materials

Review
Bone Grafts in Dental Medicine: An Overview of Autografts,
Allografts and Synthetic Materials
Maria Pia Ferraz 1,2,3

1 Departamento de Engenharia Metalúrgica e de Materiais, Faculdade de Engenharia da Universidade do

Porto, 4200-465 Porto, Portugal; [email protected] or [email protected]
2 i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4099-002 Porto, Portugal
3 INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4099-002 Porto, Portugal

Abstract: This review provides an overview of various materials used in dentistry and oral and
maxillofacial surgeries to replace or repair bone defects. The choice of material depends on factors
such as tissue viability, size, shape, and defect volume. While small bone defects can regenerate
naturally, extensive defects or loss or pathological fractures require surgical intervention and the
use of substitute bones. Autologous bone, taken from the patient’s own body, is the gold standard
for bone grafting but has drawbacks such as uncertain prognosis, surgery at the donor site, and
limited availability. Other alternatives for medium and small-sized defects include allografts (from
human donors), xenografts (from animals), and synthetic materials with osteoconductive properties.
Allografts are carefully selected and processed human bone materials, while xenografts are derived
from animals and possess similar chemical composition to human bone. Synthetic materials such
as ceramics and bioactive glasses are used for small defects but may lack osteoinductivity and
moldability. Calcium-phosphate-based ceramics, particularly hydroxyapatite, are extensively studied
and commonly used due to their compositional similarity to natural bone. Additional components,
such as growth factors, autogenous bone, and therapeutic elements, can be incorporated into synthetic
or xenogeneic scaffolds to enhance their osteogenic properties. This review aims to provide a
comprehensive analysis of grafting materials in dentistry, discussing their properties, advantages,
and disadvantages. It also highlights the challenges of analyzing in vivo and clinical studies to select
the most suitable option for specific situations.

Keywords: bone defects; bone reconstruction; bone graft; synthetic bone substitutes; dental bone
Citation: Ferraz, M.P. Bone Grafts in
substitutes
Dental Medicine: An Overview of
Autografts, Allografts and Synthetic
Materials. Materials 2023, 16, 4117.
https://doi.org/10.3390/ma16114117
1. Introduction
Academic Editor: Florin Miculescu In addition to autologous bone, several other materials are used in dentistry and oral
Received: 12 May 2023
and maxillofacial surgeries to replace or repair bone defects. The selection of the best material
Revised: 25 May 2023 depends on several factors, including tissue viability, size, shape, and defect volume [1,2].
Accepted: 29 May 2023 Bone grafting is a common procedure in dental medicine used in various situations.
Published: 31 May 2023 Some common clinical dental medical procedures in which bone grafts are needed are
dental implants, ridge augmentation, sinus lift, socket preservation, and periodontal
surgery [3–8]. Dental implants are artificial tooth roots that are placed into the jawbone to
support dental prosthetics, such as crowns, bridges, or dentures. Sufficient jawbone volume
Copyright: © 2023 by the author. and density are crucial for successful implant placement. If a patient lacks adequate bone
Licensee MDPI, Basel, Switzerland. in the implant site, a bone graft may be necessary to augment the area and provide a solid
This article is an open access article foundation for the implant [4]. When a tooth is extracted, the surrounding bone may shrink
distributed under the terms and
or resorb over time. Ridge augmentation is a procedure in which bone grafts are used to
conditions of the Creative Commons
rebuild and restore the height and width of the jawbone ridge. This procedure may be
Attribution (CC BY) license (https://
performed to create a suitable foundation for dental implants or to improve the appearance
creativecommons.org/licenses/by/
of the gumline [8]. The maxillary sinuses are air-filled spaces located above the upper
4.0/).

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Materials 2023, 16, 4117 2 of 22

jawbone. If the upper jawbone has insufficient height or volume to support dental implants
in the posterior region, a sinus lift procedure may be required. In this procedure, the sinus
membrane is lifted, and bone graft material is placed between the sinus membrane and
the jawbone to increase the bone height [6]. When a tooth is extracted, socket preservation
techniques can be used to minimize bone loss in the empty socket and preserve the bone
volume for future dental implant placement. A bone graft is typically placed in the socket
after the tooth extraction to fill the void and maintain the bone structure [7]. In some
cases of advanced periodontal disease, bone loss can occur around the teeth, leading to
tooth mobility and eventual tooth loss. Bone grafts may be used in periodontal surgery
to regenerate and restore the lost bone around the affected teeth, promoting stability and
preventing further tooth loss [3].
Under healthy conditions, small bone defects manage to regenerate spontaneously;
however, extensive bone defects or loss, pathological fractures, and bone infection due to
periodontal problems or systemic diseases can influence bone healing and regeneration,
requiring surgical intervention and the choice of a substitute bone [1,9,10].
Extensive bone defects are usually treated with autologous bone taken from the iliac
crest or the calvaria. Autologous bone contains osteogenic cells capable of synthesizing
new bone and its structure serves as a scaffold, making this procedure the gold standard of
bone grafting. However, this procedure has some disadvantages [1,2,11].
To avoid complications, other bone substitutes are often used in medium and small-
size defects and include allografts (human bone other than the patient’s own (e.g., extracted
from cadavers)), xenografts (bone from animals other than human species), and synthetic
materials with osteoconductive properties that can be reabsorbed by the body, releasing
substances that contribute to the formation of new bone (e.g., ceramics, bioactive glasses,
polymers, synthetic hydroxyapatite (HA)) [12,13].
Bone grafts should have specific requirements in order to be used and have optimal
performance: (i) unlimited supply without compromising the donor area, (ii) promote
osteogenesis, (iii) no host immune response, (iv) rapid revascularization, (v) stimulate
osteoinduction, (vi) promote osteoconduction, and (vii) be completely replaced with bone
in quantity and quality similar to that of the host [2,14,15].
Osteoinduction is defined as the process by which osteogenesis (i.e., new bone for-
mation from osteocompetent cells in connective tissue or cartilage) is induced. Osteocon-
duction is defined as the process of bony ingrowth from local osseous tissue onto surfaces.
Osteogenic materials are defined as those which contain living cells and are capable of
differentiation into bone [16].
The purpose of this review is to provide a comprehensive overview of the grafting
materials that can be used in dentistry, discussing their properties, advantages, and disad-
vantages, enlightening the problems of analysing in vivo and clinical studies in order to
choose the best option in a particular situation.

2. Bone Grafts in Dental Medicine

There are several materials available for bone grafts and the selection of the ideal
material depends on a number of factors, such as material availability, defect size, size,
shape and volume of the graft, biomechanics, handling, cost, ethical issues, biological
characteristics, and associated complications [2]. Among the available options in the area of
bone regeneration, the gold standard remains autogenous bone, due to its osteoinductive
and osteogenic capabilities. All other materials (allograft, xenograft, and synthetic biomate-
rials) have limitations, which must be taken into account, depending on their use [2]. These
categories will be briefly described below.

2.1. Autografts
Autografts are the gold standard materials for bone grafts in the field of medicine and
dentistry due to the fact that these materials have many of the requirements considered
Materials 2023, 16, 4117 3 of 22

optimal for a bone graft as they are biocompatible, non-toxic, osteogenic, osteoinductive,
and osteoconductive [17,18].
These advantages are fundamental for fast and efficient bone regeneration, mainly
in defects considered of critical size (>5 mm), since the vascularization is reduced in the
centre of these defects [17,18]. Healing time is also dependent on the material used, with
autologous bone being the most rapidly vascularized and, therefore, the most osteogenic of
all materials currently available [19,20]. It is important to emphasize that the combination
of cortical and medullary bone is one of the most advantageous in the area of bone regener-
ation, since it unites two important characteristics: the support and mechanical resistance
of the cortical bone and the osteogenic function of the medullary bone [20].
However, this procedure has some disadvantages, namely, the uncertain prognosis
and surgery at the bone removal site as well as the sequelae that may occur in the process,
such as the risk of infections. Additionally, the quantity and quality of the donor’s bone
may be insufficient, due to age-related problems or disorders that may affect the patient’s
medical condition (e.g., metabolic diseases, osteoporosis, and diabetes) [1,2,11].
In dentistry, this type of procedure is only used in critical cases, such as jaw recon-
struction, congenital bone defects, tumours, and bone defects larger than 5 mm, due to the
limited amount of intraoral bone and the need for an extra procedure to remove bone from
another area, requiring hospitalization, a hospital environment, and a multidisciplinary
team [21]. With the need for an extra surgery to remove autogenous bone, the risks inherent
to any surgery increase: pain, infection, scars, in addition to extra costs with hospitalization
and a multidisciplinary team [21–23]. Autologous bone, although still considered the best
option, has been replaced over the years by other materials, with the aim of reducing
patient morbidity, treatment costs, and surgical time, as well as the postoperative period.

2.2. Allografts
Allografts are derived from individuals within the same species. After extensive screen-
ing, these grafts are carefully selected, processed, and preserved in bone banks. Allografts can
originate from living donors or cadaveric bone material after being processed to eliminate
immune responses and prevent transmitting infectious diseases. These grafts are available in
different shapes and sizes, including cortical, cancellous, or cortico-cancellous grafts [24].
Allografts, despite being used with some frequency in regenerative treatments in some
areas of medicine, these materials are not one of the first-choice materials in dentistry. There
is still some controversy regarding their osteoinductivity, as well as their risk of immune
rejection, blood incompatibility, and disease transmission [2,12,18].
Allogeneic materials are considered a source of type I collagen and morphogenetic
proteins (BMPs), which give them osteoinductive capabilities. However, although they
originate from the human species, they have different genetic compositions, which raises
controversy about immunological rejection, blood compatibility, and transmission of dis-
eases or tumour cells [2,12,18]. Considered osteoinductive and osteoconductive, they do
not have osteogenic properties, and their processing ends up reducing their biological and
mechanical characteristics [2,12,18].
Although with some advantages similar to autogenous bone and greater availability, al-
logeneic materials have a high processing cost, in addition to the already mentioned disadvan-
tages regarding disease transmission, immunological rejection, and religious issues [2,12,18].

2.3. Xenografts
Materials of animal origin, xenografts, are widely used in dentistry, being well-documented
materials studied for more than three decades [24]. Their osteoconductivity comes from their
inorganic structure, composed mainly of HA, obtained through the removal of all organic
components [25]. Xenografts can be of the most diverse origins, the most used being those
of bovine and porcine origin; however, other origins include horses, coral exoskeleton, and
eggshells, among others [26–29]. One of the advantages of xenogeneic materials is the similarity
of their chemical composition to human bone, with a calcium/phosphate ratio of 1.67, identical
Materials 2023, 16, 4117 4 of 22

to that of human bone [30]. Their disadvantage comes from ethical, religious, and health issues,
such as the risk of disease transmission [2,31].
Xenografts are the materials most used by dentists. Their effectiveness is very well
documented in several comparative studies with other materials, mainly with autologous
bone [2,20,32,33].
One of the xenogeneic materials on which there are more publications and which
is also well known by dentists is Bio-Oss® . Bio-Oss® is obtained from bovine HA; one
of its main characteristics is its similarity in chemical composition with human HA. Its
calcium/phosphate ratio of 1.67 is identical to that found in human bone [18].
Materials from other sources, such as equine, porcine, coral exoskeletons, and even
eggshells, have been studied and commercialized [26–29,34–38].
Each material has specific characteristics, but in general, among the advantages of these
materials, it is possible to mention their low cost, great availability, and osteoconduction [2].
Consisting entirely of inorganic bone, with no organic or cellular content, some mate-
rials, such as Bio-Oss® , are also considered osteoinductive, information that conflicts with
some authors, who consider that osteoinduction occurs when there is cellular material,
such as morphogenic proteins, growth factors, or some living material in the composition
of the bone graft [2,18].
Due to this osteoinductive characteristic, materials of animal origin have been the
subject of controversies and discussions about their use in humans. As a natural material,
it is possible that they retain some of their original characteristics after processing, such as
some cellular activity that gives them the osteoinductive characteristic [31,39].
Although companies that market bones of xenogeneic origin guarantee that their
products are completely free of any organic material, some plastic surgeons have detected
proteins, such as collagen, in Bio-Oss® after orthognathic surgery [40]. In another study,
reaction to foreign bodies, which consisted of multinucleated cells encapsulated within
inorganic bovine bone particles, was reported after histological analysis [25]. These findings
contribute to the controversy about the transmission of diseases that can occur when these
materials are used. As sporadic as these cases may be, it is important to inform the patient
about this risk and alternatives.
If there is no organic component in xenogeneic materials, their osteoinductive ca-
pabilities are questionable and, although many studies confirm their osseointegration
characteristics, other materials have been the subject of studies, in order to overcome the
ethical and religious issues of xenogeneic materials, as well as to improve the manipulation
capabilities, to facilitate the procedure for doctors and dentists [20,28,30,39,41–46]. In addi-
tion to the issues mentioned above, these materials require experienced handling. As they
are particulate materials, they require the use of a membrane to keep the static particles
at the defect site and prevent the connective tissue from invading the area that must be
remodelled, which makes the procedure more complicated [22,29].

2.4. Synthetic Materials

The role of synthetic bone materials is to promote bone regeneration. Synthetic
materials have several advantages concerning the surgical method necessary for obtaining
autogenous material: biocompatibility, osteoconduction, injectability, moldability, easy
manipulation, minimally invasive procedure, scar reduction (since only the affected area is
surgically treated and only one surgery is required), in addition to the decreased risk of
infection and other complications [47–49]. Another advantage is their wide availability,
since the material can be easily manufactured in scale, unlike autogenous, allogeneic, or
xenogeneic materials.
The growing demand for materials for bone reconstruction has stimulated research in
the area of biomaterials, in order to supply the scarce source of autogenous and allogeneic
bone available [14]. Several bioceramic materials have been developed as an alternative,
and several studies—both experimental and clinical—have demonstrated the osteoconduc-
tive properties (materials that facilitate infiltration through the bone surrounding the defect)
Materials 2023, 16, 4117 5 of 22

of these materials when used for medium and small bone defects, increasing the bone crest
for implant placement, bone defects due to periodontal disease, and maxillary sinus eleva-
tion [43,50–53]. Within the group of ceramics, materials based on calcium phosphate are
extensively studied and frequently used as bone grafts due to their compositional similarity
with natural bone, with their HA demonstrating excellent biocompatibility. In addition to
the granular form, these materials can be manipulated in the form of a paste, which reduces
application time and, mainly, improves moldability to the defect [47,50,54,55]. The use
of calcium phosphates for larger defects is restricted due to their lack of osteoinductivity;
therefore, there are several studies in order to meet this need [56].
It is important to emphasize that synthetic biomaterials do not have osteoinductive
properties (the potential to induce bone formation), considered ideal for the formation of
new bone. For this reason, the use of these materials still brings some disadvantages when
used in bone defects of critical size, which encourages constant research and the inclusion
of other components in an attempt to improve their performance. Other materials can be
incorporated into scaffolds of synthetic or xenogeneic origin with the aim of improving their
osteogenic properties. Growth factors, cellular content, autogenous bone, and therapeutic
elements are some of the materials studied and incorporated into these materials with the
aim of increasing biological performance and improving the quantity and quality of new
bone [2,57–60]. This area of study, called tissue bioengineering, is based on key elements,
which form the triad: (i) scaffold or carrier material; (ii) biological components (growth
factors, drugs); (iii) cells [61].
In Table 1, bone graft categories as well as their source of origin or chemical constitution
with examples of commercially available products are exemplified.

Table 1. Bone graft categories their source of origin or chemical constitution with examples of
commercially available products.
Examples of Commercially
Graft Category Origin/Chemical Constitution Advantages Disadvantages References
Available Products
Osteogenic Donor site morbidity
Autografts Osteoinductive Limited quantity
Osteoconductive Needs for general
No disease transmission anaesthesia and
No immunogenicity hospitalization

DBX® [62]
DynaBlast® [63]
Osteoinductive Risk of disease DynaGraft® [64]
Allografts Osteoconductive Transmission Grafton™ [65]
Moderate availability Immunogenicity Opteform® [23]
OsteoSponge® [62]
Puros® [66]
Raptos® [24]
Bovine Algipore® [24]
Porcine Bio-Oss® [67]
Equine Endobon® [23]
Coraline Risk of disease Cerabone® [68]
Osteoconductive
Xenografts Algae Transmission Gen-Os® [69]
High availability
Immunogenicity OsteoBiol® [70]
Pro Osteon® [71]
THE Graft™ [24]
Biocoral® [72]
Calcium phosphate BonePlast® [73]
Hydroxyapatite Cortoss® [74]
Calcium carbonate Eurobone® [75]
EasyGraft™ crystal [76]
EasyGraft™ classic [77]
Synthetic bone Calcium sulphate Osteoconductive Vitoss® [24]
substitutes Bioactive glasses Availability Guidor® [78]
HydroSet® [79]
IngeniOs® [24]
Polymers B-OstIN® [24]
PerioGlass® [24]
Straumann® [24]
BioGran® [80]
Materials 2023, 16, 4117 6 of 22

3. Types of Synthetic Materials

To decide which material is most appropriate for a given procedure, it is necessary not
only to have a good understanding of the biological function (osteogenesis, osteoinduction,
and osteoconduction) of each material but also to consider the patient condition, as this
is an essential criterion for the incorporation of any bone graft. Bone grafts are evolving
and undergoing innumerable changes and there has long been talk of synthetic bone
grafts and bone substitutes to the detriment of autologous, allogeneic, or even xenogeneic
grafts [18,22,23].
Bioactive cements are considered good alternative bone substitutes, due to their mold-
ability, self-hardening, and osteoconductivity. However, although these biomaterials are
already widely used, they still need to improve their mechanical properties [55]. Regarding
synthetic bone grafts, scaffolds give mechanical support and serve as a substrate where
osteoblastic or osteoprogenitor cells can adhere, proliferate, and differentiate for the forma-
tion of new bone. They can also be used as carriers for other materials, with the addition of
growth factors or drugs, or mixed with other types of bone grafts to increase or improve
bone formation [2,81–83]. The most studied biomaterials among synthetic bone grafts
are cements based on calcium phosphate, calcium phosphate ceramics, calcium sulphate,
bioactive glasses, and polymers [18,20,22,28,48,50,58,84,85].

3.1. Calcium Phosphate Cements

Calcium-phosphate-based materials have been used since the 1980s in the fields of
dentistry and orthopaedics and are currently commercially available in a wide variety of
compositions [86]. Calcium phosphate cements (CPCs) have several advantages, including
being bioactive, allowing for large-scale manufacturing, easy handling, and injectability
to adapt to irregularly shaped bone defects, in addition to not having the inherent risks
of autogenous and allogeneic grafts, such as donor site morbidity and risk of infection.
Furthermore, their biocompatibility and proximity to bone composition make CPCs good
candidates for use in bone regeneration [45,47].
Among CPCs, there are two main groups: those of brushite that have a shorter
hardening time and those of apatite that have a longer hardening time. Apatite is formed
from tetracalcium phosphate (TTCP) or α-TCP, while brushite is a by-product of β-TCP
or monocalcium phosphate monohydrate (MCPM). The difference between these two
by-products derives from the fact that cements that form brushite absorb more water in
their mixing and hardening reaction, while apatite absorbs little or no water. Brushite-
based CPCs react and harden much faster than apatite CPCs; therefore, to satisfy the
necessary clinical requirements of cement application during surgery, the setting time of
CPCs materials based on brushite must be increased, while the setting time of apatite-based
CPCs should be reduced [47]. Through absorbing more water, the cements that turn into
brushite have less resistance to tension, compression, and shear [87,88].

3.2. Calcium Phosphate Ceramics

Ceramic materials based on calcium phosphate (CP) can be found in the form of
granules or blocks with none or different porosities [89–91] and include HA, tricalcium
phosphate (α-TCP and β-TCP), biphasic calcium phosphate (BCP), and amorphous calcium
phosphate (ACP), among others [18,22,92].

3.2.1. Hydroxyapatite
Hydroxyapatite’s (Ca10 (PO4 )6 (OH)2 ) (HA’s) composition has a great similarity with
the mineral part of the bone and, for this reason, it has been widely documented for its
ability to promote bone growth through its osteoconductive mechanism without causing
local or systemic toxicity, inflammation, or undesirable immune reactions [91–93]. All these
advantages make this material very useful in the area of bone repair in dentistry, such as
in the treatment of periodontal defects, alveolar crest augmentation, and maxillary sinus
elevation [27,93–95].
Materials 2023, 16, 4117 7 of 22

HA nanoparticles, with particle size smaller than 100 nm in at least one direction,
have greater surface activity and an ultrafine structure, very similar to the mineral found
in hard tissues, which stimulates their use in the area of bone regeneration. In addition to
chemical similarities with the mineral phase of bone, they also have excellent biological
properties [96–98].
Another advantage of this material, shown in several studies, would be its affinity with
certain osteogenic and anti-resorptive molecules, which can be used to create reservoirs for
growth factors, antibiotics, or medication to inhibit osteoclasts [2,99].

3.2.2. Tricalcium Phosphate

Beta-tricalcium phosphate (β-TCP) is sintered at a temperature lower than ~1125 ◦ C
and has the advantage of thermodynamic stability in a biological environment and being
more resorbable than HA at room temperature.
Alpha-tricalcium phosphate has been gaining great attention in the area of biomaterials
as a raw material, due to its properties such as injectability and biodegradation. This mate-
rial remains stable when, after the sintering process, it is cooled to room temperature [100].
Despite having similar chemical composition, α and β TCP have considerable differences
in their structure, density, and solubility, which determine their biological characteristics
and specific clinical applications. Since α-TCP is more soluble and reactive than β-TCP,
its ultrafine powder is the mostly used in the preparation of cements for bone repair, to
improve the moldability and injectability of the cement [100].

3.2.3. Calcium Sulphate

Calcium sulphate hemihydrate (CaSO4 ·1/2H2 O), also known as plaster of Paris, has
been used since the mid-1920s as a bone filler. The dissolution properties of this material
have been used in the study and development of carrier materials for molecules that
improve bone quantity or quality or as a carrier for drugs such as antibiotics [92].

3.2.4. Bioactive Glasses

Bioactive glasses (BGs) are a group of synthetic materials based on silica, calcium, and
disodium oxide. As calcium and silicate ions are progressively released from the material,
they interact with surrounding cells and thus have properties that allow it to bind to
bone [17]. They have unique properties when compared to other ceramics such as HA and
TCP, namely, the formation of an amorphous layer on their surface where proteins, collagen,
fibrin, and growth factors connect. This surface contributes to the bone reconstruction
process, as it is chemically and structurally equivalent to the bone mineralization phase [17].
Depending on their chemical composition, BGs differ in their bioactivity and resorption.
In vivo, this material showed good osteoconductivity and appears to promote new bone
growth on its surface, demonstrating a balance between intramedullary bone formation and
material resorption [28,101]. Some studies demonstrate little or no inflammatory reaction,
foreign body reaction, or fibrous encapsulation of the material when bioactive glasses are
used [17,34]. Due to their osteoconductive properties, composition, and in vitro and in vivo
results, BGs have been a group of constant study for use as a bone substitute [17,34].

3.2.5. Polymers
Studies involving polymers are based on the search for materials that can support
and maintain space for the period necessary for the formation of new bone and, after this
period, can be degraded and eliminated by the host organism [102]. The most studied
materials currently are polymers based on glycolic acid and lactic acid, also known as
PLGA and PLA, respectively. These polymers can be easily degraded by the organism, but
the lack of mechanical resistance, as well as their low osteoconductivity, make this material
unsuitable to be used alone as a scaffold [103]. Its degradability is a great advantage and,
therefore, this material has been incorporated into CPC- or BG-based materials, with the
aim of improving the handling of these materials as well as injectability [47,102]. These
Materials 2023, 16, 4117 8 of 22

polymers have also been used to improve the osteogenic properties of other materials, in
addition to being extensively studied as carriers of molecules, such as growth factors or
drugs [104].
In Table 2 examples of trademarks, composition, and mechanisms of action described
by manufacturers of synthetic materials used as bone grafts.

Table 2. Trademarks, composition, and mechanisms of action described by manufacturers.

Mechanisms of Action Described by

Trademarks Composition Reference
Manufacturers
Calcium Sulphate with/without
BonePlast® Osteoconductive; Resorbable [73]
HA granules
Conduit™ 100% β-TCP Osteoconductive; Resorbable [105]
Osteoconductive; Resorbable; Osteogenic and
OpteMx™ HA/TCP biphasic osteoinductive when mixed with medullary [2]
bone
Integra Mozaik™ 80% β-TCP, 20% collagen type I Osteoconductive; Resorbable [106]
Biphasic Calcium Phosphate (15%
MasterGraft™ Osteoconductive; Resorbable [107]
HA, 85% β-TCP)
NovaBone® Bioactive silicate Osteoconductive; Resorbable [108]
100% β-TCP/80% β-TCP + 20% Osteoconductive; Resorbable; Osteogenic and
Vitoss® collagen/70% β-TCP, 20% collagen, osteoconductive when mixed with medullary [24]
10% bioactive glass bone
Calceon® 6 Calcium sulphate Osteoconductive; Resorbable [105]
Norian® SRS® Calcium Phosphate Osteoconductive; Resorbable [109]
MIIG X3 Calcium sulphate Osteoconductive; Resorbable [110]
Osteoset® Calcium sulphate Osteoconductive; Resorbable [111]
75% calcium sulphate, 25% calcium
Pro Dense™ Osteoconductive; Resorbable [112]
phosphate
50% calcium sulphate, 10% calcium
Pro-STIM™ phosphate, 40% demineralized Osteoconductive; Resorbable; osteoinductive [113]
bovine bone
Osteoconductive; Resorbable; Osteogenic and
Biphasic calcium phosphate and
CopiOS® Bone limited osteoinductive when mixed with [114]
collagen type 1
medullary bone
Cerasorb® 100% β-TCP Resorbable [115]
Straumann Bone Biphasic calcium phosphate (60% Osteoconductive; Able toinduce vascularization
[24]
Ceramic® HA/40 β-TCP) and osteoblast migration
Biphasic calcium phosphate (60%
EasyGraft™ crystal Resorbable; Osteoregenerative [76]
HA/40 β-TCP)
EasyGraft™ classic Pure β-TCP phase (>99%) Resorbable; Osteoregenerative [77]
ENGIpore® Synthetic HA Osteoconductive [116]
Apaceram® Synthetic HA Osteoconductive [117]
Ostim® Pure HA phase Osteoconductive; Resorbable [118]
Ceros® TCP 100% β-TCP Osteoconductive; Resorbable [119]
Calciresorb® 96% β-TCP, 4% HA Osteoconductive; Resorbable [120]
Fisiograft® HA and polyethylene glycol (PEG) Partially resorbable [121]

4. Clinical Applications
In dentistry, the use of synthetic materials for bone repair has gained more and more
space, especially in the field of surgery and periodontics. Bone cements have gained
notable attention due to their injectability and moldability qualities, where there are several
comparative studies that suggest that their use brings advantages in relation to other
synthetic materials [27,41,122].
In dentistry, the use of synthetic materials has gained ground in several surgeries,
namely for maxillary sinus lift, periodontal defects, and bone crest augmentation. Most
of these procedures aim to improve the quantity and quality of bone for the insertion of
dental implants [94].
Materials 2023, 16, 4117 9 of 22

Rehabilitation with implants can be a problem if there is insufficient bone or if that

bone is of poor quality. When there is a bone defect, it is difficult to achieve the primary
stability necessary for implant placement and osseointegration [123]. It can also be difficult
to achieve this primary stability in the region close to the maxillary sinuses, where the
amount of cancellous bone is greater than cortical bone [21,39].
The use of synthetic material as a bone graft for maxillary sinus elevation has been
well documented and studies point out that some materials have demonstrated good
degradation and bone integration in humans after three months after implantation, with
no evidence of significant differences when implant placement occurs after three or six
months of bone augmentation [123].
As in any surgery, the choice of material must be based on the characteristics of the
defect; its shape, size, and location; as well as the type of intervention and the characteristics
of the material. There is still no consensus on the time required for material integration
and osseointegration, as this time depends on the type of material, the amount that is not
completely degraded, and the way the implant will be placed, depending on the torque
force and the primary implant stability [35].

5. Difficulties in Analysis of In Vivo and Clinical Trials Results

There are many materials for bone repair available on the market and the choice of the
dentist should be based on multiple factors, which include tissue viability as well as the
size, shape, and volume of the defect [2].
Many studies have been published on the most varied types of materials, but there
is still no consensus among dentists on the best option. What is agreed in this area is the
use of autologous bone whenever possible, given the proven and superior osteoinductivity
and osteogenesis of this material. Many studies prove its better efficacy in the regeneration
of bone tissues when compared to other materials [21,34,124].
In dentistry, the use of autologous bone is restricted to very specific cases, due to
its complicated procedure, invasive technique, and need for a hospital environment and
multidisciplinary team, in addition to cost [2]. Among the materials most used in dentistry
are materials of xenogeneic origin and synthetic materials. There are many articles pub-
lished about the advantages of each group, as well as their proven biocompatibility and
osteoconductivity [27,34].
Publications demonstrate great variability in the way of developing their studies. The
chosen animal model, sex, type of defect, surgical conditions, healing time, chosen material,
and the way the material is manipulated or applied are some of the variables that make
comparative analysis difficult. Although in vivo experiments follow criteria and protocols,
there is no single methodology in what concerns to sample selection, sample allocation,
measurement of analysed variables, or reading of results.
For the study of materials for bone regeneration, an understanding of each animal
specimen and specific characteristics of the bone is necessary, such as bone microstructure
and composition, the properties of bone formation and remodelling, and other characteris-
tics that should be similar to human bone as much as possible [125]. This comparison is
exemplified in Table 3 [125].

Table 3. Comparison between human and animal bone: four attributes (+ low similarity; ++ moder-
ately similar, +++ very similar).

Rodents Pigs Rabbits Dogs

Macrostructure + ++ + ++
Microstructure + ++ + ++
Bone
+ +++ ++ +++
composition
Bone remodeling + +++ + ++
Materials 2023, 16, 4117 10 of 22

Although mice are widely used animal models, they are significantly different from
human bone on many levels. As a result, regeneration resulting from the implantation of
biomaterials can hardly be used as an assumption of similar behaviour in humans [125].
Rabbits are also animals which are widely used in medical research. As with rodents,
a great disadvantage is related to their size, which does not allow the implantation of many
materials in the same model [125]. The bone structure of the rabbit also differs from human
bone; however, as an advantage, it is possible to mention bone maturation within six
months after birth, rapid skeletal change, as well as rapid bone turnover. These conditions
allow results in a shorter period of time in in vivo tests [125]. In terms of bone composition,
the animal models that most closely resemble humans, anatomically and physiologically,
are dogs and pigs. Pigs bear great resemblance to human bone, but as the pig increases in
size over time, this makes it difficult to control and handle the animal [125].
Clinical studies in humans are at the top of the medical research pyramid, as they are
the most complex and expensive, but provide the most reliable answer. In order to reach
testing in humans, the material must have been tested over several years in other animal
models, which means that newly discovered technologies cannot yet be tested in this group.
Nine publications with studies carried out in humans [26,27,30,34,39,41,122,126,127] are
going to be analysed.
In order to exemplify the difficulty of comparing the different alternatives, some
examples of studies will be reported according to the animal model. Given that allografts
are not alternatives widely used in dentistry, comparison between xenografts and synthetic
materials was chosen.

5.1. Studies in Rodents

In the case of the experiments in rats, Poehling [128] detected greater bone regeneration
when synthetic material was used with the incorporation of growth factors in the repair of
the bone defect. This study encompassed 60 specimens studied in the group of synthetic
materials and 72 specimens in the group of xenogeneic materials [128].
The study [128] evaluated a material called MD05, which is a combination of beta-
tricalcium phosphate coated with a growth factor called rhGDF-5. MD05 is being studied
as a bone graft material for dental and facial applications. The goal of the study was to
compare the bone-healing properties of MD05 with commercially available bone substitutes.
The researchers created skull defects in rats and implanted different materials in the defects,
including MD05, bovine bone mineral, and other bone substitutes. After 6 weeks, they
analysed the samples and found that MD05 showed significantly better bone regeneration
compared to the other materials. The defects filled with MD05 had more new bone forma-
tion, less fibrous tissue, and better overall bone repair. MD05 also showed the ability to
bridge the defect completely and support normal bone marrow growth. The growth factor
rhGDF-5 in MD05 seemed to play a role in promoting bone growth.
The xenogeneic materials (Bio-Oss® , Wolhusen, Switzerland) and PepGen® , Boston,
MA, USA) showed limited bone growth compared to the two synthetic materials analysed
in the study (with and without rhGDF-5) with growth restricted to the margins of the
bone defect.
Based on these results, the researchers concluded that MD05 is a promising bone
substitute for dental and facial applications, as it demonstrated superior bone regeneration
compared to conventional materials.

5.2. Studies in Minipigs/Guineapigs

Four studies using minipigs and/or guineapigs were chosen as examples to be de-
scribed [18,129–131]. Three different materials were analysed in the synthetic group HA
(Ostim® , Ankara, Turkey), β-TCP (Ceros® , New York, NY, USA), and macroporous bipha-
sic calcium phosphate MBCP. The xenogeneic group had only one material used, Bio-
Oss® [18,129–131].
Materials 2023, 16, 4117 11 of 22

The study by Jensen [129] used β-TCP (Ceros® ) and Bio-Oss® . β-TCP presented less
residual material when compared to Bio-Oss® after eight weeks of analysis. However,
the use of β-TCP induced the formation of a connective tissue layer with the presence
of macrophage cells. Moreover, at the junction between β-TCP and newly formed bone,
signs of β-TCP dissolution were observed, indicating dissolution and not direct resorption.
Higher bone formation was also observed with β-TCP when compared to the xenogeneic
material after 8 weeks.
Concerning Bio-Oss® , it was almost completely incorporated into the bone, increas-
ing bone density raising better biological support. No reduction or reabsorption of the
xenogeneic material was observed, but, as mentioned, its incorporation into the new bone
was observed, therefore suggesting that the osteoclastic cells found at the site performed
an important role in cleaning the surface of the particles for future osseointegration of
the xenogeneic material. Unlike Bio-Oss® , Ceros® demonstrated resorption in all stages
analysed and greater bone formation. Osteoclastic cells were not found along the material
but in nearby areas, with the function of phagocytizing dissolved particles.
Regarding Busenlechner’s [130] study, the authors claimed that the limited number
of samples available for simulations limits the direct comparison of different bone substi-
tutes. The main target of this study was to develop a preclinical model for guided bone
regeneration that enables testing of various bone substitutes in a specific type of bone
defect. The authors reported that up to eight titanium hemispheres can be placed on the
minipigs’ calvaria and filled with materials to be tested. Bio-Oss (a deproteinized bovine
bone mineral), Ostim (an aqueous paste of synthetic nanoparticular hydroxyapatite), and
Osteoinductal (an oily calcium hydroxide suspension) were tested using this model for 6
and 12 weeks. The results showed that hemispheres filled with Bio-Oss and Ostim exhibited
nearly complete bone formation, consistent with their documented osteoconductive prop-
erties. However, Osteoinductal did not demonstrate osteoconductive properties; instead, it
led to progressive resorption of the host bone.
In another study by the same author [131], three different areas of the defect were
analysed. HA based material (Ostim® ) and Bio-Oss® were analysed, and this study [131]
tested a different quantitative method to analyse bone volume formation based on a bi-
dimensional analysis, while other studies analyse bone formation in three dimensions
through computed micro-tomography (µCT). In both materials, the highest concentration
of formed bone was found close to the bone wall of the defect (three-walled defect). Ostim®
demonstrated large bone formation close to the defect wall, with less material visualized
when compared to Bio-Oss® in the same region. This area of intense bone formation
close to the bone wall of the defect with intense vascularization also demonstrates the
osteoconductivity of the synthetic material, given the different degree of bone formation
between both materials. Ostim® promoted greater bone formation close to the defect and
in an area up to 3 mm from the defect. Bio-Oss® promoted less formation close to the defect
wall and within 3 mm of the defect area, but it was possible to observe bone formation
beyond 5 mm from the defect, which confirms its osteoconduction.
In another study on guinea pigs, by Yazdi [18], a material based on HA and β-TCP
(MBCP) was used, with a polymeric carrier phase which creates a better-handling gel, and
compared with Bio-Oss® . It was observed in that study that with MBCP, bone formation
was distributed throughout the defect and not just at the margins. Bone formed throughout
the defect in the path of the material. It was also possible to observe material reabsorption
signs, with the presence of osteoids. No significant inflammatory reaction was observed
for both MBCP and Bio-Oss® . In this study, excellent angiogenesis and osteogenesis
were observed in the MBCP, both on the surface of the defect and in depth. This material
demonstrated better osteoconductivity compared to Bio-Oss® . This could have been caused,
as mentioned in the study, by the stability of the MBCP gel, compared to the loose particles
of Bio-Oss® . Even with stabilized Bio-Oss® , the removal of particles from the site was
inevitable. In this study, a membrane was not used to cover Bio-Oss® . As observed in the
Materials 2023, 16, 4117 12 of 22

study, this instability of the material at the defect site can inhibit bone formation and lead
to the formation of fibrous tissue during healing.
Studies with minipigs continue to be used in recent years [132,133]; however, trans-
lation of the information into humans is still difficult [134]. Notwithstanding, there is
recent information attesting that minipigs and humans have similar bone formation and
remodeling rates [134].
Several animal studies have been published reporting on dental bone graft efficacy;
however, animal models fail to mimic the complexity of the oral environment and unique-
ness of the alveolar bone [135]. In a recent review [135], the minipig intraoral dental implant
model was evaluated and a meta-analysis was conducted to estimate osseointegration
and crestal bone remodelling. They conclude that the minipig intraoral dental implant
model effectively demonstrates osseointegration and alveolar bone remodelling, similar to
what is observed in humans. However, the quality of reporting in the studies included in
this review was generally low, suggesting the need for improved reporting standards in
future research.

5.3. Studies in Rabbits

Concerning rabbits, five studies are going to be described in detail [36,44,45,136,137].
In the study by de Souza [136], the comparison between β-TCP (Cerasorb® ) and
Bio-Oss® showed similar bone formation between these materials after 60 days of experi-
ment, as well as residual material in both cases. The percentage of soft tissue found was
significantly higher in the β-TCP group after 60 days. Although angiogenic expression was
similar for both materials, Bio-Oss® allowed greater osteoblastic differentiation than the
synthetic material.
Kruse [137] used synthetic HA with silica oxide (Nanobone® ) and demonstrated
similar bone repair when compared to a xenogeneic material (Bio-Oss® ) in rabbit calvaria.
Statistical differences were not significant in this study. This indicates the similar ability of
these materials to regenerate bone. To summarize, in that study [137], results suggest that
synthetic hydroxyapatite/silica oxide granules yield comparable outcomes to a standard
xenogeneic bovine mineral in terms of bone formation and bridging non-critical size defects.
The study by Schmidlin [45] used β-TCP and BCP in the group of synthetic materials
and compared them with Bio-Oss® . This study was performed without placing periosteum
or membrane to cover the materials. In this study, the superiority of the xenogeneic material
in bone formation in rabbits was verified. In this study, BCP was more efficient in centripetal
bone formation when compared with TCP. After 16 weeks, all of the β-TCP material was
resorbed and the greatest degradation of the material was found at the periphery of the
defect in the particles involved in new bone. BCP showed no degradability after 16 weeks.
ABBM showed the greatest material degradation in the regenerated tissue.
Lee [36] conducted a study using an eggshell-based (EHA) material, which demon-
strated superiority when compared to HA. An organized lamellar island was found where
EHA was used, in addition to a lower percentage of residual material, with a statistically
significant difference in relation to HA. This study showed a lower mean percentage of
bone formed with the use of HA.
Lambert [44] used rabbits that underwent bilateral sinus elevation using three different
types of grafts: the xenograft (BHA), beta-tricalcium phosphate (β-TCP), or biphasic
calcium phosphate (BCP). In this study, researcher demonstrated that after 6 months
of observation, synthetic materials (β-TCP and BCP) had a higher percentage of bone
formation compared to the xenograft (BHA). No multinucleated cells were found in the
tissue generated via xenograft, and only lamellar bone was in close contact with the material
particles. β-TCP was no longer visible after the six months of study, which suggested its
almost complete resorption. It was possible to notice that the reabsorption of this material
is dependent on the observation time [45,136]. While β-TCP resorption occurred almost
entirely, BCP still remained with visible particles. In the case of BCP, osteoblastic activity
and osteoid tissue was found along the trabecular bone, suggesting active (osteogenic)
Materials 2023, 16, 4117 13 of 22

remodelling. Multinucleated cells were also found next to BCP, as well as capillaries,
which were not located either in xenogeneic material or β-TCP. The percentage of soft
tissue found in the xenogeneic specimens was significantly lower than the percentages
found in the other materials. This study concluded that osteogenesis was observed with
all three biomaterials in this specific animal model. After 6 months, there were significant
differences in biomaterial resorption rates among the three groups. The β-TCP showed the
highest resorption rate. After 6 months, bone closely interacted with the BHA particles,
forming a composite network, whereas BCP particles were frequently surrounded by soft
tissue. The study concluded that future investigations in humans should consider longer
follow-up periods.
Recent studies using rabbits as models for bone graft evaluation [138,139] continue to
have problems concerning translating the information into humans.

5.4. Studies in Dogs

Four studies in dogs were chosen to be described as examples [22,32,42,140]. In the
four studies described, seven different materials were analysed in the synthetic group
(β-TCP, β-TCP + mesenchymal cells (MSC), HA (Apaceram), BCP/MSC, BCP and HA
with particles of different sizes). The xenogeneic group analysed four different materials
(Bio-Oss® , Bio-Oss® + MSC, ABBM without commercial brand, with particles of different
sizes) [22,32,42,140].
In the study by Carvalho [32], materials with granules of different sizes were compared.
The best result concerning new bone formation was observed with xenografts of small
particles (150–200 µm). Xenografts with large particles (300–329 µm) also obtained better
results compared to the synthetic material with large particles of 300 µm. In this study,
xenogeneic materials had a rougher surface than HA, which may have positively affected
the adhesion of osteoblasts and their proliferation. Since the materials in this study were
experimental, the authors suggest that other factors such as the higher crystalline phase of
the materials and little amorphous phase may have affected the results.
Jafarian [140] demonstrated the highest percentage of new bone formation with
mesenchymal cells incorporated into BCP (Kasios® , L’Union, France) when compared
to Kasios® without cells and Bio-Oss® with or without cells. After six weeks, little osteo-
clastic activity and resorption was observed for both Bio-Oss® + MSC and Kasios® + MSC.
Although without significant difference, the percentage of new bone formed by Kasios +
MSC was higher than that registered with Bio-Oss® + MSC. A similar result was observed
when comparing Kasios® and Bio-Oss® materials without the presence of MSC, where a
higher percentage of new bone prevailed in the synthetic material.
Kim [42] studied a material based on synthetic HA in comparison to Bio-Oss® . The
percentage of bone formation with HA was significantly higher than that of Bio-Oss® and
the percentage of soft tissue found in the HA group was lower than in Bio-Oss® , with
16 weeks of observation. It was also verified in this study that both materials were poorly
reabsorbed by the body during this period. However, HA maintained a more appropriate
geometric structure for vessel formation and bone growth than Bio-Oss® . Particulate
xenogeneic material seems to lose most of its porosity and interconnectivity in the process
of transforming the bone block into particles, while in the synthetic material this porosity
and structure of the material can be planned and modulated, which can be beneficial for
bone remodelling.
A study in dogs by Vahabi [22] investigated the incorporation of mesenchymal cells
into BCP and compared this material with Bio-Oss® and with the synthetic material alone.
This study also demonstrated the role of mesenchymal cells in the formation of trabecular
bone, with more soft tissue involved. Although there was no statistically significant
difference between the materials, Bio-Oss® and BCP were shown to form less trabecular
and cortical bone than BCP incorporated with cellular material. The same result was
found in a study by Jafarian [140], with large bone formation in the synthetic material with
incorporation of mesenchymal cells. The highest percentage of residual material was found
Materials 2023, 16, 4117 14 of 22

in Bio-Oss® , and the highest reaction to foreign bodies was found with this material, but
without significant differences for the other materials.
Several attempts have been made to find animal models to test dental bone grafts;
however, the mandible model in beagle dogs is currently the best animal model for vertical
bone augmentation [141,142]. However, the use of the canine model is limited by socio-
ethical factors [142].

5.5. Studies in Humans

Scarano studied 96 patients who underwent maxillary sinus lift. After an observation
period of 6 months, the study concluded that all analysed materials are biocompatible and
did not show inflammatory signs [34]. The materials that obtained the greatest amount of
bone formation were the xenogeneic derivatives (Bio-Oss® and PepGen® ) in comparison
with bioactive glass and a polymer-based material (Fisiograft® sponge). Fisiograft® is a
polymer and, as such, has a faster degradation than particulate materials. Considerable
variation in the quality and quantity of formed bone has been reported in the literature in
relation to the type of material used and biopsy time [122,126,128,143].
Cordaro [126] also analysed elevation of the maxillary sinus after an observation
period of 180–240 days and concluded that BCP demonstrated greater formation of new
bone when compared to xenografts. Briefly, lateral sinus augmentation was used, with
grafting using BCP and xenogens. The difference between the materials is due to the
fact that xenografts have the amount of bone formed covering its particles, with a greater
amount of residual material compared to BCP. With regard to bone formation, both have
a similar amount of new bone, with similar histological appearance, which indicates that
both are good materials for maxillary sinus elevation and implant placement. This study is
multicentre, with different clinicians, but with a standard protocol, which included two
groups with similar characteristics, treated with an identical surgical protocol. This is an
important consideration, as there are several factors that can interfere with the results of
the study. The study concluded that there are no statistically significant differences in the
amount of new bone formed between the materials analysed when used for maxillary
sinus lift, but there are statistically significant differences in the residual material left by
the xenograft, which is surrounded by new bone and in relation to the soft tissue formed,
which was statistically higher in the case of BCP.
Simunek [41] analysed bilateral maxillary sinus elevation after nine months of ob-
servation. The particle size of both materials ranged between 1000–2000 µm. The study
concluded that xenografts obtained the highest percentage of bone formation compared to
β-TCP, but it was not possible to conclude the amount of residual material.
Froum [127] also compared bone regeneration in bilateral maxillary sinus lift, using
only two materials, and observed greater formation of new bone with BCP. Briefly, following
elevation of the lateral sinus walls, one material was placed in the right sinus and the other
material was placed in the left sinus. From the histological point of view, the two materials
proved to be osteoconductive after an observation period that varied between six and
eight months. The BCP material demonstrated a slight increase in the amount of bone
formed. The best results regarding bone formation were obtained after eight months of
observation. New bone was observed adjacent to and around the material particles, while
in xenogeneic material, the particles were surrounded by a greater or lesser amount of new
bone and osteoid.
Crespi [26] also compared materials but used tooth sockets in his study. In 15 patients,
45 extractions were performed and 30 sockets were filled with magnesium-enriched hy-
droxyapatite (MHA) or porcine bone (PB). After the four-month observation period, the
histomorphometric analysis of the biopsies revealed absence of inflammatory cells in both
materials. A small difference in percent bone volume was found with PB versus MHA,
but no significant differences. The authors concluded that the clinical performance of both
materials was similar.
Materials 2023, 16, 4117 15 of 22

Iezzi [27] also analysed materials in relation to bilateral maxillary sinus lift. The author
compared four different materials randomly applied to 15 patients (30 maxillary sinuses).
All analysed xenogeneic materials, with the exception of calcium carbonate, had a higher
percentage of new bone formation compared to BCP. The microporosity of the analysed
materials allowed the growth of new bone and blood vessels inside the pores of the partially
resorbed particles, mainly in Algipore® . The study concluded that all analysed materials
have similar characteristics and can be used for the maxillary sinus lift procedure.
Pettinicchio [122] also compared several materials in relation to the elevation of the
maxillary sinus and concluded that Engipore® and Bio-Oss® produced a similar percentage
of new bone and that none of the materials tested was completely absorbed after six
months of observation. Bio-Oss® showed that its particles appear osteointegrated in the
formed trabecular bone. This information is in line with other studies [44,126,127,129]. The
synthetic material Engipore® showed a tendency to concentrate the bone apposition within
the microporosities. The mineralized tissue appeared to be formed mainly of collagen fibres,
randomly oriented with some areas of osteoid tissue. The lowest percentage of residual
material was also found in Engipore® , which agrees with other authors [44,45,126,129].
Petinicchio’s study also concluded that the amount of bone formed depends on the type of
biomaterial and the number of residual particles was inversely proportional to the amount
of bone formed. The material derived from porcine bone (PepGen® ) demonstrated a lower
percentage of formed bone and a greater amount of residual material.
In the study by Lindgren [39], patients underwent bilateral maxillary sinus lift, which
made it possible to compare both materials used within the same biological conditions,
contrary to the study by Kurkco [30]. The BCP and xenograft materials were used and
analysed after three years of follow-up, but despite the initial number of participants
(11 patients), at the end of this observation period it was possible to use only five biopsies
of each material, given the difficulty in obtaining tissue with the necessary characteristics
around the implants that were placed. The histomorphometric study demonstrated greater
new bone formation in biopsies containing ABBM, but without significant differences
between the materials. Greater inflammatory reaction was seen in BCP biopsies, which may
affect the bone remodelling process, causing osteolytic or osteosclerotic lesions. However,
inflammatory cells also have the ability to increase the differentiation and activity of
osteoblasts and osteoclasts, but in most cases this result has more impact on bone loss than
on its remodelling [144]. The study concluded that, despite the greater bone formation of
the xenograft, the choice of biomaterial does not influence the survival of the implants.
Another recent study, by Kurkco [30], analysed the xenograft (Boneplus-xs® and
the synthetic material β-TCP (Kasios® ). Both materials, with particle sizes between
1000–2000 µm, were used for maxillary sinus lift. A negative point of this study comes
from the fact that it was not possible to compare both materials in the same patient. Pa-
tients underwent unilateral maxillary sinus lift and, therefore, the biological conditions
of each patient are considered in the study result. The mean observation period in this
study was 6.5 months, when the biopsy was performed. Both materials were mixed with
the patient’s own blood and neither material received a membrane. Bone formation was
statistically significantly different, with greater bone formation found in patients receiving
xenogeneic material. A greater amount of residual material was found with β-TCP, but
without significant differences in relation to xenogeneic material. Kurkco’s article confirms
other studies, which suggest that the configuration of the xenogeneic particles results in
better osteoconductivity, since the chemical composition, crystal and particle size, mate-
rial porosity, and surface texture of the particles have been reported as influencers of the
performance [32,41].
Only Froum [127], Crespi [26], and Lindgren [39] studied materials from different
sources in the same patient. Although the conditions of the spaces filled by the material in
the same patient may differ in size, studies that use identical methods allow a more reliable
evaluation and comparison of the healing response of the analysed materials. Among the
three studies, only the study by Froum resulted in a higher percentage of bone volume
Materials 2023, 16, 4117 16 of 22

formed when using a synthetic material, BCP. This same study confirmed other similar
results [39,41,126] when it pointed to a direct relationship between the maturation time of
the synthetic material and bone formation, being more visible bone remodelling after eight
months of study, while xenogafts did not demonstrate this trend, with no changes in bone
formation at six and eight months of observation.

6. Conclusions
The growing demand for materials for bone reconstruction has stimulated research in
the area of biomaterials, in order to supply the scarce source of autogenous and allogeneic
bone available, as well as to extinguish the issue related to the transmission of diseases that
is generated in the use of bone from xenogeneic origin.
Synthetic materials have gained ground among medicine and dentistry profession-
als due to their ease of handling, injectability, self-hardening, and because they are a
reproducible material. Their large-scale, planned, and modulated manufacture is another
advantage of these materials, since studies agree that bone formation is directly linked to
the composition of the material, size, shape, and porosity of the particles, which is difficult
to be controlled in the production of xenogeneic materials.
New synthetic bone substitutes have demonstrated good biological behavior in bone
formation compared to bone of xenogeneic origin. The initial phases of every study include
animals of reduced size, such as mice and minipigs. As research progresses, larger animals
may be included, with human studies being the final phase of the investigation. Therefore,
new materials are still in this phase of research.
Experiments on patients are the final phase of studying a product and materials with
recent technology are not yet used or commercialized or are under analysis. Thus, it is
understandable that, in clinical trials, studies have a statistically significant result in favor
of materials of xenogeneic origin, which have been on the market for over 30 years and are
very well documented, with their effectiveness proven.
Nanotechnology is creating opportunities for the development of more bioactive
bone substitutes, which release substances that improve cellular biological performance,
activate reparative cascades, or inhibit osteolytic processes. The best results in new bone
formation within the analysed studies were found when incorporating mesenchymal cells
and growth factors.
In the future, comparative studies in humans may reveal whether this evolution of
synthetic bone substitutes will be beneficial for better regeneration and remodeling with
greater bone quantity and quality than materials of xenogeneic origin, especially in critical
defects larger than 5 mm in diameter and bone defects that require a material with greater
mechanical resistance.

Funding: This research received no external funding.

Institutional Review Board Statement: Non applicable.
Informed Consent Statement: Non applicable.
Conflicts of Interest: The author declares no conflict of interest.

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