MG - Molecules-27-05529

molecules
Review
Applications of Biodegradable Magnesium-Based Materials in
Reconstructive Oral and Maxillofacial Surgery: A Review
Sanja Vujović 1 , Jana Desnica 1 , Dragana Stanišić 1 , Irena Ognjanović 1 , Momir Stevanovic 1, *
and Gvozden Rosic 2, *
1 Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69,
34000 Kragujevac, Serbia
2 Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69,
34000 Kragujevac, Serbia
* Correspondence: momirstevanovic7@gmail.com (M.S.); grosic@medf.kg.ac.rs (G.R.);
Tel.: +381-641-327752 (M.S.); +381-633-92812 (G.R.)
Abstract: Reconstruction of defects in the maxillofacial region following traumatic injuries, cranio-
facial deformities, defects from tumor removal, or infections in the maxillofacial area represents a
major challenge for surgeons. Various materials have been studied for the reconstruction of defects
in the maxillofacial area. Biodegradable metals have been widely researched due to their excellent
biological properties. Magnesium (Mg) and Mg-based materials have been extensively studied for
tissue regeneration procedures due to biodegradability, mechanical characteristics, osteogenic capac-
ity, biocompatibility, and antibacterial properties. The aim of this review was to analyze and discuss
the applications of Mg and Mg-based materials in reconstructive oral and maxillofacial surgery in
the fields of guided bone regeneration, dental implantology, fixation of facial bone fractures and soft
tissue regeneration.
Citation: Vujović, S.; Desnica, J.;
Stanišić, D.; Ognjanović, I.; Keywords: magnesium; biodegradable metals; maxillofacial surgery; guided bone regeneration;
Stevanovic, M.; Rosic, G. bone fracture
Applications of Biodegradable
Magnesium-Based Materials in
Reconstructive Oral and
Maxillofacial Surgery: A Review. 1. Introduction
Molecules 2022, 27, 5529. https://
Reconstruction of defects in the maxillofacial region following traumatic injuries,
doi.org/10.3390/molecules27175529
craniofacial deformities, defects from tumor removal or infections in the maxillofacial area
Academic Editor: Xiaoying Wang represents a major challenge for surgeons. The maxillofacial region has a significant impact
on patients’ well-being, and any facial deformity or dysfunction has a devastating effect on
Received: 25 July 2022
the patients’ quality of life [1,2]. Reconstruction or augmentation of craniofacial bones is one
Accepted: 25 August 2022
of the most frequent surgical procedures in maxillofacial surgery. After blood transfusion,
Published: 28 August 2022
bone grafting is the second-most common tissue transplantation procedure worldwide [3].
Publisher’s Note: MDPI stays neutral Extensive clinical research on bone grafting and augmentation with autografts, allografts
with regard to jurisdictional claims in and xenografts has been performed. Autografts taken from the same patient are considered
published maps and institutional affil- the gold standard for bone reconstruction, since no immune reaction is expected. However,
iations.
the need for additional surgical intervention, donor site morbidity, limited bone availability
and significant graft resorption emphasized the need for different bone substituents [4,5].
Allografts taken from genetically non-identical members of the same species carry the risk
of pathogen transfer and immune system rejection [6]. Xenografts, usually bovine-derived,
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
are most often used to augment intraoral bone defects [7]. However, the application of
This article is an open access article
animal-derived materials to humans has certain limitations concerning patients’ religion,
distributed under the terms and dietary restrictions and ethical controversy [7]. To overcome these drawbacks, extensive
conditions of the Creative Commons research on bone tissue engineering using bio-mimicking, resorbable and biocompatible
Attribution (CC BY) license (https:// bone substitutes has been performed in the past years. These synthetic bone substitutes
creativecommons.org/licenses/by/ serve as an artificial extracellular matrix to promote bone healing until they are partially or
4.0/). completely replaced by newly formed bone [8,9]. Biodegradable polymers are extensively
Molecules 2022, 27, 5529. https://doi.org/10.3390/molecules27175529 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 5529 2 of 17
studied as bone scaffolds and have proven osteoconductive properties as well as excellent
biocompatibility [8,9]. However, low mechanical strength, unstable rates of degradability
and immune reaction to products of polymer degradation limit their use in clinical prac-
tice [10]. Titanium (Ti) is the most commonly used non-biodegradable metal in maxillofacial
surgery for stabilization of fractures or osteotomies, dental implantation procedures and
guided bone regeneration (GBR). However, Ti-based materials are bioinert, and secondary
surgical intervention is often needed to remove the Ti materials from the organism mainly
due to discomfort or surgical site infection, which may occur in up to 33% of cases [11].
Biodegradable metals have been extensively studied for tissue regeneration procedures
due to their biodegradability, mechanical properties, osteogenic capacity, biocompatibility
and antibacterial properties [12]. Magnesium (Mg)-based materials have been used in
medicine since the 19th century. Mg is an essential metal for the human organism, and
it is involved in more than 300 cell enzymatic reactions, mitochondrial activity, protein
translation, DNA synthesis and cell proliferation [13]. About 60% of Mg in a healthy adult
is deposited in bones [13]. Mg is resorbed from the intestines, and its homeostasis in the
organism depends on renal function [13]. Due to its mechanical properties, an elastic
modulus similar to human bones and its biosafety, Mg had been used in orthopedic surgery
in the early 20th century until it was replaced with Ti materials [14,15]. The elastic modulus
of Mg is about 45 GPa which is much closer to that of cortical bone (10–23 GPa) compared
to Ti [16]. The development of bioresorbable Mg-based materials prevents the need for
second-stage surgery for the removal of implanted material and associated comorbidities.
The aim of this review is to analyze and discuss the applications of Mg and Mg-
based materials in reconstructive oral and maxillofacial surgery. The review is divided
into subheadings about the use of Mg-based material in: (a) GBR, (b) dental implant
coatings, (c) immobilization of facial bone fractures, and d) soft tissue regeneration. Based
on the literary data, we will discuss possibilities and directions for future development and
applications of Mg-based materials in oral and maxillofacial surgery.
2. Biological Properties of Mg-Based Materials

The biodegradability of magnesium-based materials is the major advantage of Mg
materials. Mg corrodes in the physiological environment and releases species such as
Mg ions (Mg2+ ), alloying elements, H2 gas, and OH− [9]. In an alkaline environment,
magnesium hydroxide Mg(OH)2 is deposited on the Mg matrix and forms a protective
layer [10]. In the case of fast degradation and corrosion of Mg-based materials, a locally
high concentration of Mg ions disturbs calcium-mediated bone reparation and regeneration
processes. Products of corrosion of Mg-based materials such as magnesium hydroxide
and hydrogen gas may impair tissue healing due to the formation of gas cavities and
compression to surrounding soft tissues [17,18].
Due to the roles of Mg in major cellular functions, magnesium-based materials in the
forms of bone cement, bone scaffolds, and implant coatings were evaluated as promising
candidates for bone regeneration therapies. Various in vitro studies reported Mg ions
to have positive effects on bone cells, including enhanced proliferation, migration and
alkaline phosphatase activity, increased differentiation capacity of human osteoblast cells,
and increased proliferation of bone marrow-derived stromal cells (BMSCs) [17–19]. Having
in mind that Mg-based materials are biodegradable, the osteogenic effect of Mg ions is dose-
dependent. Concentrations of Mg ions in tissue ranging from 2.5–10 mM have a positive
effect on the proliferation and differentiation of human BMSCs [19,20]. However, higher
concentrations of Mg ions in the tissue were connected with decreased mineralization
capacity and matrix deposition of BMSCs [21,22]. The inhibitory effect on osteogenesis of a
high local Mg concentration in tissue was linked with alteration in calcium metabolism in
cells due to competition between calcium and magnesium ions for the same ion transporters
and the inhibition of expression of the calcium-sensing receptor [22,23]. This resulted in a
decreased intracellular calcium concentration and decreased calcium influx in cells [22,23].
Molecules 2022, 27, 5529 3 of 17
Investigations on the implementation of Mg-based materials found no adverse effects

on health. The resorption of Mg results in elevated local concentrations of ions, which
is rarely harmful to cells because cells can handle concentrations of Mg about 16-times
higher than the physiological ones [10]. Upon implantation in the organism, degradation
of Mg does not result in increased Mg deposition in lymph nodes [24]. In vivo studies
reported that there were no health risks following Mg implantation in rats with chronic
renal failure [25]. The results of an in vivo study indicated that Mg absorption, after
implantation of Mg alloy rods, at the degradation rate of 2.32 mm/yr did not lead to
dysfunction of the heart, liver, kidney, and spleen of the rabbits [26]. Moreover, Mg alloy
rods inserted in the femoral bone of the New Zealand rabbits did not cause changes in
the Mg serum levels, kidney and liver function, and histological structure of the vital
organs, like the heart and spleen [27]. Clinical trials following the implantation of Mg
screws for the treatment of orthopedic fractures found no signs of hypermagnesemia and
demonstrated normal levels of Mg blood concentration [3]. Also, no complications, such as
allergic reactions, liver/renal dysfunction, or an increase in Mg serum levels, were observed
after the application of Mg alloy compressive screws in patients undergoing corrective
orthopedic surgeries [28].
3. Bioresorbable Mg-Based Materials for Guided Bone Regeneration (GBR)

3.1. GBR Membranes
GBR in the maxillofacial region has been extensively studied over the past decades.
Loss of jaw bones due to periodontitis, tooth extractions, operation on tumors and cysts,
systemic diseases or infections results in different jaw abnormalities and changes to the
occlusion. GBR comprises the use of bone scaffolds or substituents and biomembranes in
order to augment bone defects and induce osteogenesis [29].
Biomembranes act as a barrier between hard and soft tissues. They prevent the soft
tissues from interfering with osteogenesis, thus providing enough space for the differentia-
tion of osteoprogenitor cells. Biomembranes used in clinical practice could be resorbable
based on synthetic (poly(lactic-co-glycolic acid) (PLGA), polyethyleneimine (PEI), poly(L-
lactic acid) (PLLA)) or natural (collagen, chitosan) polymers, non-resorbable (Ti mesh, or
polytetrafluoroethylene (e-PTFE)) (Figure 1).
Resorbable membranes are widely used due to their economic benefits, biocompatibil-
ity and easy manipulation. However, these membranes are often deformed due to rapid
degradation, which may impair bone regeneration, while their low mechanical strength
makes them unsuitable for larger bone defects [29]. On the other hand, the application of
non-resorbable membranes implies the need for second-stage surgery. Biomembranes with
Mg-based materials could combine the mechanical strength of metallic alloys, biocompat-
ibility and slow degradation in natural tissues as a promising solution for this problem.
Furthermore, the mechanical properties of Mg alloys allow the membrane to maintain the
space for osteogenesis and bone height in alveolar sockets or large bone defects [30]. The
good plasticity of Mg alloys is useful in handling and adapting membranes to complex
shapes of bony defects [31]. In addition, the antibacterial properties of Mg alloys reduce
the risk of bacterial infection and bone resorption [32].
Reports on the clinical application of Mg-based GBR membranes are scarce due to
difficulties in adapting their degradation rate to clinical expectations. A recent in vivo
study evaluated the Mg-alloy GBR membrane (Mg-2Zn-0.46Y-0.5Nd) for bone healing
in a critical-sized mandibular bone defect within a study with beagle dogs [33]. The
results of this research showed good biocompatibility, osteoconduction and osteogenic
potential of the membrane. However, the authors observed almost complete postoperative
resorption of the membrane within 3 months, which led to reduced osteogenic effect in
later phases. Similarly, the results of the in vivo study with a mineralized collagen/Mg–Ca
alloy combined scaffold designed to withstand the physiological forces in the mouth did
not achieve the desired restoration of alveolar bone defects in dogs [34].
Molecules 2022, 27, 5529 4 of 17
Molecules 2022, 27, x FOR PEER REVIEW 4 of 19
Based on polymers
1. Advantages: biocompatibility,
easy manipulation
2. Disadvantages: poor
mechanical stability, fast
degradation, inflammatory
reaction
Resorbable
membranes
Magnesium-based materials
elastic modulus, osteoinduction,
biodegradation
GBR membranes 2. Disadvantages: uncontrolled
degradation rate
Titanium
Non-resorbable mechanical properties
membranes 2. Disadvantages: need for second
stage surgery
Figure 1. Guided bone regeneration membranes (GBR) for bone tissue regeneration.
Figure 1. Guided bone regeneration membranes (GBR) for bone tissue regeneration.
In Resorbable membranes
order to decrease are widely
the process used due to various
of degradation, their economic
coatingsbenefits, biocompati-
to Mg materials
bility and easy manipulation. However, these membranes
were added. In an in vitro–in vivo study on the critical-sized defect of rabbit calvaria,are often deformed due tothe
rapid
degradation, which may impair bone regeneration,
Mg-Zn-Gd membrane coated with calcium-phosphate (Ca-P) showed superior osteogenicwhile their low mechanical strength
andmakes them unsuitable
mechanical for larger bone
properties compared to thedefects
non-coated[29]. Mg-Zn-Gd
On the other hand, the[35].
membrane application
Surface of
non-resorbable
modification using membranes impliesoxidation
plasma electrolytic the needand forhydrothermal
second-stagetreatmentsurgery. on Biomembranes
Mg mesh
with Mg-based
resulted in decreased materials could combine
degradation and better thequality
mechanicalof newly strength
formed of metallic
bone in alloys,
calvariabio-
compatibility
defects and an
in rats during slow degradation
in vivo experiment in natural tissueshybrid
[36]. Complex as a promising
membranesolutionAZ31-PLGA- for this
demineralized bone matrix (DBM) had a strong ability to promote the proliferation of bone to
problem. Furthermore, the mechanical properties of Mg alloys allow the membrane
maintain
marrow stemthe space
cells and for osteogenesis
resulted in excellent andrepair
bone height in alveolar sockets
of the critical-sized calvariaordefect
largemodel,
bone de-
fects [30].
reported by inThe good
vivo plasticity
research [37]. of
A Mg alloys
similar is usefulvivo
in vitro–in in handling and adapting
study showed that themembranes
addition
to complex
of pure shapes
Mg particles of bony
to the PLGAdefects
scaffold[31]. In addition,
in order to overcome the antibacterial
the low mechanicalproperties of Mg
strength
alloys reduce
of PLGA resultedthe inrisk of bacterial
significant infection of
proliferation and bone resorption
BMSCs [32]. increased bone
and significantly
formation Reports on thepremolar
in a canine clinical application
tooth socketof[38]. Mg-based GBR membranes are scarce due to
Composite
difficulties in Mg-polymer
adapting theirmembranes
degradation and ratematerials
to clinical showed promising
expectations. results
A recent in in
vivo
bone repair.
study Photo-cross-linkable
evaluated the Mg-alloy GBR collagen/polycaprolactone
membrane (Mg-2Zn-0.46Y-0.5Nd) methacryloyl/magnesium
for bone healing in
(Col/PCLMA/Mg) composite bone
a critical-sized mandibular membranes demonstrated
defect within a study excellent
with beagle mechanical
dogs [33]. properties
The results
andofelastic modulus,
this research biocompatibility,
showed and promoted
good biocompatibility, cell attachment
osteoconduction andand osteoprogeni-
osteogenic potential
torofcell
theproliferation
membrane. when However, implanted
the authorsinto calvaria
observed bone
almostdefects of ratspostoperative
complete for 8 weeks in an
resorp-
in vitro–in
tion of thevivomembrane
study [39].within 3 months, which led to reduced osteogenic effect in later
phases. Similarly, the results of the in vivo study with a mineralized collagen/Mg–Ca alloy
3.2.combined
Mg-Based scaffold
Scaffolds designed
for GBR to withstand the physiological forces in the mouth did not
Bone tissue
achieve is a natural
the desired composite
restoration mixture
of alveolar of organic
bone defects in (collagen
dogs [34].fibers) and inorganic
substances (hydroxyapatite
In order to decreasecrystals)
the process [2]. Composite
of degradation, scaffolds
variouscombining
coatingsthe toadvantages
Mg materials
of biodegradable polymers such as PLGA and PEI with hydroxyapatite
were added. In an in vitro–in vivo study on the critical-sized defect of rabbit calvaria, (HA) ceramicsthe
have been extensively studied because they resemble the
Mg-Zn-Gd membrane coated with calcium-phosphate (Ca-P) showed superior osteogenic natural bone structure, and its
mechanical and osteoconductive properties are enhanced by
and mechanical properties compared to the non-coated Mg-Zn-Gd membrane [35]. Sur- a thin biodegradable polymer
coating [4]. In vivo studies
face modification with composite
using plasma electrolytic HA–polymer
oxidation and scaffolds resulted
hydrothermal in complete
treatment on Mg
repair of a critical-sized defect in rabbit’s calvaria, a large
mesh resulted in decreased degradation and better quality of newly formed bone defect of rabbit’s ulna, as wellin acal-
critical
variasize mandibular
defects defect in
in rats during answine
in vivo [2,4,40].
experimentHowever, [36].due to the insufficient
Complex hybrid membrane mechanical
AZ31-
properties of composite bone scaffolds, deformation and brittle
PLGA-demineralized bone matrix (DBM) had a strong ability to promote the proliferation fracture may occur [41]. For
Molecules 2022, 27, 5529 5 of 17
this reason, Mg-based materials with excellent biocompatibility and mechanical properties
were incorporated into HA to enhance their biological and physicochemical properties.
In vitro and in vivo experiments demonstrated significantly improved HA properties with
the addition of Mg [42]. The addition of Mg to HA resulted in improved chemical prop-
erties compared to stoichiometric HA, such as reduced crystallinity, high specific surface
area, and enhanced solubility in natural tissues. These factors lead to improved cell adhe-
sion, proliferation, and metabolic activity [43]. A mixture of HA and β-TCP doped with
Mg (magnesium-doped biphasic calcium phosphate) mimics the natural inorganic bone
matrix with excellent physicochemical properties [44]. Furthermore, the presence of Mg
ions during synthesis also improves the thermal stability of HA and produces a more
stable phase composition after heat treatment, which enables the production of porous or
granulated scaffolds for biomedical applications, including oral and maxillofacial surgery
and orthopedics [44,45]. Magnesium Hydroxyapatite (MgHA) scaffold was analyzed for
bone regeneration in alveolar critical-sized bone defects in several animal and human trials.
The results suggest that the MgHA scaffold could be a very effective bone substitute [46].
Various in vitro studies reported excellent biocompatibility for several cell lines [47–49].
Sartori et al. demonstrated in an in vivo study conducted on sheep that MgHA provides
osteoconductive structural support during the process of bone regeneration [50]. Santos
et al. concluded in an in vivo experiment that MgHA, when implanted in a critical bone
defect in rat calvaria, is a biocompatible and osteoconductive biomaterial [51]. A clinical
study by Grigolato et al. showed that MgHA, used as a bone substitute in a mandibular de-
fect due to ameloblastoma, exhibits excellent biological behavior and high osseointegration
potential [52]. MgHA is a relatively well-studied Mg-based bone substitute material, and
there are several commercial products researched for the reconstruction of maxillofacial
bone defects.
Teeth extractions cause significant changes in the dimensions of the alveolar ridge due
to resorption of the alveolar socket, which may impair dental implantation and prosthetic
reconstruction [53]. Resorption of the alveolar socket is rapid following tooth extraction
due to loss of function, and about 40–60% of bone is resorbed in the first two years [54]. The
preservation of the alveolar socket volume following tooth extractions and alveolar ridge
preservation or augmentation could be achieved using MgHA scaffolds. In a clinical study
by Crespo et al. a split-mouth design was used to compare histologic and histomorphomet-
ric results of MgHA and porcine bone grafts for the preservation of fresh dental sockets [55].
The results of this study showed similar biologic behavior in bone formation and resorption
processes. A similar clinical study that compared radiographic and histomorphometric
results of MgHA and calcium sulfate grafts in fresh sockets after tooth extractions found
a lower reduction of the alveolar ridge, more bone formation and more residual implant
material in the MgHA group [56].
A prospective 2-year clinical study evaluated the survival of dental implants loaded
14 weeks after vertical alveolar ridge augmentation with nano-structured MgHA covered
with Ti-polytetrafluoroethylene (e-PTFE) membrane [54]. The results of this study sug-
gested that vertical ridge augmentation around Ti implants using MgHA can be successful
in cases with early implant loading. However, an in vivo animal study with canines did
not find a significant effect of MgHA on alveolar socket preservation and osseointegration
of implants placed immediately into extraction sockets [57]. Recently, a clinical study
investigated the effectiveness of a biomimetic MgHA/collagen-based bone substitute for
alveolar socket preservation compared to deproteinized bovine bone matrix [58]. The
results after 6 months showed similar vertical and horizontal alveolar ridge resorption,
similar new bone formation between the groups and a significantly higher residual material
for deproteinized bovine bone matrix. Crespo et al. compared the use of MgHA and autol-
ogous bone graft for maxillary sinus lift procedures [59]. The results of this clinical study
suggested MgHA as a possible alternative to autologous bone graft for sinus lift operations.
There are promising results from using bovine bone grafts enriched with Mg for
bone regeneration. An in vivo study on the biological properties of bovine xenogeneic
Molecules 2022, 27, 5529 6 of 17
biomaterial enriched with Mg on the healing of critical-sized defects on rat calvaria showed
Mg biomaterial demonstrated osteoinductive properties and biodegradability during heal-
ing [60]. Similar results were reported for the rabbit calvaria defect repair in an in vivo
study [61].
Mg-based bone types of cement have been used in orthopedics for bone and tendon
repair [62]. The results of canine in vivo study that evaluated Mg-based bone cement for
bone grafting of immediate implantation of extraction sockets showed success at filling in
the bone defects without implant loss during the observation period [63]. However, the
use of Mg-based bone types of cement may be doubtful due to their 3D structure and lack
of porosity, which enables osteoconductive properties [10].
Zhang et al. developed 3D gel printing in an in vitro–in vivo study and used it to
prepare an Mg scaffold with a controllable pore structure, and its surface was modified
with a calcium phosphate coating [41]. The addition of calcium phosphate coating onto
the surface of materials improved biocompatibility and biosafety, osteogenic induction
and angiogenic ability; in addition, the degradation rate of materials can be effectively
controlled by adjusting the thickness of calcium phosphate coating [64].
4. Mg and Mg-Based Materials for Ti Implant Coating

Surface characteristics of Ti implants have a major impact on the process of implant
osseointegration, and research in the field of implant surface modification is important
despite good and predictable rates of implant success [65]. Various surface coatings on
dental implants were investigated in order to improve implant surface for stronger mi-
cromechanical retention and improved biological processes for osteogenesis [65,66]. Surface
coating with bioceramics such as hydroxyapatite, calcium phosphate, and bioactive glass
resulted in improved osseointegration. However, the practice has significant complications
due to poor mechanical strength, brittleness and bacterial infections around implants [67].
Mg and Mg-based materials were studied as possible implant surface coatings due to
elastic modulus of the material, osteogenic effect, biocompatibility and biodegradation of
these materials. Results of in vitro and in vivo studies found positive effects of Mg coatings
such as Mg carbonate, Mg fluoride, Mg oxide, Mg silicate, and HA incorporated with Mg
and Zinc (Zn) [65]. The results of in vitro studies demonstrated that Ti implants coated
with Mg-based coatings showed enhanced BMSCs proliferation and increased expression
of osteogenic markers (alkaline phosphatase, osteocalcin, osteopontin, bone sialoprotein,
RUNX-2), increased collagen type I deposition and antibacterial activity [68–74]. In an
in vivo animal study comparing antibacterial properties of Mg and Mg-Zn co-implanted,
Yu et al. showed both surfaces to have an excellent antibacterial effect against specific peri-
odontal pathogens, such as Porphyromonas gingivalis, Streptococcus mutans and Fusobacterium
nucleatum [68]. Additionally, another study found that MgO-HA and MgF2 -HA coatings
had a significantly better antibacterial effect against Enterococcus spp., Micrococcus spp. and
Candida albicans than HA coatings [72].
New bone formation is quantitatively measured with the metrics of bone–implant
contact and bone area. The results of in vivo studies revealed improved osseointegration,
better new bone architecture, higher bone volume/total volume and bone-to-implant ratio
with Mg coatings than conventional Ti surfaces [75–78]. Cho et al. found in a study on
rabbits that the concentration of Mg ions had a significant effect on osseointegration since
implants coated with 9.24% Mg had remarkably better removal torque value, bone–implant
contact, bone fill area and new bone formation [75].
The results of in vitro studies clearly demonstrated Mg coatings had positive effects
on osteoblastic differentiation of BMSCs, and increased cell proliferation and induction of
osteogenesis to obtain implant osseointegration. In vivo studies showed that Mg coatings
resulted in increased new bone formation, higher values of new bone and better new
bone architecture [78]. Clinical studies are needed to confirm further clinical effects of Mg
surface coatings.
Molecules 2022, 27, 5529 7 of 17
5. Bioresorbable Mg-Based Materials for Osteosynthesis of the Facial Bone Fractures

Resorbable Mg-based materials have been extensively studied for use in orthopedic
surgery since the beginning of the 20th century due to their biological properties and the
elastic modulus similar to natural bone [79]. However, they were replaced by bioinert Ti
materials due to superior mechanical properties for the treatment of complicated and load-
bearing fractures. Since the implantation of Ti plates and screws for fracture immobilization
requires a secondary surgical intervention and removal of Ti material due to infection,
discomfort or plate exposure, bioresorbable Mg-based materials were de novo analyzed for
the treatment of traumatic bone injuries [11]. Pre-clinical and clinical studies were mostly
performed for the stabilization of orthopedic fractures, while limited data are available for
the treatment of maxillofacial injuries.
For orthopedic injuries, both pure Mg and its alloys were evaluated. The biological
and mechanical properties of Mg and its alloys are mainly influenced by material behavior
in the tissue following implantation. In the natural conditions in the tissue, Mg corrodes
and releases Mg ions and H2 gas into surrounding tissues and may cause significant
emphysema in the rapid corrosion process [79]. There are pieces of evidence that H2 may
induce osteogenesis and reduce osteoclastogenesis and thus benefit bone reparation [80].
The corrosion of Mg and Mg alloys depends on material structure (heterogeneity, metal
purity and microstructure of the alloy), mechanical loads, pH of the surrounding tissues
and vascularization [81–83]. The corrosion rate and degradation of Mg and its alloys are
the main factors influencing their clinical application [81–83]. Pure Mg (99.99%) has a
low corrosion rate and low mechanical strength [84]. However, pre-clinical studies found
pure Mg promotes osteogenesis and fracture healing on rabbit femoral condyle fractures
using Mg screws [84]. Mg alloys with rare earth elements (RE) such as scandium (Sc),
yttrium (Y), gadolinium (Gd), zirconium (Zr) and neodymium (Nd) were synthesized in
order to decrease corrosion and reduce degradation rate of 99.99% pure Mg. The most
widely studied Mg-based alloys comprise AZ (Mg-Al-Zn system) and WE alloys (Mg-RE-Zr
system) [85]. AZ alloys such as AZ31 (Mg-3Al-1Zn) and AZ91 (Mg9Al-1Zn) have excellent
mechanical properties, but the high degradation rate and local toxicity of aluminum limit
their clinical use [86]. On the other hand, WE43 alloy (Mg-4Y-3RE) is coated with a RE-oxide
layer, improving corrosion resistance and biocompatibility [87]. WE43 alloy (Mg-3.5% Y-
2.3% Nd-0.5% Zr, wt.%), MgYREZr alloy and Mg-Nd-Zn-Zr alloy were assessed in in vitro
and in in vivo studies for bone repair, which resulted in good bone repair when used as pins
or screws for bone fixation in orthopedic patients [88,89]. ZX00 (Mg-Zn-Ca alloy) is another
resorbable alloy that revealed good results in pre-clinical studies on bone regeneration [90].
Recent clinical trials investigating the use of Mg and its alloys for stabilization of
orthopedic fractures revealed excellent results in fracture reduction of displaced femoral
neck fractures, hallux valgus and medial malleolar fractures, with the bone regeneration
rates comparable to Ti screws [91–95]. Most of these trials investigated the use of MgYREZr
alloy screws to stabilize unstable fractures. Due to the release of H2 ions due to corrosion, a
radiolucent zone around screws was observed in the majority of postoperative radiological
exams. However, no severe complications were observed [96].
Reports on the use of Mg and its alloys in the treatment of facial bone fractures are
scarce. Traumatic injuries to the facial bones are among the most common injuries to the
body, mostly reported in traffic accidents and interpersonal violence. Fractures in the
maxillofacial area have a significant impact on patients’ appearance, speech and mastica-
tion [1,2]. The treatment of facial bone fractures requires the repositioning of fractured bone
fragments to the anatomical state and osteosynthesis with Ti plates and screws. Ti plates
and screws are used due to the excellent biocompatibility and biomechanical properties
of Ti and usually are left for life [11]. However, they sometimes need to be extracted due
to an infection or discomfort [66]. Biodegradable plates and screws may be beneficial
in avoiding second-stage surgery. Biodegradable materials for use in the maxillofacial
area must overcome some factors specific to this region. These include factors such as
significant masticatory muscle forces, presence of saliva and intraoral pathogens. This is
Molecules 2022, 27, 5529 8 of 17
because most of the surgical interventions are performed through an intraoral approach,
with different elastic modules of facial bones as well as various shapes of bones [80,97].
Biodegradable polymer fixation plates made from PLLA and PLGA have poor mechanical
properties and may cause an inflammatory reaction [98]. Mg-based materials possess good
mechanical strength and biocompatibility with proven clinical applications. However, the
compressive yield strength of Mg-based alloys is lower than Ti alloys which questions their
use for load-bearing fractures such as mandible fractures [99]. Pre-clinical studies revealed
Mg-based materials as promising candidates for maxillofacial bone osteosynthesis [99–110]
(Table 1).
Table 1. Magnesium (Mg)-based materials for osteosynthesis of maxillofacial bones.
Reference Study Materials Fixation Type Methodology Evaluation Results

Bilateral Mg screws maintained
Mg (pure)
Finite element mandibular Stress dis- stability at osteotomy sites
Lee et al. [100] Polymer Screw
modeling ramus sagittal tribution superior to the
Ti
split osteotomy polymer material
Mg-Ca-Zn screws
Mg-Ca-Zn Bilateral maintained stability at
Finite element alloy mandibular Stress dis- osteotomy sites and
Lee et al. [101] Screw
modeling Polymer ramus sagittal tribution displayed masticatory
Ti split osteotomy loading superior to the
polymer material
Animal
Schaller et al. Implantation on Histology Sufficient stability of the
experiment WE43 alloy Rivet
[102] mandibular angle Micro-CT rivets during 12–24 weeks
(minipigs)
Animal Unicortical Sufficient stability of the
Naujokat et al. Histology
experiment WE43 alloy Plate + screws osteotomy at plates and screws for
[103] Micro-CT
(minipigs) mandibular angle 8 weeks, no side effects
Animal Mg Sufficient stability of the
Henderson et al. Implantation on Histology
experiment AZ31 alloy Screw screws, physiological
[99] mandibular angle Micro-CT
(rabbits) Stainless steel bone remodeling
Sufficient stability of the
Animal Le Fort I plates and screws for
WE43 Histology
Byun et al. [104] experiment Plate + screws osteotomy of the 24 weeks; significant gas
Ti Micro-CT
(beagles) maxilla formation in the first
12 weeks
Animal Le Fort I Rapid biodegradation of
ZK60 coated
Byun et al. [105] experiment Plate + screws osteotomy of the Micro-CT ZK60 resulted in
with PLLA
(beagles) maxilla insufficient results
Osteotomy at
Animal WE43 Sufficient stability of the
Schaller et al. supraorbital rim Histology
experiment Polymer Plate + screws plates and screws in the
[106] and zygomatic Micro-CT
(minipigs) (PLGA) midface region
arch
Sufficient stability,
Animal biocompatibility and
WE43 Osteotomy at Histology
Kim et al. [107] experiment Plate + screws osteogenic activity of the
polymer zygomatic arch Micro-CT
(beagles) plates and screws in the
midface region
Animal WE43 sufficient stability of
Naujokat et al. WE43 Frontal bone Histology
experiment Plate + screws the plates and screws in the
[108] Ti osteotomy Micro-CT
(minipigs) calvaria compared to Ti
Animal WE43 sufficient stability of
Schaller et al. WE43 Frontal bone Histology
experiment Plate + screws the plates and screws in the
[109] Ti osteotomy Micro-CT
(minipigs) calvaria compared to Ti
Ca-P coated Ca-P coated Mg-Zn-Gd
Animal Defect of the
Mg-Zn-Gd Histology scaffold resulted in excellent
Zhang et al. [110] experiment Mesh medial orbital
scaffold Micro-CT bone regeneration, no
(canines) wall
Ti gas formation
Mg—Magnesium; Ti—Titanium; Ca—Calcium; Zn—Zinc; Micro-CT—Micro-computed tomography; PLLA—
Poly(L-lactic acid); PLGA—Poly(lactic-co-glycolic acid); Ca-P—Calcium phosphate; Gd—Gadolinium.
Molecules 2022, 27, 5529 9 of 17
Mandibular fractures are the most common fractures in the maxillofacial area, and
their treatment consists of thick Ti plates and locking screws to restore the bone’s anatomical
shape along with occlusion, and avoid postoperative movement of the fragments by heavy
masticatory forces [102]. Only one animal study by Nujokat et al. used MgYZrRee (WE43)
custom-made fixation plates and screws for the stabilization of mandibular osteotomy
at the mandibular angle [103]. The results of this in vivo study proved good mechanical
stability at the osteotomy site. However, the performed osteotomy was monocortical and
did not represent a full bicortical fracture line. Mg screws were investigated in several
studies and reported better mechanical properties compared to the polymeric material
but lower mechanical and torsional strength than Ti controls [98–100]. Interesting are the
results of Mg screws for stabilization of osteotomy lines for bilateral ramus sagittal split
osteotomy (BSSO) performed for orthognathic surgery procedures where the mandibular
setback or advance is performed to correct maxillofacial deformities. The results of two
studies based on finite element modeling found the use of Mg or Mg-Ca-Zn screws could
stabilize the osteotomy lines even with masticatory loading [100,101]. Further pre-clinical
and clinical trials are needed in order to obtain an Mg-based fixation system for mandible
fractures and osteotomies to overcome current disadvantages regarding mechanical stress
and low torsional strength.
On the other hand, the results of animal studies on the fixation of the midface complex
fractures are more promising. Midface fractures, mainly fractures of the maxilla and
zygomatic bone, are load-shearing types of fractures where no significant masticatory
forces are implied to reduce the stability of the fracture line. The use of WE43 plates and
screws for the fixation of fractures in the midface resulted in good osteotomy lines stability,
biocompatibility, and osseointegration [103–106]. The gas formation was observed for
12 weeks postoperatively without side effects on bone regeneration and wound healing,
proposing that the material’s degradation rate is adequate. The use of PLLA-coated ZK60
plates and screws for fixation of Le Fort I osteotomy in beagles resulted in significant gas
formation and local inflammation due to the fast biodegradation of the material [107].
Although ZK60 plates showed good mechanical properties, it seemed that PLLA coating
failed to prevent the rapid absorption of the alloy due to micro-cracks on the surface [107].
Further research is needed to obtain alloys with more predictable rates of biodegradation
and mechanical properties for these types of fractures. Fixation systems based on Mg
materials used in these studies were thicker and had a bigger volume compared to Ti
fixation systems, although there was no significant discomfort to the subjects
Promising results of pre-clinical studies have been published regarding the use of
WE43 plates and screws for the fixation of fractures in the frontal bone [108,109]. The
stability of the plates and biocompatibility were comparable to the Ti fixation system.
The repair of orbital fractures represents a significant challenge to the surgeons due
to the proximity of intracranial structures, paranasal sinuses, the poor blood supply of
the bones and osteoprogenitor cell insufficiency [110]. The thin bony walls of the orbit,
especially the inferior and medial walls, are the most prominent locations for fractures.
Blow-out fractures of the orbital floor are the most common fracture of the orbit. Current
materials used for fracture reduction and reconstruction of the orbital volume are bioinert
Ti meshes, plates, and polyethylene meshes. Zhang et al. developed Ca-P coated Mg-Zn-Gd
scaffold to reconstruct a large defect of the medial orbital wall in a canine model [110]. The
results showed excellent osteoconductivity, angiogenesis and bone regeneration with the
scaffold. The authors observed no gas formation and orbital emphysema.
Only two clinical studies by Leonhardt et al. reported the effectiveness of Mg-based
materials for the treatment of fractures in maxillofacial surgery [111,112]. These studies
reported repositioning and fixation of mandibular condyle fracture with Magnezix® CS
2.7 mm screw (MgYREZr alloy). The authors reported excellent stabilization of fragments
and complete restoration of temporomandibular joint (TMJ) function. Gas formation
around screws was reported and seen as radiolucent areas on control CBCT exams. One
year follow-up was uneventful, and there was no need for screw removal (Table 2).
Molecules 2022, 27, 5529 10 of 17
Table 2. Clinical studies on magnesium (Mg)-based material for stabilization of fracture of the
mandibular condyle.
Reference Study Fracture Pattern N Material Results Complications

Displaced fractures of
the condylar head with 4 patients with
Magnezix® CS 2.7 Stabilization of
a loss of height on the unilateral One accidental
mm screw fracture, restored
Leonhardt et al. mandibular ramus, and fractures fracture of the
Case series (Syntellix AG, function of TMJ, no
[111] clinical signs such as 1 patient with screw which
Hanover, gass formation
pain, malocclusion, and bilateral was replaced
Germany) during 3 months
jaw movement, fracture
limited excursions
Restoration of
Displaced fractures of
occlusion and
the condylar head with
Magnezix® CS 2.7 function of TMJ, gas
a loss of height on the
Retrospective mm screw lacunas visible for
Leonhardt et al. mandibular ramus, and
observational 6 patients (Syntellix AG, 6 months none
[112] clinical signs such as
study Hanover, afterwards filled
pain, malocclusion, and
Germany) with bone, partial
jaw movement,
resorption of screws
limited excursions
in first year
TMJ—Temporomandibular joint.
6. Mg-Based Materials for Soft Tissue Regeneration

The application of Mg and Mg-based materials for bone tissue regeneration is well-
known. Several studies revealed Mg has a positive impact on the regeneration of soft tissue
in the maxillofacial region.
Mg scaffolds induce cell proliferation, migration, and osteogenic differentiation of
human dental pulp cells and participate in the process of pulp repair [113–115].
Mg ions have positive effects on the migration and adhesion of human fibroblasts and
oral mucosa regeneration [116,117]. The effects of Mg on fibroblast activity could have a
promising effect on the alteration of the Ti implant surface and promote soft tissue healing
around the neck of the implant [118,119]. In an in vitro study by Okawachi et al. [120],
hydrothermal treatment of Ti with an Mg solution improved the integration of gingival
epithelial cells and fibroblasts with the Ti surface. Furthermore, Mg has antibacterial
properties against common periodontal pathogens [78].
Previous studies reported biomimetic scaffolds with Mg nanoparticles combined with
polymers had promising results for cartilage regeneration [86]. This scaffold may positively
impact the treatment of TMJ disorders. Having in mind the joint cartilage is mainly
fibrous, lacks blood supply, and has limited self-repair, as well as that the properties of Mg
include anti-inflammatory effect, enhanced synthesis of the cartilage matrix, promotion
of chondrocyte proliferation, and enhanced chondrogenic differentiation of hBMSCs, the
application of Mg-based materials may be a promising new strategy in the treatment of
chronic TMJ conditions [121–123].
It is known that Mg ions are involved in neurotransmission through the n-methyl-
D-aspartic acid receptor and the inhibition of the production of glutamatergic excitation
signals [124]. Several pre-clinical studies showed that Mg supplementation positively
affected sciatic nerve regeneration and repair [125,126]. One animal study revealed that
oral or intravenous Mg might reduce the signs of trigeminal neuralgia [127]. Sensory nerve
neuropathies in the maxillofacial area may cause significant impairment to patients’ quality
of life. Primary trigeminal neuralgia is a form of chronic neuropathic pain that affects
branches of the trigeminal nerve. Current treatment procedures involve therapeutic drugs,
and surgical interventions when drug treatment is ineffective. Peripheral nerve branches
in the maxillofacial area may be injured during surgical interventions: great auricular
nerve during parotidectomies, inferior alveolar nerve during operation of cysts or tumors
in the lower jaw, and infraorbital nerve during surgical procedures in the maxilla. Mg
supplementation may be beneficial in the treatment of these neuropathic conditions [124].
Molecules 2022, 27, 5529 11 of 17
In addition, the trauma to the peripheral motoric branches of the facial nerve during
parotid gland surgery or mastoidectomy can result in facial paralysis. Restoring the function
of motor nerves is much more difficult and uncertain compared to sensory nerves [128].
Gougoulias et al. reported in an in vivo study that subcutaneous injection of Mg in neonatal
rats reduced motor neuron death after sciatic nerve axotomy [129]. In vitro studies showed
Mg ions could promote the proliferation of neural stem cells [130]. Further studies are
needed to evaluate the role of Mg in sensory and motor nerve repair.
Table 3 summarizes application areas of Mg-based materials in reconstructive oral and
maxillofacial surgery.
Table 3. Overview of applications of magnesium (Mg)-based materials in reconstructive oral and

maxillofacial surgery.
Study
Application Advantages Disadvantages Future Directions
In vitro In vivo Clinical
Mandible -biocompatibility -low resistance to -improvement of
+ + +
fracture -degradation masticatory stress mechanical resistance for
Fracture Midface -elastic modulus -uncontrolled load-bearing fractures
reduction + + − -mechanical properties -development of Mg
fracture degradation rate
-no second alloys with predictive
Frontal bone stage surgery -uncontrolled degradation rate
+ + −
fracture degradation rate
-biocompatibility
-osteoconductivity -improvement of 3D
Scaffolds + + + -low porosity
-bone repair porosity
-biocompatibility
GBR
-degradation-
mechanical properties -improvement of
-uncontrolled
Membrane + + − -osteogenic effect mechanical properties
degradation rate
-small and large and degradation rate
bone defects
-antibacterial activity
-biocompatibility
-need for clinical trials
-degradation-
-development of
Oral implantology + + − osteoblastic -degradation rate
techniques for
differentiation
Mg coating
-antibacterial activity
-no trials on the possible
-protective effect -no data on
TMJ + − − use on TMJ
on cartilage TMJ regeneration
cartilage regeneration
-no trials on the
Dental pulp + − − -dental pulp repair
Soft tissue preclinical or clinical use
regeneration -fibroblast activation
-possible use in
Oral mucosa + − − -mucosa regeneration
dental implantology
-antibacterial properties
-possible use in sensitive
Nerve tissue + + − -nerve regeneration
nerve neuropathy
GBR—Guided bone regeneration; TMJ—Temporomandibular joint.
7. Conclusions
Mg-based materials have been extensively studied for their use in biomedicine in the
past decade. Mg-based materials represent a very promising group of biomaterials for
application in reconstructive medicine. Mg has an essential role in cell metabolism, and it
is involved in more than 300 enzymatic processes. Mg-based materials are biodegradable,
biocompatible, with elastic modulus similar to that of bone and with a positive effect
on bone regeneration. In the field of reconstructive oral and maxillofacial surgery, its
positive effects were reported in the areas of guided bone regeneration, improvement
of dental implant osseointegration, fixation of facial bone fractures and regeneration of
soft tissues. Due to the positive effect on bone repair and differentiation of osteoblasts,
Molecules 2022, 27, 5529 12 of 17
Mg-based materials were successfully evaluated in clinical studies for guided regeneration
of jaw bones. In vitro and in vivo studies reported improved osseointegration when Mg
coating was applied to the Ti implant surface. Clinical studies on the application of Mg-
based materials for the treatment of maxillofacial fractures have been published, and
further research is needed to develop the Mg alloy with adequate mechanical strength
and degradation rate. Further research is still needed to improve the characteristics of
Mg-based materials for application in the maxillofacial area.
Author Contributions: Conceptualization, S.V. and G.R.; writing—original draft preparation, S.V.,
J.D., D.S., I.O. and M.S.; writing—review and editing, S.V. and G.R.; supervision, M.S. and G.R. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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molecules

Molecules 2022, 27, 5529. https://doi.org/10.3390/molecules27175529 https://www.mdpi.com/journal/molecules

2. Biological Properties of Mg-Based Materials

Investigations on the implementation of Mg-based materials found no adverse effects

3. Bioresorbable Mg-Based Materials for Guided Bone Regeneration (GBR)

4. Mg and Mg-Based Materials for Ti Implant Coating

5. Bioresorbable Mg-Based Materials for Osteosynthesis of the Facial Bone Fractures

Table 1. Magnesium (Mg)-based materials for osteosynthesis of maxillofacial bones.

Reference Study Materials Fixation Type Methodology Evaluation Results

Reference Study Fracture Pattern N Material Results Complications

6. Mg-Based Materials for Soft Tissue Regeneration

Table 3. Overview of applications of magnesium (Mg)-based materials in reconstructive oral and

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