Abstract
Purpose
To investigate the effect of xenogeneic collagen matrix (XCM) with polydeoxyribonucleotide (PDRN) for gingival phenotype modification compared to autogenous connective tissue graft.
Methods
Five mongrel dogs were used in this study. Box-type gingival defects were surgically created bilaterally on the maxillary canines 8 weeks before gingival augmentation. A coronally positioned flap was performed with either a subepithelial connective tissue graft (SCTG) or XCM with PDRN (2.0 mg/mL). The animals were sacrificed after 12 weeks. Intraoral scanning was performed for soft tissue analysis, and histologic and histomorphometric analyses were performed.
Results
One animal exhibited wound dehiscence, leaving 4 for analysis. Superimposition of STL files revealed no significant difference in the amount of gingival thickness increase (ranging from 0.69±0.25 mm to 0.80±0.31 mm in group SCTG and from 0.48±0.25 mm to 0.85±0.44 mm in group PDRN; P>0.05). Histomorphometric analysis showed no significant differences between the groups in supracrestal gingival tissue height, keratinized tissue height, tissue thickness, and rete peg density (P>0.05).
Conclusions
XCM soaked with PDRN yielded comparable gingival augmentation to SCTG.
Keywords: Alveolar ridge augmentation, Animal model, Autografts, Polydeoxyribonucleotide, Tissue scaffolds
Graphical Abstract
INTRODUCTION
The tissue phenotype, especially the gingival phenotype, has received considerable attention in modern dentistry [1]. One determinant of the gingival phenotype is the tissue thickness [2]. A thin gingival phenotype may be characterized by a reduced extracellular matrix, a less dense collagen network, and decreased vascularity [3]. This could explain why individuals with a thin gingival phenotype are at higher risk of experiencing gingival recession throughout their lives or after prosthodontic/orthodontic treatments [1,2,4]. Consequently, modifying the gingival phenotype is considered to prevent or address insufficient gingival thickness.
A gold-standard treatment for increasing gingival thickness is the autogenous subepithelial connective tissue graft (SCTG) [5]. Numerous studies have demonstrated the predictability of SCTG [5,6,7,8]. However, the need for an intraoral donor site may contribute to patient morbidity and reduce the acceptance of the treatment [9].
To overcome these drawbacks, several collagen-based matrices have been developed and evaluated in both clinical and preclinical settings. Although these collagen matrices have demonstrated promising results, their performance generally has not exceeded, or has even been inferior to, that of SCTG in terms of soft tissue volume gain [10,11,12]. Furthermore, significant volume shrinkage has been observed over time at sites treated with collagen matrix.
One approach to improve the effectiveness of the collagen matrix involves using a healing enhancer [13]. A potential candidate material for this purpose is polydeoxyribonucleotide (PDRN). PDRN is a mixture of deoxyribonucleotides (molecular weight: 50–1,500 kDa; high purity [>95%]) derived from Oncorhynchus keta and Oncorhynchus mykiss [14,15,16]. PDRN promotes wound healing by supporting fibroblast differentiation and maturation, increasing the level of vascular endothelial growth factor, reducing levels of inflammatory cytokines, and repairing damaged DNA with low energy consumption [14,15,16,17,18,19,20]. The collagen matrix can thereby become rapidly vascularized and replaced with new tissue, leading to predictable tissue volume reconstruction. However, limited data are available on the use of PDRN in the dental field.
The aim of this preclinical study was to investigate the effect of xenogeneic collagen matrix (XCM) soaked with PDRN on increasing gingival thickness.
MATERIALS AND METHODS
Animals
In this study, 5 mongrel dogs (over 2 years old and weighing 12–17 kg) were used. The dogs were housed in separate cages with ad libitum water access. A soft diet was provided to the animals throughout the study period. The study protocol was approved by the local ethical committee (approval No. CRONEX-IACUC 202004-007), and the ARRIVE guidelines were followed [21].
Animal experiments
An intramuscular injection of Zoletil 50 (Virbac SA, Virbac Laboratories, Carros, France) was administered to induce general anesthesia. Subsequently, an endotracheal tube was inserted for inhalation anesthesia (Gerolan; Choongwae Pharmaceutical, Seoul, Korea). One veterinarian monitored the vital signs of the dogs during the experiments.
Gingivectomy
A box-type gingival defect (5 mm high and between the mesial and distal line angles in width) was created on the labial surface of the maxillary canines. Upon exposure of the alveolar bone, the bone above the gingival margin (GM) (after gingival excision) was carefully removed using a chisel.
Soft tissue grafting with a coronally positioned flap
After 2 months, gingival recession and a thin GM were observed at the experimental sites. Two vertical incisions were made 3 mm away from the mesial and distal line angles of the canine, followed by horizontal incisions along the interproximal areas and an intrasulcular incision. A full-thickness flap was reflected on the coronal portion of the mid-facial alveolar bone, approximately 2–3 mm high. Next, partial-thickness flaps were elevated on the mesial and distal papillae, connecting to the full-thickness flap in the mid-facial area. The entire flap was then released for coronal advancement. The root surface was thoroughly scaled using a Gracey curette.
The bilateral canines were allocated to 2 groups:
1) group SCTG: A free gingival graft was taken from the adjacent area, followed by de-epithelialization. The SCTG was 10 mm wide, 4 mm high, and 1.5 mm thick.
2) group PDRN: XCM (Mucograft; Geistlich Pharma, Wolhusen, Switzerland) was soaked with PDRN (2 mg/mL; 5 mL for 5 minutes). The concentration of PDRN used in this study was determined based on a commercially available product (1.875 mg/mL) [15]. The XCM was 10 mm wide and 6 mm high.
The graft materials were secured using interrupted sutures on the mesial and distal sides of the tooth (7-0 Vicryl; Ethicon, Somerville, NJ, USA). The flap was coronally advanced and sutured with sling and interrupted sutures (5-0 Nylon; Ailee Co. Ltd., Busan, Korea) (Figure 1). The sutures were removed after 1 week.
Figure 1. Clinical photographs of the procedure.
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide.
Post-surgical care
A 0.2% chlorhexidine solution (Hexamedin; Bukwang Pharmaceutical, Seoul, Korea) was used for daily irrigation during the 2 weeks following surgery. An antibiotic (enrofloxacin, Komi Biotril; Komipharm International Co. Ltd., Siheung, Korea) and an analgesic (meloxicam, Metacam; Labiana Life Sciences, Barcelona, Spain) were administered intramuscularly for 5 days.
Sacrifice
After 3 months, the animals were euthanized via an intravenous injection of an overdose of sodium pentobarbital. Tissue samples were harvested from the experimental sites.
Intraoral scanning and soft tissue analysis
Intraoral scanning (I500; Medit, Seoul, Korea) was performed on the experimental sites before soft tissue augmentation (T0) and after 3 months (T1). The obtained STL files were imported into SMOP software (Swissmeda, Baar, Switzerland) and superimposed based on the outline of the teeth, primarily the canines. The GMs at T0 and T1 were identified on the superimposed image. Then, the following parameters were measured: 1) change in GM, 2) change in gingival thickness at the level of the GM (at T0) and at 1 mm, 2 mm, and 3 mm below the GM, and 3) profilometric change in gingival tissue in the region of interest (between 1 mm and 3 mm below the GM, with a width of 6 mm) at T1.
Histological preparation
Tissue specimens were immersed in 10% neutral-buffered formalin prior to decalcification, trimming, and embedding in paraffin. The specimens were sectioned in the labio-palatal direction at a thickness of 5 μm. The most central section was selected for histological analysis. Masson’s trichrome staining was applied, and digital scanning was performed for all histological slides using a PANNORAMIC 250 Flash III scanner (3DHISTECH, Budapest, Hungary).
Histomorphometric analysis
The following parameters were measured using Case Viewer software (3DHISTECH): 1) the distance between the GM and the mucogingival junction (MGJ); 2) the distance between the GM and the bone crest (BC); 3) the distance between the GM and the apical extension of the junctional epithelium (aJE); 4) the distance between the aJE and the BC, representing connective tissue attachment; 5) the total tissue thickness at the MGJ and 1 mm, 2 mm, and 3 mm above the MGJ; 6) the epithelial thickness at the MGJ and 1 mm, 2 mm, and 3 mm above the MGJ; 7) the connective tissue thickness at the MGJ and 1 mm, 2 mm, and 3 mm above the MGJ; and 8) the density of rete pegs between the GM and the MGJ. Due to the corrugation of the epithelium, the thickest portion was assessed for the measurement of epithelial thickness at each level. The density of rete pegs was calculated by dividing the number of rete pegs by the length of the keratinized epithelial surface (Figure 2).
Figure 2. Histomorphometric analysis.
GM: gingival margin, aJE: apical end of junctional epithelium, MGJ: mucogingival junction, BC: bone crest.
Statistical analysis
Means ± standard deviations were calculated. Due to the small sample size, the non-parametric Wilcoxon signed-rank test was employed to identify statistically significant differences between the groups. P-values less than 0.05 were considered to indicate statistical significance.
RESULTS
No particular adverse events were observed throughout the experimental period.
Clinical healing
At the time of suture removal, the coronally positioned gingiva appeared reddish and slightly swollen. Except in 1 dog (No. 5), the gingival level was comparable to that observed post-surgery. In dog No. 5, wound dehiscence was noted at the suture margin; however, the gingival level still remained above the pre-soft tissue augmentation level.
At the 3-month mark, the gingival level was more coronally positioned (Figure 1), and the gingival thickness had increased in all dogs (compared to pre-soft augmentation levels) except for dog No. 5. Consequently, this animal was excluded from both STL and histomorphometric analyses.
No specific clinical differences were noted between the groups in gingival level, thickness, or color.
Superimposition of the STL files
At 3 months post-surgery, the GM exhibited a coronal shift compared to its pre-surgical position (Figure 3). In group SCTG, the coronal shift measured 1.27±0.25 mm, while in group PDRN, it measured 0.62±0.37 mm. The increase in gingival thickness was similar for both groups (Figure 3), with values ranging from 0.69±0.25 mm to 0.80±0.31 mm in group SCTG and from 0.48±0.25 mm to 0.85±0.44 mm in group PDRN. No statistically significant differences were observed between the groups in terms of coronal gingival shift and gingival thickness (P>0.05; Table 1, Figure 4).
Figure 3. Superimposition of STL files (yellow color: pre-augmentation, green color: 3 months post-augmentation).
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide.
Table 1. Superimposition of STL files.
| Group | SCTG | PDRN | |
|---|---|---|---|
| Gingival level change (mm) | 1.27±0.25 | 0.62±0.37 | |
| Linear change (mm) | |||
| Pre-GM | 0.80±0.31 | 0.85±0.44 | |
| Pre-GM – 1 mm | 0.69±0.25 | 0.76±0.39 | |
| Pre-GM – 2 mm | 0.79±0.37 | 0.78±0.39 | |
| Pre-GM – 3 mm | 0.72±0.32 | 0.48±0.25 | |
| Profilometric change in region of interest | |||
| Linear difference (mm) | 0.84±0.74 | 0.63±0.22 | |
| Volumetric difference (mm3) | 12.48±10.44 | 11.46±3.72 | |
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide, GM: gingival margin.
Figure 4. Gingival level and linear tissue changes.
GM: pre-augmentation gingival margin, GM_1, 2, and 3: 1, 2, and 3 mm below the pre-augmentation gingival margin, respectively, SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide.
In the region of interest, the linear tissue gain was 0.84±0.74 mm for group SCTG and 0.63±0.22 mm for group PDRN (P>0.05). Profilometrically, the increase in tissue volume was 12.48±10.44 mm3 in group SCTG and 11.46±3.72 mm3 in group PDRN (P>0.05; Table 1).
Histological findings
The histological features in the augmented region were similar to normal gingival tissue. The SCTG and XCM regions were not differentiated from surrounding oral tissues. Connective tissue indentation (i.e., rete pegs) were observed towards the basal layer of the epithelium, with no distinct difference between the groups in number or morphology. A few lymphocytes were present near the junctional epithelium. The collagen fibers in the connective tissue layer appeared mature. The density of connective tissue fibers was greater in group SCTG than in group PDRN (Figure 5).
Figure 5. Representative histological views of the groups. (A, C) Histological views at low magnification. (B, D) High magnification of the boxed areas in Figures 5A and 5C.
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide.
Histomorphometric analysis
The mean height of the keratinized gingiva was 4.20±0.35 mm in group SCTG and 3.95±0.70 mm in group PDRN (P>0.05). The supracrestal gingival height was greater in group SCTG (5.80±0.94 mm) than in group PDRN (4.57±0.47 mm), but the connective tissue attachment height was similar between groups (1.50±0.83 mm vs. 1.60±0.46 mm, respectively). No statistically significant difference was observed between the groups (P>0.05; Table 2).
Table 2. Supracrestal gingival tissue.
| Group | SCTG | PDRN |
|---|---|---|
| GM-MGJ | 4.20±0.35 | 3.95±0.70 |
| GM-BC | 5.80±0.94 | 4.57±0.47 |
| GM-aJE | 4.31±1.64 | 2.97±0.13 |
| Connective tissue attachment | 1.50±0.83 | 1.60±0.46 |
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide, GM: gingival margin, MGJ: mucogingival junction, BC: bone crest, aJE: apical end of junctional epithelium.
In group SCTG, the mean gingival thickness ranged from 1.11±0.39 mm to 1.92±0.41 mm, while in group PDRN, it ranged from 1.34±0.09 mm to 1.73±0.20 mm. The corresponding connective tissue thickness varied between 0.86±0.46 mm and 1.77±0.30 mm in group SCTG and between 0.85±0.08 mm and 1.59±0.27 mm in group PDRN. No statistically significant difference was noted in tissue thickness between the groups (P>0.05). The apical portions of total tissue and connective tissue thickness were thicker than their coronal counterparts. The mean epithelial thickness in both groups was less than 0.2 mm (Table 3, Figure 6).
Table 3. Tissue thickness.
| Group | SCTG | PDRN | |
|---|---|---|---|
| Total thickness | |||
| MGJ | 1.92±0.41 | 1.73±0.20 | |
| MGJ + 1 mm | 1.76±0.52 | 1.83±0.56 | |
| MGJ + 2 mm | 1.51±0.54 | 1.55±0.50 | |
| MGJ + 3 mm | 1.50±0.83 | 1.60±0.46 | |
| Connective tissue thickness | |||
| MGJ | 1.77±0.30 | 1.59±0.27 | |
| MGJ + 1 mm | 1.55±0.51 | 1.63±0.53 | |
| MGJ + 2 mm | 1.23±0.52 | 1.22±0.46 | |
| MGJ + 3 mm | 0.86±0.46 | 0.85±0.08 | |
| Epithelial thickness | |||
| MGJ | 0.11±0.11 | 0.14±0.08 | |
| MGJ + 1 mm | 0.13±0.03 | 0.19±0.05 | |
| MGJ + 2 mm | 0.19±0.05 | 0.20±0.03 | |
| MGJ + 3 mm | 0.16±0.03 | 0.22±0.02 | |
| Density of rete pegs (No./mm) | 10.34±3.29 | 10.98±5.30 | |
SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide, MGJ: mucogingival junction, No.: number.
Figure 6. Histomorphometric analysis of gingival thickness.
MGJ: mucogingival junction level, MGJ +1, +2, and +3 mm: 1, 2, and 3 mm above the MGJ, respectively, SCTG: gingival augmentation using subepithelial connective tissue graft, PDRN: gingival augmentation using xenogeneic collagen matrix soaked with polydeoxyribonucleotide.
The rete peg density was similar between the groups: 10.34±3.29 in group SCTG and 10.98±5.30 (number/mm) in group PDRN (P>0.05; Table 3).
DISCUSSION
The present study investigated the effect of XCM soaked with PDRN on gingival phenotype modification. The results demonstrated that XCM with PDRN led to comparable effects to SCTG in terms of enhancing soft tissue thickness and gingival level.
The gingival phenotype can impact both periodontal health and esthetics. A thick phenotype offers mechanical and biological stability due to its mechanical strength and high connective tissue content. These characteristics may help prevent gingival recession over time and potentially reduce periodontal inflammation. Consequently, gingival phenotype modification was suggested. Recent consensus papers from the American Association of Periodontology indicated that phenotype modification contributes to the maintenance of periodontal health [22].
The standard of care material for gingival phenotype modification is autogenous tissue grafts, such as free gingival graft or SCTG. A recent systematic review demonstrated that autogenous tissue graft is more effective in altering phenotype than soft tissue substitute materials [1], highlighting the need for enhancing materials to improve the effect of soft tissue substitutes. In this study, PDRN was applied to XCM as a healing enhancer, given its capability to support soft tissue healing.
On the superimposed STL images, SCTG and PDRN were similarly effective in increasing gingival thickness, which may suggest that PDRN promotes soft tissue healing. However, the current study did not include a positive control (that is, XCM only), so the full effect of PDRN could not be completely verified. In previous research, XCM has been extensively studied, particularly in relation to keratinized tissue augmentation and root coverage procedures. For the former, XCM showed varied treatment results [23,24,25,26,27]. Notably, in the posterior mandible, the effect of XCM did not appear to be equivalent to that of autogenous tissue [28]. For root coverage procedures, the outcomes appeared more promising; however, the increase in gingival thickness was statistically significantly lower in an XCM-treated group compared to an SCTG group [29,30]. This may indirectly support the interpretation that PDRN can enhance the effect of XCM in increasing gingival thickness.
The increase in gingival thickness in the present study was more pronounced than in other preclinical studies. Within 3 months, Schmitt et al. reported increases in thickness of 0.05±0.25 mm with SCTG and 0.04±0.14 mm with collagen matrix [12]. In a study by Song et al., bovine- and porcine-derived collagen matrices increased the thickness by 0.14±0.11 mm and 0.27±0.13 mm, respectively [3]. This discrepancy may be due to the surgical protocol of phenotype modification. The protocol in the present study was similar to that of root coverage surgery: the flap was elevated, each graft material was secured coronal to the bone crest, the tension of the flap was released, and the flap was coronally positioned. By doing so, the graft materials could be placed predominantly on the root surface (close to the GM, above the bone crest), and the pressure on the materials could be minimized. However, in the studies by Schmitt et al. [12] and Song et al., [3] a tunnel was prepared to create a soft tissue pouch for inserting graft materials. In such a situation, the pressure on the graft material may be stronger considering the lower resilience of the gingiva. An in vitro study revealed that buccal gingival tissue exhibited the highest elastic modulus compared to other oral tissues [31].
Histomorphometric analyses in the present study further support the positive impact of XCM soaked with PDRN. The supracrestal connective tissues exhibited similar dimensions in both groups, and no significant differences in histologic keratinized tissue were found. Regarding thickness, the total, epithelial, and connective tissue thicknesses were comparable in both groups. Additionally, no specific differences were observed in the histologic features of the groups. All specimens displayed typical stratified squamous epithelium accompanied by an underlying dense connective tissue layer. The orientation and density of collagen fibers within the connective tissue layer was not differentiated.
Rete pegs are one of the specific structures in the gingiva. The number and morphology of rete pegs may serve as indicators of tissue maturity and solidity [32,33]. In a preclinical study, the number of rete pegs within a region of interest was measured, demonstrating that specific collagen matrices increased the number compared to non-grafted control sites [3]. In the current study, the density of rete pegs was calculated within the area of keratinized epithelium. Approximately 10 rete pegs per millimeter were observed, with no significant differences between the groups. Consequently, it can be hypothesized that gingiva thickened by XCM with PDRN exhibits tissue stability comparable to that of gingiva formed through autogenous tissue grafting.
The present study had several limitations. First, the sample size was small. Second, animal behavior was uncontrollable. For instance, dog No. 5 experienced wound dehiscence in the vertical incision area during suture removal, ultimately leading to an apical shift in the GM. Consequently, the effect of phenotype modification could not be evaluated in that dog. Third, certain parameters, such as newly formed bone and cementum, were not measured in the histomorphometric analysis. The objective of this study was to evaluate the enhancement of gingival thickness despite the surgical protocol resembling that of root coverage surgery. Thus, notches were not made to mark the bone crest and cementoenamel junction. Fourth, a positive control (XCM only) could not be established due to the limited number of canines.
In conclusion, XCM with PDRN demonstrated a comparable capability to SCTG in the increase of gingival thickness. This study is the first to evaluate the effect of PDRN on phenotype modification. Considering the aforementioned limitations, further preclinical and clinical research is necessary to verify the effect of PDRN.
Footnotes
Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2020R1C1C1008201). The PDRN was kindly provided by Genoss.
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: Hyun-Chang Lim, Yeek Herr.
- Formal analysis: Chang-Hoon Kim, Gyewon Jeon.
- Investigation: Chang-Hoon Kim, Han-Kyu Lee.
- Methodology: Hyun-Chang Lim, Jong-Hyuk Chung.
- Project administration: Han-Kyu Lee.
- Writing - original draft: Hyun-Chang Lim.
- Writing - review & editing: Yeek Herr, Jong-Hyuk Chung.
References
- 1.Barootchi S, Tavelli L, Zucchelli G, Giannobile WV, Wang HL. Gingival phenotype modification therapies on natural teeth: a network meta-analysis. J Periodontol. 2020;91:1386–1399. doi: 10.1002/JPER.19-0715. [DOI] [PubMed] [Google Scholar]
- 2.Cortellini P, Bissada NF. Mucogingival conditions in the natural dentition: narrative review, case definitions, and diagnostic considerations. J Clin Periodontol. 2018;45(Suppl 20):S190–S198. doi: 10.1111/jcpe.12948. [DOI] [PubMed] [Google Scholar]
- 3.Song YW, Kim S, Waller T, Cha JK, Cho SW, Jung UW, et al. Soft tissue substitutes to increase gingival thickness: histologic and volumetric analyses in dogs. J Clin Periodontol. 2019;46:96–104. doi: 10.1111/jcpe.13034. [DOI] [PubMed] [Google Scholar]
- 4.Rasperini G, Acunzo R, Cannalire P, Farronato G. Influence of periodontal biotype on root surface exposure during orthodontic treatment: a preliminary study. Int J Periodont Restor Dent. 2015;35:665–675. doi: 10.11607/prd.2239. [DOI] [PubMed] [Google Scholar]
- 5.Zucchelli G, Tavelli L, McGuire MK, Rasperini G, Feinberg SE, Wang HL, et al. Autogenous soft tissue grafting for periodontal and peri-implant plastic surgical reconstruction. J Periodontol. 2020;91:9–16. doi: 10.1002/JPER.19-0350. [DOI] [PubMed] [Google Scholar]
- 6.Chambrone L, Sukekava F, Araújo MG, Pustiglioni FE, Chambrone LA, Lima LA. Root-coverage procedures for the treatment of localized recession-type defects: a Cochrane systematic review. J Periodontol. 2010;81:452–478. doi: 10.1902/jop.2010.090540. [DOI] [PubMed] [Google Scholar]
- 7.Chambrone L, Tatakis DN. Periodontal soft tissue root coverage procedures: a systematic review from the AAP Regeneration Workshop. J Periodontol. 2015;86(Suppl):S8–51. doi: 10.1902/jop.2015.130674. [DOI] [PubMed] [Google Scholar]
- 8.Zuhr O, Bäumer D, Hürzeler M. The addition of soft tissue replacement grafts in plastic periodontal and implant surgery: critical elements in design and execution. J Clin Periodontol. 2014;41(Suppl 15):S123–S142. doi: 10.1111/jcpe.12185. [DOI] [PubMed] [Google Scholar]
- 9.Tavelli L, Barootchi S, Rasperini G, Giannobile WV. Clinical and patient-reported outcomes of tissue engineering strategies for periodontal and peri-implant reconstruction. Periodontol 2000. 2023;91:217–269. doi: 10.1111/prd.12446. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pietruska M, Skurska A, Podlewski Ł, Milewski R, Pietruski J. Clinical evaluation of Miller class I and II recessions treatment with the use of modified coronally advanced tunnel technique with either collagen matrix or subepithelial connective tissue graft: a randomized clinical study. J Clin Periodontol. 2019;46:86–95. doi: 10.1111/jcpe.13031. [DOI] [PubMed] [Google Scholar]
- 11.Lee KS, Shin SY, Hämmerle CH, Jung UW, Lim HC, Thoma DS. Dimensional ridge changes in conjunction with four implant timing protocols and two types of soft tissue grafts: a pilot pre-clinical study. J Clin Periodontol. 2022;49:401–411. doi: 10.1111/jcpe.13594. [DOI] [PubMed] [Google Scholar]
- 12.Schmitt CM, Matta RE, Moest T, Humann J, Gammel L, Neukam FW, et al. Soft tissue volume alterations after connective tissue grafting at teeth: the subepithelial autologous connective tissue graft versus a porcine collagen matrix - a pre-clinical volumetric analysis. J Clin Periodontol. 2016;43:609–617. doi: 10.1111/jcpe.12547. [DOI] [PubMed] [Google Scholar]
- 13.Cha JK, Sun YK, Lee JS, Choi SH, Jung UW. Root coverage using porcine collagen matrix with fibroblast growth factor-2: a pilot study in dogs. J Clin Periodontol. 2017;44:96–103. doi: 10.1111/jcpe.12644. [DOI] [PubMed] [Google Scholar]
- 14.Galeano M, Pallio G, Irrera N, Mannino F, Bitto A, Altavilla D, et al. Polydeoxyribonucleotide: a promising biological platform to accelerate impaired skin wound healing. Pharmaceuticals (Basel) 2021;14:1103. doi: 10.3390/ph14111103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kim TH, Heo SY, Oh GW, Heo SJ, Jung WK. Applications of marine organism-derived polydeoxyribonucleotide: its potential in biomedical engineering. Mar Drugs. 2021;19:296. doi: 10.3390/md19060296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Squadrito F, Bitto A, Irrera N, Pizzino G, Pallio G, Minutoli L, et al. Pharmacological activity and clinical use of PDRN. Front Pharmacol. 2017;8:224. doi: 10.3389/fphar.2017.00224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.An J, Park SH, Ko IG, Jin JJ, Hwang L, Ji ES, et al. Polydeoxyribonucleotide ameliorates lipopolysaccharide-induced lung injury by inhibiting apoptotic cell death in rats. Int J Mol Sci. 2017;18:1847. doi: 10.3390/ijms18091847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Jeong W, Yang CE, Roh TS, Kim JH, Lee JH, Lee WJ. Scar prevention and enhanced wound healing induced by polydeoxyribonucleotide in a rat incisional wound-healing model. Int J Mol Sci. 2017;18:1698. doi: 10.3390/ijms18081698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lee DW, Hyun H, Lee S, Kim SY, Kim GT, Um S, et al. The effect of polydeoxyribonucleotide extracted from salmon sperm on the restoration of bisphosphonate-related osteonecrosis of the jaw. Mar Drugs. 2019;17:51. doi: 10.3390/md17010051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Shin DY, Park JU, Choi MH, Kim S, Kim HE, Jeong SH. Polydeoxyribonucleotide-delivering therapeutic hydrogel for diabetic wound healing. Sci Rep. 2020;10:16811. doi: 10.1038/s41598-020-74004-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577–1579. doi: 10.1111/j.1476-5381.2010.00872.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kao RT, Curtis DA, Kim DM, Lin GH, Wang CW, Cobb CM, et al. American Academy of Periodontology best evidence consensus statement on modifying periodontal phenotype in preparation for orthodontic and restorative treatment. J Periodontol. 2020;91:289–298. doi: 10.1002/JPER.19-0577. [DOI] [PubMed] [Google Scholar]
- 23.Thoma DS, Alshihri A, Fontolliet A, Hämmerle CH, Jung RE, Benic GI. Clinical and histologic evaluation of different approaches to gain keratinized tissue prior to implant placement in fully edentulous patients. Clin Oral Investig. 2018;22:2111–2119. doi: 10.1007/s00784-017-2319-4. [DOI] [PubMed] [Google Scholar]
- 24.Lorenzo R, García V, Orsini M, Martin C, Sanz M. Clinical efficacy of a xenogeneic collagen matrix in augmenting keratinized mucosa around implants: a randomized controlled prospective clinical trial. Clin Oral Implants Res. 2012;23:316–324. doi: 10.1111/j.1600-0501.2011.02260.x. [DOI] [PubMed] [Google Scholar]
- 25.Sanz M, Lorenzo R, Aranda JJ, Martin C, Orsini M. Clinical evaluation of a new collagen matrix (Mucograft prototype) to enhance the width of keratinized tissue in patients with fixed prosthetic restorations: a randomized prospective clinical trial. J Clin Periodontol. 2009;36:868–876. doi: 10.1111/j.1600-051X.2009.01460.x. [DOI] [PubMed] [Google Scholar]
- 26.Tarasenko S, Ashurko I, Taschieri S, Repina S, Esaya N A, Corbella S. Comparative analysis of methods to increase the amount of keratinized mucosa before stage-two surgery: a randomized controlled study. Quintessence Int. 2020;51:374–387. doi: 10.3290/j.qi.a44216. [DOI] [PubMed] [Google Scholar]
- 27.Lim HC, An SC, Lee DW. A retrospective comparison of three modalities for vestibuloplasty in the posterior mandible: apically positioned flap only vs. free gingival graft vs. collagen matrix. Clin Oral Investig. 2018;22:2121–2128. doi: 10.1007/s00784-017-2320-y. [DOI] [PubMed] [Google Scholar]
- 28.Qiu X, Li X, Li F, Hu D, Wen Z, Wang Y, et al. Xenogeneic collagen matrix versus free gingival graft for augmenting keratinized mucosa around posterior mandibular implants: a randomized clinical trial. Clin Oral Investig. 2023;27:1953–1964. doi: 10.1007/s00784-022-04853-8. [DOI] [PubMed] [Google Scholar]
- 29.Cardaropoli D, Tamagnone L, Roffredo A, Gaveglio L. Treatment of gingival recession defects using coronally advanced flap with a porcine collagen matrix compared to coronally advanced flap with connective tissue graft: a randomized controlled clinical trial. J Periodontol. 2012;83:321–328. doi: 10.1902/jop.2011.110215. [DOI] [PubMed] [Google Scholar]
- 30.Aroca S, Molnár B, Windisch P, Gera I, Salvi GE, Nikolidakis D, et al. Treatment of multiple adjacent Miller class I and II gingival recessions with a Modified Coronally Advanced Tunnel (MCAT) technique and a collagen matrix or palatal connective tissue graft: a randomized, controlled clinical trial. J Clin Periodontol. 2013;40:713–720. doi: 10.1111/jcpe.12112. [DOI] [PubMed] [Google Scholar]
- 31.Choi JJ, Zwirner J, Ramani RS, Ma S, Hussaini HM, Waddell JN, et al. Mechanical properties of human oral mucosa tissues are site dependent: A combined biomechanical, histological and ultrastructural approach. Clin Exp Dent Res. 2020;6:602–611. doi: 10.1002/cre2.305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Vignoletti F, Nuñez J, de Sanctis F, Lopez M, Caffesse R, Sanz M. Healing of a xenogeneic collagen matrix for keratinized tissue augmentation. Clin Oral Implants Res. 2015;26:545–552. doi: 10.1111/clr.12441. [DOI] [PubMed] [Google Scholar]
- 33.Grossman ES, Forbes ME. Studies related to reaction of supporting soft tissue to denture wear: the histological response of vervet monkey oral epithelium to a -80 mmHg vacuum. J Oral Rehabil. 1990;17:587–597. doi: 10.1111/j.1365-2842.1990.tb01430.x. [DOI] [PubMed] [Google Scholar]