Review of Allogeneic Dentin Graft for Maxillofacial Bone Defects

Abstract

Although autogenous demineralized dentin matrix (auto-DDM) has shown promising clinical and histological results, it has certain limitations beyond its osteoinductivity and osteoconductivity. Therefore, the application of dentin graft material from other individuals—allogeneic DDM (allo-DDM)—has been considered an alternative to auto-DDM. However, few studies have investigated the osteoinductivity and antigenicity of allo-DDM. Herein, we reviewed all human studies related to allogeneic dentin application for the management of maxillofacial bone defects. Clinical studies have shown the osteoinductivity of allo-DDM in extraskeletal and skeletal sites, regardless of occasional antigenicity.

Impact statement

Although autogenous demineralized dentin matrix (auto-DDM) has shown promising clinical and histological results, it has certain limitations beyond its proven osteoinductivity and osteoconductivity. Therefore, the application of dentin graft material from other individuals—allogeneic DDM (allo-DDM)—has been considered as an alternative to auto-DDM. However, few studies have investigated the osteoinductivity and antigenicity of allo-DDM. This is the first review of all human studies related to allogeneic dentin grafts for the management of maxillofacial bone defects. Clinical studies have shown the osteoinductivity of allo-DDM in extraskeletal and skeletal sites, regardless of occasional antigenicity.

Introduction

The dentin has a chemical composition similar to that of the bone, such as biological apatite (hydroxyapatite: 70% weight/volume [w/v]), collagen (18% w/v), noncollagenous proteins (2% w/v), and body fluid (10% w/v); however, in addition to the aforementioned chemical components, the bone has osteocytes and vessels. Among noncollagenous proteins, bone morphogenic proteins (BMPs) and fibroblast growth factors are matrix-binding proteins, whereas osteocalcin is a mineral-binding protein.¹ The demineralization process, developed by Urist in 1965,² exposes collagen fibers and osteoinductive factors normally contained in the dentin, and increases their bioavailability. The demineralization of dentin matrix involves the removal of inorganic salts with minimal leaching or denaturation of the organic components of the matrix; thus, a demineralized dentin matrix (DDM) is a cell-free matrix defined as an acid-insoluble highly cross-linked type I collagen with matrix-binding proteins such as BMPs and microporous dentinal tubules.³ The osteoinductive and growth factors in DDM contain 5% of the full array of naturally occurring growth factors such as transforming growth factors, insulin growth factors, fibroblast growth factors, and BMPs.^4,5 Moreover, human dentin matrix-derived BMPs have the same action as bone-derived BMPs in vivo.⁶

The application of autogenous DDM (auto-DDM) with osteogenic potential has shown promising clinical and histological results as an alternative to autogenous bone grafts.^7–9 The first auto-DDM application in humans was reported for maxillary sinus augmentation in 2003.¹⁰ In 2006, Gomes et al.¹¹ conducted the first human clinical study using auto-DDM and reported that the rate of bone formation was higher in the auto-DDM group than in the control (empty) and polytetrafluoroethylene membrane without graft groups. Since then, several human clinical studies^12,13 have reported the regenerative potential of auto-DDM in guided bone regeneration (GBR),^9,14 maxillary sinus augmentation,¹⁵ and socket preservation.¹⁶ However, beyond its osteoinductivity and osteoconductivity, auto-DDM has the following limitations: patients may not accept their own teeth instead of conventional materials, the quantity is dependent on the number of teeth indicated for extraction, the quality of the graft depends on the nature of the extracted teeth, and the processing method of auto-DDM has not been standardized. Consequently, the use of teeth extracted from other individuals, such as teeth extracted before orthodontic treatment and impacted third molars, to obtain allogeneic DDM (allo-DDM), has been considered an alternative to auto-DDM.¹⁷

The idea of allo-DDM came from a demineralized bone matrix (DBM), largely developed by Urist in 1965. DBM is a type of refined allograft that has great biocompatibility and a low probability of transmitting diseases.^2,18 DBM has been clinically used since the beginning of the 1980s; however, studies have reported heterogeneous results.^18–20 Many preclinical studies have reported that allo-DDM is an “inductive substrate” because the bone inducer originating from the extracellular dentin matrix has similar osteoinductivity to that of auto-DDM,^21–25 which, in turn, is similar to that of DBM.^2,26 Allo-DDM transforms the mesenchymal fibroblasts into cartilage or bone cells.²⁷ One of the transforming factors present in both the dentin and bone matrix is BMP.^28,29

After implantation of decalcified dentin and bone, the cell sequences of transformation suggest that the graft is invaded by the vascular mesenchyme with a brief inflammatory reaction. Some mesenchymal cells become multinucleated giant cells that erode the tunnels in the matrix and enlarge pre-existing cavities. The matrix surrounding the eroded chambers is recalcified, presumably because of the diffusion of mineral ions from the new blood vessels. Thereafter, osteoblasts replace the multinucleated cells on the eroded and calcified surfaces and begin to deposit the bone matrix. The amount of new bone induced by allo-DDM is almost twice as high as that induced by decalcified cortical bone grafts.^25,30 Bakhshalian et al.³¹ reported that allo-DDM significantly increased bone mass and improved bone quality without causing an inflammatory reaction or infection at the tissue level in a rat calvarial defect model. Koga et al.³² reported that partially demineralized (70%) human dentin matrix powder showed superior bone regeneration compared with completely DDM and mineralized dentin. In addition, Um et al.³³ were the first to report that partially demineralized (% not specified) allo-DDM showed osteoinductivity and osteoconductivity, which facilitates bone formation.

Regarding the clinical application of allo-DDM, Register et al.³⁴ first introduced the use of human allo-DDM as an osteoinductive material in 1972. There is little evidence of clinical effectiveness due to the heterogeneity of clinical outcomes.³⁵ In the 2010s, a tooth from a biological family member was used as an allo-DDM bone graft material. Familial tooth bone grafts have shown successful clinical results comparable with those of auto-DDM.^36,37 Earlier clinical studies on allo-DDM, although few, reported mixed results on its osteoinductivity and antigenicity. To date, few studies have investigated the use of allo-DDM in alveolar bone repair for dental implantation. This review summarizes the clinical outcomes of allo-DDM for bone regeneration in the maxillofacial region to determine its feasibility for human clinical applications.

Methods

Search strategy

In this review, we included human clinical studies that analyzed or used allo-DDM. We excluded studies that were not published in English. The Google Scholar, ISI Web of Knowledge, PubMed, EMBASE (1950–2021), and Cochrane databases were searched in March 2021 using the keywords allogeneic and dentin.

The primary objective outcomes were histological and radiological outcomes with other clinical signs and symptoms. A total of 14 human clinical studies on allo-DDM application were included in the analysis.^{17,34,35,37–47} Three studies reported the histological and clinical features of the gingiva, frenum, and buccal mucosa.^34,35,38 Five studies reported clinical results of allo-DDM grafts in subperiosteal and infrabony periodontal pockets.^39–43 Six studies reported the histological and radiological changes in the height and width of the alveolar ridge after socket preservation in relation to dental implants^{17,37,44–47} (Table 1).

Table 1.

Summary of Human Clinical Studies on the Use of Allogeneic Dentin Graft

Year Authors (Reference)	Type of study (follow-up period)	Graft site	Processing of graft	Degree of demineralization	Geometry of graft	Significant findings at the end of the study
Soft tissue
1972 Register et al.³⁴	Report of two cases (90 days and 6 months)	Gingiva	Demineralization (0.6 N HCl at 2°C for 5 days, lyophilization, 0.2 Mrad, 70% ethyl alcohol)	Complete	Slice (1 mm³)	Osteoinduction by the cell-free organic matrix of dentin. No clinical evidence of allergic or immunological responses noted on repeated implantation.
1974 Knudsen et al.³⁸	Report of 12 cases (30 weeks)	Gingiva (6 patients) Frenum (6 patients) (total 15 implants)	Demineralization (0.2 N HCl at 4°C for 2 days, lyophilization, EO sterilization)	Not available	Pieces (Gingiva: 4 × 4 × 2 mm; Frenum: 2 × 2 × 1)	No osteoinduction: lack of inflammation no foreign body reaction hard tissue formation in one case no heterotopic bone formation.
1978 Morris³⁵	Report of 13 cases (7 adult male patients and 6 adult female patients) (4–13 weeks)	Lower right buccal mucosal pocket within the soft connective tissue	Demineralization (5% EDTA for 3 weeks)	Complete	Root slice (length: 5–7 mm)	No new bone formation: human dentinal matrix is not a bone inducer but a bone conductor.
1978 Morris³⁵			Demineralization (0.6 N HCl at 4°F for 3 weeks)	Complete	Root slice (length: 5–7 mm)	No new bone formation: antigenic effect: extensive resorption of implant.
Periodontal osseous defect
1975 Nordenram and Bang³⁹	Report of one case (2 years)	Subperiosteum: alveolar process of upper left incisor	Demineralization (0.2 N HCl at 4°C for 6 days, lyophilization, EO sterilization)	Complete	Pieces (1/4 root)	Aesthetically and functionally satisfactory result.
1975 Nordenram et al.⁴⁰	Report of 33 cases (66 months)	Cystic jaw cavity	Demineralization (0.6 N HCl at 20°C for 1 day, lyophilization, EO sterilization)	Complete	Pieces (1/4 root)	Radiological evaluation: satisfactory More immediate postoperative symptoms than in the control group. Higher incidence of complete healing of the cystic cavity. Lower incidence of operational defects.
1982. Movin and Borring-Møller⁴¹	Randomized controlled trial; 22 patients (12 months)	2–3 walls periodontal defect (10 patients, 14 defects)	Demineralization (0.2 N HCl at 4°C for 6 days, lyophilization, EO sterilization for 3 h)	Complete	Root dentin pieces without pooling (1 mm³)	Clinical evaluation: not satisfactory Delayed soft tissue healing in the first week Allo-DDM is not recommended for the treatment of infrabony periodontal defects.
		(12 patients, 6 defects)	Autogenous bone
		(12 patients, 6 defects)	No graft
1983 Schwartz⁴²	Report of 13 cases (24 weeks) Allogeneic immune reaction	Subperiosteal implant for augmentation of an edentulous alveolar ridge	Demineralization (0.4 N HCl at 4°C for 6 days, lyophilization, EO sterilization)	Complete	Root slice without pooling (2 mm thickness)	Immunity: implantation of allo-DDM occasionally elicits a measurable allogeneic immune response that is not contraindication for a later allogeneic transplantation.
1986 Fugazzotto et al.⁴³	Report of 15 cases (at least 6 months)	Periodontal osseous defect	Mineralization (freeze-drying, EO sterilization)	Nondemineralized	Powder (300–500 μm)	Osteoinductive function: merits as an osteoinductive material in periodontal osseous defects.
Alveolar bone repair for dental implant placement
2014 Kim et al.³⁷	Report of two cases (8 months and 3 months)	Upper anterior with daughter's third molar Upper left molar with son's third molar	Partial demineralization (0.6 N HCl, at 20°C for 1 h, Freeze-drying, EO sterilization)	Partial (10–30% residual Calcium contents)	Root block and powder (300–800 μm)	Successful bone formation confirmed histologically.
2017 Kim et al.⁴⁴	Observation study of seven cases (average 40 months)	Alveolar bone augmentation with 19 implants	Partial demineralization (0.6 N HCl, at 20°C for 1 h, freeze-drying, EO sterilization)	Partial (10–30% residual calcium contents)	DDM powder (300–800 μm)	Successful bone augmentation, socket preservation, and maxillary bone grafting performed using familial tooth bone graft materials.
						No postoperative complications (wound dehiscence or infection) Successfully functioning implants without failure of osseointegration.
						Marginal bone loss: 0.1–3.5 mm at a mean follow-up of 40 months.
2017 Kim et al.⁴⁵	Retrospective clinical study of 18 patients (average 12 months)	Socket preservation with dental implant	Partial demineralization (0.6 N HCl, at 20°C for 1 h, Freeze-drying, EO sterilization)	Partial (10–30% residual calcium contents)	DDM powder (300–800 μm)	Clinical aspects of Allo-DDM: completely remodeled and newly formed bone with vascularization
						Early immune response until postoperative day 10; Rare early signs of redness and occasional swelling in 4 of 18 cases
						Histology at 4–6 months: Hard tissue formation around allo-DDM. Allo-DDM particles completely remodeled at a later stage.
2017 Joshi et al.¹⁷	Randomized controlled trial of 15 patients (average 4 months)	Mineralized WTA	Mineralization (freeze-drying, EO sterilization)	Nondemineralized	Powder without pooling (300–500 μm)	Radiology and histology: mineralized dentin is more promising than FDBA in achieving minimum volumetric alveolar bone loss in alveolar ridge preservation procedures.
		Mineralized DA	Mineralization (freeze-drying, EO sterilization)
		FDBA	Mineralization (freeze-drying, EO sterilization)
		No graft (negative control)	—
2019 Joshi et al.⁴⁶	Report of one case (4 months)	Ridge augmentation on the upper right canine	Mineralization (freeze-drying, EO sterilization)	Nondemineralized	Pooling (WTA+autologous fibrin glue)	Clinical and radiological outcomes: WTA resulted in substantial gain in alveolar bone width and height.
2020 Um et al.⁴⁷	Retrospective clinical trial of 96 patients (12 months after prosthetic loading)	Socket preservation with dental implant	Partial demineralization (0.6 N HCl, at 20°C for 1 h, freeze-drying, EO sterilization)	Partial (10–30% residual calcium contents)	DDM powder (300–800 μm)	Mean marginal bone loss: 0.69 mm and 0.48 mm in 12 months after the placement of auto-DDM and allo-DDM, respectively.
2020 Um et al.⁴⁷		Socket preservation with dental implant		Partial (10–30% residual calcium contents)	DDM powder (300–800 μm)	Use of allo-DDM in GBR showed successful clinical results comparable with those with auto-DDM in terms of buccal marginal bone resorption during the first year of functional loading.

allo-DDM, allogeneic DDM; auto-DDM, autogenous demineralized dentin matrix; DA, dentin allograft; DDM, demineralized dentin matrix; EDTA, ethylenediaminetetraacetic acid; EO, ethylene oxide; FDBA, freeze-dried bone allograft; GBR, guided bone regeneration; WTA, whole tooth allograft.

Clinical Considerations of Allo-DDM

To assess the antigenicity of allo-DDM, each slice of root dentin (2 mm thickness) was demineralized with 0.4 N HCl before subperiosteal implantation for augmentation of an edentulous alveolar ridge and followed up for 24 weeks.⁴² The antidonor cell-mediated immunity and humoral-mediated immunity of the 13 patients were monitored during the first 6 postoperative months. The results suggested that allo-DDM implantation occasionally elicited a measurable allogeneic immune response.⁴² In Korea, Kim et al.^37,44,45 assessed clinical, histological, and radiological outcomes of dental implantation and reported that no remarkable immune rejection or inflammation, which could delay healing, occurred, and all dental implants were successfully osseointegrated. These findings are consistent with those of Urist et al.⁴⁸ and Schwartz,⁴² who showed that although allo-DDM retained some antigenic effect in extraskeletal sites, there was no contraindication for allo-DDM transplantation.

With regard to the recipient site, significantly different aspects of the proliferating progenitors of bone cells were found between the intra- and extraskeletal sites. Friedenstein et al.⁴⁹ and Owen⁵⁰ termed osteogenic precursors or stem cells in the bone marrow as determined osteogenic precursor cells (DPOCs). DPOCs are similar to proliferating progenitors of bone cells, which can form bone without any osteoinductive agents. In connective tissues with induced osteogenic precursor cells (IOPCs), osteogenesis occurs only in the presence of an inducer that is released after osteoclastic demineralization or resorption of the dentin matrix. To maintain osteogenic activities, inducing agents such as BMPs and PDGFs, which can be burstly released by compression under physiological conditions, are required.⁵¹ Therefore, allo-DDM application should be considered depending on recipient characteristics.

Allo-DDM transplantation in soft tissues

In a study by Register et al.,³⁴ 1 mm³ slices of allo-DDM transplanted into the gingiva demonstrated osteoinductive potential as follows: (1) acceptance of processed allogeneic dentin matrix by human tissues; (2) stimulation of mesenchymal cells to differentiate into osteoblasts; (3) deposition of osteoid against an inductively active matrix; (4) formation, early calcification, and maturation of bone; and (5) survival of the induced bone for 6 months. In two studies,^35,38 4 × 4 × 2 mm and 2 × 2 × 1 mm allo-DDM pieces in the gingiva and frenum, respectively, and 5–7 mm root slices in the buccal mucosal pocket failed to induce osteogenesis and resulted in a severe antigenic effect and extensive resorption of the allo-DDM pieces.

Allo-DDM causes an insignificant immunological reaction.^{24,35,42,52–55} Moreover, the temporal sequence of fibroblast–chondroblast–osteoblast transformation is profoundly influenced by the geometry of the dentin matrix.³⁰ Hence, the authors speculated that the antigenic effect in the aforementioned studies may be due to the geometrical influences of the pieces rather than the inherent immunological response to dentin. Regarding the geometrical characteristics of dentin pieces, Reddi and Huggins³⁰ indicated that in subcutaneous tissues of rats, 5–7-mm long dentin pieces acted as osteoconductors, not osteoinductors. Compared with dentin blocks without microholes, DDM with 0.5 mm microholes resulted in more effective bone formation.⁵⁶ The absence of pores may have resulted in a hypoxic environment due to the hindrance to capillary infiltration, as reported previously.^55,57–59 Another reason might be the difference in cell populations in the vicinity of the alveolar bone between the gingiva and buccal mucosa. According to the definitions of DPOCs and IOPCs,^49,50 pieces and slices of allo-DDM were thought to be inadequate to act as continuous inducers of IOPCs in soft tissues.

Allo-DDM transplantation in periodontal osseous defects

In 1975, Nordenram and Bang³⁹ used a dentin graft treated with 0.2 N HCl to reconstruct a traumatic subperiosteal defect of the alveolar process around the maxillary left incisors. The clinical outcomes were satisfactory, both aesthetically and functionally. However, no radiological or histological reports were provided.³⁹ In a subsequent study of cystic jaw cavities with an average follow-up period of 66 months,⁴⁰ 33 patients in the allo-DDM group showed more immediate postoperative symptoms than 37 patients in the negative control group. However, the allo-DDM group had a lower incidence of operational defects and a higher incidence of complete healing of the cystic cavity on radiological examination than the negative control group.⁴⁰

Large cystic defects treated with subperiosteal grafts of 1-mm³ Allo-DDM pieces⁴¹ and mineralized powder (300–500 μm,⁴³) showed satisfactory but different clinical outcomes. Defects filled with allo-DDM pieces showed⁴¹ delayed soft tissue healing in the first week and a similar degree of regeneration as the negative control (ungrafted defects); however, definite bone regeneration was observed in cavities filled with mineralized dentin powder.⁴³ Considering the small volume of periodontal osseous defects, an allo-DDM piece (1 mm³) might be too large to be an osteoinducer, unlike mineralized dentin powder (300–500 μm) that showed complete osseous regeneration in periodontal osseous defects despite a time-lag effect on osteoinductivity in muscles and bones.^21,24 Another speculation might be the presence of DPOC, which is abundant in periodontal osseous defects and can form bone without an inducing agent. Hence, mineralized dentin with an appropriate geometry can stimulate DPOCs.^49,50 This result was in line with that reported in an in vivo study by Al-Namnam et al. (2–4 mm particles),⁶⁰ and Borman et al. (allo-DDM slice with 300 μm pores),⁵⁵ in which bone formation in skeletal defects was successfully achieved with mineralized dentin grafts. These results showed DDM as an osteoinductive substrate in extraskeletal sites^21,25,61 and mineralized dentin as an osteoconductive scaffold in skeletal sites.^55,60 Therefore, the aforementioned differences in outcomes might be due to the combination of geometrical influence and the size of the bone defect.

With regard to geometry, DBM powder with a particle size of 420–850 μm showed the maximum inductive effect on local fibroblasts for endochondral bone formation, whereas smaller sized particles (≤74 μm) showed delayed development of cartilage and scanty chondroblasts.⁶² In the 2010s, allo-DDM powder with a particle size of 300–800 μm exhibited excellent bone-forming capacity.^31,33 Recently, Koga et al.³² reported that in a rat calvarial defect model, human DDM (70% demineralized) with smaller particle sizes (180–212 μm and 425–600 μm) showed superior bone regeneration capacity compared with that with a large particle size (1000 μm). Unlike DBM, dentinal tubules in DDM are a critical three-dimensional structure, considering the microporous structure for exchanging proteins in host tissues. Human dentinal tubules (20,000–60,000/mm³, ∼3 μm in diameter) have a unique spatial structure that is enlarged into a microporous geometric structure (3–20% of porosity) during the demineralization process. This enhances osteoinductivity and facilitates the release of the dentin matrix-derived growth factors.^63–67 Overall, the defect size and geometry of the dentin matrix, regardless of demineralization, might be more influential in bone formation in periodontal osseous defects.

Allo-DDM transplantation for dental implant placement in alveolar bone repair

In 2014, Kim et al. reported two cases of allo-DDM grafting for alveolar bone augmentation to place a dental implant.³⁷ Allo-DDM was obtained from the wisdom teeth of the daughter and son of the two patients. Partially demineralized dentin powder (300–800 μm) and block-type root dentin (AutoBT, Korea Tooth Bank, Seoul, Korea) were prepared from the wisdom teeth. Excellent clinical outcomes were achieved, and new bone formation around dental implants was confirmed histologically.³⁷

In 2017, Kim et al. reported two clinical studies on allo-DDM grafts.^44,45 The first study was a retrospective observational study of seven patients who received allo-DDM grafts, which were fabricated from the teeth of biological family members.⁴⁴ They reported successful clinical outcomes in terms of alveolar bone augmentation, socket preservation, and maxillary bone grafting. Postoperative complications, such as wound dehiscence and/or infection, did not occur. All 11 dental implants were successfully osseointegrated and functioned properly without any complications. The average marginal bone loss around dental implants at the 85-month follow-up was 1.1 mm (range, 0.1–3.5 mm).⁴⁴

In the other retrospective clinical study on allo-DDM with dental implants for alveolar bone repair, DDM was obtained from unrelated donors.⁴⁵ They reported occasional postoperative swelling without early signs of redness in 4 of 18 patients. Histological examination at 4–6 months after grafting revealed collagenolytic degradation of the dentin matrix encapsulated in dense fibrous tissue and filled with cells. The dentin particles over the cover screw of the dental implant were completely remodeled with vascularization and filled with highly cellular and loose connective tissue.⁴⁵

The first randomized controlled trial to assess the clinical efficacy of allo-DDM for alveolar ridge preservation was performed in India.¹⁷ After atraumatic extractions, four experimental groups were defined as follows: mineralized whole-tooth allograft (WTA group, 300–500 μm), mineralized dentin allograft (DA group, 300–500 μm), freeze-dried bone allograft (FDBA group), and no graft (negative control group). Clinically uneventful healing was observed in all groups. At 4 months, compared with the other groups, the WTA and DA groups consistently showed superior results, with significantly less reduction in alveolar ridge height and width. No statistically significant differences were observed between the WTA and DA groups. Furthermore, histological analysis confirmed new bone formation with more promising outcomes for achieving minimum volumetric alveolar bone loss in the WTA and DA groups than in the FDBA group.¹⁷ Based on the above results, Joshi et al.⁴⁶ further applied mineralized WTA mixed with autologous fibrin glue in an alveolar bone augmentation procedure. Three-dimensional changes in clinical and radiological parameters were evaluated at baseline and at the 4-month follow-up. The clinical and radiological measurements of volumetric change confirmed substantial gain in alveolar bone width and height; thus, successful outcomes were achieved for alveolar bone augmentation.⁴⁶

In 2020, Um et al.,⁴⁷ in a retrospective clinical study of 96 patients, compared the GBR outcomes between auto- and allo-DDM in terms of buccal marginal bone loss around dental implants using partially DDM powder (300–800 μm). During 12 months after prosthetic loading, the mean buccal marginal bone loss in patients with auto- and allo-DDM was 0.69 and 0.48 mm, respectively.⁴⁷ Another study reported up to 1.67 mm of resorption in the first year after autogenous bone graft,⁶⁸ and the results of auto- and allo-DDM grafting around the dental implant were comparable with those of autogenous bone grafting.⁴⁷

To date, few studies have grafted allo-DDM around dental implants. At the time of article preparation, only two groups were working on allo-DDM application in humans in Korea^37,44,45,47 and India.^17,46 All six studies (five with powder and one with block and powder) reported successful clinical, histological, and radiological outcomes in terms of volume maintenance and marginal alveolar bone resorption around dental implants without immune rejection or inflammation that delayed healing. In addition, mineralized dentin powder showed more promising results than FDBA in achieving minimum volumetric alveolar bone loss in the alveolar ridge preservation procedure.¹⁷

Overall, clinical studies have reported acceptable clinical results; however, because of the limited number of randomized controlled trials and significant heterogeneity among studies on clinical applications, no interim conclusions could be drawn. As another limiting factor, there might be a publication bias, as journals, in general, favor articles reporting positive-outcome findings.^69,70 In addition, concerns regarding viral safety owing to the allogeneic origin have not been eliminated; however, the demineralization procedure extensively reduces the viral DNA in hepatitis B virus (HBV)-infected fresh dentin because of the avascular and acellular structure of dentin.⁷¹

In 2020, Ku et al.⁷² studied the in vivo efficacy of gamma irradiation for eliminating or inactivating HBV in dentin obtained from patients with chronic HBV infection by measuring the levels of HBV DNA. They suggested that gamma radiation doses of 15–25 kGy significantly reduced the levels of HBV DNA and expanded the margin of safety with regard to allogeneic application for both HBV and viruses that were not tested or unknown. However, few studies have validated viral load inactivation and its effects on the osteoinductivity of DDM. Hence, further studies addressing the issues of clinical application, including pooling, standardized processing methods, and optimal decontamination methods against HIV, Treponema pallidum, and the hepatitis C virus, in infected dentin should be conducted.

Conclusion

The number of clinical studies retrieved was insufficient to provide reasonable evidence or to draw acceptable conclusions. Although there could be a publication bias, clinical studies have shown the osteoinductivity and bone-forming capacity of allo-DDM in extraskeletal and skeletal sites, regardless of occasional antigenicity. The geometry of the dentin matrix is an important factor in determining its inductive ability. Hence, a particle size >300 μm, which was extrapolated from DDM powder, is recommended. Further studies are warranted to suggest the rationale for clinical applications, such as standardized processing for clinical safety and effectiveness, including prevention of disease transmission, optimal demineralization process, and gamma irradiation dose.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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