Dental alloplastic bone substitutes currently available in Korea

Abstract

As dental implant surgery and bone grafts were widely operated in Korean dentist, many bone substitutes are commercially available, currently. For commercially used in Korea, all bone substitutes are firstly evaluated by the Ministry of Health and Welfare (MOHW) for safety and efficacy of the product. After being priced, classified, and registration by the Health Insurance Review and Assessment Service (HIRA), the post-application management is obligatory for the manufacturer (or representative importer) to receive a certificate of Good Manufacturing Practice by Ministry of Food and Drug Safety. Currently, bone substitutes are broadly classified into C group (bone union and fracture fixation), T group (human tissue), L group (general and dental material) and non-insurance material group in MOHW notification No. 2018-248. Among them, bone substitutes classified as dental materials (L7) are divided as xenograft and alloplastic bone graft. The purpose of this paper is to analyze alloplastic bone substitutes of 37 products in MOHW notification No. 2018-248 and to evaluate the reference level based on the ISI Web of Knowledge, PubMed, EMBASE (1980–2019), Cochrane Database, and Google Scholar using the criteria of registered or trademarked product name.

I. Introduction

As dental implant surgery for edentulous patients became a gold standard, bone grafts such as guided bone regeneration and sinus lift were widely operated in Korean dentist. There has been increased in the number of bone substitute products available to the dental clinician. Still the autologous bone is considered to gold standard, because of its three properties with osteoconduction, osteoinduction and osteogenesis. Osteogenesis is, the property of autogenous graft, generation of new bone from osteogenic cells within the graft. Osteoinduction is the property of the autogenous graft, allogenic graft and intrinsic bone matrix proteins such as transforming growth factor and bone morphogenetic proteins (BMP) to recruit of host stem cells. Osteoconduction is the property of a mechanical structure with biocompatibility for the migration of osteogenetic cells1,2.

Allograft has been widely used and is an attractive alternative as it avoids donor site morbidity. It has the following advantage: (1) donor site is not needed, (2) abundant supply, and (3) little risk of transmission of infectious diseases3. The ideal alloplastic bone substitutes is biologically stable and maintain its volume with allowing cell infiltration and remodeling process4. The alloplastic bone substitutes has various osteoconductive capabilities depending on the manufacturing methods, crystal structure, size of pores, mechanical properties, composition and absorption rate5.

Hydroxyapatite (HA) is the main mineralized of bone tissue and it exerts an osteoconductive ability when grafted in the defect. Synthetic calcium phosphate ceramics (β-tricalcium phosphate [β-TCP] and HA) could be altered to autogenous graft, allogenic graft and xenogenic graft and it was used as block, cement, pastes, powder, granules and putty type with carboxymethyl cellulose or hyaluronic acid6. In Korea, the development of implant dentistry has led to the development of many dental synthetic bone substitute in many domestic companies.

As dental implant surgery for edentulous patients became a gold standard, bone grafts such as guided bone regeneration and sinus lift were widely operated in Korean dentist. All bone substitutes used commercially in Korea are firstly evaluated by the Ministry of Health and Welfare (MOHW) for safety and efficacy of the product. They are commercialized after being priced, classified, and registration by the Health Insurance Review and Assessment Service (HIRA). The post-application management is obligatory for the manufacturer (or representative importer) to receive a certificate of Good Manufacturing Practice (GMP) by Ministry of Food and Drug Safety (MFDS).

According to Korea Food and Drug Safety (KFDS) No. 2016-156 of ‘medical device manufacturing and quality control standards’, after the approval of commercially use, the manufacturer or importer is required to renew the conformity certification every three years or immediately if the information of product changed7. If any information of the product changed, the certificate of conformity should be issued or reissued by the manufacturer or the importer. Therefore, the manufacturer or importer of registered in the MFDS could be important factors in terms of quality control of currently available bone substitutes.

However, it is difficult for clinicians to know whether the certification or the quality of product is properly managed. Therefore, the purpose of this study is to analyze ingredients, manufacturers, importers, current status and reference levels of dental synthetic bone listed in MOHW notification No. 2018-248.

II. Materials and Methods

Commercially available dental alloplastic bone substitute which was approved MOHW notification (No. 2018-248)8 is analyzed the details of manufacturer, importer, composition, available form, Food and Drug Administration (FDA, USA) approval.

This review of literature included studies that detailed the use of bone graft substitute in dental situation, animal, in vivo, and in vitro studies. We excluded studies in the orthopedic and neurosurgery field and those not published in English or Korean. The Google Scholar, ISI Web of Knowledge, PubMed, EMBASE (1980–2019) and Cochrane Databases were searched in February 2019 using the criteria of registered or trademarked product name. The authors read the full text of the studies and classified it according to the ‘level of evidence’ presented by Wright et al.9.(Table 1)

Table 1. Level of evidence for research questions9.

Type	Level	Description
Published human studies	I	Randomized controlled trial (RCT)
		Split-mouth study
	II	Prospective cohort1
		Systematic review with level II studies
		Poor-quality RCT (e.g., <80% follow-up)
	III	Case-control study2
		Retrospective cohort study3
		Systematic review with under level III studies
	IV	Case series or case report no/or historical, control group and poor designed human studies
Animal studies
In vivo studies (cell culture)
In vitro studies

¹Patients were compared with a control group of patients treated at the same time and same institution.

²Patients with a particular outcome (‘cases’) were compared with those who did not have the outcome (‘controls’).

³The study was initiated after treatment was performed.

Human study level I evidence is a prospective, randomized, or splint-mouth study with definite results that support the use of alloplastic bone substitute in clinical condition. The case report was classified as level IV. Clinicial studies used alloplastic bone substitute as carrier of osteoinductive growth factors or as comparison of membrane efficacy have not been evaluated for osteoconductive capacity, but have been assigned to human study level IV as showing clinical stability. The animal, in vivo, and in vivo study were separately indicated. All authors reviewed each paper and independently assigned evidence levels. If there is a disagreement on the assigned level, discussion and resolution were made. All studied with human study level I, II, III, or IV were included to be citation10.

III. Results

In December 2018, thirty-seven dental alloplastic substitutes were registered in MOHW and HIRA8. However, there were two products (BIO-C [Cowellmedi, Busan, Korea] and OssPol-Dental [Genewel, Seongnam, Korea]) that were not commercially available and one product of DualPor COLLAGEN D-INJECTION (OssGen, Daegu, Korea) that was discontinued in the market. Of the remaining 34 alloplastic substitutes, 28 products (82.4%) could be obtained information and included in this review. To approve certificate of GMP from MOHW and MFDS, the company should submit the researches for safety and efficacy of its product, as same procedure as U.S. FDA.(Table 2) The researches, however, were not published and the authors could not include in this review. The available information regarding the delivery form, component, indications, morphology (porosity, biomechanical structure, particle size), and property are shown in Tables 3, 4, 5, 6, 7, 8.

Table 2. Dental bone graft substitutes which Food and Drug Administration (FDA) 510(k) approved.

Product name	Approved date (mo/day/yr)	Indications with FDA 510(k) approved
Cerasorb M granules	7/22/2005	Alveolar augmentation
		Filling of defects after root resection, apicoectomy, and cystectomy
		Filling of extraction sockets
		Elevation of the maxillary sinus floor
		Filling of periodontal/perio-implant defects for GTR and GBR
MBCP	12/11/2003	Bone void filler for bony voids or gaps of the skeletal system
		Used with autograft as a bone graft extender
		Osseous defects and/or from traumatic injury to the bone.
		Without initial mechanical properties. Therefore, rigid fixation techniques may often be recommended. Gradually resorbs and is replaced with bone.
MBCP Plus, MBCP+	7/30/2007	Periodontal/infrabony defects
		Ridge augmentation
		Extraction site (for implant)
		Sinus graft and cyst defect
OSTEON	7/8/2010	Periodontal/infrabony defects
		Ridge augmentation
		Extraction site (for implant)
		Sinus lifts
		Cystic cavities
OSTEON II	12/26/2011	Periodontal/infrabony defects
		Ridge augmentation
		Extraction site (implant preparation/placement)
		Sinus lifts
		Cystic cavities
OSTEON III	9/14/2016	Periodontal/infrabony defects
		Ridge augmentation
		Extraction site (implant preparation/placement)
		Sinus lifts
		Cystic cavities
TCP Dental	11/10/2004	Cystic cavities
		Packed into bony voids or gaps of the skeletal system (such as the extremities, spine and the pelvis).
		Osseous defects and/or from traumatic injury to the bone.
		Resorbs and is replaced with bone during the healing process.
		-Approved for KASIOS TCP not (KASIOS) TCP Dental

(GTR: guided tissue regeneration, GBR: guided bone regeneration)

Table 3. Dental bone graft substitutes with manufactures, importer, components and inconsistency with registered in Korean Ministry of Health and Welfare and Korean Health Insurance Review and Assessment Service.

Product name	Manufacturer	Nationality	Importer name	Registered components	Remarks
OSSABASE-HA	LASAK	Czech	Mono Dent	HA	OSSABASE-HA → OssaBase-HA
OVIS BONE HA	DENTIS	Korea	DENTIS	HA	OVIS BONE HA → Ovis BONE HA
COLLAOSS (BLOCK), OOSSBONE COLLAGEN	SK Bioland	Korea	SK Bioland	HA (90%±5%)+collagen (10%±5%)	COLLAOSS (BLOCK), OSSBONE COLLAGEN → CollaOss (BLOCK), OssBone collagen
COLLAOSS (PUTTY)	SK Bioland	Korea	SK Bioland	HA (90%±5%)+collagen (10%±5%)	COLLAOSS (PUTTY) → CollaOss (PUTTY)
					Role out xenograft
COLLAOSS (SYRINGE)	SK Bioland	Korea	SK Bioland	HA (90%±5%)+collagen (10%±5%)	COLLAOSS (SYRINGE) → CollaOss
					Only block and putty type of CollaOss
DUALPOR COLLAGEN D-PUTTY	OssGen	Korea	OssGen	HA (60%)+bovine atelo collagen (0.3%)+distilled water (39.7%)	DUALPOR COLLAGEN D-PUTTY → DualPor Collagen D-Putty
					HA (60%)+β-TCP (40%)+bovine collagen
DUALPOR COLLAGEN D-INJECTION	OssGen	Korea	OssGen	HA (60%)+bovine atelo collagen (0.3%)+distilled water (39.7%)	DUALPOR COLLAGEN D-INJECTION → DualPor Collagen Injection
					NA
BONESIGMA TCP	SigmaGraft	USA	KodentTMS	β-TCP 100%	BONESIGMA TCP → BoneSigma TCP
EXCELOS INJECT	BioAlpha	Korea	BioAlpha	β-TCP etc.	EXCELOS INJECT → Excelos INJECT
					BioAlpha → CGbio
EXCELOS (TCPGLD)	BioAlpha	Korea	BioAlpha	β-TCP 100%	EXCELOS (TCPGLD) → Excelos (TCPGLD)
					BioAlpha → CGbio
EXCELOS (TCPGMD, TCPGLD)	BioAlpha	Korea	BioAlpha	β-TCP 100%	EXCELOS (TCPGMD, TCPGLD) → Excelos (TCPGMD, TCPGLD)
					BioAlpha → CGbio
MEGA-TCP (CGL)	CGbio	Korea	CGbio	β-TCP 100%	MEGA-TCP (CGL) → Mega-TCP
					CG bio → MegaGen
Mega-TCP (CGM, CGL)	CGbio	Korea	CGbio	β-TCP 100%	MEGA-TCP (CGM, CGL) → Mega-TCP
					NA
SORBONE	META-BIOMED	Korea	META-BIOMED	β-TCP 100%	SORBONE → Sorbone
SYNCERA	Oscotec	Korea	Oscotec	β-TCP	SYNCERA → Syncera
CERASORB	Curasan	Germany	B.ITRADING	β-TCP	Cerasorb → Cerasorb M
BIO-C	Cowellmedi	Korea	Cowellmedi	β-TCP+HA	NA
BONCELOS	BioAlpha	Korea	BioAlpha	β-TCP+HA	BONCELOS → Boncel-Os
					BioAlpha → CGbio
BONESIGMA BCP	SigmaGraft	USA	KODENT TMS	β-TCP (40%)+HA (60%)	BONESIGMA BCP → BoneSigma BCP
CERASORB M GRANULES	Curasan	Germany	Mono Dent	β-TCP+HA	CERASORB M GRANULES → Cerasorb M
					HA+β-TCP → 99% β-TCP
FRABONE DENTAL	Inobone	Korea	Inobone	β-TCP (40%±5%)+HA (60%±5%)	FRABONE DENTAL → FRABONE
FRABONE DENTAL INJECT	Inobone	Korea	Inobone	β-TCP+HA	FRABONE DENTAL INJECT → FRABONE-Inject
					Hyaluronic acid addition
GENESIS-BCP	DIO	Korea	DIO	β-TCP (40%)+HA (60%)	N/S
MBCP	Biometlante	France	Purgo Biologics	β-TCP+HA	N/S
MBCP PLUS	Biometlante	France	Purgo Biologics	β-TCP+HA	MBCP PLUS → MBCP or/with syringe type
NEW BONE	GENOSS	Korea	GENOSS	β-TCP+HA	NEW BONE → Newbone
OSSPOL DENTAL	Genewel	Korea	Genewel	β-TCP (40%)+HA (60%)	OSSPOL DENTAL → OssPol
					NA
OSTEON	GENOSS	Korea	GENOSS	HA (β-TCP)	N/S
OSTEON II	GENOSS	Korea	GENOSS	β-TCP+HA	N/S
OSTEON III	GENOSS	Korea	GENOSS	β-TCP+HA	N/S
OSTEON III COLLAGEN	GENOSS	Korea	GENOSS	β-TCP+porcine collagen (95%)	N/S
OSTEON SINUS	GENOSS	Korea	GENOSS HA (β-TCP)		Only syringe type of OSTEON I, II, and III
OVIS BONE HA	DENTIS	Korea	DENTIS	β-TCP+HA	OVIS BONE HA → Ovis BONE HA
TCP Dental	Kasios SAS	France	B.IMTECH	β-TCP (95%)+HA (5%)	β-TCP (95%)+HA (5%) → β-TCP (99.9%)
Q-OSS+	OSSTEM IMPLANT	Korea	OSSTEM IMPLANT	β-TCP (80%±5%)+ HA (20%±5%)	N/S
TOPGEN-S	Toplan	Korea	Toplan	β-TCP (80%±5%)+ HA (20%±5%)	N/S
INNO CAP	Cowellmedi	Korea	Cowellmedi	Calcium phosphate (100%)	INNO CAP → INNO-CaP

(HA: hydroxyapatite, β-TCP: β-tricalcium phosphate, NA: not available, N/S: nothing special)

Table 4. Commercially available dental alloplastic bone substitutes according to components.

Commercially available dental alloplastic bone substitutes	Total (n=28)
Hydroxyapatite (HA)	4
β-Tricalcium phosphate (β-TCP)	8
β-TCP+HA	15
Calcium phosphate (CaP: composition not confirmed)	1

Table 5. Dental bone graft substitutes which was consisted with hydroxyapatite (HA).

Product name	Delivery	Component	Indication	Morphology	Property	Level of evidence
OssaBase-HA	Granule	HA:CaP (1.65), Ca10(Po4)6(OH)2	Remodeling of the alveolar ridge	Macro-nano bone like structure	Volume maintenance	Human study level (IV: GBR22)
			Treatment of periodontal defects	83% interconnected porosity	Low substitution rate	Animal, in vivo , in vitro studies
			Treatment of bone defects around dental implants	Narrow size ranges of available granules	No risk of immunological reactions or pathogen transmission
			Sinus lift	Enough space for bone ingrowth over large distances
			Filling of bone defects after surgical extractions to prevent alveolar atrophy
			Filling of bone defects after extirpation of cysts
Ovis BONE HA	Granule	100% HA	Periodontal bone defect	Well-formed macro/micro porous	Osteoconductivity	NA
			Intrabony defect	Porosity	Biocompatibility
			Extraction site		Non toxicity
			Ridge augmentation		Non inflammatory nature
			Sinus lift		Easy manipulation
			Cystic cavity
CollaOss (Block), Ossbone Collagen	Plug	HA 90%±5%+ collagen 10%±5%	Periodontal bone defect	Well-formed macro/micro porous	Easy manipulation and adhesion due to collagen	Human study (III: extraction socket18, IV: peri-implant defect19)
			Intrabony defect	Porosity	Slow absorption and partial remodeling
CollaOss (Putty)	Granule	HA 90%±5%+collagen 10%±5%	Periodontal bone defect	Well-formed macro/micro porous	Easy manipulation and adhesion due to collagen	Animal study
			Intrabony defect	Porosity	Slow absorption and partial remodeling

(CaP: calcium phosphate, GBR: guided bone regeneration, NA: data not available)

Table 6. Dental bone graft substitutes which was consisted with β-tricalcium phosphate (β-TCP).

Product name	Delivery	Component	Indication	Morphology	Property	Level of evidence
BoneSigma TCP	Powder	β-TCP 100%	Extraction socket	>95% β-TCP	Osteoconductive	In vitro study
			Horizontal and vertical augmentation	Interconnected macro and micro porous structure	High resorption rate: rapid osseointegration and recovery in dental implants
			Peri-implant defects
			Periodontal regeneration
			Ridge augmentation
			Sinus floor elevation
Excelos Inject	Injectable	β-TCP 100%	Sinus lift	β-TCP particle (size: 45-75 μm) with hydrogel (poloxamer, hydroxypropyl methylcellulose [HPMC])	Hemostasis and injectable by poloxamer-based hydrogel	Human study level (IV: extraction socket30)
			Guided bone regeneration		High moldability	Animal studies (for BMP carrier), in vivo, in vitro studies
			Socket preservation		Osteoconductive
					High resorption rate
					Space maintaining for new bone formation
Excelos (TCPGLD)	Powder	β-TCP 100%	Sinus floor elevation	100% β-TCP	Osteoconductive	Animal, in vitro studies
			Alveolar bone augmentation	Average 80% macro-porosity (pore size: 100-300 μm)	Faster absorption and biodegrade rate
			Extraction socket preservation		Space maintaining for new bone formation
MEGA-TCP (CGL)	Powder	β-TCP 100%	NA	Porous structure like human cancellous bone	Biocompatibility	NA
				>99% interconnectivity	Biodegradable
				Average 75% macro-porosity (pore size: 100-300 μm)
Sorbone	Powder	β-TCP 100%	Extraction socket	Average 55%-60% macro-porosity	Osteoconductive	Human study (level II, socket preservation34 and periodontal defect35)
			Cystic cavities		High resorption rate
			Periodontal defects		Biocompatibility
			Intrabony defects		Easy handling
			Ridge augmentation
			Sinus floor elevation
SynCera	Powder	β-TCP 100%	NA	Macro- and micro-porosity	Osteoinduction	Animal, in vivo, in vitro studies
					>70% new bone formation
Cerasorb M	Powder	β-TCP 99%	Augmentation or reconstructive treatment of alveolar ridge	Micro-meso-macro pore (pore size 5-500 μm) about 65% porosity with full range of pore size and interconnected porosity	99% resorption	Human study level (I: sinus38,39, III: cystic lesion, periodontal defect, cleft alveolus40, extraction socket preservation41, IV: peri-implant defect44, periodontal defect with enamel matrix derivative 42,43)
			Infrabony periodontal defects		Optimal microencironment for osteoblast adhesion proliferation and Subsequent bone remodeling	Animal, in vivo, in vitro studies
			Defects after root resection, apicoectomy, and cystectomy
			Extraction socket
			Sinus lift
			Guided tissue regeneration
			Guided bone regeneration
			Peri-implant defect
TCP Dental	Granule	β-TCP 99%	Sinus graft	Interconnected macro-porosity	Osteoconductive	Human study (III: sinus graft57)
			Bone loss correction	>90% porosity (pore size: 0.2-0.5 mm)	Early resobable and angiogenesis	Animal, in vivo , in vitro for osteoconduction
			Filling alveoli	Particle size: 0.15-2.0 mm
			Periodontology

(BMP: bone morphogenetic proteins, NA: data not available)

Table 7. Dental bone graft substitutes which was composed with hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP).

Product name	Delivery	Component	Indication	Morphology	Property	Level of evidence
Boncel-Os	Granule	β-TCP (70%)+HA (30%)	Ridge augmentation	High porosity	High biocompatibility	Animal study
			Extraction sockets	Interconnected porous structure	Osteoconduction
			Periodontal defect		Excellent wettability
			Sinus lift
BoneSigma BCP	Granule	β-TCP (40%)+HA (60%)	Ridge augmentation	Micro- and macro-porosity	Osteoconductive properties	In vivo study
			Extraction sockets		Long-term volume stability
			Cystic cavities
			Sinus floor elevation
			Periodontal defects
			Peri-implant defects
DualPor COLLAGEN D-PUTTY	Block	β-TCP (40%)+HA (60%)+bovine collagen (5.5%)	NA	Trabecular like structure	Biocompatibility	NA
				Interconntected macro- and micro-porosity 80% of porosity	Bioabsorbable
					Easy handling and moldable
					Hemostasis and anti-adhesion effect
FRABONE	Granule	β-TCP (40%)+HA (60%)	NA	Haversian canal like structure (international patent: PCT/KR2011/005509-USA and Germany), 150-300 μm macropore	Biocompatibility
				Average 8.1 μm micropore0.7 mm size of porous particles	Bioactive
					Osteoconductivity
					Osteoinductivity
					Mechanical strength
					Structural feature reserves stable room and filled up with vessels and new bone material, resulting in faster regeneration
FRABONE-Inject	Injection	β-TCP (40%±5%)+HA (60%±5%)+coated with hyaluronic acid	NA	Haversian canal like structure (international patent: PCT/ KR2011/005509-USA and Germany),100-300 μm micropore 0.7 mm size of porous particles	Highly biocompatible and bioresorbable due to hyaluronic acid	NA
					Osteoconductivity
					Osteoinductivity
					High mechanical strength
					Structural feature
					Moldability
					Injectability
GENESIS-BCP	Granule	β-TCP (40%)+HA (60%)	NA	70% of complete interconntected porosity 75% macropore (300-700 μm)	High mechanical strength	Human studies (level II: periodontal defect70, level IV: horizontal augmentation71)
				25% micropore (<10 μm)	Highly biocompatible	Animal, in vivo, in vitro studies for osteoconduction
MBCP Plus	Granule	β-TCP (80%)+HA (20%)	Sinus lift augmentation	70% porosity with 35% microporosity	Permeable	Human study (level IV: extraction socket84)
			Ridge augmentation	1/3 micropores (<10 μm)	Resorbable	Animal, in vivo, in vitro for osteoconduction
			Alveolar regeneration	2/3 macropores (300-600 μm)	Hydrophilic
			Alveolar regeneration		Bioactive
			Intra-osseous pockets		Osteoconductive
					Regeneration
NEW BONE	Granule	β-TCP (80%)+HA (20%)	Ridge augmentation	80% porosity (pore size: 200-400 μm)	Osteoconductive synthetic bone graft	Animal study
			Extraction site and osteotomy	0.2-2.0 mm size of porous particles	Highly resorbable due to 80% β-TCP
			Cystic cavities		Easy manipulation
			Sinus lift
			Periodontal defect
OSTEON	Granule/syringe	β-TCP (30%)+HA (70%)	Periodontal/infrabony defects	HA coated with β-TCP	Osteoconductive	Human study (level III: sinus lift94)
			Ridge augmentation	Interconnected porous structure similar to that of human cancellous bone		Animal, in vivo, in vitro for osteoconduction
			Extraction site (implant preparation/placement)	77% porosity (pore size: 300-500
			Sinus lift	Irregular shaped particles of size
			Cystic cavities	Particle size (granule): 0.3-2.0 mm
				Particle size (sinus, syringe): 0.5-2.0 mm
				Particle size (lifting, syringe): 0.3-1.0 mm
OSTEON II	Granule/syringe	β-TCP (70%)+HA (30%)	Periodontal/infrabony defects	Interconnected porous structure similar to that of human cancellous bone	Highly resorbable due to higher β-TCP content	Human study (level III: extraction socket99, level IV: sinus lift100, vertical ridge augmentation101, ridge augmentation102,103, periodontal defect105)
			Ridge augmentation	>70% porosity (pore size: 250 μm)	Easy manipulation	Animal, in vivo for osteoconduction
			Extraction site (implant preparation/placement)	Irregular shaped particles of size	Excellent wettability
			Sinus lift	Particle size (granule): 0.2-2.0 mm	Osteoconductive
			Cystic cavities	Particle size (sinus, syringe): 0.5-2.0 mm
				Particle size (lifting, syringe): 0.2-1.0 mm
OSTEON III	Granule/syringe	β-TCP (40%)+HA (60%)	Periodontal/infrabony defects	Interconnected macro and micro porous structure	Biocompatible	Animal study (BMP carries)
			Ridge augmentation	<80% porosity	Osteoconductive
			Extraction site (implant preparation/placement)	Particle size (granule): 0.2-2.0 mm
			Sinus lift	Particle size (sinus, syringe): 0.5-2.0 mm
			Cystic cavities	Particle size (lifting, syringe): 0.2-1.0 mm
				>70% crystallinity
				CaP=1.59
OSTEON III Collagen	Cylinder	β-TCP (40%)+HA (60%)+type I collagen (>95% porcine tendon collagen)	Alveolar bone defect	Particle size: 0.2-1.0 mm	Easy manipulation	NA
					Excellent wettability
Ovis BONE BCP	Granule	β-TCP (80%)+HA (20%)	Periodontal bone defect	70% porosity (pore size: 20 μm)	Osteoconductive	NA
			Intrabony defect	Particle size: 0.3-2.0 mm	Excellent wettability
			Extraction site		Easy manipulation
			Ridge augmentation		Biocompatibility and great bioactivity
			Sinus lift
			Cystic cavitiy
Q-OSS+	Granule	β-TCP (80%)+HA (20%)	NA	Porous structure	Excellent hydrophilicity	Cell culture
					Osteoconductive
					Biocompatibile
					Bioasorbable
					Rapid osteogenesis rate
TOPGEN-S	Granule	β-TCP (80%)+HA (20%)	NA	Interconnected macro and microporous	Excellent hydrophilicity	NA
				Particle size: 1.0-2.0 mm	Osteoconductive

(NA: data not available, CaP: calcium phosphate, BMP: bone morphogenetic proteins)

Table 8. Dental bone graft substitutes which was consisted with calcium phosphate.

Product name	Delivery	Component	Indication	Morphology	Property	Level of evidence
INNO-CaP	Granule	Calcium phosphate (100%)	Sinus lift	0.41-1.4 mm of particle size	Completely resorpted and progressively replaced by normal-structured bone	NA
			Guided bone regeneration		Biocompatibility
					Osteoconductivity
					Safety

(NA: data not available)

1. The products approved in FDA

Seven products were approved in FDA11,12,13,14,15,16,17.(Table 2) Although TCP Dental (Kasios SAS, L'Union, France) was not licensed for dental indication in intended use of FDA17. However, the authors included TCP Dental in this category because manufacturer did not distinguish between KASIOS TCP and (KASIOS) TCP Dental.

2. Registered in MOHW and commercially available information for product name, manufacturer, importer, and component

The details of dental alloplastic bone substitute which was approved by MOHW notification No. 2018-248 were analyzed8.(Table 3) Among them, BIO-C and OssPol-dental were officially discontinued. CollaOss (SK Bioland, Cheonan, Korea) is registered as 60% of HA, 0.3% of bovine-derived collagen (0.3%) and 39.7% of distilled water and as block, syringe and putty types. Currently, only bock and putty type are available in the manufacturer. DualPor COLLAGEN D-PUTTY and DualPor COLLAGEN D-INJECTION is available as DualPor Collagen D-Putty and DualPor Collagen Injection, but no any information could be found.

There are seven products that do not match the manufacturer or importer registered in MOHW: (1) MBCP+ (Biometlante, Vigneux-de-Bretagne, France; sold only as MBCP and MBCP syringe type, not MBCP+), (2) Excelos Inject (Bio-Alpha, Seongnam, Korea; produced by CGbio, Seongnam, Korea), (3) Excelos (TCPGLD) (BioAlpha; produced by CGbio, sold exclusively by Excelos), (4) Boncel-Os (BioAlpha; produced by CGbio), (5) Mega-TCP (manufactured by CGbio; MegaGen, Seoul, Korea, sold as a single product without discrimination between CGM and CGL), (6) Cerasorb and Cerasorb M granule (sold only by Curasan, Kleinostheim, Germany: Cerasorb M, registered as importer) BI Trading currently available is not available), and (7) OSTEON Sinus (GENOSS, Suwon, Korea: sold as syringe type of OSTEON I, II, or III).(Table 3)

CollaOss is listed as a dental synthetic bone in the MOHW and HIRA data. Although it was represented as xenograft in the journal18,19,20,21; however, it was included in this review.(Table 3)

There are three products that do not match in the component registered in MOHW: (1) Cerasorb M granules (99% β-TCP not β-TCP combined with HA; Curasan), (2) FRABONE-Inject (Inobone, Cheonan, Korea: hyaluronic acid addition with HA+β-TCP), and (3) TCP Dental (99% β-TCP not 95% β-TCP combined with 5% HA).(Table 3)

As a result, out of the 33 dental bone substitutes that are currently registered in MOHW and HIRA, 28 products could be commercially available when considering the products that are different form registered information as below: Excelos (TCPGLD) and Excelos (TCPGMD, TCPGLD) are sold exclusively by Excelos, Mega-TCP (CGL) and Mega-TCP (CGM, CGL) are sold only by Mega-TCP, Cerasorb and Cerasorb M granules are sold by Cerasorb M, Cerasorb M is 99% β-TCP, FRABONE-Inject is sold by adding hyaluronic acid, CollaOss is sold in putty and block form without syringe type, DualPor COLLAGEN D-INJECTION is not produced, and TCP Dental (99% β-TCP).

3. Analysis of dental alloplastic bone substitutes according to constituents

The main components of dental alloplastic bone substitute are tricalcium phosphate (Ca₃(PO₄)₂, β-TCP), calcium phosphate (CaP), and hydroxiapatitie (Ca₁₀(PO₄)₆(OH)₂, HA) which is crystalline form of CaP.(Table 4)

1) Dental alloplastic bone substitutes consist of hydroxyapatite

HA is an inorganic material which account for 65% of bone matrix and can be classified as dense and porous, sintered ceramic and non-ceramic, and bovine, coralline and synthetic depending on the origin. Typical characteristics are as below. (1) As large as the particle size, it remains for a long time with slow absorption. (2) The higher the porosity, the easier the penetration of new bone and the quicker absorbed. (3) The larger the crystallinity, the longer the absorption period. (4) Rigid and dense block-form products have high compressive strength but are susceptible to fracture. (5) The higher the porosity, the lower the strength5.

Among the dental alloplastic bone substitutes allowed for use in Korea, there were four products that consisted of HA. OssaBase-HA (LASAK, Praha, Czech) has a retrospective study of guided bone regeneration in 2018, but it was obtained human study level IV due to a poor study design22. However, many other animal, in vivo, and in vitro studies for osteoconductivity23,24,25,26. No journals were found for Ovis BONE HA (DENTIS, Seoul, Korea). CollaOss consists of 90% porcine-deriven HA and 10% porcine deriven collagen. It was classified as alloplastic graft in MOHW and HIRA, on the other hands, it was introduced as xenograft in many studies18,19,20,21. In the manufacturer (SK Bioland), it is commercially available in plug type and putty type. In comparison with the collagenated bovine bone (Bio-Oss collagen; Geistlich Biomaterials, Woulhusen, Switzerland) into the extraction socket, it was received the human study level III because there was no difference in the efficacy18. Human study level IV was received in a clinical study to comprare the effects of membranes on peri-implant defect19. Animal studies showed osteoconductivity20,21.(Table 4)

2) Dental alloplastic bone substitutes consist of tricalcium phosphate

TCP has a composition of calcium and phosphorus in ratio of 3 and 2. It was known as partially transition into HA and absorption in vivo, but various absorption periods of three to 24 months have been reported depending on the products. The rate of absorption varies according to the chemical structure, porosity and particle size of the material5. The general characteristics suggested by the manufacturer of TCP are as follows. (1) Use with platelet-rich plasma is effective. (2) It is absorbed at the same time as new bone graft. (3) Due to the interconnection of the pores, bone fibers are rapidly penetrated and could promote the regeneration. (4) Since the particle is rounded, there is little mechanical irrigation in surrounding tissues and little inflammatory reaction. (5) High mechanical stability prevents early collapse and inhibits undesirable macrophage activity.

Of the approved products for Korean dental alloplastic bone substitute, seven products that consist with TCP were commercialization. BoneSigma TCP (SigmaGraft, Fullerton, CA, USA) has been described as one of the in vitro studies27, and clinically available products28,29 but no clinical studies have been published. Excelos is registered as β-TCP etc. in MOHW and has two types of powder and injection and registered. Injection type is a mixture of biodegradable polymers such as poloxamer and hydroxypropyl methylcellulose (HPMC) to enhance injectable property, moldability and hemostasis. A clinical study comparing putty type Excelos with extraction and using as BMP carriers received a human study level IV30. Excelos has animal studies for BMP carrier31,32 and in vivo study for osteoconduction33. No journals were found for Mega-TCP. Sorbone (META-BIOMED, Cheongju, Korea) was validated and received human study level II by a split-mouth study as a control of cockle-shell bone substitute in socket preservation34, and used as a control material for the effect of alendronate on periodontal intra-osseous defect35. SynCera (Oscotec, Seongnam, Korea) had animal and in vivo study for osteoconductivity36,37. Cerasorb was approved by the FDA and commercially available to Cerasorb M which reduced porosity from 80% to 65%11. It was received human study level I by randomized controlled trial and systematic review that was equivalent to an autogenous graft in sinus lift38,39. It was received human study level III in cystic lesion, periodontal defect and cleft alveolus40. Also, as a result of histologically sufficient alveolar bone regeneration, human study level III was obtained in extraction socket41. As human study level IV, it was used with an enamel matrix derivative in the periodontal defect42,43, peri-implant defect after immediately implantation after extraction44, every lots of animal, in vivo, and in vitro studies for osteoconduction6,45,46,47,48,49,50,51,52,53,54,55,56. TCP Dental was registered as 5% of HA and 95% of β-TCP in MOHW and HIRA. However, the manufacturer (Kasios SAS) and importer (B.IMTECH, Yongin, Korea) advertised as 99% of β-TCP. Many studies and FDA 510(k) also represented as β-TCP17,57,58,59,60,61,62,63,64,65. It was received human study level III by successful histologic and clinical result comparing Xenograft (BonePlus-xs; Integros, Adana, Turkey) in sinus lift57. Animal, in vivo, and in vitro studies for osteoconductivity58,59,60,61,62,63,64,65.

3) Dental alloplastic bone substitutes consist with hydroxyapatite and tricalcium phosphate

The mixing ratio of HA and TCP varies from 2:8 to 7:3. It has the following characteristics. (1) It has micropore and macropore. They could induce effective tissue reaction and growth of new bone tissue. Micropores could enable ion exchange and form new contact surfaces for cell adhesion through the deposition of bone crystals. Macropores could help in angiogenesis and remodeling and growth of new bone. (2) HA acts as a mechanical support until the new bone tissue could be remolded for structural stability, and TCP could spread the adhesion surface of osteoblast by ion exchange through rapid resorption. (3) It has porosity of 70% to 90%5.

Boncel-Os (CGbio) consists with 30% of HA and 70% of β-TCP. It was introduced as one of the clinically available products66, and there is an animal study used as a BMP carrier56. BoneSigma BCP (SigmaGraft) consists with 60% of HA and 40% of β-TCP. In vivo study has been published that it inhibited osteoclast formation with plate-rich fibrin67. Dualpore Collagen D-Putty was registered as 60% of HA, 0.3% of bovine-derived collagen, and 39.7% of distilled water by the MOHW and HIRA. On the other hand, the manufacturer (OssGen) advertised the product as 60% HA and 40% β-TCP in 94.5% of biphasic CaP, and with an additional 5.5% bovine collagen but there are no reports of any evaluations of the evaluating its information provided. In MOHW and MFDS, Inobone has registrated its products as FRABONE DENTAL and FRABONE DENTLA INJECT, but they are commercially available as FRABONE and FRABONE-Inject. FRABONE (Inobone) consists with 60% of HA and 40% of β-TCP and it was received patent in USA, Germany, and Korea as mimic the harversian canal structure68,69. FRABONE-Inject (Inobone) is a product of hyaluronic acid addition to FRABONE, which advertised to increase moldability and absorption rate by act as soluble granules of hyaluronic acid. However, there was no related researched were found. GENESISBCP (DIO, Busan, Korea) consists with 60% of HA and 40% of β-TCP. It was received human study level II by prospective controlled clinical trial which results good outcome in periodontal defect70. In horizontal augmentation, it was showed successful result with NanoBone (HA and silica gel matrix; Artoss GmbH, Warnemünde, Germany) in case report and it obtained human study level IV71. There were many animal, in vivo, and in vitro studies for osteoconductivity72,73,74,75,76,77. Manufacturers have the two types of MBCP as combination of HA and β-TCP as ratio as 60:40 and 20:80, and a moldable MBCP (In'Oss) made by mixing hydrogel to MBCP. However, represented importer (Purgo Biologics, Seongnam, Korea) only has granule or syringe type of MBCP+ which consists with 20% of HA and 80% of β-TCP. MBCP and MBCP+ were received in FDA 510(k) approved12,16. There were many clinical studies from MBCP which consists with 60% of HA and 40% of β-TCP78,79,80,81,82,83,84. On the other hand, MBCP+ was published only animal studies85,86,87,88 and in vitro studies89,90. Although not introduced as MBCP+, a combination of 20% of HA and 80% of β-TCP was as same resorption and bone growth as combination of 60% of HA and 40% of β-TCP in retrospective clinical trial for extraction socket and it could be human study level IV84. Newbone (GENOSS) consists with 20% of HA and 80% of β-TCP. Although there were animal and in vivo studies for osteoinductivity91,92,93, no clinical studies were found. Boncel-Os consists with 30% of HA and 70% of β-TCP. It was introduced as one of clinically available products66 and used as BMP carrier in animal study56.

OSTEON series (GENOSS) were available as vial, sinus, and lift type. OSTEON, OSTEON II, and OSTEON III were received FDA 510(k) approval13,14,15. In registration of MOHW and HIRAO, OSTEON and OSTEON Sinus were separated but OSTEON Sinus is not available product to commercially use. The manufacture (GENOSS) has classified OSTEON Sinus and OSTEON Lifting according to the size of syringe. In FDA 510(k), there also received approval as same as OSTEON, OSTEON Sinus, and OSTEON Lifting13. OSTEON consists with 70% of HA and 30% of β-TCP. In retrospective clinical study for sinus lift, OSTEON alone could result well-developed lamellar bone as same as Xenograft (Bio-Oss; Osteohealth, Shirley, NY, USA) and it could be received human study level III94. There were many animal and in vivo studies for osteoconductivity95,96,97,98. OSTEON II consists with 30% of HA and 70% of β-TCP. In retrospective clinical study for extraction socket, OSTEON II and OSTEON II Collagen were significantly more effective than collagen or native defect and the histological result was shown in animal studies99. Therefore, it could be received human study level III in extraction socket. It was received human study level IV by retrospective study as control group for sinus lift100, 6 months after vertical augmentation which particulated OSTEON II was showed no significantly difference on volume change and peri-implant marginal bone loss compared with autogenous block and allogenous block bone101, successful results on clinical and histologically in ridge augmentation102,103, successful outcome on graft after implant removal104, and clinically effective on periodontal defect105. Many animal and in vivo studies for osteoconductivity95,96,97,106,107. OSTEON III consists with 60% of HA and 40% of β-TCP. There was animal study as BMP carrier108. Although there was no OSTEON III Collagen related study, OSTEON II Collagen had animal and in vivo studies for osteoconductivity109,110. Ovis BONE BCP (DENTIS) consists with 20% of HA and 80% of β-TCP. No journals were found for Ovis BONE BCP. Q-Oss+ (OSSTEM IMPLANT, Seoul, Korea) consists with 20% of HA and 80% of β-TCP. It was received human study level IV by the clinical study on peri-implant defect111. There were in vivo study for osteoconductivity112 TOPGEN-S (Toplan, Seoul, Korea) consists 20% of HA and 80% of β-TCP and there could not be found for journals for TOPGEN-S.

4) Dental alloplastic bone substitutes consist with CaP (composition not confirmed)

INNO-CaP (Cowellmedi) was advertised that consists CaP, however, the composition was not cleary known and no relevant research were found.

IV. Discussion

Commercially available dental alloplastic bone substitute which was approved MOHW notification No. 2018-248 were broadly divided into 4 groups as C group (bone union and fixation group), L group (general materials), T group (human tissue), and non-insurance group. In the subcategory, there were C0 group (bone substitutes: xenograft, alloplastic graft), L7 group (dental material: dental xenograft, dental alloplastic graft), TB group (bone, demineralized bone matrix, bone block, bone chip, bone powder), non-insurance group (treatment material, human-derived bone, bone substitute containing bone morphogenetic protein [rhBMP-2])8. Among them, dental alloplastic bone substitutes in L7 of L group were included in this study.

The post-application management is obligatory for the manufacturer (or representative importer) to receive a certification of GMP by MFDS. According to FKDS No. 2016-156 of ‘medical device manufacturing and quality control standards’, the certification of GMP of human tissue or functional replacement product should be renewed every three years in article 9. According to article 10 of KFDS No. 2016-156, the certification of GMP should be reissued when any information for the products changed (change of the name of the importer or manufacturer, change of location of the importer or manufacturer). In article 12 and 15, the quality control examination agency reports periodic on the compatibility of medical device to director of KFDA7. Therefore, the manufacturer or importer of registered in the MFDS could be important factors in terms of quality control of currently available bone substitutes.

However, nineteen products (51.4%) were different information among the 37 products registered in MOHW. Four products (10.8%) were different registered ingredients from journal or advertisement including DualPor COLLAGEN D-PUTTY (OssGen), Cerasorb M granules, FRABONE-Inject, and TCP Dental. Nine products (24.3%) were differ in product name or not available including CollaOss (Syringe), Mega-TCP (CGL), Cerasorb, Cerasorb M granules, BIO-C, Excelos (TCPGMD, TCPGLD), MBCP Plus (Biometlante), OssPol DENTAL, and OSTEON Sinus. Especially, CollaOss (Block) and CollaOss (Putty) were registered as dental alloplastic bone substitute in MOHW but they were introduced as xenograft in advertisement and journals. Five products (13.5%) had different manufacturer or importer including Excelos Inject (CGbio), Excelos (TCPGLD), Excelos (TCPGMD, TCPGLD), Mega-TCP (CGM, CGL), Boncel-Os.

For a successful clinical outcome, it cannot be overemphasized that the quality of the materials or medical device should be constant and strictly controlled. Unfortunately, it is hard to identify the certification of GMP or to verify the quality in every clinical situation. Therefore, it is necessary to leave certificate to the government agency or the company which is responsible for the product. In addition the related dental institute or academy should to consider the security on quality of the product.

Implant dentistry has become a common treatment in Korea, many studies and development have been made on implant and bone graft materials. Among dental alloplastic bone substitutes which were registered in MOHW, twenty-nine (78.4%) products were domestically produced, of which three out of seven approved by FDA were made in Korea11,12,13,14,15,16,17. However, there are only ten products (27.0%) have been published with clinical study, of which six are Korean products. In the view of reference, the reference level could not be as directly same as the efficiency of the product, but it could be the basis of product selection for the clinician since minimal safety and efficiency can be regarded as verified. Reference level I received Cerasorb M (β-TCP 99%) as a sinus lift38,39. Reference level II received Sorbone (β-TCP 100%) in extraction socket and periodontal defect34,35, GENESIS-BCP (β-TCP 40% and HA 60%) in periodontal defect70. Reference level III received Cerasorb M (β-TCP 99%) in cystic cavity, periodontal defect, cleft defect and extraction socket40,41, CollaOss (HA 90% and collagen 10%) in extraction socket18, OSTEON (β-TCP 30% and HA 70%) in sinus lift94, OSTEON II (β-TCP 70% and HA 30%) in sinus lift99, TCP Dental (β-TCP 99.9%) in sinus lift57. Reference level IV is insufficient to verify the efficiency, could be seen as a step that clinically confirms safety. Cerasorb M was in peri-implant and periodontal defect42,43,44, CollaOss was in peri-implant defect19, OssaBase-HA (HA 100%) was in guided bone regeneration22, Excelos (β-TCP 100%) was in extraction socket30, MBCP+ (β-TCP 80% and HA 20%) was in extraction socket84, GENESISBCP was in ridge augmentation71, OSTEON II was in sinus lift100, ridge augmentation101,102,103, periodontal defect105 achieved for reference level IV. In addition, there were many animal, in vivo, and in vitro studies for osteoconductivity or role as carrier of osteoinductive growth factors or control material. In order to obtain MOHW and MFDS approval for commercial use in Korea, a data based on research or experiments should be required, but these data could not be included in this study because they were not publicly available. Because dental bone graft surgery has been performed in various environments such as sinus lift, ridge augmentation, cystic lesion, periodontal defect, peri-implant defect, extraction socket, it could be difficult to obtain high reference level in all dental bone grafting fields. However, it is nevertheless necessary to demonstrate the clinical level of Korean dental operation and the development level of bone graft substitutes.

In conclusion, there is not enough information about the effectiveness and safety of currently available alloplastic bone substitute in dental performance. Further clinical trials including well designed RCTs are necessary to evaluation the clinical efficacy of dental alloplastic bone substitutes in Korea. It should be aware of the limited information and developed the clinical evidences and regulations for clinicians.