Clinical Applications of Photofunctionalization on Dental Implant Surfaces: A Narrative Review

Dental implant therapy is a common clinical procedure for the restoration of missing teeth. Many methods have been used to promote osseointegration for successful implant therapy, including photofunctionalization (PhF), which is defined as the modification of titanium surfaces after ultraviolet treatment. It includes the alteration of the physicochemical properties and the enhancement of biological capabilities, which can alter the surface wettability and eliminate hydrocarbons from the implant surface by a biological aging process. PhF can also enhance cellular migration, attachment, and proliferation, thereby promoting osseointegration and coronal soft tissue seal. However, PhF did not overcome the dental implant challenge of oral cancer cases. It is necessary to have more clinical trials focused on complex implant cases and non-dental fields in the future.


Introduction
Dental implant therapy is a common clinical procedure for the restoration of missing teeth. Further, the surface wettability of dental implant might affect osseointegration [1]. It was first found in 1997 that ultraviolet (UV) irradiation could induce superhydrophilicity in titanium dioxide (TiO 2 ) because the surface oxygen vacancies at bridging sites result in the conversion of relevant Ti4 + sites to Ti3 + sites for more water adsorption [2,3]. In addition to applications in antifogging and self-cleaning materials, the concept was also used in dental implant treatment [3][4][5].
Photofunctionalization (PhF), first described in 2009, is defined as an overall phenomenon of titanium surface modification after UV treatment, including the alteration of physicochemical properties and the enhancement of biological capabilities [4,5]. UV radiation is categorized into UVA (wavelength λ = 320-400 nm), UVB (λ = 280-320 nm), and UVC (λ = 200-280 nm). The effects of PhF include the modification of the implant surface from hydrophobic to superhydrophilic and the reversal of its biological aging [1,[6][7][8]. Moreover, PhF could also decrease the amount of bacterial attachment/accumulation and maintain the antimicrobial surface in vitro [9][10][11].
The clinical application of PhF was first reported in 2013 and included seven implants in four implant complex cases utilizing PhF before implant placement [12]. Herein, we introduce the effects of PhF and its recent clinical applications. The aim of this article was to focus on clinical studies of PhF from January 2013 to June 2022. The digitally searched papers from PubMed used "photofunction" and "dental implant" as key words. After abstract review, there were two double-blind clinical trial studies, three prospective studies, four retrospective studies, and one case series in the present paper [12][13][14][15][16][17][18][19][20][21]. Furthermore, PhF applied in the spine surgery of 13 patients was included [22]. Except for some pre-clinical review papers on in vitro or animal studies, to my best knowledge, this paper is the first review focused on the clinical application of photofuctionalization [4,[23][24][25].

In Vitro Studies
A brief summary of in vitro studies is shown in Table 1.  The water contact angle on the titanium surface was reduced to 0.5 • after PhF; thus, the surface was changed from hydrophobic to super-hydrophilic [1,41]. The titanium implant surfaces had harmful and time-dependent degradation due to carbon contamination (hydrocarbons), which was defined as "the biological aging of titanium" [6,27,28]. Roy reported that titanium implant surfaces, as little as 4 weeks from production, are contaminated by atmospheric hydrocarbons [26]. The 4-week-old titanium implants required more osseointegration time than the newly prepared titanium implants by two-fold. The bone-to-implant contact (BIC) percentage on the 4-week-old surfaces was less than the BIC on the new surfaces (60% vs. 90%). Additionally, only 20% to 50% of the levels of recruitment, attachment, and proliferation of osteoblasts showed on the 4-week-old surface when compared with new surfaces [3]. The PhF could reduce the concentration of surface hydrocarbons on different implants by three-to four-fold, thus improving biologic results [26,27,29] and no change in the topography of implant surfaces [7,27,29]. Furthermore, PhF could increase the oxygen concentration of the zirconia implant surfaces and decrease carbon concentration [30]. There was increased protein adsorption, as well as the improved migration, attachment, and proliferation of osteoblasts on photofunctionalized surfaces in vitro [12,31,32]. In addition, UV treatment could restore the reduction in the bioactivity of titanium implants, which was adverse effect of temperature deviations when handling titanium materials [35]. With the exception of osteoblasts, the attachment of gingival fibroblasts or epithelial cells was also enhanced on UV-treated titanium and the zirconia abutment surface, which could enhance the soft tissue seal of the peri-implant interface [36,[38][39][40]. In addition, the UV-photofunctionalization of instruments could prevent infection by restricting the growth of oral bacteria and biofilm and suppressing the proinflammatory gene expression of IL-1β [9][10][11]37].Therefore, PhF may be a useful and easy adjunctive method to improve osseointegration by utilizing a combination of these advantages.
The average BIC is reported to be 45%, which is lower than the ideal 100% [12]. PhF could result in a super-hydrophilic implant surface, reversed the biological degradation of the implant surface, and optimized surface electrostatic charges [3,4,12]. Thus, PhF improves BIC by up to 98.2% and promotes osseointegration [3][4][5]. The bone morphogenesis around UV-irradiated titanium surfaces was known as "superosseointegration" [3,5,6]. Additionally, reduced stress on the surrounding tissues with improved stress distribution was found on UV-treated implants when compared with UV-untreated implants using a three-dimensional finite element analysis model, especially under vertical loading [31,32].

Preclinical Animal Studies
Additional hydrocarbons on titanium implant/instrument surfaces decreases bonebinding ability by aging [22]. However, PhF could promote osseointegration by reducing hydrocarbons [22,33]. Shen reported that UV PhF eliminated hydrocarbon contamination with resultant enhanced BIC and osseointegration in a rabbit model [42]. This increase in BIC was found in rat, rabbit, and dog models [1,[43][44][45][46][47][48][49][50]. However, there were no significant differences in BIC and implant stability quotient (ISQ) between the UV treatment and control group 9 months after implant placement in the jaw bone of mini-pigs [51]. Except for titanium, the BIC was also enhanced in zirconia-based material by 3 to 7-fold in smooth surfaces and by 1.4 to 1.7-fold in rough surfaces [43].
The osseointegration of custom-made or commercial dental implants was accelerated by PhF in different animal models; in other words, an earlier osseointegration was achieved by UV treatment [5,8,34,49,51]. The biological enhancing effect remained even after 12 weeks of healing in a rabbit model [52]. A 2.2~2.3-fold increase in the strength of osseointegration was found in normal rats, and the genetically modified rats (close to human diabetes) showed a 1.8 to 3-fold increase after using UV treatment (TheraBeam Affiny device) for 15 min [53,54]. The strengtth of osseointegration in the aged rats was enhanced by 40% after UV treatment (TheraBeam SuperOsseo device) for 12 min [55]. Moreover, bone-implant integration after PhF was 80% higher than that of the control titanium implants in ovariectomized rats (close to osteoporosis) [41].
When implants were subjected to constant lateral force during healing, an increased implant success rate was seen in photofunctionalized surface group as compared with the control group (100% vs. 28.6% respectively) in a rat study [56]. In addition, PhF increased the orthodontic mini-screw's resistance against tipping force by 1.5~1.7-fold and resulted in less displacement under a lateral tipping force in rats [57,58]. Therefore, it is impossible to gain more anchorage of orthodontic mini-screws clinically by using UV treatment. Except for the PhF with commercial UV machines, the use of a bacterial UV bench lamp (wavelength of 254 nm) for 48 h also increased the volume of cortical-like tissue in the coronal region in a rabbit study [9]. The early osseointegration of aged titanium implants in a dog model could be enhanced by ultraviolet-C light photofunctionalization. However, the effect was independent on UVC exposure within a range from ten minutes to one hour [59]. Therefore, the UV treatment time using a bench lamp is too long for clinical use when compared with UV machines that require 12 or 15 min.
Finally, a summary of the preclinical animal studies is shown in Table 2.

•
There were significantly higher BV/TV and bone-implant contact at 4 weeks; however, there were no significant differences at 12 weeks.

•
The effect was independent on the UV-C duration.

Clinical Studies
Ten clinical papers were associated with dental implant therapy using photofunctionalization. Most papers (7/10) were from the Ogawa study group in Japan [12][13][14][15][16][17][18]. These papers are summarized in Table 3.    The first clinical report in 2013 by Funato et al. revealed that the ISQs for seven implants placed in compromised bone after PhF for 15 min increased from a range of 48~75 at placement to 68~81 at loading [12]. Funato's further retrospective study showed that PhF could shorten healing time from 6.6 months to 3.2 months before loading when compared with the control group; however, the implant survival rates of both groups were similar [13]. This means that PhF would enhance the dental implant osseointegration speed index (OSI) [12,13]. In addition, the same result was also found in Suzuki's prospective research [14]. Moreover, the implant stability dip was eliminated by PhF; especially implants with less primary stability could obtain more ISQs gain using a TheraBeam Affiny machine [12,14,15]. UV treatment has chemical and biological effects on the osseous-implant interface, and PhF for as little as 15 min could enhance BIC and promote osseointegration [64].
In comparison with regular cases, PhF was more effective in complex cases, including cases with ridge augmentation, sinus elevation, and immediate implant [16]. PhF is a stronger determinant of implant stability than the other patient-related and implant-site-related factors [16]; thus, PhF results in a lower early failure rate than that in the non-UV treatment group (1.3% vs. 4.3%) in a large retrospective study [17]. However, PhF still did not overcome the pathophysiological condition of cancer-related complex cases with bone resection, segmental defect, or radiation, in which the implant survival rate was only 22.2% [18].
In addition to Japan's studies, which used a TheraBeam Affiny (Ushio Inc., Tokyo, Japan) for 15 min, a recent Korean clinical trial also used the same UV machine [29]. The UV light of the TheraBeam Affiny was delivered as a mixture of spectra via a single source UV lamp at λ = 360 nm and λ = 250 nm [7]. The study focused on the effect of PhF on implants, which was placed in different groups of the posterior maxilla according to CBCT (cone-beam computed tomography) grayscale for bone density [29]. The results showed that PhF could increase initial implant stability in posterior maxilla, thus allowing a faster loading protocol [29]. Another UV device, the TheraBeam SuperOsseo (Ushio Inc., Himeji, Japan) was used in a clinical trial from Germany, which used the implant removal torque value as an indirect reference of BIC in 360 implants of 180 patients [19]. The UV light of the TheraBeam SuperOsseo was delivered as a mixture of spectra; the intensity was 0.05 mW/cm 2 at λ = 360 nm and 2 mW/cm 2 at λ = 250 nm [34]. The finding from this research showed that PhF improved early-phase healing and stability and promoted the speed of osseointegration [19]. Shah reported that the pretreatment of dental implants with UV light revealed a statistically significant difference only in implant stability but not in other parameters, including mean marginal bone loss, pink/ white aesthetic score, and success/survival rate [21].
In the spine surgery of 13 patients, the result showed no significance in osteosclerosis between UV-treated and UV-untreated cages in lumbar fusion [22]. The ratio of the carbon attachment of titanium cages (20% at one year) in orthopedics was less than that in dental titanium instruments (60% at 4 weeks); thus, the effect of the UV photofunctionalization of titanium instrumentation in spine surgery was questionable [22]. However, UV-treatment could improv the osseointegration of aged 3D-printed porous Ti6Al4V scaffolds in the femur condyles of rabbits in a recent study [62]. It is possible that photofunctionalization has a positive effect in the further application of orthopedics.

Discussion
The mechanisms behind the enhanced osseointegration of dental implants after photofunctionalization are due to improving hydrophilicity and eliminating hydrocarbon contamination on the implant surface [25]. The UVA (wavelength range from 320 to 400 nm) and UVC (wavelength range from 200 to 280 nm) irradiation could result in hydrophilicity and the nano-scale modification of the titanium surface [25,65]. However, the vital mechanism behind excellent osseointegration might be because of carbon removal from the titanium surface by UVC [4,5]. In addition to antibacterial effects, UV activation would enhance the adsorption of plasma proteins of human body and improve osteogenic cell attachment, spreading, and proliferation [11,25,60]. Thus, it is possible to shorten the dental implant treatment time.
There is a conspicuous bacterial colonization on implants only 30 min after implant insertion [66,67], which may be prevented by UV-photofunctionalization restricting the growth of oral bacteria and biofilm [9][10][11]. Peri-implant-diseases-associated biofilms would affect the long-term outcome of dental implants. The microbial composition between periodontitis and peri-implantitis are similar; however, dental implants are more susceptible to oral infections due to anatomic and physiologic differences from natural teeth [67,68]. In addition, the peri-implant tissue response, including pro-inflammatory state, is influenced by transmucosal abutment geometry and surface [68]. Thus, the positive effect of photofunctionalization for the attachment of gingival fibroblasts or epithelial cells on implant abutment surface, which may decrease the severity of peri-implant infection [36,[38][39][40].
There were some disadvantages in pre-clinical studies, which resulted in a risk of bias [23,24]. The quality assessment revealed that no animal study revealed a low risk of bias for all domains [23,24]. However, photofunctionalization still showed a benefit in the initial phase of osseointegration in different animal models [24]. The limitations in the clinical studies included differences in the age of patients, photofunctionalization protocol, experience of users, and follow-up period. Except for one German study, other studies were performed in Asia. The publication bias in the clinical studies would limit the significance of this contribution to implant dentistry. Thus, it is necessary to prove a positive effect in Western people through more studies. Photofunctionalization could overcome the challenge of complex dental implant cases, except for cancer-related cases with bone resection, segmental defect, or radiation [18]. Changing the photofunctionalization protocol (UV treatment for 15 min, then cleaning ozone for 5 min) may have an advantage in these complicated cases.

Conclusions
Many methods have been used to promote osseointegration for successful implant therapy, including photofunctionalization. UV photofunctionalization can change the surface wettability and eliminate the hydrocarbons that are generated by aging on the implant surface. Photofunctionalization can also enhance cell migration, attachment, and proliferation to promote osseointegration and coronal soft tissue seal. However, photofunctionalization did not overcome the cancer-related pathological condition and had little effect on the resistance to oblique forces. Moreover, the clinical assistance of photofunctionalization is still limited by the field of dental implants. To use the results, therefore, it is necessary to have more clinical trials focused on complex implant cases and non-dental fields in the future.