Int. J. Environ. Res. Public Health 2020, 17, x doi: FOR PEER REVIEW www.mdpi.comjournal ijerph [606826]

Int. J. Environ. Res. Public Health 2020, 17, x; doi: FOR PEER REVIEW www.mdpi.com/journal/ ijerph
Review 1
The Impact of Diabetes on Implant Oral 2
Rehabilitations: A Bibliometric Study and Literature 3
Review. 4
Felice Lorusso1, Francesca Postiglione2, Maurizio Delvecchio3, Biagio Rapone4 and Antonio 5
Scarano5*. 6
1 Department of Medical, Oral and Biotechnological Sciences, University of Chieti -Pescara, Via dei Vestini, 7
31, 66100 Chieti, Italy; email: [anonimizat] 8
2 Department of Medical, Oral and Biotechnolo gical Sciences, University of Chieti -Pescara, Via dei Vestini, 9
31, 66100 Chieti, Italy; email: francesca -[anonimizat] 10
3 Department of Metabolic and Genetic Diseases, Giovanni XXIII Childr en's Hospital, 70126 Bari, Italy; 11
email: [anonimizat] 12
4 Department of Basic Medical Sciences, Neurosciences and Sense Organs, Bari, Italy; “Aldo Moro” 13
University of Bari, 70122 Bari, Italy; email: [anonimizat] 14
5 Affiliation 2; Department of Medical, Oral and Biotechnological Sciences, University of Chieti -Pescara, 15
Italy; email: [anonimizat]. 16
* Correspondence: Prof. Antonio Scarano; Department of Medical, Oral and Biotechnological Sciences, 17
University of Chiet i-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Email: [anonimizat] . 18
Received: date; Accepted: date; Published: date 19
Abstract Background: Diabetes represents a potential risk factor for bone healing and de ntal 20
implant treatment predictability. The aim of the present investigation was to perform a bibliometric 21
evaluation of articles on the topic of the impact of diabetes on implant oral rehabilitations. Methods: 22
A Boolean keyword search was performed on Scop us database and record ed the list of articles, 23
authors and affiliations. The journal impact factor was calculated by the Journal Citation Report 24
Clarivate electronic database. The total papers, number of citations and journal impact factors were 25
calculated . Results: a total of 476 papers and 162 authors were assessed. The mean authors total 26
citations were 2880.11± 4070.24 and the mean impact factor value was 1.942±1.15 Conclusions: 27
uncontrolled diabetes impact s on dental implant rehabilitation with an incre ased risk of implant 28
failure and peri -implant disease in long -term rehabilitation. 29
Keywords: Diabetes ; Dental Implant. Bibliometric study ; Peri-implantitis 30
31
1. Introduction 32
The osseointegrated dental implant is an effective procedure for rehabilitation of function and 33
aesthetics of the jaws [1,2] . The success of the procedure is correlated to an intimate contact between 34
the dental implant surface and the surrounding bone tissue [3–5]. The early bone healing of a dental 35
implant is determined by the recruitment of osteogenic progenitors and migration to the implant 36
surface, the generation of bone m atrix and growth and finally , the remodelling processes [6]. The 37
long -term adap tation, remodelling and maintain ing of the bone is determined by the local 38
physiological biomechanical and physical stimulation of the healing site , generated during the 39
functional activity of the implant [6–10]. The procedure for dental implant positioning is related to a 40
sequence of phases from osteotomy trauma, b one debris deposition, blood hemostasis and clot 41
organization and hypoxia of the tissues [11]. The healing phases can be influenced by the immune 42
system activity and negatively affected by the involv ement of systemic pathological diseases such as 43
diabetes, osteopenia and pharmacological therap ies [12]. Moreover, other local factor s can influence 44

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 2 of 19
the healing such as implant features and surface properties , screw positioning insertion torque, 45
drilling temperature , and micro – movements [13]. Also , the local presence of residual metal particles 46
and ions is able to induce the release of proinflammatory factors , and osteoclast resorption activity at 47
the level of the peri-implant tissues [14–16]. 48
The release in the oral cavity of metals and ions such as titanium, vanadium, and aluminum by 49
corrosion has been reported to produce inflammation and reactions at the level of peri -implant soft 50
and hard tissues with local osteolysis [17]. Diabetes mellitus is a multi -systemic d isorder that affects 51
the regulation of blood glucose levels and it is a global impact disease [18,19] . Saeedi et al. reported 52
that the diabetes world -wide prevalence was about 9.3% in 2019, with a non -homogeneous 53
distribution of the population affected by the disease [20]. In fact, the prevalence rate seems to be 54
increased in urban environment s if compared to other regions, while it has been calculated that half 55
of the affected patients do not have a diagnosis of diabetes [20]. In literature, three main classes of 56
diabet ic disease are known [20]: 57
-type 1: insulin -dependent or juvenile diabetes, due to autoimmune beta -cell destruction leading 58
to progressive insulin deficiency; this accounts for 5 –10% of diabetes; 59
-type 2 mellitus: insulin resist ant or adult diabetes, due to inadequate insulin secretion , usually 60
with insulin resistance; this accounts for 90–95% of diabetes; 61
-gestational diabetes: ranging from glucose intolerance to diabetes that was not present before 62
pregnancy; the prevalence has not been estimated as it usually disappears after the pregnancy . 63
Another uncommon type of diabetes is due to genetic causes (monogenic or syndromic diabetes), 64
disorders of the exocrine pancreas, and drug – or chemical -induced diabetes; it accounts for < 5% of 65
diabetes [21]. 66
In literature, the negative effects of diabetes on oral tissu e healing are related to the levels of 67
glycemic and glycated hemoglobin (HbA1c) control and the presence of chronic micro -vascular 68
alterations and wound infections, defects of immunity and granulocyte activity [14,22] . In literature, 69
it was reported that high glycemic levels are correlated to an increased release and tissue 70
accumulation of advanced glycation end products (AGEs). Moreover, the advanced glycation end 71
products seem to be accumulated at the level of the collagenic bone matrix , proportionally with 72
ageing [20]. In literature , it was reported that the advanced glycation end products are also able to 73
decrease the biomechanical properties of the bone tissue, with a significantly higher prevalence of 74
fracture events in patients affected by diabetes mellitus if compared to healthy subjects [23]. Higher 75
levels of blood HbA1c seem to negatively influence the production, and remode lling of collagenic 76
matrix at the level of periodontal and peri -implant soft and hard tissues [15,24] . Higher advanced 77
glycation end products (AGEs) are also correlated to a decre ased bone density, alteration of the 78
microarchitecture, bone remodeling, vascular microdamage, and collagen matrix alteration [25]. 79
Histologically, advanced glycation end products (AGEs) and an associated diabetic condition are able 80
to induce a significant increase o f osteocyte lacunae density and a significant lower volume of the 81
vascular canal [20]. A reduction of vascular canal volume is related to the action of high glycemic 82
levels in a diabetic condition that is abl e to alter the micro – and macro -vascular network of the bone 83
tissue [26]. In literature , it was reported that the advanced glycation end products (AGEs) are 84
associated to nonenzymatic glycosylation with a significant alteration of extracellular matrix that 85
show s an increased weakness against the action of pathogens and agents. This condition is also 86
correlated to an increase d expression of proinflammatory markers and molecules an d a hyper – 87
reactive immune tissu e response [20,27] . In the oral environment, these molecules produce their 88
effects on gingiva and periodontal cell receptors and they are able to alter fibroblastic physiological 89
activity an d proliferation in oral tissues [12,23,28] . 90
A similar negative activity has been reported for the peri -implant tissues, where chronic 91
hyperglycemia seems to produce a significant effect on local inflammation and loss of implant 92
supporting tissues [29]. The degree of glycaemic levels and pharmacological therapy can represent a 93
strong influence for the post -operative healing period and complications [19]. In fact, this condition 94
induces a functional alteration of the immune response of the site with a higher risk of infection due 95
to a modified microbiocide activity and a decreased potential wound healing [18]. Clinically, the high 96

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 3 of 19
glycemic level is able to induce the proliferation of several bacteria and pathogens and affect s the 97
surgical flap healing due to the diabetic microangiopathy, that could produce an impairment of the 98
barrier of the surgery access site [22]. 99
Peri-implant diseases are pathologies induced by bacteria biof ilm characterized by chronical 100
inflammation of hard and soft tissue with resorption of surrounding bone [13]. Peri-implant disease s 101
are a category of pathologies that include mucositis and peri -implantitis. The absence of signs of 102
surrounding bone loss and the inflammation of the peri -implant soft tissue is commonly associated 103
with mucositis [20]. Moreover, the contemporary presence of resorption of supporting bone loss is 104
associated to peri -implantitis [20]. In the literature , it has been demonstrated that diabetes and 105
smoking habits play a crucial role for the development and the progression of peri -implant disease s 106
[18]. In fact, diabetes induce s a decrease of wound healing potentiality, local tissue hypoxi a and it 107
inhibits the chemotaxis of the immunity cells [30]. In literature, it has been reported that 108
hyperglycaemia show s a higher prevalence in diabet ic patients wit h a hyperinflammation response 109
in the periodontal tissues [19]. The pathogenesis of the periodontal AGE -related damage seems to be 110
correlated to an increased a ctivity of pro -inflammatory cytokines, interleukins and release of 111
metalloproteinases [22,26,29,31] . Moreover, long -term uncontrolled high gl ycemic levels are able to 112
produce important alterations of the tissue physiology, to affect the barrier function and local 113
immunity , capab le of neutraliz ing the periodontal agents and to alter the neutrophil chemotaxis and 114
phagocytosis [14,19,26] . In an oral enviro nment, these pathological modifications are able to generate 115
a decrease of the healing processes capability of the soft and bone tissues du ring the implant and 116
odontostomatological procedures [28,31] . The aim of the present investigation was to perform a 117
bibliometric evaluation and to review the scientific production rel ated to diabetes mellitus in implant 118
oral rehabilitations and the relative scientific activity. 119
2. Materials and Methods 120
2.1. Search Strategy 121
The detection of the suitable keywords for electronic database research was performed by the 122
use of Pubmed/MeSH t erms function to identify the descriptors and their synonyms that would 123
enable us to identify the topic being studied with the maximum possible precision. 124
The following Bolean search equation was applied for the electronic search strategy conducted 125
on Web of Science (SCI) and Scopus® database: (dental AND implant OR maxillary AND implant 126
OR mandibular AND implant OR endosseous AND implant OR osseointegrated AND implant) AND 127
diabetes). The electronic database research and data collection was performed by two expert 128
reviewers (F.L. and A.S.) independently on June 28th 2020. The present review and bibliometric 129
analysis was performed according to the PRISMA guidelines [32]. 130
131

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Figure 1 . Flowchart of the study selection process according to PRISMA guidelines 132
133
2.2 Inclusion Criteria 134
In vitro studies, review and studies, research papers, editorial letters in the English language 135
assessing dental implant and diabetes were included in the present investigations . No limitations 136
about publication date were applied to the research. Publications that did not comply with the 137
inclusion criteria were excluded from the evaluation. 138
139
2.3 Selection of the Studies 140
The selection of the studies was performed independently by two expert reviewers (FL, AS) and, 141
if the abstract was not available, the full text of all eligible papers was obtained and evaluated to 142
assess the inclusion criteria. For excluded articles, a report was performed about the reasons for 143
exclusion. 144
2.2. Data extraction 145
The electronic search and data extraction were independently performed by two expert 146
reviewers (FL and AS) on Web of Science (SCI) and Scopus® database. For the present investigation 147
papers were considered in the English language; conference proceedings and book chapters were 148
excluded in the present investigation. The papers ’ full-text were collected and in the case these not 149
being availa ble, the abstracts were evaluated. The title of the article, journal, subject area, document 150
type, institute, country, author list, affiliations, citation counts, h -index were recorded into a special ly 151
designed calculation database (Excel, Microsoft Corpor ation, Redmond WA USA). 152

Records identified through
database searching
(n = 482 papers ) Screening Included Eligibility Identification
Additional records identified
through other sources
(n = 47 papers )
Records screened
(n = 529 papers )
Full-text articles assessed
for eligibility
(n = 529 papers ) Full-text articles excluded,
with reasons (40 papers)
29 papers for text
language ;
11 papers out of topic
10 book contributions
3 conference proceedings

Studies included in
qualitative synthesis
(n = 476 papers )
Studies included in
quantitative synthesis
(bibliometric evaluation )
(n = 476 pap ers)

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 5 of 19
2.3. Bibliometric parameters 153
The bibliometric impact of the scientific production on the research topic being studied was 154
evaluated by the analysis of contributions, authors and their affiliations, and scientific journal s. The 155
scien tific production impact on the topic of diabetes in dental implant procedures was evaluated by 156
the total count of contributions, citations amount h -index of authors and affiliations. The authors self – 157
citations were excluded from the data evaluation. 158
The jo urnal impact factor (JIF) and average JIF percentile were calculated by the Clarivate – 159
Journal Citation Reports (JCR) database. 160
The authors ’ “Publication % Ratio” and “Publication % Ratio” were calculated by the following 161
formula: 162
163
𝑃𝑢𝑏 % 𝑟𝑎𝑡𝑖𝑜 : 𝑇𝑜𝑡𝑎𝑙 𝑎𝑢𝑡ℎ𝑜𝑟𝑠′ 𝑝𝑎𝑝𝑒𝑟𝑠 𝑜𝑛 𝑡𝑜𝑝𝑖𝑐
𝑇𝑜𝑡𝑎𝑙 𝑎𝑢𝑡ℎ𝑜𝑟𝑠𝑥 100
(1)
𝐶𝑖𝑡𝑎𝑡𝑖𝑜𝑛 % 𝑟𝑎𝑡𝑖𝑜 : 𝑇𝑜𝑡𝑎𝑙 𝑐𝑖𝑡𝑎𝑡𝑖𝑜𝑛𝑠 𝑜𝑛 𝑎𝑢𝑡ℎ𝑜𝑟𝑠′ 𝑝𝑎𝑝𝑒𝑟𝑠 𝑜𝑛 𝑡𝑜𝑝𝑖𝑐
𝑇𝑜𝑡𝑎𝑙 𝑎𝑢𝑡ℎ𝑜𝑟𝑠 𝑐𝑖𝑡𝑎𝑡𝑖𝑜𝑛𝑠𝑥 100
(2)
3. Results 164
3.1. Study Population 165
The database search generated a total of 482 manuscript. A total of 47 papers were also included to 166
the list by performing a manual search for a total of 529 papers retrieved. Performing a title and 167
manuscript evaluation, 40 papers were excluded: 29 papers for language (no English language), 11 168
articles were out of the topic, 10 manuscripts were part of books and 3 contributions were 169
conference proceedings. At the end of the search procedure, a total of 476 papers satisfied the 170
inclusion criteria and were included in the bibliometric investigation. 171
In the present bibliometric investigation, a total of 476 papers and 162 authors were assessed: 172
473 final full papers and 3 articles in press for a total of 12247 citatio ns (mean: 75.60 ± 59.4; max: 9; 173
min: 0) (Tab.1 -2) 174
. 175

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Table 1. Bibliometric evaluation of the most productive authors on the research topic compared to their total paper production.
Authors Affiliations Total
Papers H-
Index Total
Citations Topic
Papers Topic
Citations Publ.
%Ratio Cit.
%Ratio
Song, Y. The Fourth Military Medical University, Xian, China 49 14 528 9 50 18.37 9.47
Abduljabbar, T. King Saud University, Riyadh, Saudi Arabia 96 14 649 8 50 8.33 7.70
Javed, F. Eastman Institute for Oral Health, Rochester, United States 220 32 3632 7 254 3.18 6.99
Quirynen, M. KU Leuven, Leuven, Belgium 268 66 13899 7 825 2.61 5.94
Fiorellini, J.P. University of Pennsylvania, Philadelphia, United States 89 33 5587 6 402 6.74 7.20
Garrett, N.R. The UCLA School of Dentistry, Los Angeles, United States 66 21 1538 6 253 9.09 16.45
Hamada, M.O. University of California, Los Angeles, Los Angeles, United States 11 7 270 6 253 54.55 93.70
Kapur, K.K. Division of Advanced Prosthodontics, Biomaterials and Hospital Dentistry,
Los Angeles, United 84 26 1970 6 253 7.14 12.84
Oates, T.W. University of Maryland Dental School, Baltimore, United States 132 32 4252 6 199 4.55 4.68
Roumanas, E.D. The UCLA School of Dentistry, Los Angeles, United States 42 21 1369 6 253 14.29 18.48
Vohra, F. King Saud University, Riyadh, Saudi Arabia 143 18 1035 6 51 4.20 4.93
Zhang, S. The Fourth Military Medical University, Xi'an, China 14 3 13 6 10 42.86 76.92
Al Amri, M.D. King Saud University, Riyadh, Saudi Arabia 37 10 300 5 92 13.51 30.67
Al-Aali, K.A. Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia 27 6 94 5 23 18.52 24.47
Al-Kheraif, A.A. King Saud University College of Applied Medical Sciences, Riyadh, Saudi
Arabia 116 18 1034 5 89 4.31 8.61
Alrabiah, M. King Saud University, Riyadh, Saudi Arabia 20 5 74 5 23 25.00 31.08
Diener, R.M. VA Greater Los Angeles Healthcare System, Los Angeles, United States 10 6 247 5 240 50.00 97.17
Duarte, P.M. University of Florida, Gainesville, United States 123 33 3132 5 64 4.07 2.04
Lauritano, D. University of Milano – Bicocca, Milan, Italy 216 30 2795 5 81 2.31 2.90
Song, Y.L. The Fourth Military Medical University, Xi'an, China 49 14 529 5 50 10.20 9.45
Van Steenberghe,
D. KU Leuven, 3000 Leuven, Belgium 321 79 19319 5 711 1.56 3.68
Wei, H. The Fourth Military Medical University, Xi'an, China 10 6 66 5 17 50.00 25.76
Bissada, N.F. Case Western Reserve University, Cleveland, United States 154 33 3509 4 55 2.60 1.57
Castellanos –
Cosano, L. University of Seville, Sevilla, Spain 39 11 427 4 18 10.26 4.22
Freymiller, E. University of California, Los Angeles, Los Angeles, United States 50 22 1541 4 219 8.00 14.21
Han, T. University of California, Los Angeles, Los Angeles, United States 22 16 1593 4 219 18.18 13.75
Karimbux, N.Y. Tufts University School of Dental Medicine, Boston, United States 154 26 2823 4 252 2.60 8.93
Kuchler, U. Medizinische Universitat Wien, Vienna, Austria 26 13 473 4 45 15.38 9.51
Levin, L. Medizinische Universitat Wien, Vienna, Austria 248 34 3496 4 243 1.61 6.95
Levin, S. David Geffen School of Medicine at UCLA, Los Angeles, United States 102 30 3276 4 219 3.92 6.68
Li, D.H. The Fourth Military Medical University, Xi'an, China 69 18 959 4 76 5.80 7.92
Liu, H. General Hospital of People's Liberation Army, Beijing, China 181 20 1366 4 42 2.21 3.07
Liu, Z. Yantai Stomatological Hospital, Yantai, China 42 10 241 4 25 9.52 10.37

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Maló, P. Maló Clinic, Lisbon, Portugal 72 24 2512 4 35 5.56 1.39
Marcantonio, E. UNESP -Universidade Estadual Paulista, Sao Paulo, Brazil 171 34 3080 4 133 2.34 4.32
Mombelli, A. Université de Genève, Geneva, Switzerland 172 51 8946 4 363 2.33 4.06
Nevins, M.L. Private Practice, Boston, United States 81 31 3457 4 338 4.94 9.78
Romanos, G.E. Stony Brook University, Stony Brook, United States 302 43 6555 4 244 1.32 3.72
Tangl, S. Medizinische Universitat Wien, Vienna, Austria 70 22 1764 4 20 5.71 1.13
Torres -Lagares, D. University of Seville, Sevilla, Spain 164 19 1295 4 18 2.44 1.39
Wang, F. Shanghai Jiao Tong University, Shanghai, China 40 12 435 4 100 10.00 22.99
Wang, H.L. University of Michigan School of Dentistry, Ann Arbor, United States 436 62 14412 4 341 0.92 2.37
Zhou, W. Yantai Stomatological Hospital, Yantai, China 18 6 107 4 25 22.22 23.36
de Araújo Nobre,
M. Maló Clinic, Lisbon, Portugal 72 21 2126 4 35 5.56 1.65
Table 2. Institutional paper production activity on the research topic.
Institutions Countries Articles Citations
University of Bern Switzerland 18 682
King Saud University Saudi Arabia 17 174
The Fourth Military Medical University China 15 162
University of Texas Health Science Center at San Antonio United States 14 410
Eastman Institute for Oral Health United States 9 315
University of California, Los Angeles United States 9 775
UNESP -Universidade Estadual Paulista Brazil 8 147
Medizinische Universitat Wien Austria 8 68
VA Medical Center United States 8 581
KU Leuven Belgium 8 855
University of Rochester United States 8 309
Harvard School of Dental Medicine United States 6 412
The University of Hong Kong China 6 308
Karolinska Institutet Sweden 6 463
Göteborgs Universitet Sweden 6 980
The UCLA School of Dentistry United States 6 593
University of Michigan, Ann Arbor United States 6 193
Stony Brook University United States 6 99
University of Seville Spain 6 24
Xijing Hospital China 6 111
Case Western Reserve University United States 5 72
King Abdulaziz University Saudi Arabia 5 19
Columbia University College of Dental Medicine United States 5 60
Goethe -Universität Frankfurt am Main Germany 5 129
Universidade de Sao Paulo – USP Brazil 5 98

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University of Milano – Bicocca Italy 5 81
King Saud University College of Applied Medical Sciences Saudi Arabia 5 90
University of Washington, Seattle United States 5 157
University of Ferrara Italy 5 81
The University of Sydney Australia 5 76
Universidad de Granada Spain 5 121
Universidade Guarulhos Brazil 5 64
Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine China 5 101
Princess Nourah bint Abdulrahman University Saudi Arabia 5 23
Departement Beeldvorming & Pathologie Belgium 5 699
Yantai Stomatological Hospital China 4 25
University of G. d'Annunzio Chieti and Pescara Italy 4 44
Tel Aviv University Israel 4 247
University of Groningen, University Medical Center Groningen Netherlands 4 99
Università Vita -Salute San Raffaele Italy 4 23

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 9 of 19
The authors ’ bibliometric characterization showed a mean total paper amount of 109.73± 96.37 148
(Range 436 -0, IQR: 116.75), mean citations 2880.11± 4070.24 (Range 19319 -1, IQR: 2857.75) (Fig. 2). 149
150
Figure 2. Summary graph of the most productive authors: the total paper production, on topic articles, 151
Pub%Ratio and Cit.%Ratio was calculated. 152
3.2. Research journal assessment 153
A total of 158 scientific journals were assessed in the present research with a mean impa ct factor 154
value of 1.942±1.15 (range: 4.164 -0; IRQ: 1.48) and the average JIF percentile was 83.79±18.68 (range: 155
96.154 -0; IRQ: 1.48). 156
The scientific journal with the most amount of papers was Clinical Oral Implants Research with 157
a total of 31 papers (mea n: 10.98 ±6.18; IRQ: 12). 158
The authors with most publications are presented in fig. 1. The bibliometric characterization of 159
the authors is presented in tab 1. The papers with the higher citation count are presented in tab. 3. 160
161 1 2 4 8 16 32 64 128 256 512Bissada, N.F.Freymiller, E.Karimbux, N.Y.Levin, L.Li, D.H.Liu, Z.Marcantonio, E.Nevins, M.L.Tangl, S.Wang, F.Zhou, W.Al Amri, M.D.Al-Kheraif, A.A.Diener, R.M.Lauritano, D.Van Steenberghe, D.Fiorellini, J.P.Hamada, M.O.Oates, T.W.Vohra, F.Javed, F.Abduljabbar, T.
Log2AUTHORS WITH MOST PUBBLICATIONS ON THE
TOPIC
total papers topic articles Publ. %Ratio Cit. %Ratio

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Table 3. Most cited articles on the research topic.
TOP CITED TOPIC ARTICLES CITATIONS PAPER TYPE
Lindhe, J., Meyle, J. Peri -implant diseases: Consensus Report of the Sixth European Workshop on Periodontology (2008) Journal of Clinical
Periodontology, 35 (SUPPL. 8), pp. 282 -285. 739 Consensus Paper
Heitz -Mayfield, L.J.A. Peri -implant diseases: Diagnosis and risk indicators (2008) Journal of Clinical Periodontology, 35 (SUPPL. 8), pp. 292-304. 479 Review Paper
Moy, P.K., Medina, D., Shetty, V., Aghaloo, T.L. Dental implant failure rates and associated risk factors (2005) Internationa l Journal of Oral and
Maxillofacial Implants, 20 (4), pp. 569 -577. 362 Research Paper
Alsaadi , G., Quirynen, M., Komárek, A., Van Steenberghe, D. Impact of local and systemic factors on the incidence of oral implant fa ilures, up to
abutment connection (2007) Journal of Clinical Periodontology, 34 (7), pp. 610 -617. 230 Research Paper
Ferreira, S.D., Silva, G.L.M., Cortelli, J.R., Costa, J.E., Costa, F.O. Prevalence and risk variables for peri -implant disease in Brazilian subjects (2006) Journal
of Clinical Periodontology, 33 (12), pp. 929 -935. 229 Research Paper
Rosen, P., Clem, D., Cochran, D., Froum, S., McAllister, B., Renvert, S., Wang, H. -L. Peri -implant mucositis and peri -implantitis: A current understanding
of their diagnoses and clinical implications (2013) Journal of Periodontology, 84 (4), pp. 436 -443. 199 Review Paper
Van Steenberghe, D., Jacobs, R., Desnyder, M., Maffei, G., Quirynen, M. The relative impact of local and endogenous patient -related factors on implant
failure up to the abutment stage (2002) Clinical Oral Implants Research, 13 (6), pp. 617-622. 172 Research Paper
Javed, F., Romanos, G.E. Impact of diabetes mellitus and glycemic control on the osseointegration of dental implants: A syste matic literature review
(2009) Journal of Periodontology, 80 (11), pp. 1719 -1730. 171 Review Paper
Thomas, M.V., Puleo, D.A. Infection, inflammation, and bone regeneration: A paradoxical relationship (2011) Journal of Dental Research, 90 (9), pp. 1052 –
1061. 157 Review Paper
Alsaadi, G., Quirynen, M., Komárek, A., Van Steenberghe, D. Impact of local and systemic factors on the incidence of late oral implant loss (2008) Clinical
Oral Implants Research, 19 (7), pp. 670 -676. 152 Research Paper
Bornstein, M.M., Cionca, N., Mombelli, A. Systemic conditions and treatments as risks for implant therapy (2009) International Journal of Oral and
Maxillofacial Implants, 24, pp. 12 -27. 150 Review Paper
Morris, H.F., Ochi, S., Winkler, S. Implant survival in patients with type 2 diabetes: placement to 36 months. (2000) Annals of periodontology / the
American Academy of Periodontology, 5 (1), pp. 157 -165. 147 Research Paper
Klokkevold, P.R., Han, T.J. How do smoking, diabetes, and periodontitis affect outcomes of implant treatment? (2007) Internat ional Journal of Oral and
Maxillofacial Implants, 22, pp. 173 -202. 142 Review Paper
Nordberg, G.F., Fowler, B.A., Nordberg, M. Handbook on the Toxicology of Metals: Fourth Edition (2014) Handbook on the Toxico logy of Metals: Fourth
Edition, 1, pp. 1 -1385. 141 Book Chapter
Salvi, G.E., Carollo -Bittel, B., Lang, N.P. Effects of diabetes mellitus on periodontal and peri -implant conditions: Update on associations and risks (2008)
Journal of Clinical Periodontology, 35 (SUPPL. 8), pp. 398 -409. 140 Review Paper

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The visual bibliometric countries network based on citation, bibliographic coupling, co -citation, 163
or co -authorship relations is presented in Fig. 3 and Fig. 4. 164
165
Figure 3. Network activity on the impact of diabetes on implant oral rehabilitations. 166
Figure 4. Network activity of each representative author on the impact of diabetes on implant oral 167
rehabilitations . 168

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Song, Y., affiliated to the Fourth Military Medical University of Xian in China, s howed the 169
highest number of total publications on the diabetes and dental implant topic, with a publication % 170
ratio of 18.37% and a citation % ratio of 9.47% (Fig.1 -2). Moreover, Song.Y showed the most complex 171
and active network on paper activity on the im pact of diabetes on implant oral rehabilitations. 172
According to the bibliometric evaluation of the author list select ion, Wang, H.L., affiliated to the 173
University of Michigan School of Dentistry in United States, showed the highest amount of total 174
papers wi th 436 articles, h -index 62 and a total of 14412 citations with a publication % ratio of 0.92% 175
and a citation % ratio of 2.37%. The University of Bern in Switzerland was evidenced as the 176
institution with the highest number of studies on the research topic with a total of 18 papers selected 177
and 682 citations, while the Göteborgs University in Sweden was the most cited with a total of 980 178
citations and 6 papers. The Clinical Oral Implants Research was the journal with the highest number 179
of documents with 31 papers, while Journal of Clinical Periodontology received the highest quantity 180
of citations (2346) on 20 papers (Tab.4). 181
Table 4. Institutional papers production activity on the trend topic. 182
Scientific journals Articles Citations IF (2018) Average JIF percentile
Clinical Oral Implants Research 31 1431 3.825 89.09
International Journal Of Oral And Maxillofacial Implants 28 1416 1.734 56.593
Implant Dentistry 24 1060 1.214 23.626
Journal of Periodontology 21 977 2.768 85.165
Journal of Clinical Periodontology 20 2346 4.164 96.154
Clinical Implant Dentistry And Related Research 14 115 3.212 89.56
Journal of Oral And Maxillofacial Surgery 13 369 1.781 58.791
Journal of Oral Implantology 13 146 1.062 17.033
Periodontology 2000 12 246 1.062 17.033
International Journal of Oral and Maxillofacial Surgery 10 128 1.961 61.254
Medicina Oral Patologia Oral Y Cirugia Bucal 10 197 1.284 42.593
Journal of Contemporary Dental Practice 8 36 0 0
Journal of Prosthetic Dentistry 8 442 2.787 86.264
Quintessence International 6 155 1.392 33.516
Implantologie 5 2 0.074 0.549
Journal of the American Dental Association 5 60 2.572 79.67
European Journal of Oral Implantology 4 70 2.513 78.571
Journal of Biological Regulators and Homeostatic Agents 4 47 1.558 16.353
The most cited article on the research topic was Consensus Report of the Sixth European 183
Workshop on Periodontology published on Journal of Clinical Periodontology in 2008 by Lindhe, J. 184
et al (Tab.3). 185
4. Discussion 186
Diabetes is a risk factor for bone healing and thus , predictability , dental implant treatment, 187
prompting researchers to evaluate the results of odontostomatological procedures. Type 1 diabetes 188
mellitus (T1DM) is associated with decreased bone mass and microarchitectural bone alterations [15]. 189
On the other hand, patients with type 2 diabetes mellitus exhibit normal to high Bone Mineral Density 190
and present an increased risk of fractures [33]. In type 1 diabetes, the bone can be affected from the 191
diagnosis , even in childhood, leading to reduc ed peak of bone mass and growth impairment, with 192
risk of osteoporosis and fra ctures later in life. 193
In type 2 diabetes, the reduced levels of bone turnover markers observed in the circulation , 194
suggest that the activity of the bone cells is altered, even if the underlying mechanisms of the skeletal 195
outcomes are still unclear. Some u nderlying mechanisms have been reported to account for bone 196
metabolism impairment. The most important seem to be vitamin D deficiency [34] and poor glycemic 197
control , impairing the response of bone cells to Vitamin D3 [35]. In literature it was reported that in 198
patients affected by type 2 diabetes with obesity , a higher prevalence of decreased vitamin D levels 199
are present in younger and adult patients [34]. The vitamin D decrease has been reported as a 200
potential critical factor for diabetes mellitus. In fact, in literature it was reported that the metabolites 201
of vitamin D seem to influence the regulation of glucose tolerance , insulin sensitivity , glucose 202

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 13 of 19
homeostasis [33]. The vitamin D metabolites also induce the inhibition of inflam mation, insulin 203
release and higher insulin resistance [30]. Another mechanism of action of the metabolite s is that these 204
molecules are able to decreas e the incidence and protect the bone tissue from osteopenia in patients 205
affected by diabetes mellitus . The vitamin D metabolites seem to produce positive influence on 206
diabet ic patients and attenuate the negative effects on AGEs [34]. The molecular mechanisms of the 207
decrease of vitamin D levels in type 2 di abetes is not completely clarified . The association seems to 208
be influenced by several factors ethnicity, geography, bone mass index and patients’ age[34]. 209
The impairment of bone metabolism is suggest ed by the high levels of sclerostin and Dickkopf – 210
1, both in type 1 and type 2 diabetes [36–41]. The sclerostin protein is a molecule released in osteocytes 211
line cells and is a key factor for bone homeostasis. In fact, the binding of sclerostin t o its receptor is 212
able to induce a signaling process that induce s and inhibit s new bone formation by osteoblastic line 213
cells [37]. In literature it was reported that, high glycemic levels are able to induce an inhibition of 214
the differentiation of osteoblasts and an alteration of the parathyroid hormone activity. 215
Consequently, these events induce a modification of the calcium and phosphorus ion homeostasis 216
with negative effects on the bone matrix forma tion and osteoid apposition [14,30] . Regarding dental 217
implant implantation, diabetes is able to induce a decreased bone remodelling activity and poorer 218
mineraliz ation with a slowe r osseointegration of the implant screw and lower bone -implant contact 219
in diabetics. 220
In the present investigation and characterization of the most cited papers, the University of 221
Berna showed the most intense mono -institutional activity on diabetes mellitus on implant oral 222
rehabilitations. Moreover, the tracking of the spread of literature about the topic, and data showed 223
that the largest ac tivity is from China, which showed a structured and elaborated network between 224
different nuclei research teams. This is confirmed by the evaluation of the most productive authors 225
and institutions regarding the present research topic and the network, while Song Y. of the Fourth 226
Military Medical University, Xian in China is the author with the most documents on the topic. 227
Diabetes is a common endocrine disease that could produce a negative effect o n repair processes 228
and wound healing, with a decrease of grow factors and local release of platelet -derived growth 229
factor (PDGF) [42–44]. Davies et al. reported that PDGF provide a mitogenic and chemiotaxis activity 230
for the fibroblast cell line, and osteoblasts. Moreover, PDGF seems to produce a stimulation of bone 231
marrow -derived progenitors for differentiation and proliferation. PDGF is released w ith 232
transforming growth factor beta (TGF -beta), arachidonic acid, serotonin and histamine [6]. Also , an 233
increased interleukin -6, nuclear factor kappa -light -chain -enhancer of activated B cells 1, and 234
phosphatidylinositol -4,5-bisphosphate 3 -kinase catalytic subunit gamma expression ha ve been 235
proposed by Yu et al in the crevicular fluids and the authors suggested them as top molecular 236
candidates for peri -implant tissue damage with type 2 diabetes mellitus [20]. The nuclear factor 237
kappa -light -chain -enhancer of activated B cells 1 has been described as a factor that is involved with 238
the pat hway activation of the nuclear -factor kappa beta, a molecule signaling related with type 2 239
diabetes [45]. The interleukin -6 and phosphatidylinositol -4,5-bisphosphate 3 -kinase catalytic subunit 240
gamma has been described as pro -inflammatory molecules able to induce insulin resistance [46,47] . 241
Moreov er, Morris et al. reported that the disease seems to produce an increase of risk of dental 242
implant failure if compared to non -diabetic patients [12]. Uncontrolled diabetes is ab le to influence 243
the bone -to-implant contact, that seems to histologically decrease with time in several animal studies 244
[43,48,49] . Javed et al. reported that hyperglicemia reduce s the osteoblast differentiation and 245
proliferation in favor of osteoclastic activity, increase s the IL -1beta, IL -6, IL -8 and TNF -alfa and 246
prostaglandins PGE2 release [27]. These factors reduce the new bone formation in favor of a n osseous 247
resorption activity [27,50] . 248
The administration of antiseptic mouthrinses and an accurate oral hygiene maintenance is able 249
to increase the prognosis of de ntal implant rehabilitation in diabetic patients [51,52] . Also, the 250
preoperative administration of antibiotic drugs seems to increase the survival rate of implant s by 251
10.5% in diabetics [12]. Lindhe et al. reported that diabet es is an important risk indicator for peri – 252
implant disease with poor oral hygiene, a history of periodontitis, and smoking [53]. In literature it 253
was reported that a poor metabolic and glycemic control of diabetes was related to an increase of the 254

Int. J. Environ. Res. Public Health 2020, 17, x FOR PEER REVIEW 14 of 19
risk of peri -implant dis eases and late dental implant failure. Peri-implant disease is a bacteria -related 255
pathology that include s peri-implant mucositis, which represents a pathological inflammatory 256
affection of the superficial mucosa, while the peri -implantitis is associated wit h a resorption of the 257
peri-implant bone [22,51,54,55] . 258
De Morajs et al., reported that insulin drug administration seems to produce a positive effect on 259
the bone density around osseointegrated implants with diabetes mellitus [56]. In fact , insulin 260
pharmacological therapy showed a higher mainte nance of bone density in diabetic rats. Moreover, 261
the authors reported that a significant lower BIC level was observed in the insulin -treated samples if 262
compared to non -diabetic animals [56]. In literature, it was reported that insulin is able to stabilize 263
the glucose level and normal modulation of skeletal homeostasis [56,57] . The hormone is able to 264
induce the deposition of bone matrix by osteoblast cells similar to insulin growth factor -1 (IGF -1), 265
with a documented activity on the synthesis of collagenic and non -collagenic molecules [27]. 266
Few studies focalized on the effects of a pre-diabetic condition , also known as obese -insulin 267
resistance, on dental implant rehabilitations, while this condition is clinically characterized by 268
hyperinsulinemia and euglycemia , and more randomized clinical trials are recommended to clarify 269
this particular condition [58]. Obesity is clinically associated to a higher fatty diet that is able to 270
produce an increased pheripheral insulin resistance, a decreased signaling activity on osteoblast line 271
cells by insulin receptor (IR), insulin receptor substrate -1 (IRS -1) and protein kinase B (PKB/Akt) [59]. 272
Moreover, the condition pre -diabetic disease is associated with a low grade chronic inflammation , 273
with an increased macrophage activity and altered proinflammatory interleukin release such as 274
tumor necrosis factor, IL -6 and IL -1 [59] In fact, in literature it was reported that obesity is able to 275
induce flogosis of surrounding natural teeth and a more severe periodontal disease as sociated with 276
an increased alveolar bone resorption [58]. Moreover, obesity is associated with a significantly higher 277
probing score (BOP) and an increased peri -implant probing depth if compared to healthy patients. A 278
higher expression of IL -1 beta and IL6 expression has been reported in patients affected by pre – 279
diabetic condition [59]. In lit erature , it was reported that advanced glycation end products (AGE) are 280
released also in peri implant crevicular fluid ; moreover , these molecules are significantly increased 281
in patients affected by pre-diabetic condition [58]. The release of advanced glycation end products 282
(AGE) seems to be significantly correlated to the flogistic response and local inflammation at the level 283
of the peri -implant surrounding tissue [59]. 284
5. Conclusions 285
In conclusion, the da tabase search showed a strong interest for the topic with an intense activity 286
of the scientific production on the research topic. The selected papers characterization showed that 287
an accumulation of low metabolic control, microangiopath y and advanced glycat ion end products 288
could be related to a lower predictability of dental implant rehabilitation that could represent a 289
potential contraindication for implantology procedure s. 290
6. Patents 291
Author Contributions: Conceptualization , AS and FL .; methodology, AS and FL.; software, FL.; validation, AS 292
FL., MD, BR ; formal analysis, FL AS ; investigation, AS FL .; data curation, AS FL MD BR .; writing —original draft 293
preparation, AS, FL .; writing —review and editing, AS, FL .; visualization, AS, FL MD, BR .; supervision, AS.; 294
Funding: This research received no external funding . 295
Acknowledgments: The authors declare no acknowledgments for the present investigation. 296
Conflicts of Interest: The authors declare no conflict of interest for the present research. 297
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