Bone Morophogenetic Protein Application as Grafting Materials for Bone Regeneration in Craniofacial Surgery: Current Directions

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Copyright © 2021 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Bone Morophogenetic Protein Application as Grafting
Materials for Bone Regeneration in CraniofacialSurgery:
Current Application and Future Directions
Marco Cicciu`, DDS,PhD,Luca Fiorillo,DDS,Gabriele Cervino,DDS,PhD,
and Mutaz B.Habal,MD, FRCSC
Abstract: Rebuilding atrophied alveolar ridges can present a signifi-
cant challenge for the maxillofacial surgeons. A multitude of treatment
options including guided bone regeneration, onlay block grafting, and
distraction osteogenesis are today available as safe procedures.
The recent Food and Drug Administration approval of recombinant
human bone morphogenetic proteins (rhBMPs) has given clinicians an
added treatmentoption forreconstructing localized and large jaw
defects. Currently, several patients have been successfully treated with
the combination of bone graft and rhBMP-2 and the results have been
documented as predictable and safe by clinical and radiologic exam-
inations follow-up.In this study,a literature review was conducted
using Medline,Medpilot,and Cochrane Database ofSystematic
Reviews. It was concentrated on manuscripts and overviews published
in the last20 years (2000–2020).The key terms employed were
platelet-rich plasma, rhBMPs, and their combinations with the com-
mon scaffolds used for bone regeneration techniques. The results of
clinicalstudies and animaltrials were especially emphasized.The
statements from the literature were compared with authors’own
clinical data.
The potential to reconstruct these large bone defects with a growth
factorthus limiting oreven avoiding a secondary harvestsite is
exciting and it represents a new frontier in the field of surgery. This
study data confirm how there are excellentdocuments aboutthe
possible combination of using substitute materials and growth factor
for treating large and minor craniofacial bone defects.
Key Words: Bone regeneration,recombinant human bone
morphogenetic protein-2,tissue engineering
(J Craniofac Surg 2021;32: 787–793)
Rationale
Severalsurgicaltechniques and technologies aiming atbone
augmentation and osteointegration ofprosthetic implants in
the axialand body skeleton are continuously introduced.Thus,
orthopedics,oral/maxillofacial,and periodontalsurgeonsoften
confrontthe dilemma of selecting 1 technology or therapy over
the other.1In orthopedics and maxillofacial surgery, novel tools and
techniques are being sought to improve the regeneration of bone
tissue.Numerous attempts have been made to enhance the osteo-
conductivity of titanium prostheses, including modifications in their
surface properties and coating with layers of calcium phosphate.
The decision-making process about the treatment choice for atro-
phic ridge reconstruction and the next dental implant positioning
becomes difficult and often it depends by the surgeons skills and
experience aboutthe treatmentdefects.The treatmentof severe
atrophies of the jaw is not so rare and clinicians had no references
both for the surgical technique decision, and for the graft material
choice.1–3
The investigationssupporting the clinicalevaluationsoften
focusjust on the statisticalsignificance ratherthan clinically
evaluate the significanteffectiveness of the biomaterials applied
to the surgicalprocedures.Moreover,the preclinicaldata are
usually referred to in vitro or clinical animal model observations,
and the clinical human study can be related with clinical reports or
surgical technical strategies.4
At the same way,in the last20 years,the number of dental
implants applied for oral prosthodontics procedures has increased
steadily worldwide, reaching about 1 million dental implantations
per year; but this procedure is related with adequate volume and
bone quality of the jaws.4 The use of dental implants for the oral
rehabilitation of fully and partially edentulous patients has greatly
broadened the scope of clinical dentistry, creating additional treat-
ment options in complex patients in which functional rehabilitation
was previously limited or inadequate. The predictability and long-
term success of dental implants have been well documented, both in
removable and fixed prostheses and their clinical success is con-
nected to the early osteointegration,so to the bone quality and
healing.In this field of knowledge and experience,the advent of
tissue engineering and specifically growth factors applied to max-
illofacialreconstruction procedure signed a fundamentalstep to
obtain bone tissue adequate in volume as wellin quality,with a
minimally invasive surgery.The main problem stillremains the
better choice of the ‘‘carrier’’ as well as the age of patients involved
in the surgery.5
About bone morhogenic proteins (BMPs) discoveries and their
clinical applications,firstly the Dr Marshal Urist investigated a
group ofproteins sequestered in bone and aptly named them
BMPs. Uristobserved thatbone matrix preparations contained
BMPs that induced cartilage, bone, and marrow formation when
implanted intramuscularly in rodentmodels.6 The BMPs have
been studied extensively and represent a significant addition to
From the Department of Biomedicaland Dental Sciences and Morpholo-
gical and Functional Images,University of Messina, Messina, Italy.
Received May 6,2020.
Accepted for publication June 22,2020.
Address correspondence and reprint requests to Prof. Marco Cicciu`, DDS,
PhD,Department of Biomedical and Dental Sciences and Morpholo-
gical and Functional Imaging,University of Messina, Via Consolare
Valeria,98100 Messina, Italy; E-mail: [e-mail],
[e-mail]
The authors report no conflicts of interest.
Supplementaldigitalcontents are available forthis article.DirectURL
citations appear in the printed text and are provided in the HTML and
PDF versions of this article on the journal’s Web site (www.jcraniofa-
cialsurgery.com).
Copyright# 2020 by Mutaz B.Habal,MDISSN: 1049-2275
DOI: 10.1097/SCS.0000000000006937
SCIENTIFIC FOUNDATION
The Journalof CraniofacialSurgery Volume 32, Number 2, March/April2021 787

Copyright © 2021 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
our understanding of bone biology and development. The influ-
ence of BMPs may begin as early as at gestation and continues
throughout postfetal life,recapitulating processes in embryonic
bone formation.The BMPs actas growth and differentiation
factors, and as chemotactic agents. They stimulate angiogenesis,
migration, proliferation, and differentiation of stem cells from the
surrounding mesenchymal tissues into bone-forming cells in an
area of injury.7 – 9
The BMPs can be defined as multifunctionalgrowth factors
belonging to the transforming growth factor b superfamily. Family
members are expressed during limb development,endochondral
ossification,early fracture,and cartilage repair.The activity of
BMPs was firstidentified in the 1960s,buthuman BMPs were
unknown until their purification and cloning in the 1980s. To date,
about 15 BMPs family members have been identified and charac-
terized,but the most used in craniofacial surgery is currently the
recombinant human bone morphogenetic protein-2 (rhBMP-2).5,10
In the craniofacial surgery, to be efficacious at a biologic target
site, rhBMP-2 as well as other growth factors should be delivered
locally by a suitable carrier system. Numerous materials have been
tested fortheirefficiency in carrying rhBMP-2.Among these
materials,collagen,synthetic or naturalceramics,demineralized
bone matrix (DBM),and polyglycolic acid have been mostfre-
quently investigated.However,none ofthese carriermaterials
meets all of the requirements of an ideal osteoinductive system.11,12
Thanks to the improvementof surgicaltechniques and bio-
materials, it is now possible to regenerate portions of tissues that
have been lost,thanks to oral surgery techniques.Guided bone
regeneration (GBR) and guided tissue regeneration are surgical
procedures that use barrier membranes to direct the growth of new
bone and gingival tissue at sites with bone or gum volumes or sizes
for proper functioning,aesthetics,or insufficientimplant-pros-
thetic restoration.7 – 9
The GBR is similar to guided tissue regeneration, but is focused
on the development of hard tissues in addition to the soft tissues of
the periodontal attachment.At present,GBR is mainly applied in
the oral cavity to support growth of new hard tissue on an alveolar
ridge to allow stable positioning of dental implants. The bone graft
used in combination with membranes and otherbiomaterials of
differentderivation are now predictable surgicaltechniques.13,14
The bone is the 2nd most transplanted tissue after the blood,the
need for bone tissue transplantation occurs in the eventof major
trauma, in which there is nothing to do with a fracture, but with a
real bonegap,osteoporoticvertebralfractures,osteomyelitis,
bone gaps due notto trauma butto removalof tumors and bone
cysts.In these patients,the bone can be replaced with natural
autograft or autologous tissue, allograft or homologous, xenograft
or heterologous.13,14
As seen therefore, it is possible to use biomaterials of different
derivation,the osteoinductive properties typicalof these proteins
can act in synergy with osteoconductive biomaterials and improve
their characteristics, being this a highly debated topic in maxillofa-
cial surgery and dentistry, it was defined as the main objective of
this review.15
Objectives
Aim of this revision is to compare the recentresults of the
rhBMP-2 applicationin craniomaxillofacialreconstruction
defects,trying to highlightdata from recentliterature about
clinical effectiveness,patientsatisfaction,bonequality,and
long-term results.The main purpose of this review is therefore
to evaluate allthe randomized clinicaltrials published in the
literature and to examine the raw results,to understand the real
efficacy and safety of BMPs.
The Population-Intervention-Comparison-Outcome(PICO)
questions that summarize the aim of this review are:
In GBR need patients,whatis the effectof BMP on bone
features compared with no BMP use?
Does BMP influence bone quality and volume in patients who
needs oral bone regeneration?
METHODS
Protocol and RegistrationScientific protocols have been followed for the preparation of
thisreview.A search wasconducted in the systematic review
databasesto highlightsimilarstudiesor not.Subsequently the
systematic review has been registered on PROSPERO (international
database of prospectively registered systematic reviews in health
and social care, welfare, public health, education, crime, justice, and
internationaldevelopment,where there isa health-related out-
come).The PROSPERO is produced by Center for Review and
Dissemination and funded by the NationalInstitute forHealth
Research.The number and date of registration (under review) on
PROSPERO are as follows: number 183834 on May 2nd 2020.
The systematic review was conducted in accordance with the
Preferred Reporting Items for Systematic Reviews and Meta-Anal-
yses (PRISMA) statement, all the guidelines were followed (Check-
list/Flow diagram),the division into chapters and paragraphs was
respected. The analysis of the risk of bias and the setting up of the
research,including the drafting of the objective questions of the
systematic review, respected the PRISMA criteria, and in particular,
in the latter patient the PICO guidelines (Fig.1).
Eligibility Criteria
The full text of all studies of possible relevance was obtained for
assessment against the following inclusion criteria:
1. Study about bone regeneration techniques with and without use
of BMPs
FIGURE 1.Preferred Reporting Items for Systematic Reviews and Meta-Analyses
flow chart.
Cicciu` et al The Journalof CraniofacialSurgery Volume 32, Number 2, March/April2021
788 # 2021 Mutaz B.Habal,MD

Copyright © 2021 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
2. Study of patients’ side effect of BMPs
3. Clinical studies on BMPs use and control groups
4. Articles published in the last 20 years
The applied exclusion criteria for studies were as follows:
1. Studiesinvolvingsubjectswith other specificdiseases,
immunologicdisorders,oncologicpatients,osteo-porosis,
and genetic diseases
2. Not enough information regarding the selected topic
3. No access to the title and abstract in English language or letters,
commentary,PhD thesis and editorials
4. Not randomized clinical trial (RCT) studies
Information Source
A literature review was conducted using Medline, Medpilot, and
Cochrane Database of Systematic Reviews.A hand search of the
reference lists in the articles retrieved was carried out to highlight
any additional publications and to improve the sensitivity.
Search
The review concentrated on manuscripts and overviews pub-
lished in the last 20 years (2000–2020). The key terms employed
were ‘‘bone morphogenetic proteins’’ and scaffolds used in combi-
nation.Statements from the literature with our own publications
have been compared. The search term was: ‘‘bmp[All Fields] AND
(‘‘mouth’’[MeSH Terms] OR ‘‘mouth’’[AllFields] OR ‘‘oral’’[All
Fields]) AND ‘‘bone regeneration’’[All Fields] in January 2020.
Study Selection
Two independent reviewers (LF and GC) of the University of
Messina singularly analyzed the results to selectinclusion and
exclusion criteria.They compared decisions and resolved differ-
ences through help of a 3rd expert reviewer (MC). For the stage of
reviewing of full-text articles, a complete independent dual revision
was performed. The results have been compared at the end of the
research with a 4th externalseniorreviewer(MH). A possible
disagreement regarding the inclusion of the studies was discussed
among the authors.
Data Collection Process
The firstphase of the research consisted in abstractreading,
which allowed us to make a firstscreening ofthe manuscript
eliminating those not concerning our research. Finally, the full text
of all studies was obtained and according to the expected inclusion/
exclusion criteria,articleswereselected and included in the
present review.
Data Items
After the firstliterature analysis,all articles were screened to
excludeirrelevantpublications,clinicalreports,and thenon-
English language publications. Then, researches were not selected
based on data obtained from screening the abstracts. Some studies
included did not present sufficient data to conduct review, or data
were unclearor absent.The finalstage ofscreening involved
reading the full texts to confirm each study’s eligibility,based on
the inclusion and exclusion criteria.
Risk of Bias in Individual Studies
This type ofreview analyses allthe studies in the literature
in the last 20 years presenting a review of recent data about BMPs
effectsin bone regeneration.Regardlessof the resultsof the
studies taken into consideration,the evaluation was carried out
on the field of action of the analyses carried outby the studies.
Risk of bias analysis has been conducted according to PRISMA
guidelines.16–18
Summary Measures
Data were collected from results and arranged in the following
fields as seen in tables:
Supplementary DigitalContent,Table 2,http://links.lww.-
com/SCS/B749
Authorsand Year:authorsand yearof publication ofthe
selected study
Type of study: research type
Sample: sample size and type
Follow-up: follow-up of the RCT
Supplementary DigitalContent,Table 5,http://links.lww.-
com/SCS/B752
Authorsand Year:authorsand yearof publication ofthe
selected study
Group type: type of groups division and administrated drug
Methods: used method to evaluate outcomes
Raw data: results of the studies,and obtained measures
Statistical results: statistical analysis of the single study
Synthesis of Results
The results of individualstudies have been shown in Supple-
mentary Digital Content, Table 1, http://links.lww.com/SCS/B748.
In synthesisof resultsparagraph,individualresultshave been
manually summarized and main results have been highlighted in
temporal order.
Risk of Bias Across Studies
Risk of bias assessment (sometimes called ‘‘quality assessment’’
or ‘‘critical appraisal’’) helps to establish transparency of evidence
synthesis results and findings.A risk of bias assessmentis often
performed for each included study in your review.A risk of bias
analysis has been conducted according to PRISMA guidelines.
Additional Analyses
The Mann-Whitney U-testhas been performed between com-
parable results of individual studies to conduct a meta-analysis. The
Mann-Whitney U-test is a nonparametric test that allows 2 groups or
conditionsor treatmentsto be compared withoutmaking the
assumption that values are normally distributed.
RESULTS
Study SelectionFrom the first research, a total of 410 results were obtained from
the scientific databases.Subsequently these results,subjected to
screening and application of the inclusion and exclusion criteria,
were reduced as follows. Subsequently, only the articles published
in the last20 years were considered,for a totalof 394 results
remaining. Therefore, only the accessible and available data articles
(383)and subsequently the RCT with sufficientinformation to
conduct a review were considered (16).
Study Characteristics
Study characteristics have been shown according to Methods
section and they are in Supplementary Digital Content,Tables 2,
The Journalof CraniofacialSurgery Volume 32, Number 2, March/April2021 BMP Application as Grafting Material
# 2021 Mutaz B.Habal,MD 789