Materials Science and Engineering C 61 (2016) 1018–1028

Contents lists available at ScienceDirect

Materials Science and Engineering C

journal homepage: www.elsevier.com/locate/msec

Review

Dental materials for cleft palate repair

Faiza Sharif a,b,⁎, Ihtesham Ur Rehman a, Nawshad Muhammad b,⁎⁎, Sheila MacNeil a
a
Department of Materials Science & Engineering, Kroto Research Institute, University of Sheffield, Broad Lane, Sheffield, UK
b
Interdisciplinary Research Centre in Biomedical Materials, COMSATS Institute of Information Technology, Lahore, Pakistan

a r t i c l e i n f o a b s t r a c t

Article history: Numerous bone and soft tissue grafting techniques are followed to repair cleft of lip and palate (CLP) defects. In
Received 9 July 2015 addition to the gold standard surgical interventions involving the use of autogenous grafts, various allogenic and
Received in revised form 8 September 2015 xenogenic graft materials are available for bone regeneration. In an attempt to discover minimally invasive and
Accepted 10 December 2015
cost effective treatments for cleft repair, an exceptional growth in synthetic biomedical graft materials have oc-
Available online 11 December 2015
curred. This study gives an overview of the use of dental materials to repair cleft of lip and palate (CLP). The el-
Keywords:
igibility criteria for this review were case studies, clinical trials and retrospective studies on the use of various
Cleft palate types of dental materials in surgical repair of cleft palate defects. Any data available on the surgical interventions
Synthetic graft to repair alveolar or palatal cleft, with natural or synthetic graft materials was included in this review. Those
Dental materials datasets with long term clinical follow-up results were referred to as particularly relevant. The results provide en-
Craniofacial repair couraging evidence in favor of dental and other related biomedical materials to fill the gaps in clefts of lip and pal-
Bone substitute ate. The review presents the various bones and soft tissue replacement strategies currently used, tested or
explored for the repair of cleft defects. There was little available data on the use of synthetic materials in cleft re-
pair which was a limitation of this study. In conclusion although clinical trials on the use of synthetic materials are
currently underway the uses of autologous implants are the preferred treatment methods to date.
© 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
3. Procedures used in the treatment of cleft palate abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
3.1. Pediatric craniofacial growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
3.2. Timeline approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
3.3. Surgical evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
3.4. Natural bone materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
3.4.1. Autografts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
3.4.2. Allografts of bone and skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
3.4.3. Xenografts (bovine/porcine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
3.5. Synthetic bone substitute materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
3.5.1. Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
3.5.2. Bioceramics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
3.5.3. Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025
3.5.4. Biocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026

⁎ Correspondence to: F. Sharif, Department of Materials Science & Engineering, Kroto Research Institute, University of Sheffield, Broad Lane, Sheffield, UK.
⁎⁎ Corresponding author.
E-mail addresses: f.sharif@sheffield.ac.uk (F. Sharif), nawshadmuhammad@ciitlahore.edu.pk (N. Muhammad).

http://dx.doi.org/10.1016/j.msec.2015.12.019
0928-4931/© 2015 Elsevier B.V. All rights reserved.
 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028
1. Introduction
Clefts of lip and palate are congenital deformities of the craniofacial
region with a gap in the upper lip and roof of the mouth. The prevalence
of this group of malformations is around 1 in 700 live births in the UK
and USA and 1 in 500–700 worldwide [1]. Cleft palate accounts for
75% of all craniofacial defects encountered in the US each year, affecting
nearly 225,000 children per annum [2].According to WHO data the inci-
dence of cleft lip and palate is 69 out of 10,000 live births around the
globe [1].This means that the incidence of cleft palate is almost about
475 cleft palates per month or 15 clefts per day in the US alone [2].
CLP (cleft of lip and palate) originates from failures in the fusion of
oronasal processes within the first five to six weeks of gestation [3,4].
A more detailed classification of deformities has been explained by
Dixon et al. [4] and is given in Fig. 1. When a cleft is limited to the lip
only; it is termed as cleft lip, if accompanied by the cleft of the palate
it is termed as cleft lip and palate. In terms of facial structures, two
main maxillary regions can be distinguished: the anterior primary pal-
ate and the posterior secondary palate. Clefts in the anterior or primary
region are called primary clefts and ones in the posterior or secondary
palate are called secondary clefts. The complete cleft of both palates in-
volving both parts is also very common and these can be unilateral or bi-
lateral. Each of these conditions is depicted by Dixon et al. [4,5] (Fig. 1).
Cleft of the palate may occur in isolation or may be a part of chromo-
somal, Mendelian or teratogenic origin [4,6].
There are moderate links between the heavy uses of alcohol;
smoking and low folic acid levels in the origin of CLP [7–9]. Babies
born to diabetic mothers are also at a higher risk for CLP compared to
non-diabetic mothers. It is known that neural tube defects are caused
by low folic acid levels and the CLP originates at the same time, there-
fore, some correlation between the two is envisaged [8,10]. In addition,
use of certain drugs, such as, phenytoin, sodium valproate, benzodiaze-
pines and corticosteroids may increase the risk of anomaly [11]. Some
Fig. 1. Types of CLP. a and e show unilateral and bilateral clefts of the soft palate; b, c and d, unilateral cleft lip and palate; e, bilateral cleft of soft palate; and f, g and h, bilateral cleft lip and
palate.
This figure is modified from Dixon et al. [4] and used with permission from Nature Publications.
1019
other factors related to family history and consanguineous marriages
may also play a pivotal role in increasing the incidence of this malforma-
tion [1,12].
Many psychological and behavioral problems are also associated
with these facial deformities. Looking different can develop a sense of
insecurity and inadequacy and in turn result in lowered self-esteem
and lack of confidence. Children with CLP are usually unable to perform
well at school due to constant bullying and criticism. In addition, speech
impediment may induce isolation and shyness in them. Peer interaction
in response to less attractive facial features and speech may further
cause social alienation. Being teased in childhood has been reported to
have led to behavioral problems in CLP children [13]. The support
from parents of the CLP affected children influences their own accep-
tance and adjustment to the cleft impairment [14]. This means that
the children while growing if loved cared and cherished by parents,
have more acceptance of their appearance and tend to develop more
normal personality. Cleft of lip and palate does not only influence the es-
thetics but is a real problem when it comes to feeding and related diffi-
culties. Not having a barrier between the oral and nasal cavities results
in insufficient suckling which generates a cascade of troubles highlight-
ed by Devi et al. [15]. Briefly, the food escapes into the nose and is regur-
gitated causing coughing, choking and vomiting. Inability to suckle
leaves the infant with inadequate milk intake, fatigue, irritability, poor
weight gain and slow growth [15]. Hearing issues and ENT infections
are also common [16].
In order to address the issue of cleft palate abnormalities, some in-
tervention is necessary to first, repair and then hold the further defor-
mation of facial features during the growth of an individual. There is
some data available on the techniques and procedures to treat the de-
fect surgically but very little and scattered information is available on
the use of synthetic and dental materials in the repair of CLP. The aim
of this article is to present an overview of the range of current method-
ologies and materials available for cleft repair with an emphasis on
1020 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028

currently available synthetic materials. The efficacy of dental materials

for cleft palate or alveolar cleft bone reconstruction has also been stud-
ied. Particular attention has been paid to hard tissue reconstruction re-
gardless of primary or secondary repair, soft tissue repair has not been
included as it is not generally considered a surgical problem where ma-
terials are required in contrast to hard tissue reconstruction.

2. Methodology

PubMed/MEDLINE and Cochrane electronic databases were

searched for articles published using selected keywords. Book Chapters,
Conference/Symposium's proceedings, and clinical trial findings were
searched from 1964–2015. The data sources, such as, NCBI and Web of
Science were used to search the data related to “biomaterials alveolar
cleft”, “cleft palate polymer”, “cleft palate synthetic grafts”, “cleft palate
repair scaffolds”, “composites cleft palate”.
In addition to the abovementioned databases, the literature was also
acquired from Scopus, Google scholar, etc. and was selected after
discarding unrelated and duplicate results for analysis. The reference ci-
tations in the abovementioned papers were further studied to obtain
more relevant information. Wherever possible the full texts of papers
were obtained from the journals. However, if it was not possible to ob-
tain a particular journal, the available abstracts, were considered in this
study. Case–control and cohort studies that reported data on alveolar or
palatal cleft repair were included. Isolated or multiple defects were also
included. Craniofacial defects other than CLP were excluded. Animal tri-
als were excluded and only human data was included in this review.
The inclusion criteria for articles were: (i) cleft palate autogenous,
xenogenous and synthetic grafts. Moreover, clinical trials on bone filler
implants were also included; (ii) any literature not published in widely
available, refereed journals or in a foreign language was not examined,
though wherever possible an abstract was sought for these. (iii) The lit-
erature or information not reported in the peer reviewed scientific liter-
ature was rejected. (v) References in papers were checked and cross-
matched with those from the original MEDLINE search. Additional refer-
ences identified through these sources and meeting the inclusion
criteria were also included in the review. After implementation of the
search strategy, the titles and abstracts of the articles, the selection
was performed by consensus with the objective of complementing the
database searches. The original search strategy resulted in more than
200 articles (Fig. 2). The total number of papers which met the inclusion
Fig. 2. A schematic presentation of the screening criteria used in this study.
criteria for the review was 110. Non-automated manual searches were
also conducted on the references within the selected articles. The pres-
ent review on the various types of materials used for cleft repair includ- The magnitude of stress and strain forces in craniofacial defects is not
ed 62 articles — 14 on natural materials [47–61] and 48 on synthetic fully understood since the complexity of these defects outweighs the
materials [62–110]. current understanding [21]. The masticatory muscles of the jaw sub-
stantially contribute to the stress existing in the craniofacial region. To
3. Procedures used in the treatment of cleft palate abnormalities have a better understanding of the amount of stress and strain on max-
illary bones ex vivo studies have been attempted in large animals but
3.1. Pediatric craniofacial growth more evidence is required to further establish these forces in human
CLP [22].
Within the first three years of a patient's age, the skull grows expo-
nentially and similarly the maxilla undergoes dramatic changes, dou- 3.2. Timeline approach
bling in volume within the first 5 years of life [17]. Therefore, it is
difficult to perform surgical procedures until a specific developmental The current treatment timeline applied in most of the world recom-
stage has been reached. The primary growth centers consist of the mends a series of surgeries and interventions to resolve the anomaly
chondral matrix of the skull from where the ossification occurs to in- (Fig. 3). According to this, the cleft defects in the lip need to be surgically
crease the size of skull. The primary and secondary growth centers in repaired as early as possible, preferably, within the first three months.
the maxillary region are controlled and connected through the muscles At about six to twelve months it is recommended that the cleft in the
of the face as shown by histology and MRI studies [18]. In patients with hard palate is covered with soft tissue around the cavity [23,24]. From
CLP the muscles around the nose and mouth are dislocated, as a result, eight to eleven years, the alveolar ridge is repaired using a bone graft.
the facial mid-sagittal axis is deviated to the non-cleft side [19]. There- This procedure helps restore the bony ridge, where the teeth descend.
fore the normal facial features can be achieved with functional repair Then orthodontic treatments are undertaken from two to fifteen years
of the growth centers [20]. as necessary to accommodate teeth and allow normal growth of the pal-
Irrespective of the composition of implant material, it will be under ate and maxilla [25]. A similar treatment timeline is adopted in the UK
tremendous amount of stress and strain within the craniofacial defect. and in the US. This is a long and complex process which spans many
 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028
Fig. 3. Treatment timeline.
years as children grow to adulthood. Unfortunately developing coun-
tries are an exception to this timeline as their health facilities are poor
and thus the majority of children born with CLP are rarely treated ac-
cording to recommended guidelines.
3.3. Surgical evidence
The current staged approach to treatment is based on clinical indica-
tions of scarring caused by well-intentioned early surgical interven-
tions. Such interventions if done too early or incorrectly may lead to
craniofacial growth retardation. Thus until recently the palates were su-
tured together at a very early time point but these were found to then
develop into immobile scarred hard tissue. This not only resulted in
speech and swallowing difficulties but also retarded the growth of max-
illa and alveolus [26,27].
Growth related facial asymmetries commonly occur despite the use
of sophisticated and timely surgical procedures. Thus secondary alveo-
lar bone grafts and lip and nose surgeries are done near adolescence.
The repair of the hard palate needs to be done at a relatively late time
point [28]. In nature there is a fine tuned harmony in the growth of
mid facial features including the soft and hard palates. The interaction
between the primary and secondary growth centers in CLP is important
for the normal growth of maxilla [23,29].
Cleft palate repair is essential to improve the quality of life of the af-
fected child. From a surgical perspective it is important to close the
oronasal fistula to provide stability to the alveolar ridge, eruption of
aligned teeth and bony support to the nose [4]. While initial plastic sur-
gery can achieve good repair of the soft tissue defects of lip and palate,
critical sized bone defects cannot be repaired without the use of extra
material. Bone grafts are commonly used to correct the alveolus and
mandible of the growing patient. The timing of these grafts should be
assessed on an individual basis to assist the natural tooth eruption in
the cleft region. Corrective surgeries are performed using autologous, al-
logenic and synthetic materials for cleft reconstruction materials for
bone regeneration in cleft repair.
Bone grafts are used for reconstruction in the absence of a natural
bone (cleft palate) or damage due to injury and disease (cancer or trau-
ma). These grafts may be natural or synthetic in origin. The natural allo-
genic implants are modified into bone powders, bone chips and bone
fragments which are processed to remove the live cells and immuno-
genic factors [30,31]. These natural materials are fairly osteoconductive
but sparingly osteoinductive. The commercial demineralized natural
bone is available from tissue banks but with donor related immunologic
implications [32].
The synthetic implants are favored as scaffolds for tissue regenera-
tion due to the plasticity of their physical and biological properties
and availability in large quantities. The major classes of synthetic bio-
materials for bone repair include ceramics such as hydroxyapatite
(HA) and tri-calcium phosphate (TCP) or bioactive silicates (SiO2). The
use of polymers like glycolic acid derivatives, lactic acid derivatives,
and other polyester derivatives for bone repair is also being explored
[32]. More recently the interest has shifted towards the use of compos-
ite biomaterials, such as, HA + TCP, SiO2 + HA or SiO2 + Ha + TCP for
bone replacement [33]. The applications of these different materials to
1021
cleft reconstruction are discussed in detail in this section. A summary
of the use of these materials is presented in Table 1.
3.4. Natural bone materials
3.4.1. Autografts
An estimated 36,000 or more craniofacial bone graft surgeries are
performed every year in the US [34]. The osteogenic, osteoinductive,
and osteoconductive properties of autografts make them the gold stan-
dard approach in treating bone defects including CLP. An advantage of
autologous graft tissue is the ready availability from different anatomi-
cal sites of the patient's own body [35].
It is important to repair the alveolar cleft effectively at an appropri-
ate time to attain normal dentition. In current clinical practice the can-
cellous bone chips harvested from the iliac crest or the chin bone are
grafted into the alveolar cleft. The implanted bone is then covered
with the gingival flaps [36]. The bone of the hard palate is normally
left untreated while the mucosa of the palate is repaired to join the
two halves together to facilitate development.
Several attempts have been made to reduce the donor site morbidity
by using alternative materials (Table 1). A case study reported complete
bridging of the alveolar cleft region and subsequent eruption of canine
teeth in a single 9 year old female patient with platelet-rich plasma
and autologous mesenchymal stem cells isolated, expanded and in-
duced to osteogenic potential [37]. Another clinical study reported the
treatment of alveolar cleft defects with minimally invasive iliac crest
bone graft in combination with demineralized bone matrix and cancel-
lous allograft. This allograft supplemental surgical technique is stated to
be associated with low morbidity, shorter operative times, and higher
rates of bone graft survival [38]. However, autografts do present some
limitations: firstly, the graft may fail as a consequence of lack of integra-
tion into the host tissue: secondly, donor site morbidity, chronic postop-
erative pain, hypersensitivity and infection may occur. Another factor is
the size limitations in surgically harvested donor site bone tissue, which
may leave with only a small quantity of graft material compared to the
area of defect [39]. In cases where the defect is large, the graft material
extracted from any one place may not be enough to repair the whole
area of defect.
3.4.2. Allografts of bone and skin
Allogenic bone graft is a bone tissue harvested from an individual ge-
netically unrelated to the recipient. Allografts are used to fill the alveolar
and palatal clefts as alternative to autografts. The innate osteoconductive
properties of allografts make them valuable in cases where there is a gap
wider than 15 mm [40]. An allograft in the form of acellular dermal ma-
trix provides a scaffold for cell growth, vascularization, and mucosal ep-
ithelialization. While being easy to handle during surgical procedures
these are also stronger and less susceptible to infection or rejection com-
pared to xenografts [41]. Clark et al. [42] used Alloderm® an acellular ca-
daveric dermal matrix as an adjunct to the primary repair of cleft palate.
The allograft was implanted in the oral cleft of primary surgery patients
ranging from 12 to 18 months of age with a cleft defect larger than
15 mm. The follow-up of patients looked for dehiscence, fistula,
infection, rejection, scarring, and contracture. Out of 7 patients 5 had
1022 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028

Table 1
Summary of dental materials used in cleft palate repair.

Number Type Nature Use Reference

1. Autograft Iliac crest bone Alveolar cleft augmentation [36]

Chin bone Alveolar cleft augmentation
Iliac crest bone graft in combination with demineralized bone matrix Alveolar cleft augmentation [38]
and cancellous allograft
Platelet-rich plasma and autologous mesenchymal stem cells Mesenchymal stem cells isolated, expanded and induced to [37]
osteogenic potential in bone augmentation procedures
2. Allograft Cadaveric acellular dermal matrix Alveolar cleft [43]
Fresh frozen bone Alveolar cleft [44]
Freeze dried bone graft Alveolar cleft [44]
Demineralized freeze dried bone graft Alveolar cleft [45]
3. Xenograft Porcine absorbable haemostatic gelatin sponge Alveolar cleft [46]
Deproteinized bovine bone Alveolar cleft [47]
Resorbable collagen sponge and bone marrow stem cells Alveolar cleft [48]
4. Ceramic Hydroxyapatite (HA) Alveolar ridge augmentations [1,108]
HA Craniofacial reconstruction [109,110]
Bovine-derived hydroxyapatite Alveolar cleft [70]
Silicon substituted β-TCP Alveolar ridge augmentations [111]
Biphasic calcium phosphate (BCP) set in platelet rich plasma (PRP) gel Alveolar cleft [69]
Micro-structured, resorbable β-TCP Alveolar cleft [71]
Calcium substitute paste or crystals Primary alveolar cleft repair [68]
Particle biphasic calcium phosphate (BCP) Alveolar cleft [69]
β-TCP Secondary and tertiary alveolar cleft grafting [72]
5. Polymers Methyl methacrylate vinylpyrrolidine hydrogel Animal cleft model [112]
PCL-TCP scaffolds were found to have increased the bone volume Craniofacial defect [82]
fraction in grafted defects
PCL in combination with HA increased the amount of new bone formed Craniofacial defect [83]
PCL/PLLA/PGA Cleft defect [100]
Porous polyethylene Craniofacial defect [113–115]
Poly(1,8-octanediol co-citric acid) (POC), and hydroxyapatite (nHA) Animal cleft model [115]
6. Biocomposites β-TCP granules and autogenous bone graft [106]
Autogenous bone and interconnected porous hydroxyapatite ceramics Craniofacial reconstruction [115]
(IP-CHA) and resorbable poly-L-lactic/polyglycolic acid screws
PCL/PLLA/PGA +bioactive glass Cleft repair [100]

complete repair without any fistula appearance. Oral mucosa dehiscence
was encountered in two patients, in two other patients nasal mucosal
tears were caused during closure of nasal layer. In all cases the
decellularized dermal graft was mucosalized and was incorporated into
the wound. No infection or inflammation was noted. Therefore large de-
fects of hard and soft palates as well as fistula can be closed using
decellularized dermal graft [42].
Acellular dermal matrix has been successfully applied by Cole et al.
2006 to treat oronasal fistula in CLP patients. These patients had under-
gone unsuccessful fistula repair surgeries three times prior to the im-
plantation of decellularized dermal graft. After implantation of the
graft no infection inflammation or rejection was encountered [43]
(Table 1). Bone allografts are commercially available in three forms:
fresh frozen, freeze dried and demineralized freeze dried bone grafts.
Fresh frozen bone can cause viral disease transmission, hence, these
are mostly avoided [44]. Demineralized allograft bone matrix is com-
mercially available and has been used in craniofacial regeneration. Au-
togenous bone fragments added by freshly extracted autogenous bone
marrow cells have been implanted to fill the alveolar cleft site. The CT
scan results after 6 months of implant showed that the tissue-
engineered bone achieved better bone volume compared to the gold
standard autograft [45] (Table 1).
It is worth considering, that the techniques like freeze drying, irradi-
ation or lyophilization, alter the material properties besides removing
immunogenic factors. In addition to the compromised mechanical and
biological integrity of the material, these allografts are expensive [43].
3.4.3. Xenografts (bovine/porcine)
Xenogenic bone grafts are de-proteinized skeletal tissues from bo-
vine or porcine origin. The xenografts are sometimes used as replace-
ment for autografts since there is a lack of availability of human grafts.
Only the inorganic component of the xenograft containing natural
structural matrix for new bone formation is used. This natural bone
although from animal origin contains calcium, which serves as a calcium
source for neo-bone formation at the recipient site. Bovine derived xe-
nograft is currently used after processing to treat maxillary defects. A
porcine absorbable hemostatic gelatin sponge has also been used as a
stem cell carrier for residual cleft repair. The commercial availability of
this scaffold as a low cost, easy to handle, biocompatible, transparent,
re-absorbable and osteo-inductive biomaterial makes it attractive for
cleft regeneration [46].
Alveolar cleft repair using composite autogenous bone combined
with deproteinized bovine bone (DBB) reduces the hospitalization
time and suffering in comparison with autogenous bone graft [47].
Bridging the alveolar cleft defects with a resorbable xenogenic collagen
sponge and bone marrow stem cells is also helpful in reducing donor
site morbidity, pain intensity and frequency [48] (Table 1).
Although useful, xenografts do pose some challenges, such as, histo-
compatibility issues between the animal tissue and human recipient.
Thus the use of xenografts is not permitted in some countries such as
the US. It is worth mentioning that there is a very limited acceptability
for xenografts by the patients, as religious/personal priority also plays
an important role in the final selection of the implant material.
3.5. Synthetic bone substitute materials
Synthetic bone substitute grafts have been used in regenerative den-
tistry for many years [49]. In routine clinical settings, bone replacement
materials are considered necessary after tooth extraction for alveolar
ridge preservation. The major categories of synthetic grafts available
commercially are metals, ceramics, polymers and composites (Fig. 4).
The ideal synthetic material for bone replacement needs to have cer-
tain inherent properties, such as, osteoconduction, osteoinduction, and
biodegradation. Although stable (non-degradable) implants are often
used, biodegradable materials are more favored. As resorbable graft ma-
terials do not restrict growth of the native tissue, thus these are
 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028
Fig. 4. Schematic of bone graft materials.
preferred for use in children. Compared to metal implants the biode-
gradable implants are radio-transparent and do not impede radiological
treatments if required.
3.5.1. Metals
Use of metals such as steel and titanium orthodontic appliances in
conjunction with surgical procedures is a regular supporting treatment.
Cleft defects especially after 7–8 years are managed with metallic appli-
ances applied intra-orally or intra plus extra-orally as shown in Fig. 5
[50]. Metals are by far the most extensively used dental materials. His-
torically the use of gold and silver is well known in craniofacial repair,
while the use of platinum, lead and aluminum are prohibited because
of their toxic effects [51]. Autogenous bone particles from the anterior
iliac crest mixed into titanium mesh have been used very recently for al-
veolar ridge augmentation with very high predictability in patients with
cleft lip/palate [52]. Hydrogels to expand the nascent soft tissue in cleft
palate patients with the support from titanium mesh is being hailed re-
cently as novel tissue expansion method for cleft repair. Titanium plates
and screw are known to induce growth limitations especially where the
recipient is a growing young child [53–57]. The inflexible nature of
metal implants in general causes growth related morphological defor-
mities [58]. Metallic implants are not only held responsible for stress
shielding effects, bone fragility, and fractures and at the same time
they speed up bone resorption [59,60]. Also some leachable compounds
from metallic implants when released into the system cause toxic and
carcinogenic effects [61,62]. Metal ions have been found to affect the vi-
ability of osteoblasts even at sub-toxic concentrations [63]. In the case of
cranio-maxillary defects like CLP the metallic implants may get
dislocated during the growth of the child, and plates, screws, or wires
can get embedded in the tissue. Metal implants can also cause problems
while doing MRI and other imaging techniques [64]. Therefore, it is
Fig. 5. Left and middle figures show preoperative status of cleft deformity, (right) post–treatment.
[50]
1023
recommended to remove any metallic implants used in children after
a short period of implantation [65].
3.5.2. Bioceramics
Ceramics used for the repair and reconstruction of hard tissue are
termed bioceramics. These may be bioinert (alumina, zirconia), resorb-
able (TCP), bioactive (HA, bioactive glasses, and glass-ceramics), or po-
rous for tissue in growth (HA-coated metals, alumina). In addition to
their remarkable osteo-conductivity, these have excellent mechanical
and degradation properties. Their degradation rate is also easily manip-
ulated by changing the calcium to phosphate ratio. Calcium phosphates
are scaffolds made to mimic the natural bone content in combination
with HA and tricalcium phosphate or biphasic calcium phosphate.
These ceramic materials are in regular use for orthopedic repair [66,
67]. Calcium phosphate curable wet paste is also used clinically to repair
cranial defects. An interesting study by Lazarou et al. [68] used calcium
substitutes as bone grafts in the absence of ideal autologous bone grafts
for primary alveolar repair, before eruption of the canine teeth. The
mean age of CLP patients at the time of surgery was 10.4 months and
follow-up was conducted for 3 to 7 years post-surgery. Radiologic eval-
uation of the alveolar ridge was performed at the age of 4 years. The au-
thors used 1 to 3 mL of calcium sulfate paste or crystals in the cleft
region of eight patients. The anterior alveolar mucosa was closed with
sutures after implantation. The alveolar region of the cleft healed
completely and allowed the growth of primary canines. Secondary ca-
nines were also confirmed to have descended through the newly
formed bone [68]. This study was claimed to be the first evidence of
tooth eruption through the regenerated bone after implantation of syn-
thetic material which has been tabulated in Table 1 [68].
A mix of autologous bone, harvested in the operative field, and par-
ticles of biphasic calcium phosphate (BCP) set in platelet rich plasma
(PRP) gel were used in a single patient with complete unilateral cleft
1024 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028

lip and palate. Radiological evidence of an 8 year follow-up showed
complete filling of the initial bone defect, progressive resorption of ce-
ramics, and spontaneous eruption of the cuspids [69].
In another study, secondary alveolar bone grafting was done in 23
patients with unilateral CLP using bovine-derived hydroxyapatite ver-
sus autogenous bone. The follow-up was undertaken for up to 4 years
after surgery. The radiologic results concluded that the repair was com-
parable to the use of autogenous bone grafts [70]. In children with uni-
lateral or bilateral cleft of lip and palate solid bone formation was
induced when micro-structured, resorbable β-TCP was applied surgical-
ly as replacement to autologous bone. The clinical trial was followed up
for one year post-operation, which also confirmed complete resorption
of β-TCP [71]. In a larger set of CLP population a commercial β-TCP
was implanted as a bone substitute in 152 patients with or without
autologous bone (Fig. 6A & B). Biopsies after 12 months indicated
complete bone regeneration, confirming the osteoconductive proper-
ties of β-TCP [72]. In another single case study a guided bone regenera-
tion approach was used, where hydroxyapatite in conjunction with a
bio-resorbable membrane completely filled the alveolar gap in a gingi-
val invagination caused by orthodontic treatment [73].
A long term evaluation (7.2 years) using porous block hydroxyapa-
tite for orthognathic surgery including hard palate and alveolar cleft re-
pair showed a high percentage of success. It was further concluded that
implant success depends on adequate soft tissue coverage on the nasal

Fig. 6. A. Secondary alveolar cleft reconstruction in mixed dentition: (a) prior to operation, (b) directly after β-TCP implantation (arrow), and (c) 12 months following defect filling with a
combination of β-TCP and cancellous bone of the chin region [72] (reused with permission). B. Histomorphological results 3 months (a) and 12 months (c) after implantation of β-TCP.
H&E staining (a and c).
[72]
 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028
and oral sides of the mid palatal implants. The authors, however, did not
support the use of block hydroxyapatite implant for alveolar cleft due to
stress shielding effects [74].
In a retrospective study, the efficacy of the use of porous block hy-
droxyapatite was evaluated. The maxillary advancement was done
using bone plates for skeletal stabilization and porous block hydroxyap-
atite (PBHA) as a bone graft substitute for interpositional grafting in
cleft and non-cleft patients. Rigid fixation and interpositional PBHA
grafting during bimaxillary surgery proved to be a stable procedure
with good predictability in cleft and non-cleft patients [75].
Bioceramics whether used alone or in combination with some other
materials, such as, polymers show great osteogenic potential. All of the
studies so far show the regeneration of bone in the cleft region. The
eruption of teeth proves the efficacy of these ceramic implant materials.
Many studies have been conducted to evaluate the safety of these mate-
rials inside the body after long term implantation. Neovius et al. 2010
have analyzed a large dataset of articles which presented the use of
bioceramics and many other polymers as implant materials for craniofa-
cial reconstruction. They analyzed complication rates, infections and ex-
posure of implant material. Among 21 articles, 6 mentioned infection
caused by HA ranging from 2.5 to 25%. Calcium phosphate was used in
5 studies with variable patient numbers (1–27) and the complication
rate ranged from 0 to 20% [76].
3.5.3. Polymers
Polymers have emerged as the material of choice to fabricate scaf-
folds and GTR membranes intended for bone tissue engineering. Con-
sidering their inherent biocompatibility and the ability to tailor
physiochemical properties and degradation rates these are good candi-
dates for many applications [77]. They are highly versatile and one can
alter their degradation rates by copolymerization, selecting from a
range of molecular weights, and varying crystallinity. This explains the
widespread interest in these materials for bone repair (Table 1).
Poly(-hydroxyl acid) related polymers, such as, poly-lactic acid
(PLA) [78], poly-glycolic acid (PGA) [79], poly-caprolactone (PCL) [80]
and their copolymers, have been extensively studied. PLA–PGA copoly-
mers for example have been used as binders for bioceramics and
decalcified allogeneic bone and as delivery systems for bone growth fac-
tors. However, polymer synthesis conditions affect the degradation rate
Fig. 7. Morphology of random electrospun scaffolds of (A) PLA (scale bar is 100 μm), (B) PHBV (scale bar is 100 μm), (C) PCL (scale bar is 100 μm) and (D) PLGA (scale bar is 200 μm). Note
that PLA, PCL and PLGA are all micro-fibrous uniform scaffolds. PHBV nanofibers connecting 5–20 μm sized beads.
[87,87] Reused with permission from Editor JoVE.
1025
and mechanical properties of polymers selected for bone replacement
[81]. In an animal study, the authors reconstructed palatal bone defects
in rats using absorbable 3D poly-L-lactic acid scaffolds seeded with
osteogenically differentiated fat-derived stem cells. (PCL-TCP) scaffolds
were found to have increased the bone volume fraction in grafted de-
fects [82].
Porous PCL-HA scaffolds for alveolar cleft repair in mouse calvarial
model were found to have increased the amount of new bone formed
[83]. An American team developed a new material known as a shape-
memory polymer or SMP. It is made from poly(ε-caprolactone) coated
in polydopamine. The elastic and biodegradable properties of this PCL
scaffolds were used to fabricate it into a shape memory material.
Polydopamine is considered to improve the osteogenic potential of the
material to heal defects like cleft palate [84,85].
Polyhydroxyalkanoates (PHAs), another group of degradable
polyester polymer, can also be developed into electrospun nanofi-
bers for bone regeneration [86]. Poly(hydroxybutyrate) (PHB) and
poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanofibers
with relatively large total surface area exhibit better cell growth be-
havior compared to flat films (Fig. 7) and are considered good candi-
dates for reconstructive surgeries [87].
Polyurethanes (PUs) are being experimentally exploited for bone
and visceral organ replacement material. PUs belong to a large family
of polymeric materials with an enormous diversity of chemical compo-
sitions, mechanical properties, tissue-specific biocompatibility, and bio-
degradability [88]. The flexible nature of polyurethanes has been
utilized to design degradable polymers for hard and soft tissue engi-
neering [89,90]. These materials may be exploited further for pediatric
applications like cleft palate repair and alveolar ridge augmentation,
where materials with higher tensile strength are required.
Most recently a hydroxyapatite agarose composite gel (HA gel) was
prepared as an absorbable bone-graft material. This polymer can be de-
graded faster than any other existing material. The clinical data on an
implant of HA gel combined with autologous chin bone has been
found to improve the repair of CLP alveolar bone defects [91].
Clinical data on cleft repair with polymers is lacking, however, these
materials are explored for bone regenerative capabilities complementa-
ry to natural collagen. Bioresorbable elastic composites have been tested
in ex vivo porcine model to manipulate craniofacial bones. The
1026 F. Sharif et al. / Materials Science and Engineering C 61 (2016) 1018–1028
composites were made of poly(1,8-octanediol co-citric acid) (POC), and
hydroxyapatite (nHA). These were found to be able to apply mechanical
contractive forces which were expected to facilitate osteogenesis and
craniofacial bone repair as in the case of cleft palate repair in man
[92]. For soft tissue repair hydrogels composed of methyl methacrylate
and vinylpyrrolidine have been developed as tissue expander for pedi-
atric applications including cleft palate but there has been no biological
evaluation of these polymers as yet [93].
The osteoconductive properties of polymer scaffolds can also be
improved when combined with ceramics [83]. Natural polymers used
in bone tissue engineering include collagen, fibrin, alginate, silk,
hyaluronic acid, and chitosan [115].
Data on complications or infections posed by long term implantation
has been presented by Neovius et al. 2010. The authors analyzed data
from studies conducted on implantation response of polyethylene
alone. Infection rate varied between 0 and 29% with a 0–9.7% exposure
of implant materials. There is a link between the implant site and expo-
sure rate for example there was a higher exposure risk in nose, maxilla
and ear [76].
3.5.4. Biocomposites
Composite materials are made up of two or more different materials
combined together or fabricated as combinations of ceramic–ceramic,
ceramic–polymer or polymer–polymer [94], tabulated in Table 1. The
combined properties of two or more ceramics, polymers or both give
better mechanical properties and functions for bone repair potential
than the individual materials [95]. Some of the examples of combined
materials are collagen Type I with TCP and collagen Type 2 with HA,
etc. Composites of PLLA [96], PDLLA [97], PLGA [98], chitosan [98],
chitosan + PLGA [99] and collagen each with HA have been used for
bone augmentation procedures other than cleft palate. Self-reinforced
PLLA and PGA rods have been used in a rabbit model of femoral bone re-
pair. Bioabsorbable PCL and LLA film and PLA96 mesh gave good guided
bone regeneration results in a rabbit maxillary cleft model [100]. Com-
posite scaffolds can be stable or degradable, the ones which are used
in skeletal regeneration are biodegradable polymers reinforced with ce-
ramic particles [101]. The high mechanical flexibility of polymers and
high toughness of ceramics hydroxyapatite (HA) are already known,
and when combined together the properties change [101,102]. Com-
posites of polyurethane and hydroxyapatite possess improved mechan-
ical properties, provided that a strong interfacial bond strength is
established between the ceramic phase and the polymer matrix [101,
103,104]. Composite materials can be fabricated into highly porous scaf-
folds by a number of foaming techniques, such as thermally induced
phase separation, salt leaching/freeze-drying, wet spinning, and
electrospinning [94]. These scaffolds have several applications and
have been evaluated in the animal bone regeneration studies [105]. β-
TCP granules can be used in addition to the autogenous bone graft to re-
generate mandibular bone or to make up for the lack of amount of har-
vested tissue to fill the alveolar cleft. The bone heals in the alveolar
region similar to the autologous bone graft within one year's time. The
advantage of combining an autograft with a ceramic material in this
study relates to getting more implantable material from a small amount
of harvested tissue [106] Collagen/hydroxyapatite (Col/HA), was used
as a drug delivery device for neurotrophic-nerve growth factor-β
(NGF beta) to repair bone defects including cleft palate. In vivo tests
were conducted on rats for 30 days and histologic evidence suggested
successful incorporation of the implant material in host tissue [107].
Neovius et al. 2010 also mentioned the related complication after long
term implantation of biocomposites. The infection rates varied between
0% and 25% [76,76].
4. Conclusions
Autografts are currently considered the best solution in reconstructing
small bone defects with strong osteogenic characteristics. However the
donor site morbidity, visceral injuries and vascular damage during har-
vesting and pain that they inflict, leads to a desire to find alternatives.
Bone allografts are another option but these also have limitations, such
as, rejection, disease transmission, and high cost. Xenografts, although
easier to harvest compared to allografts, also pose a risk of transmission
of diseases, and a more aggressive rejection of the graft. Accordingly in ad-
dition to the gold standard of bone graft treatment, there is a parallel
growth of synthetic materials to remodel critical sized craniofacial bone
defects.
Synthetic bone substitute graft materials have significant advan-
tages over the conventional bone and skin grafting techniques in
terms of quantity, ease of access, significantly less cost and less invasive
surgical applications. Therefore, the synthetic biomaterials are currently
being extensively explored since these can be made available in large
quantities. These materials are most actively used in the field of dentist-
ry, and from here they provide a cohort of evidence on their effective
bone regeneration capabilities. Although there is insufficient clinical
data on the efficacy of these newly emerging osteogenic biomaterials
for cleft of lip and palate their availability holds out hope that the num-
ber of painful procedures that currently dominate the childhood of CLP
patients can both be reduced and simplified.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
The authors gratefully acknowledge the support of a Pakistan–UK
Fellowship from COMSATS University of information Technology
Lahore, in compiling this review article. We would like to thank our
colleague Dr. Abdul Samad Khan for the valuable discussions.
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