Soft Tissue Substitutes to Increase the Thickness of Attached Gingiva: An Animal Study

doi:10.21203/rs.3.rs-1947338/v1

Background:This study aims to compare the histological and thickness changes of attached gingiva following grafting with three groups of different soft tissue substitutes at labial aspect of canines.

Methods: In three beagle dogs, attached gingival thickening was performed with double layer allogeneic acellular dermal matrix membrane (AADM), bovine acellular dermal matrices membrane (BADM) combined with concentrated growth factor membrane (CGF) or BADM combined with collagen sponge. Thickness was measured before augmentation (baseline [BL]), and after 1, 2, 3, and 4 months. Descriptive histological analyses were performed after 4 months.

Results: Four months post-operatively, thickness increase differed significantly among three groups (AADM: 1.88±0.28 mm; BADM combined with CGF: 0.27±0.19 mm; BADM combined with collagen sponge: 0.10±0.11 mm). Compared to BL, AADM group showed significant difference (3.24±0.22 mm vs. 1.36±0.72 mm), while the BADM combined with CGF group showed no significant difference (1.50±0.07 mm vs. 1.23±0.15 mm) and neither of the BADM combined with collagen sponge group (1.54±0.15 mm vs. 1.44±0.15 mm). Histological analyses revealed that AADM was integrated with gingival tissues, and new fibrous tissue and blood vessels were formed. But the grafts in the other two groups were absorbed and the augmentation area was remodeled into a structure consistent with the surrounding host tissue.

Conclusions: . AADM is superior to BADM combined with CGF and BADM combined with collagen sponge with regard to gingival augmentation.

acellular dermal matrix

concentrated growth factor

collagen sponge

gingiva thickening

Implant therapy has become one of the important ways to repair missing teeth. The success of implant includes biological and aesthetic success[1]. The focus has shifted from simple implant survival to long-term aesthetic effect[2]. Therefore, more attention has been paid to the importance of the quality and quantity of peri-implant soft tissue, especially the keratinized mucosa of peri-implant. Lack of keratinized gingiva leads not only to gingival recession in the aesthetic area, but also to plaque accumulation around teeth and implants[3]. In contrast, adequate thickness of peri-implant attached gingiva can reduce the plaque and gingival index, improving the stability of peri-implant marginal bone levels[4, 5]. Linkevicius et al[6]. found that over 2 mm thickness is sufficient to ensure a stable bone level around the implants. Therefore, according to whether the threshold of 2 mm is reached, the gingival biotype is divided into thin and thick types[7]. In addition, the mucosal thickness of ≥ 2mm is considered the threshold for better aesthetic effect[8]. After tooth loss, the soft and hard tissue atrophies in the edentulous area. Therefore, soft tissue augmentation is needed to increase the thickness of soft tissue around the implant. However, autogenous connective tissue grafts (ACTG) need second surgical site, which will prolong the surgical time and increase the pain of patients[9]. This makes soft tissue substitutes become a research hotspot. The purpose of this study was to compare the histological and thickness changes of attached gingiva following grafting with three groups of different soft tissue substitutes

Animals

The study protocol was approved by the Medical Ethical Committee of Hospital of Stomatology, Hebei Medical University (Approval Number: 2020012)，The three female beagle dogs were purchased from Beijing Fangyuanyuan Farm (Beijing, China), ages 12–18 months, weight 10 kg, with complete dentition and healthy periodontal tissue, were reared in the Animal Center of Hebei Medical University, and the experiment was conducted after 1 week of adaptive feeding. This study conformed to the Arrived guidelines.

Preparation of CGF

Beagle dogs took supine position, with their limbs fixed on the operating table. We prepared the skin and collected blood 9 mL from the small saphenous vein of the hind limb after disinfection. Immediately we placed the sterile blood collection tube into the Medifuge centrifuge and started the concentrated growth factor preparation procedure. After centrifugation 15 min, the blood was divided into three layers: the top layer was the serum layer, the middle layer the CGF fibrin layer, and the bottom layer the erythrocyte layer. The upper serum was poured out and the sterile ophthalmic scissors were used to cut off the junction of the middle layer and the bottom layer. The CGF gel was placed on the inside of the double-layer of bovine acellular dermal matrices membrane (Fig. 1) , then the CGF gel was pressed with a special tool to make a membrane for operation.

Preparation of BADM

BADM (Haiao biofilm, ZH-Bio, China) is an absorbable collagen membrane derived from calf skin. The spatial structure of natural collagen fibers is preserved, which has two distinct surfaces: dense surface (UP side) and loose surface. We trimmed BADM to a suitable size, prepared 8-10 holes with aseptic mucosal needles, and then placed them in normal saline(Fig. 1a).

Preparation of collagen sponge

Collagen sponge (KejibangⓇ, Wuxi Biot Biology Technology Co., Ltd.), extracted from bovine Achilles tendon, is a spongy freeze-dried product of high purity collagen. We trimmed the collagen sponge to a suitable size.

Preparation of AADM

AADM (Beijing JayyaLife Bio-tissue Engineering Co. Ltd., Beijing, China), derived from human cadaveric tissue donated by the Charity Federation, with removed cellular components of epidermis and dermis, has two distinct surfaces: basement membrane surface and dermal surface. The dermal surface is conducive to the rapid vascularization of acellular dermal matrix after grafting, and the basement membrane surface is conducive to rapid epithelialization. We trimmed AADM to a suitable size, and then prepared 8-10 holes with aseptic mucosal needles. (Fig. 2)

Experimental grouping

Twelve augmentation areas on the labial side of bilateral upper and lower canines in three beagle dogs were randomly divided into three groups. Group A: double-layer AADM; Group B: BADM combined with CGF membrane; Group C: BADM combined with collagen sponge. Grafts size: 15 mm × 10 mm× 1.6 mm-1.8 mm (length × width × height).

Surgical procedure

Three beagle dogs were anesthetized with intramuscular injection of Xylazine Hydrochloride Injection 0.1 ml/kg (JiLing, China) and fixed on the operating table with lateral recumbent position. Then 0.5% iodophor was used to disinfect perioral skin and oral mucosa, and the sterile towels were spread. After local infiltration anesthesia with articaine hydrochloride, and epinephrine tartrate injection (Produits Dentaires Pierre Rolland, Merignac, France) on surgical site, a mesial vertical subepithelial incision was made on the attached gingiva at the canine area, then a microsurgical blade was inserted into the incision line and the attached gingiva was tunneled in a mesiodistal direction with a split-thickness flap. Subsequently, the tunnel was augmented with three groups of different soft tissue substitutes. In the double-layer AADM group, AADM was folded one time, with the dermal side in contact with gingiva and periosteum, while the basal side was inside the double-layered matrix. Then the graft was inserted and the mesial vertical incision was closed using resorbable sutures (Fig. 3). In the BADM combined with CGF group, BADM was placed on both sides of CGF, and CGF was pressed into a membrane with a special tool, forming BADM-CGF-BADM "sandwich" composite membrane, which then was inserted and the incision was tightly sutured. In BADM combined with collagen sponge group, BADM was placed on both sides of collagen sponge to form BADM-collagen sponge-BADM "sandwich" composite membrane, which then was inserted and the incision was tightly sutured.

Postoperative procedure

Beagle dogs were reared in separate cages after awakening from the operation, and 1.6 million units of penicillin (Shandong, China) were injected intramuscularly once a day for 3 days. They were given liquid diet and the oral cavity was rinsed routinely with normal saline every day to keep the surgical area clean.

Thickness measurement

The attached gingival thickness was measured before operation and after 1, 2, 3, and 4 months. It was measured at the point of 19 mm from the apical to the root along the central longitudinal axis of canine. We used the sterile needle with a stop to penetrate the attached gingival surface vertically, gently pressed into the soft tissue to the surface of the hard tissue, and then moved the stop to gently contact the attached gingival surface. Then carefully taking out the sterile needle, we used Vernier caliper with 0.02 mm resolution to measure the penetration depth (the distance from the tip of the sterile needle to the stop), which is the thickness of attached gingiva. The thickness was measured repeatedly by the same examiner for 3 times, and the average value was taken as the measured thickness of the attached gingiva (Fig. 4).

Histological analysis

After 4 months, under anesthesia, excision of gingival tissue from the augmentation area was made. The samples were fixed with 4% paraformaldehyde for 24 h and the sections were embedded with paraffin. Then HE and Masson staining were performed for descriptive histological analyses.

Statistical analysis

Spss21.0 software was used for statistical analysis. The mean difference and standard deviation were used to describe the attached gingival thickness and the thickness augmentation. Shapiro-Wilk test was used for normal analysis. If the data showed normal distribution, paired t-test was used to evaluate the change of attached gingival thickness before and after operation. One-way ANOVA was used for comparison among the three groups, LSD-t test was used for pairwise comparison. If the data showed non-normal distribution, rank sum test was used. All statistics were treated with bilateral test. (p < 0.05)

General situation

During the whole process, the beagle dogs were in good condition, and the diet, defecation, and other activities were normal. There was no obvious discomfort, no wound sutures falling off, no redness or swelling, no infection, and no rejection.

Attached gingival thickness

After 1, 2, 3, and 4 months, the attached gingival thickness of AADM group was 3.61±0.11 mm, 3.46±0.04 mm, 3.33±0.03 mm, and 3.24±0.22 mm respectively, and the increment of attached gingival thickness was 2.25±0.08 mm, 2.10±0.07 mm, 1.97±0.10 mm, and 1.88±0.28 mm respectively. The gingival thickness of the BADM combined with CGF membrane group was 2.05±0.33 mm, 1.73±0.24 mm, 1.50±0.08 mm, and 1.50±0.07 mm respectively, and the increment of attached gingival thickness was 0.83±0.37 mm, 0.50±0.28 mm, 0.28±0.20 mm, and 0.27±0.19 mm respectively. The attached gingival thickness of the BADM combined with collagen sponge group was 2.36±0.48 mm, 1.93±0.17 mm, 1.62±0.18 mm, and 1.54±0.15 mm respectively, and the increment of attached gingival thickness was 0.93±0.52 mm, 0.49±0.17 mm, 0.18±0.14 mm, and 0.1±0.11 mm respectively. The attached gingival thickness showed no significant difference among the three groups before operation (p > 0.05). After 1 month, the thickness increment differed significantly among the three groups (p < 0.05), then showed a downward trend. After 1, 2, 3, and 4 months, AADM group showed the highest attached gingival thickness, followed by the BADM combined with collagen sponge group, and then by the BADM combined with CGF group, with statistical significance among the three groups (p < 0.05). But there was no significant difference between the BADM combined with collagen sponge group and the BADM combined with CGF group in the attached gingival thickness and the increment of attached gingival thickness at different measurement point (p > 0.05). After 3 months, the attached gingival thickness values of the BADM combined with collagen sponge group and the BADM combined with CGF group gradually approached and the thickness changes tended to be stable, and the change rate of attached gingival thickness of AADM group also decreased. After 3 months, the gingival thickness of the BADM combined with CGF group and the BADM combined with collagen sponge group revealed no significant differences compared to BL (p > 0.05). After 4 months, the average attached gingival thickness of the AADM group were still significantly higher than BL (p < 0.05). (Table 1; Fig. 5)

Table 1 Attached gingival thickness and the changes

		A(mm)	B(mm)	C(mm)	p
BL	Mean ± SD	1.36±0.72	1.23±0.15	1.44±0.15	0.145
BL	Median	1.38	1.25	1.45	0.145
1M	Mean ± SD	3.61±0.11	2.05±0.33	2.36±0.48	<0.05
1M	Median	3.56	1.98	2.24	<0.05
2M	Mean ± SD	3.46±0.04	1.73±0.24	1.93±0.17	<0.000^b
2M	Median	3.46	1.64	1.95	<0.000^b
3M	Mean ± SD	3.33±0.03	1.50±0.08	1.62±0.18	<0.000^b
3M	Median	3.34	1.51	1.64	<0.000^b
4M	Mean ± SD	3.24±0.22	1.50±0.07	1.54±0.15	<0.000^b
4M	Median	3.3	1.51	1.55	<0.000^b
BL to 1M	Mean ± SD	2.25±0.08	0.83±0.37	0.93±0.52	<0.05
	Median	2.28	0.83	0.81
	P^a	<0.001	<0.05	<0.05
BL to 2M	Mean ± SD	2.10±0.07	0.50±0.28	0.49±0.17	<0.000^b
	Median	2.08	0.49	0.43
	P^a	<0.001	<0.05	<0.05
BL to 3M	Mean ± SD	1.97±0.10	0.28±0.20	0.18±0.14	<0.000^b
	Median	1.96	0.32	0.19
	P ^a	<0.05	>0.05	>0.05
BL to 4M	Mean ± SD	1.88±0.28	0.27±0.19	0.1±0.11	<0.000^b
	Median	1.92	0.31	0.09
	P ^a	<0.05	>0.05	>0.05

Abbreviations: BL, baseline; 1M, follow-up at 1 month; 2M, follow-up at 2 months; 3M, follow-up at 3 months; 4M, follow-up at 4 months; SD, standard deviation. Note: P a, within group (changes versus baseline); b, Statistically significant difference among three groups, but there was no statistically significant difference between group B and group C.

Descriptive histology

After 4 months, descriptive histological analysis showed that in the AADM group, the dermal matrix was integrated with the host gingival tissue, the structure of collagen fibers of ADM is intact, with the fibers arranged compactly and neatly, there was no obvious degradation, host’s new fibrous tissue and fibroblasts grew into AADM, and new blood vessels and red blood cells were seen in the dermal matrix (Fig. 6). In the BADM combined with collagen sponge group and the BADM combined with CGF group, mucosal tissue was covered with stratified squamous epithelium and there was a lot of fibrous connective tissue in the lamina propria, which means typical anatomical characteristics of the gingiva. The grafts in the two groups were completely degraded and no residue of the grafts was found. The augmentation area was reconstructed into a structure consistent with the surrounding host tissue and the mature fibrous connective tissue in the area was rich in blood vessels and fibroblasts (Fig. 7, Fig. 8).

Allogeneic ADM has been widely used in plastic and reconstructive surgeries, and its application in periodontics has been established

as a safe and feasible substitute to natural collagen[10]. It is proved that AADM is equivalent to autologous connective tissue grafts for root coverage procedures[11]. In this study, AADM acts as a scaffold for cell migration from adjacent gingival tissues. After blood clot becomes stable, early vascularization occurs on the dermal side of AADM, because this side is in direct contact with the host tissue, which ensures rapid blood penetration into the grafts and promotes revascularization and subsequent healing[12]. In a recent study, zang et al[13], who used AADM to increase the vertical gingival thickness of implants, pointed out that AADM folding may produce greater increment of the soft tissue, but it may also lead to potential postoperative morbidity. In this study, tunnel technique was used to increase gingival thickness, which is a minimally invasive surgical method, preserves the integrity of gingival papilla, and demonstrates faster healing compared with coronally advanced flap (CAF) technique. It increases the blood supply, provides better nutrition to the grafts and better postoperative aesthetic effects[14]. In our study, the process of integration, degradation, and regeneration of acellular scaffold was smooth without any complications. AADM is well integrated with host gingival tissue, which indicates that AADM has good biocompatibility and has a full integration process with the host tissue. Full integration is the premise to ensure the smooth progress of vascularization and tissue remodeling. New fibrous connective tissues and blood vessels grew into the matrix at the integration site, which indicates that AADM is partially remodeled and a dynamic balance of extracellular matrix with the surrounding host tissue is established.

Puisys et al[12]. used non-crosslinked AADM (AlloDerm, BioHorizons, Birmingham, USA) to augment vertical peri-implant soft tissue thickness. After 3 months, the thickness increased by 2.21 mm. In our study, we used cross-linked AADM (Beijing JayyaLife Bio-tissue Engineering Co. Ltd., Beijing, China). Some studies pointed out that ADM cross-linking increases resistance against collagenase degradation and delays the process of tissue remodeling[15, 16], achieving durability and long-term strength[15]. It is inferred that cross-linked AADM may be better than non-cross-linked one in soft tissue augmentation, but there still lacks randomized controlled clinical trials to compare the differences of soft tissue increment between the two kinds of dermal matrix. Schmitt et al[17]. stated that crosslinkers are more likely to cause inflammation, leading to poor clinical results and wound healing complications, but no healing complication occurred in our entire study period in AADM group, which indicates that cross-linked ADM may be suitable for use as a soft tissue substitute. After 1 month, the thickness of attached gingiva in ADM group increased to 3.61±0.11 mm and decreased to 3.24±0.22 mm after 4 months, which means some shrinkage of the augmentation area occurred. Till now, no specific explanation has been given by scholars for the shrinkage. In the augmentation of attached gingival thickness, the whole dynamic biological process of AADM from tissue integration, to degradation, and to complete transformation into host tissue has not been entirely clarified. Therefore, understanding this process may better explain the shrinkage of AADM and the decrease of augmentation area thickness in the process of soft tissue healing.

In this study, BADM was combined with collagen sponge or CGF membrane to make "sandwich" composite membrane. These two groups obtained a substantial thickness gain of attached gingiva during the early follow-up period (1 month). However, the increased thickness was decreased and gradually stabilized after 3 months, which may be related to the process of grafts degradation and tissue remodeling, in which the grafts were gradually absorbed and the augmentation area was remodeled into a structure consistent with the surrounding host tissue. Collagen-based biomaterials, which are often used as scaffolds for tissue engineering, are combined with BADM as a cell growth scaffold. The ideal cell growth scaffold should not only have good biocompatibility but also maintain the long-term structure stability. The thickening value of attached gingiva in the BADM combined with collagen sponge group was much lower than that in AADM group, which may be related to the rapid degradation rates of collagen sponge. The degradation period of collagen sponge in our study is 2-3 weeks. Dalmia et al[18]. used collagen sponge (BiofilSponge ©- EucarePharma, India) to increase the thickness of palatal mucosa, in which grafts degraded about 3-4 weeks. In addition, the poor mechanical properties cannot help maintain the spatial structure. Compared with collagen sponge, AADM can better resist mechanical load and the extracellular matrix remodeling was slow, which ensures the long-term structural integrity and increased durability of AADM. CGF, the third generation of platelet concentrate, is similar to the second generation of PRF in composition, structure, performance, and clinical application, and has higher content of growth factor and stronger ability to promote tissue regeneration than PRF[19]. Qi et al[20].used CGF to increase gingival thickness in periodontal accelerated osteogenesis orthodontics (PAOO) and 0.34 mm was increased during 6-month follow-up. The CGF membrane, which is rich in growth factors, is mainly composed of fibrin and takes about 2 weeks to degrade completely in vivo. The degradation cycle of BADM is longer than that of CGF, with about 3 months, but it cannot release growth factors. The combination of the two grafts to increase the thickness of attached gingiva not only provides a scaffold for cell growth, but also contains a large number of growth factors and fibrin to promote tissue regeneration. However, the thickening effect of BADM combined with CGF or with collagen sponge is not as good as that of AADM, possibly because most of the grafts are simply degraded and only a few lead to the formation of new connective tissues.

AADM has been widely used in various medical fields. The results of this study will surely contribute to better understanding AADM and provide reference for its use as an autologous tissue substitute. Further research can focus on the comparison between AADM and other soft tissue substitutes. The collagen sponge preparation can be further optimized so as to improve mechanical properties, prolong degradation time, and expand its application in the field of thickness increment. The effect of CGF on gingival thickening still needs to be confirmed by more studies. Some limitations of this study include small sample size and short observation time. Therefore, larger sample size and longer follow-up time in the future are needed. Meanwhile, a standardized research program should be established for thickness augmentation so as to compare different studies.

During the 4-month observation period, AADM has the best effect on attached gingival thickening, and BADM combined with collagen sponge and BADM combined with CGF can’t produce obvious thicknessing effect after 3 months. Therefore, when choosing soft tissue substitute to increase the thickness of attached gingiva, AADM is a better choice than the other two groups of grafts, but the shrinkage of AADM should be considered in clinical practice.

AADM: acellular dermal matrix membrane; BADM:bovine acellular dermal matrices membrane; CGF: combined with concentrated growth factor membrane.

Acknowledgements

We wish to thank Prof. Limei Liu for English polishing.

Authors’ contributions

XL conceived the idea and supervised the administration. HZ contributed in the statistics and writing the manuscript. XG, XZ, SM, HM and TZ performed the animal surgery. All authors have read and approved the manuscript.

Funding

This research was funded by Hebei Provincial Government-funded Clinical Medicine Talent Training and Basic Research projects [Project No: 361029 (MXZB00267)].The authors declare that the funding bodies had no role in the design of the study or the collection, analysis, and interpretation of data, or in writing the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study protocol was approved by the Medical Ethical Committee of Hospital of Stomatology, Hebei Medical University (Approval Number: 2020012) and conducted in accordance with relevant guidelines and regulations. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All methods are reported in accordance with ARRIVE guidelines.

Consent to publish

Not Applicable.

Competing interests

The authors declare that they have no competing interest.

Author details

¹Department of Oral and Maxillofacial Surgery, Hebei Key Laboratory of Stomatology, Hebei Clinical Research Center for Oral Diseases, School and Hospital of Stomatology, Hebei Medical University, Shijiazhuang 050017, P R China

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No competing interests reported.

Soft Tissue Substitutes to Increase the Thickness of Attached Gingiva: An Animal Study

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Abstract

Figures

Background

Materials And Methods

Results

Discussion

Conclusios

Abbreviations

Declarations

References

Additional Declarations

Status:

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