography of DDM/rhBMP-2 application.
Implants were placed on the extraction socket of the lower left first molar (Figure 2) together with DDM/rhBMP-2 powder to prevent buccal wall resorption otherwise buccal wall collapse could hinder the dental implant management (Figure 2a). During the secondary surgery, 4 months post-implantation, sound bone and well organized tissues around the dental implant can be seen. DDM/rhBMP-2 powder seemed to be well incorporated with the extraction socket wall because both the border between the defect and DDM/rhBMP-2 particles was no longer visible (Figure 2b).
Socket preservation on lower left first molar without covering membrane. (a). Dental implant was placed in the extraction socket with primary stability, and the gap between the implant and socket wall was filled with DDM/rhBMP-2 powder without membrane. (b) Four months later, well organized bone was seen that surround the dental implant and repair all the gaps. Remnants of DDM/rhBMP-2 particles can not be seen.
Implants was placed on the extraction socket of the upper right first molar (Figure 3) together with DDM/rhBMP-2 powder to prevent anticipated buccal wall resorption (Figure 3a). A cone beam computerized tomography (CBCT, Vatech, Seoul, Korea) image of the upper right first molar, taken three months after first surgery showed the graft which patched up the thin buccal cortical bone (Figure 3b). Six months post-implantation, i.e., at the time of secondary surgery, the buccal cortical bone seems to be resorbed and replaced with newly formed bone with the volume of socket wall maintained (Figure 3c). Three year seven months later with final prosthesis, the alveolar housing, surrounded dental implant, maintain its volume and shape as natural alveolar bone (Figure 3d).
CBCT of socket preservation on upper right first molar with simultaneous implant placement. (a) Immediate postoperative image showed gap between the implant and thin buccal cortical bone which is expected to be resorbed. (b) Three months after graft, thinning buccal cortical bone indicated the beginning of remodeling. (c) Six months after graft, buccal cortical bone was almost disappeared with the volume of extraction socket maintained. (d) Three year 7 months after, alveolar bone around the dental implant turned into a mature cortical-cancellous bone complex (arrow = alveolar bone).
Comparing 3D reconstructive images of immediate post operation to 3 year 7 months later indicated that the thin buccal cortical bone which was expected to be resorbed due to slightly demineralized appearance (Figure 4a), and the alveolar bone surround the dental implant neck have been completely remodeled into a mature cortical bone which was fully supported by cancellous bone and marrow (Figure 4b).
3D reconstructive image from CBCT. (a) The demineralized buccal cortical bone which was expected to be resorbed. (b) The alveolar bone surround the implant neck have been completely remodeled into a mature cortico-cancellous bone complex.
Upper right central incisor was extracted due to intermittent pain, swelling, and mobility for the past three years. One week after extraction, the implant (diameter: 3.8 mm, length: 13 mm; Dio, Busan, Korea) was placed and the DDM/rhBMP-2 was grafted simultaneously with securing excellent primary stability (Figure 5a).
GBR on upper right central incisor. (a) Exposed dental implant and labial defect immediate after implant placement. (b) Exposed defect were covered with DDM/rhBMP-2 powders. See the wettability of DDM with blood that provides immobility to the powders without membrane. (c) Six weeks after, well organized, newly formed bones filled the labial defect and surround the dental implant.
The labial defect and exposed implant were covered with DDM/rhBMP-2 powders (Figure 5b). The muco-periosteal flap was replaced and stabilized without a covering membrane. After one and half months, the patient underwent secondary surgery earlier than the conventional waiting period of 6 months due to her inevitable schedule. Newly formed bone was covered the labial defect and exposed implant completely. The volume was maintained and the remained particles were no longer seen (Figure 5c).
A CBCT image taken before and immediately after the primary surgery showed the missing part of the labial cortex and exposed implant that had been patched up by the DDM/rhBMP-2 powder (Figure 6a and b). There were clear border lines separating the graft from the remaining labial cortex (Figure 6b). After 3 years with final prosthesis, the labial defect appeared completely repaired by sound cortico-cancellous bone. The border at the upper labial defect had completely disappeared, indicating good incorporation of the graft into the alveolar bone as well as remodeling capacity into sound cortico-cancellous bone complex around implant neck (Figure 6c).
CBCT images of GBR on upper right central incisor. (a) Before extraction of upper right central incisor; (b) placement of dental implant and GBR was done for labial defect; (c) Three years follow up. The cortico-cancellous bone complex was recovered completely (arrow = alveolar bone).
Ridge split procedure was performed to secure the labio-lingual dimension for implant placement (diameter: 3.8 mm, length: 13 mm; Daemul, Seoul, Korea) on lower central incisors (Figure 7a). The gaps created by ridge split and implant placement were filled with DDM/rhBMP-2 powders (Figure 7b). Two and a half months later, the whole DDM/rhBMp-2 particles have changed into well-organized bone-like structure with remarkably increased ridge width and height (Figure 7c). Well organized tissues covered screw was retrieved for histological examination (Figure 7d). There were no inflammatory cells or foreign body reactions and were no gaps between the DDM particle and the newly formed bone (Figure 7e).
DDM/rhBMP-2 powder application on lower central incisors. (a) Implant placement after ridge split procedure. (b) The space between the implants and labial cortical plate is filled with DDM/rhBMP-2. No membrane is used. (c) Two and a half months later, a well-organized bone-like structure surrounded implant. The ridge width increased remarkably. (d) Uncovering implant. Tissue over the implant is used for histological evaluation. (e) Histologic specimen shows active new bone formation around DDM particle. Void space is the DDM which was detached during histologic processing. (Hematoxylin and eosin staining, Scale bar = 5.0 μm). From Um et al. [22] (
Histologic specimens of DDM alone at this area have shown that the particle was surrounded by a dense fibrotic capsule consisting of 3–4 cell layers where there are no inflammatory cells or foreign body reactions as the evidences of biocompatibility of DDM due to the environmental factors of poor blood supply in between the cover screw and the gingiva, we could not find the bone formation at this area before. [22] However, DDM/rhBMP-2 specimen in this case showed remarkable amount of bone formation around DDM/rhBMP-2 particles (Figure 7e). This may be explained by the positive effect of additional rhBMP-2 on DDM.
A CBCT image taken seven months after surgery showed a completely repaired labial bone. The demarcated border between the remaining labial cortex and the repaired bone has almost disappeared (Figure 8a and b). After 3 years with final prosthesis, the labial cortex becomes more thickened and fully supported by cancellous bone and marrow (Figure 8c).
Cone beam computerized tomography (CBCT) of DDM/rhBMP-2 application on lower central incisor. (a) Immediately after implant placement and DDM/rhBMP-2 graft. There is obvious lower labial defect. (b) After 7 months. Labial cortical bone is completely repaired and the demarcated defect border has almost disappeared. (c) After 3 years. The labial cortex becomes thicker and shows fully developed cortico-cancellous bone complex (arrow = alveolar bone). From Um et al. [22] (
Extraction of canine, which were sent to Korea Tooth Bank for fabrication of DDM/rhBMP-2, were performed one week before implant placement. Full thickness flaps were elevated to expose the alveolar crest and locate the defective area. Cleaning and removal of the granulation tissues revealed a huge, crater-like defect with complete destruction of the labial wall (Figure 9a). The implant (diameter: 3.8 mm, length: 13 mm; Dio, Busan, Korea) was placed and an excellent primary stability was obtained (Figure 9b). The huge defect and exposed implant were filled and augmented with DDM/rhBMP-2 that was prepared for easy molding and shaping (Figure 9c). The DDM/rhBMP-2 was placed and carefully packed into the destroyed area of the lingual wall and extended to the surface of the lateral buccal wall, without applying excessive pressure. The mucoperiosteal flap was replaced without a covering membrane (Figure 9d).
DDM/rhBMP-2 application on lower left canine. (a). There was huge defect after removal of all granulations on lower left canine. (b). Placement of implant (diameter: 3.8 mm, length: 13 mm) ensuring initial stability. (c). DDM/rhBMP-2 particles can be molded and shaped easily. (d). DDM/rhBMP-2 is packed into the lingual wall gap and along the labial wall. No membrane is used. (e). Well-organized bone tissue was found, filling the gap and surround the implant completely. None of the particles can be seen. (f). The tissue over the cover screw is typically removed in order to go through the prosthetic procedure and histological evaluation. From Um et al. [22] (
When the patient underwent secondary surgery, six months later, well-formed bone, which surrounds the implant and fill the gap, can be seen (Figure 9e). All routine prosthetic procedures after removal of bone over cover screw were performed (Figure 9f).
A CBCT image taken immediately after surgery showed that the missing part of the labial cortex had been patched up by the DDM/rhBMP-2 powder. There was clear border line separating the graft from the remaining labial cortex (Figure 10a). After three years with final prosthesis, the alveolar bone was repaired completely in both volume and shape. The border at the lower labial defect had completely disappeared, indicating good incorporation of the graft into the alveolar bone. The repaired labial cortical bone seemed to be fully supported by cancellous bone and marrow (Figure 10b).
Cone beam computerized tomography (CBCT) of lower left canine repaired by DDM/rhBMP-2. (a) Immediately after implant placement and graft. DDM/rhBMP-2 particles surround the implant, patching up the labial and crestal alveolar bone. (b) After 3 years, the border line at the lower labial defect has completely disappeared. The repaired labial cortical bone was fully supported by cancellous bone and marrow (arrow = alveolar bone). From Um et al. [22] (
After extraction of lower left first molar, there was collapsed buccal wall resulting in huge, crater-like defect (Figure 11a and b). Using the extracted tooth, block and powder type DDM/rhBMP-2 were prepared (Figure 11c). Buccal wall was repaired by block and the alveolar proper was repaired by powder (Figure 11d). Six months later for the staged procedure of implant placement, there was a bone-like tissue that was completely transformed from the block and powder of DDM/rhBMP-2. Alveolar bone seemed to be repaired completely without any remnants of block and powder (Figure 11e). So that the implant can be secured safely on the repaired alveolar bone (Figure 11f).
GBR for the repair of alveolar wall on lower left first molar. (a) Collapsed buccal wall after extraction of lower left first molar. (b) Reflection of flap and removal of granulation tissues. Huge defect and resorbed buccal wall can be seen. (c) Fabricated DDM/rhBMP-2 block from extracted tooth. (d) The huge defect was repaired by DDM/rhBMP-2 block and powder. (e) Six months later, whole DDM/rhBMP-2 was completely transformed into bone like structure. (f) Implant placement (staged procedure).
A CBCT image taken before and after extraction showed complete loss of buccal wall (Figure 12a and b). The alveolar proper was repaired by DDM/rhBMP-2 powder while the missing part of buccal wall was repaired by DDM/rhBMP-2 block. There was clear border line separating the block graft from the remaining buccal cortical bone (Figure 12c). After 6 months, the border line began to disappear that indicate good incorporation and remodeling (Figure 12d), and 12 months later, radiopaque outer cortex and remodeled powder can be seen (Figure 12e). The alveolar bone surround the implant appeared completely repaired in both volume and shape.
GBR for the repair of alveolar wall on lower left first molar. (a) Before extraction. (b) Immediate after extraction. Complete loss of buccal wall can be seen. (c) Repair the alveolar proper with DDM/rhBMP-2 powder and the buccal wall with DDM/rhBMP-2 block. (d) Six months later, placement of implant. See the remodeled powder. (e) Seven months after. Powders are remodeled in the alveolar proper, while the block repaired buccal cortical bone (arrow = alveolar bone).
After placement of implant, there was an atrophy of buccal cortical area (Figure 13a). DDM/rhBMP-2 block and powder was put on the buccal resorbed area that showed sound wettability with patients own blood and immobilization. The color change of the DDM/rhBMP-2 is mainly due to soaking with the patient’s own blood into the macropores and collagenous dentin matrix (Figure 13b). Flap was closed without using membrane. The flap reflected again for the prosthetic procedure 4 months later, there were no discernible block and powders remained and well organized tissues replaced the onlay graft with the volume and shape maintained (Figure 13c and d).
Onlay graft on upper right first molar for volume expansion. (a) Atrophied buccal area can be seen after placement of implant. (b) DDM/rhBMP-2 block and powder were put on the buccal resorbed area. No membrane was used due to the wettability of block and power with patient’s own blood resulting in immobilization. (c) Four months later, there were no DDM particles and block that have changed into well-organized tissues maintaining the whole volume of DDM/rhBMP-2. (d) See the increased volume of buccal gingiva and texture.
CBCT images after implant placement on upper right first molar. As a result of long term missing of tooth, alveolar ridge became narrow and the buccal cortical bone around the dental implant is too thin and close to implant neck (Figure 14a). Increased alveolar bone width and volume by DDM/rhBMP-2 application can be seen (Figure 14b). Seven years later, increased volume of alveolar housing, remodeled completely, shows mature cortico-cancellous bone complex (Figure 14c).
CBCT images of onlay graft on upper right first molar. (a) After placement of 3.8 mm diameter implant, the buccal cortical bone around the dental implant is too thin and close to implant neck. (b) Increased alveolar bone volume around implant neck area by DDM/rhBMP-2 application can be seen. (c) Seven years later, onlay DDM/rhBMP-2 was well incorporated with the buccal cortical bone under continuous remodeling, that create new cortico-cancellous bone complex (arrow = alveolar bone).
Unlike other scaffolds, for example, ACS which has a limited capacity for controlled release, lacks of structural stability, risk of physiologically excessive doses, and the insufficient retention of BMP-2 [14, 15, 16], DDM has adequate porosity to allow cell and blood vessel infiltration, appropriate mechanical stability to withstand compression and tension, biocompatibility, biodegradability, amenability to sterilization, adhesiveness to adjacent bone, affinity for BMPs, and the ability to retain the protein for a sufficient period [17, 26]. DDM has a microporous structure with dentinal tubules 3–5 μm in diameter, which allows it not only to contain BMPs, but also to efficiently release them at surgical site [20]. Numerous studies have reported on the performance of DDM as a scaffold for BMPs; the osteoconductive and osteoinductive abilities of DDM are deemed to be its greatest strengths [18, 19, 20].
As a candidate for an rhBMP-2 carrier, Ike et al. reported that xenogenous rhBMP-2 adsorbed into pulverized root and partially DDM proved to be as osteoinductive as an autogenous bone graft [18]. Murata also showed that human DDM particles are osteoinductive, insoluble collagenous matrices, and that DDMs might be effective as an rhBMP-2 carrier for bone engineering [19].
The first report of human DDM/rhBMP-2 have demonstrated that DDM displays the highest released to loaded rhBMP-2 ratio, the lowest release speed, and the highest induction of osteonectin expression, resulting in augmented mature bone formation compare with tricalcium phosphate (TCP) [12]. Um et al. examined the bone induction capacity of DDM/ rhBMP-2 compare with conventional TCP in the muscle pouches of nude mice. The results were that the early cellular reaction on the surface of particles was superior in the DDM/ rhBMP-2 group, more osteoid was deposited on the DDM/ rhBMP-2 group [25].
In the rabbit’s calvarial defect, the DDM and anorganic bovine bone combined with rhBMP-2 (ABB/rhBMP-2) groups showed osteoconductive bone formation, while the DDM/rhBMP-2 group showed osteoconductive and osteoinductive bone formation. The DDM/rhBMP-2 group showed a twofold greater amount of bone formation compared to the DDM alone and ABB/rhBMP-2 groups. The μCT analysis showed markedly increased bone volume in the DDM/rhBMP-2 group at eight weeks compared with that of the DDM group [21]. Kim et al. evaluated the efficacy of DDM/rhBMP-2 in the unilateral upper second and third premolars of eight beagles compare with the autogenous bone and reported equality of DDM/rhBMP-2 to autogenous bone [24].
Case series study of comparing short term outcome of DDM/rhBMP-2 (Bioα, Seongnam, Korea) with hydroxyapatite (HA)/rhBMP-2 (Bioα, Seongnam, Korea), reported that rhBMP-2 combined with HA or DDM scaffolds can be used for bone graft procedures such as guided bone regeneration [20].
About the effectiveness of DDM/rhBMP-2 (CowellMedi, Busan, Korea) for alveolar bone repair [27, 28], the clinical findings with respect to the healing process were that there were no remarkable inflammation and immune rejection that impair the healing process and are coincident with those of the previous studies of DDM alone [8, 10, 29]. The nanopore structure of dentinal tubules in unique avascular and acellular Type I collagenous dentin matrix seems to make it feasible to carry and release rhBMP-2 effectively on local site based on the previous study [30, 31].
In the clinical study of histological comparison of autogenous and allogenic DDM/rhBMP-2 at the site between the implant cover screw and gingiva, as the poor blood supply allows it to simulate a heterotopic condition, three patients undergoing simultaneous implant placement and receiving a different type of graft were included: allogenic DDM loaded with rhBMP-2 (DDM/rhBMP-2), autogenous DDM/rhBMP-2 and autogenous DDM. After 3–6 months of grafts, the antigenicity and immunogenicity of the carrier allogenic DDMs are low enough to maintain both the biocompatibility of the scaffold and the activity of the loaded rhBMP-2 [22].
Jeon et al. reported study to evaluate soft tissue volume change after socket preservation using DDM alone, DDM/rhBMP-2 and Bio-Oss collagen (Geistlich, Wolhusen, Switzerland). According to soft tissue volume changes, each groups showed statistically meaningful volume decreases. Bio-Oss collagen showed 15.4% volume decrease, DDM showed 18.8% and DDM/rhBMP-2 showed 16.1% decrease, respectively. However, there were no significant differences among groups [23].
In the clinical study of a total of 23 patients who received bone grafts using human DDM/rhBMP-2 with implant placements (36 implants; maxilla: 14, mandible: 22). The implant stability, marginal bone loss, and clinical outcome were evaluated. Favorable osseointegration was obtained in 35 out of 36 implant sites (one case of osseointegration failure) and severe complications were not observed in all cases [24].
Each case report represent socket preservation, GBR, ridge split and expansion, onlay graft with simultaneous or staged implant placement. Besides the crucial factors for implant success such as stability, peri-implantitis, the first critical observation in this case presentation is the texture of tissues formed around the implant at second surgery time without using any membranes. The powder or block that were no longer visible when the flap reflected at 3–6 months after graft indicated good incorporation and remodeling capacities of DDM into host bed. These phenomena might be explained by the synergistic effect of exogenous rhBMP-2 with endogenous growth factors in DDM that is both increased bone formation and accelerated DDM degradation. This is assumption raised and explained in the previous report [18, 19, 31].
Second observation is the structure of bone around the implant neck area where the major peri-implantitis start and accumulated. What we need for ideal osseointegration is sound alveolar bone with appropriate volume and shape at this defense front area. The sound alveolar bone consist of cortical bone with enough thickness, and cancellous bone with mature bone marrow that is inevitable for continuous remodeling with standing for occlusal forces. At least one year after final prosthesis, we found sound cortical bone supported by fully developed cancellous bone in CBCT analysis. And the time to achieve sound bone around the neck area might be faster than that of DDM alone [8].
Third observation is histologic evidences we presented recently that shows more bone formation at each time point and accelerated resorption of DDM compare to other carriers such as HA and TCP [25].
Finally, the rationale for not using membrane is that carrier DDM is a collagenous scaffold with minerals to be able to absorb enough blood resulting in space maintenance and invasion of blood vessels from the host. In the clinical study of DDM/rhBMP-2 application in on extraction socket preservation, there were no cellular invasion from gum tissues to hinder bone formation clinically and radiologically [25].
The clinical application of DDM/ rhBMP-2 showed successful alveolar socket preservation, GBR, onlay graft in implant dentistry without any complications. Furthermore, this clinical success may open the way to new technology for alveolar bone repair, even though the cases presented here are small numbers and not representative to conclude the clinical superiority compare to others. For example, because the long term data of DDM/rhBMP-2 in sinus augmentation are not established yet, we need to collect more data from well controlled prospective studies.
Based on several other reports that have shown favorable results from using DDM/rhBMP-2 in implant dentistry, we are going to perform more number of clinical studies such as prospective, randomized, controlled clinical trials for the purpose of assuring the safety and efficacy of DDM as a promising carrier for rhBMP-2.
By the application of rhBMP-2 from experimental researches to clinical reality, the number of choice of alternative bone graft substitutes has been increased in implant dentistry. Although significant effort has been made to find a safer, cheaper, and more efficient scaffold for rhBMP-2 carrier, there have not been sufficient studies and efforts that focused on the application of rhBMP-2 in dental field.
By the discovery and successful applications of DDM as rhBMP-2 carrier in implant dentistry, we might have cheaper, safer and more efficient bone graft substitute. Reduced concentration of rhBMP-2 with similar or superior efficacy in inducing bone formation without the adverse effects made the DDM/rhBMP-2 revolutionary cost-effective and safe that eliminates most of the side effects associated with supraphysiologic overdose concentration.
Up to date, the long term results of DDM/rhBMp-2 are clearly promising in biologic activities and cost-benefits for the patients that would open the door to develop DDM as carrier of stem cells to be applied in implant dentistry.
This study was provided the data by the Seoul National University Bundang Hospital, Peking University, and the In-Dental Clinic.
The authors have declared that no conflict of interests exists.
Originated from Asia, soy is the largest oilseed in volume, production and international trade. In terms of food, soy is the main source of protein and the second most consumed oil in the world, only behind palm [1]. Furthermore, it has an importance that involves the development of a productive complex including the processing of the bean and its main products: crude oil and bran; also, its use for animal food edible oil and fuel (see Figure 1).
Soy production chain.
The soybean industrial processing can be summarized in two steps: (1) the crude oil production with soybean residue; (2) Crude oil refining to obtain other products (e.g.: refined oils, margarine, hydrogenated fat).
The volume of soy sold is extremely important for the economy, especially for the main world producers, such as Brazil. In order to have a positive trade balance, Brazil needs to export tons of primary products, which have low unit values to offset the import of value-added products, such as electronic appliances and machines. In addition, processing soybeans increases the job offer, further heating up the economy. Therefore, adding value to the soy production process is very important for a country’s economy.
Based on this, this chapter aims to discuss and present routes for the processing of soy, especially the Deodorized Soybean Oil Distillate (DSOD) and viable options to produce biodiesel to add value to the soy chain.
Refining consists of a set of processes that aim to transform crude oils into edible oils. The refining process aims to improve the appearance, odor and taste of the oil, which occurs with the removal of certain components from the crude oil. There are two types of refining, chemical and physical. These names are related to the process of removing unwanted fatty acids in the oil. The main steps in the refining processes are: degumming (hydration), neutralization (deacidification), whitening (clarification) and deodorization.
The removal of traces of components responsible for undesirable odors and tastes occurs in the step called deodorization. According to Sangoi and Almeida [2], the reduction of free fatty acids contained in oils promotes the removal of flavors and odors, at a range of 0.01% to 0.03%, eliminating the undesirable characteristics of the oil. This step generates a residue known as a distillate from soybean oil deodorization. According to Ma and Hanna [3], this substance is concentrated in tocopherols (vitamin E), sterols and fatty acids. DSOD is obtained from the precipitation of an aqueous phase during deodorization, and the compounds of interest are insoluble in water [4].
According to Aranda and Morlock [5], to produce a ton of biodiesel 0.91 tons of fatty acids are needed. According to Fontana [6], 0.1% of DSOD are generated in the refining of soybean oil, which would provide a quantity of 6440 tons of fatty acids, considering a production of 9.2 million tons of oil, according to Abiove [7] and an average percentage of 75% of fatty acids in DSOD. These values show the potential of the residue, increased by the logistical facility, as it is found in oil refining industries, unlike residual oils, which have a high logistical cost and variable production.
The most interesting components present in the sludge are fatty acids, however some works have evaluated the potential of other components such as sterols, tocopherols and squalene.
There are studies in the literature that evaluated the extraction of components from the deodorized distillate, such as sterols using supercritical extraction. The results show a recovery of 76% with a purity of 60%, both by weight. These substances are important because they act in the reduction of cholesterol in the blood, being of great interest to the pharmaceutical industry [8]. Similar works using enzymes are also presented and recovery of up to 87.7% of sterols [9].
Biodiesel is currently an important biofuel of global interest, as it is considered a sustainable energy source of renewable origin [10]. As the most used raw material for production is refined soy oil, the production of fuel has the potential to close the carbon cycle [11]. In addition, the use of biodiesel generates less pollutants than fossil diesel, mainly CO2, CO and SO2, although it presents higher NOx emissions [12, 13].
Brazil is a major world producer of biodiesel, ranking second in production volume in 2021, totaling approximately 6.9 billion liters, only behind the United States, which will produce more than 8.5 billion liters [14].
Another option to add value with deodorized distillate is direct esterification, that is, the synthesis of fatty acids to esters. This pathway was evaluated in a subcritical environment, as fatty acids are miscible in ethanol, unlike triglycerides, which are constituents of refined oils. These conditions, even though they demand high temperatures, dispense with the catalyst separation step, allowing for greater gains in the process. Some studies point to a 97% conversion of fatty acids into esters using subcritical environments at 100°C [15].
The economic potential of a complete process is available in the literature [16]. The work evaluated the potential of DSOD for the supercritical synthesis of esters and recovery of squalene. The squalene recovered was 31 g per kg DSOD with 98% purity by weight, the esters had a purity of 88% plus a mixture of tocopherols and sterols. The results of the economic analysis show, for the worst scenario, that is, with higher raw material values and lower product sales, a gross margin (MB) of 35% and the contribution margin index (BMI) of 29% for DSOD. These indicators are presented in Eq. 1 and 2.
Other alternative routes are discussed in this chapter. The focus is on the synthesis of biodiesel via chemical reactions other than transesterification via heterogeneous, enzymatic and medium catalysis conventional supercritical, which promote the synthesis under different conditions.
As the formation of glycerol as a by-product is linked to the transesterification of triglycerides by alcohols, other supercritical routes propose to use other reagents for the same purpose – methyl acetate, acetic acid and dimethyl carbonate –, generating by-products of greater economic value than glycerol. These alternative routes, therefore, have all the advantages and disadvantages mentioned for the supercritical transesterification process, with the difference that they present more economically attractive by-products [13].
This route consists of a single step, in which the interesterification between the methyl acetate and the triglyceride of the oil takes place, forming the fatty acid methyl esters and the triacetin as a by-product. The reaction, like the transesterification, occurs in three reversible steps: in the first, a triglyceride molecule reacts with a methyl acetate molecule to form a FAME (fatty acid methyl esters) and monoacetyl diglyceride molecule. Then, one molecule of monoacetyl diglyceride reacts with the second molecule of methyl acetate to form another of FAME and diacetyl monoglyceride; finally, diacetyl monoglyceride reacts with a methyl acetate molecule to form the third FAME molecule and triacetin, as can be seen in Figure 2.
Overall FAME synthesis reaction from triglycerides and methyl acetate.
If fatty acids are present in the oil, they are esterified by methyl acetate in FAME, generating acetic acid as a by-product. Other parallel reactions that can occur are the hydrolysis of triglycerides due to the presence of water, forming fatty acids and glycerol. This, in turn, reacts with acetic acid derived from esterification, forming triacetin and water [17, 18].
Triacetin formed as a by-product is the great advantage of this route. Although, its commercial value is greater than that of glycerol, the sale of biodiesel with this substance in its composition can be even more advantageous as it will increase the volume of biofuel generated, now a mixture of FAME and triacetin. Thus, there would be no need to purify triacetin in the process [18].
This final product alternative is only possible because triacetin, in addition to being miscible with fatty acid methyl esters, does not influence the fuel properties in a way that leaves them out of the pattern. Important properties of biodiesel as a fuel, such as kinematic viscosity, pour point, cloud point, cold filter plugging point, flash point and cetane number, are not changed with the addition of the by-product, remaining within European and North American standards [19]. However, due to the influence on the heat of combustion and density of the biofuel, the ideal is a mixture with a maximum of 10% by mass of triacetin - the European standard establishes 900 kg/m3 as a density limit, as well as the Brazilian legislation on ANP [18, 20, 21].
Figure 3 shows a preliminary scheme for the process was proposed by Saka and Isayama [18].
Simplified diagram for the interesterification process with methyl acetate. Source: [
This route consists of two steps: in the first, triglycerides, when reacting with acetic acid, are converted into fatty acids, which are esterified by methanol to FAME. The main justification for this route is the adoption of reaction temperatures of up to 300°C, avoiding thermal degradation of the esters.
The route begins with the breakdown of triglycerides in the oil by acetic acid, a reaction in which one mole of triglyceride reacts with three moles of acid, forming one mole of triacetin and three moles of fatty acid, as shown in Figure 4. The reaction also takes place in three reversible steps: first, an acetic acid molecule reacts with a triglyceride molecule, forming a fatty acid molecule and a monoacetyl diglyceride molecule, which reacts with another acetic acid molecule to form the second fatty acid molecule and diacetyl monoglyceride; this reacts with the last acetic acid molecule to form again fatty acid and finally triacetin [22].
Hydrolysis reaction between triglyceride and acetic acid. Source: [
Regarding the cost of raw materials, acetic acid is a viable obtaining reagent because it is a commodity of the chemical industry, mainly used for the production of the acetate monometer of vinyl, for the production of polyvinyl acetate (PVA) [23].
The second reaction of this route takes place in just one reversible step, in which a fatty acid molecule reacts with a methanol molecule, forming a FAME molecule and a water molecule, as shown in Figure 5.
Esterification reaction between fatty acids and methanol.
After step 1, where the oil reacts with acetic acid through subcritical hydrolysis, the reaction products are separated by aqueous washing, from which triacetin and acetic acid are recovered in the step aqueous and fatty acids are taken to the second reactor with methanol under supercritical conditions for esterification. A phase separator is used to recover some of the excess methanol, followed by an unspecified scrubber that will separate the rest of the methanol and water from the FAME. The aqueous phase of the first stage is also subjected to unspecified purification to obtain triacetin, which will be mixed with FAME and, thus, composes the biodiesel in the final product. Performing an intermediate separation between the two steps can be advantageous to reduce the size of equipment in the second step. However, this imposes successive heating and cooling on the process, increasing energy expenditure, which can be one of the biggest disadvantages of this route [22].
Literature reports a yield of 95% in mass compared to the oil used in the first step, with only 2 minutes of reaction at 300°C and 15 minutes of reaction at 270°C. This approach to this process is interesting because, in addition to avoiding the saturation of the triacetin market, a phenomenon observed for glycerol, it is possible to increase the net production of FAME [24]. Saka et al. [22] suggested a diagram for this route, shown in Figure 6.
Diagram of the process of hydrolysis with acetic acid and esterification with methanol. Source: [
The third route is to obtain FAME from a reaction between triglycerides and dimethyl carbonate. Unlike all the other pathways described, this reaction takes place in two reversible steps: in the first, a DMC molecule reacts with a triglyceride molecule, releasing two FAME molecules and an intermediate, the fatty acid glycerol carbonate (FAGC - fatty). acid glycerol carbonate). In the second step, the FAGC molecule reacts with the second DMC molecule to form a FAME molecule and the by-product of the route, glycerol dicarbonate [25]. The reaction and its stoichiometry are shown in Figure 7.
Two-step reaction with dimethyl carbonate. Source: adapted from [
DMC is an attractive reagent because it can be considered a green alternative in the organic synthesis industry and has several applications as a methylation and carbonylation agent. It is a non-toxic and biodegradable substance, which is obtained by environmentally interesting routes. The most used industrial route today is the oxidative carbonylation of methanol with carbon monoxide and oxygen, catalyzed by copper(I) chloride. As methanol and carbon monoxide can be obtained from biomass synthesis gas, obtaining biodiesel using DMC from this route would only use reagents of renewable origin [26, 27, 28].
Another important point is the fact that DMC does not decompose at temperatures lower than 390°C, so using it as a reagent in supercritical processes is viable [29].
Biodiesel production by this route via supercritical process was studied using crude oils of
The two-stage route, as well as for the methanol and acetic acid routes, has the advantage of being able to apply milder process conditions to avoid product degradation. However, this pathway generates glycerol as a by-product, although this can be converted to glycerol carbonate, a compound with greater added value, when reacting with DMC [29, 31].
The mixture of FAME and glycerol dicarbonate can be used as biodiesel, without harming its properties, as well as with triacetin. After the reaction to obtain FAME and the removal of excess dimethyl carbonate, the remaining product – FAME and DCG – was analyzed, showing that its properties were within the parameters established by the American and European standards. However, as it is an intermediate for glycerol carbonate, a compound with a high market value, glycerol dicarbonate and FAME can also be separated in a distillation column, depending on the strategy and economic feasibility of the process [30]. The complete flowsheet for the described process is shown in Figure 8.
Process using DMC as a reagent, producing FAME and glycerol dicarbonate (DCG) as products. Source: [
This chapter shows the potential of soy as a raw material for a biorefinery, that is, obtaining several high added value products through different technological routes. The residues of this oilseed can be used to obtain these products with high added value without competing with the food sector. Routes that make the production of biodiesel viable are real and technically feasible, in addition to the generation of co-products of greater interest such as: tocopherols, sterols, squalene, triacetin, DCG. Another interesting point is the flexibility that some products allow when generated together with the esters, as they do not interfere with the quality of the biofuel. Soy has a wide range of exploration possibilities, and its production follows the pace of industrial production. Studies that make its development economically viable are the biggest challenge, as the technical feasibility is well consolidated.
The authors are grateful to SENAI CIMATEC for their financial support.
The authors have no conflict of interest.
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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\n\nIntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. 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Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. 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She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. He then completed his Fellowship in Cardiothoracic Surgery at Monash Health, Melbourne, Australia in 2008. He has served in the Malaysian army as a Medical Officer with the rank of Captain upon completing his Internship before joining USM as a trainee lecturer. He is now serving as an academic and researcher at Monash University Malaysia. He is a life-member of the Malaysian Association of Thoracic & Cardiovascular Surgery (MATCVS) and a committee member of the MATCVS Database. He is also a life-member of the College of Surgeons, Academy of Medicine of Malaysia; a life-member of Malaysian Medical Association (MMA), and a life-member of Islamic Medical Association of Malaysia (IMAM). Recently he was appointed as an Interim Chairperson of Examination & Assessment Subcommittee of the UiTM-IJN Cardiothoracic Surgery Postgraduate Program. As an academic, he has published numerous research papers and book chapters. He has also been appointed to review many scientific manuscripts by established journals such as the British Medical Journal (BMJ). He has presented his research works at numerous local and international conferences such as the European Association for Cardiothoracic Surgery (EACTS) and the European Society of Cardiovascular Surgery (ESCVS), to name a few. He has also won many awards for his research presentations at meetings and conferences like the prestigious International Invention, Innovation & Technology Exhibition (ITEX); Design, Research and Innovation Exhibition, the National Conference on Medical Sciences and the Annual Scientific Meetings of the Malaysian Association for Thoracic and Cardiovascular Surgery. He was awarded the Darjah Setia Pangkuan Negeri (DSPN) by the Governor of Penang in July, 2015.",institutionString:null,institution:{name:"Monash University Malaysia",country:{name:"Malaysia"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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