Abstract
Purpose:
Enucleation of the maxillo-mandibular cysts will create post-surgical bone defects, which may take more than a year for complete bone healing. Bone grafts are common to aid bone regeneration in large defects. The aim was to evaluate the clinical and radiographical healing and bone formation capabilities of polymer of i-PRF and hydroxyapatite in maxilla-mandibular defects compared to hydroxyapatite (HA) alone. The primary objective was to do a clinical assessment of healing at postoperative days 1, 3, and 7; and a radiological evaluation of bone formation postoperatively at the 2nd month and 4th month. A secondary objective was to identify if any, local or systemic side/ill effects of polymer of i-PRF with HA.
Material and Methods:
After surgical enucleation of 19 maxillo-mandibular cysts/tumors, either HA or HA + i-PRF graft was adapted to the defect. Clinical outcome variables such as Pain (VAS score), edema, and mucosal color were evaluated on postoperative days 01, 03, and 07 while radiological outcome variables such as volume of the defect (cc), and Density of new bone (HU) on Computed Tomography were evaluated at 2nd and 4th month. The results obtained were tabulated and compared with the inferential analysis.
Results:
Clinical parameters are better in the HA + i-PRF group but the result was non-significant. Radiologically, the mean healing ratios were significantly greater in the HA + i-PRF group (63.5 ± 2.34 at 2nd month, 90.3 ± 7.32 at 4th month) compared to the HA group (57.2 ± 5.21at 2nd month, 80.8 ± 5.33 at 4th month). When comparing the mean density of new bone, there was a statistically significant difference with a mean difference of 95.2 HU more in the HA + i-PRF (623 HU ± 42.9) compared to the HA group (528 HU ± 96.5) in 2nd month.
Conclusion:
The polymer of i-PRF and HA prepared as the sticky bone yields faster and better bone healing in post-enucleation maxilla-mandibular bony defects as compared to hydroxyapatite alone based on radiological findings till 4 months.
Keywords: Bone defect, density of new bone, hydroxyapatite, injectable platelet-rich fibrin, maxillomandibular cysts, surgical defect
INTRODUCTION
Odontogenic cysts and tumors can occur across all patient demographics across age, gender, race, and socioeconomic status, as alteration in remnants of dental tissues.[1] Maxillomandibular cysts vary in size, all of which would lead to loss of normal bone structure. Treatment modality depends on various factors like size, nature of cyst, adjacent structures, etc., Various surgical modalities have been described such as decompression alone, decompression followed by enucleation, marsupialization alone, marsupialization followed by enucleation; enucleation alone, with packing, with primary closure, or with primary closure with bone grafting/reconstruction; enucleation along with excision of overlying oral mucosa, enucleation followed by various adjuvant therapies, peripheral ostectomy, segmental resection, etc., The most common is enucleation, 80% of the time.[2,3,4]
Enucleation will lead to the creation of post-surgical bone defects which may take more than a year for complete bone healing.[5] Until the healing period, the patient remains deprived of various kinds of food/nutrition either because of missing teeth or because of lack of masticatory force. It is only after the healing period that the patient can go for dental implants for dental rehabilitation.[6] To overcome this limitation various types of bone grafts are available.
The use of bone grafts is common to aid bone regeneration in large defects. Varieties of bone grafts included autograft, allograft, xenograft, and synthetic bone substitute.[3,4] Bone-graft substitutes have also been developed as alternatives to autografts or allografts. They are three-dimensional scaffolds made of natural or synthetic biomaterials that would promote the migration, proliferation, and differentiation of bone-forming cells required for bone regeneration[7] These biomimetic materials are thus characteristically osteoconductive, without having osteoinductive or osteogenic potential of their own.[8] Some of them are collagen, hydroxyapatite (HA), β-tricalcium phosphate (β-TCP) calcium-phosphate cement, and glass ceramics.[9]
Hydroxyapatite as a bone graft substitute has shown promising results. Hydroxyapatite (HA) belongs to the apatite family, crystalline compounds with crystalline hexagonal lattice. HA is nothing but Ca10(PO4) 6(OH) 2 and is the primary mineral component of bones and teeth. Thus, it is extremely biocompatible and does not aggrandize any inflammatory responses.[10] HA is a widely used material as a bone graft. However, there are still some limitations. The use of hydroxyapatite alone might lead to fibrous encapsulation of the graft material and thus does not permit an ideal periapical healing outcome.[11] Moreover, it has only osteoconductive properties. The addition of i-PRF to HA can increase its osteoinductive, antibacterial, and anti-inflammatory properties, making it suitable for use as bone graft material in bone defects.[12]
PRP and PRF are platelet concentrates, which are a potential source of growth factors that play a crucial role in bone regeneration. Moreover, as an autologous product, it eliminates concerns about cross-contamination, disease transmission, and immune reactions.[13] Drawbacks of PRP include additional use of anti-coagulants (known suppressors of wound healing), multi-step centrifugation, risk of coagulopathies, and antibodies to factor V and XI.[14] For these reasons, a second-generation platelet concentrate termed platelet-rich fibrin (PRF) was developed to further improve wound healing in comparison to PRP.[11,12,14] A liquid form of PRF, recently developed and named i-PRF can be used to mix grafts cohesively and to spray over surgical sites.[15]
The advantages of PRF are that it is completely autologous, simple to prepare, cost-effective, and it provides sustained release of growth factors over time. Also compared to PRP, PRF provides a stable matrix that remodels slowly unlike PRP which resorbs quickly. i-PRF also provides a rich source of growth factors, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF). These growth factors are the key to healing as they potentiate vital functions such as cellular proliferation and bone formation.[11,15]
In literature, HA has been widely used for bone regeneration either alone or in combination with other grafts. Even though a few studies assessing the in vitro properties of i-PRF have been published, there are no studies detailing the clinical applications of i-PRF plus HA in bone regeneration with clinical and radiographic evaluation. Thus, the study was planned to evaluate the clinical and radiographically healing and bone formation capabilities of polymer of i-PRF and hydroxyapatite as bone graft substitute in maxillomandibular post-surgical defects compared to hydroxyapatite alone.
MATERIALS AND METHODS
This randomized control trial was exclusively researched, coordinated, and conducted in the Department of Dentistry, All India Institute of Medical Sciences, Patna. Informed consent was obtained from all the study participants/patients. All procedures performed in the study were conducted by the ethical standards provided by the “World Medical Association Declaration of Helsinki on ethical principles for medical research involving humans for studies”.[16] Ethics approval was obtained from the ethical review committee of the same institution with IRC reference no. IRC-AIIMS/Pat/IEC/PGTh/July 20/43 on 20/09/2021. The study was registered in the clinical trials registry India with registration number (ICMR-NIMS) CTRI/2023/02/049568. The present research was done in line with the Consort statement (http://www.consort-statement.org).[17]
Study population, setting, and design
This is a Randomized Control Trial (RCT), which included patients reporting to the Department of Dentistry, meeting with inclusion criteria.
Inclusion criteria
Cases of maxillomandibular cysts/tumors of size not lesser than 2cm and more than 6cm in greatest dimension can be managed by surgical enucleation with primary closure.
Exclusion criteria
Patients with any systemic disorders contraindicated for surgery, patients with metabolic bone diseases like osteoporosis, osteomalacia (rickets), hyperparathyroidism, etc., Patients who do not give consent for the procedure, Patients not willing or will not be able to come up to 4 months for follow, and patients with unavailable space for grafting after cyst enucleation, for example, cysts encroaching maxillary sinus, nasal floor, etc.
Sample size calculation
The sample size was estimated using the following assumptions from a reference article.[17] Level of significance – 5% (alpha error), Power of study – 80%, Group size - Equal (1:1). Anticipated mineral bone density in new graft on radiology at the end of 2 months- 160 g/cm3 and anticipated mineral bone density in standard graft on radiology at the end of 2 months- 140 g/cm3. Standard Dev- 20 g/cm3 and Superiority margin assumed = 10.
The sample size was calculated as 10 in each group. Considering a 10% loss to follow-up, each group would have 11 cysts/tumors. Thus, making a total of 22 cyst/tumor.
Randomization, allocation concealment, and blinding details
A simple block randomization technique was advocated for the creation of a randomization list. Random numbers were generated using randomization software by an investigator not involved with providing intervention and collection of information. The sequence of random numbers generated was sealed in the envelope for allocation concealment thus we used the SNOSE (Sequentially numbered, opaque, sealed envelope) technique for allocation concealment.
As and when a patient was enrolled in the study after inclusion and exclusion criteria after written consent; the investigator who had generated a random number was approached to obtain the sealed envelope in sequence. After obtaining the sealed envelope for the participant, it was opened in the presence of another physician/doctor not involved in the project. Based on the envelope, the intervention will be provided.
We used a double-blinding technique in this study. Patients as well as investigators did not know the type of graft received. Only the surgeon would know the group allocated.
METHODOLOGY
Meticulous medical history of each participant was taken along with the patient’s age, gender, and detailed extraoral and intraoral examination. All patients meeting inclusion criteria were subjected to presurgical computer tomography evaluation on a 256-slice MDCT Siemens Somatom Definition Flash CT scanner. Based on group allocation the patients were allocated into either of the two groups i.e. group 1- HA group and group 2-HA + i-PRF group.
Surgical enucleation was done under strict aseptic protocol under LA/GA [Figure 1a]. As per the group allotment, either HA (synthetic hydroxyapatite granules, G-BONE) alone or HA (synthetic hydroxyapatite granules, G-BONE) +i-PRF graft adapted in the defect [Figure 1b]. The flap was repositioned and sutured. Postoperatively gentle pressure was applied with a sterile gauze pack to the surgical flap to facilitate the reattachment of the flap to the underlying bone. Post-operative instructions along with antibiotics and analgesics were prescribed.
Figure 1.
a) Post-enucleation bone defect b) Graft packed in the defect
Pre-operative data collection was done using a pre-structured data collection sheet comprising of patient’s details along with the clinical and radiological findings. Postoperatively data was collected in the same sheet with clinical assessment (on days 1, 3, and 7) and Radiographic assessment on Non-contrast computerized tomography (NCCT) in the 2nd and 4th month.
Procedure of HA
The required amount of autologous blood was withdrawn possibly from the median antecubital vein using a large bore syringe. Blood was directly mixed with the HA graft in a metal kidney tray.
The procedure of HA + i-PRF
The required amount of autologous blood was withdrawn possibly from the median antecubital vein using a large bore syringe. Tubes were placed in the horizontal centrifuge for two minutes at 3300 rpm. After centrifugation, the bottom layer fraction consisting of red blood cells, and the top layer consisting of plasma, platelets, and coagulation factors still in uncoagulated form were obtained. A light-yellow colored, separated plasma and platelets layer obtained in liquid form, was nothing but i-PRF. The tube was carefully opened to avoid homogenization of the material, i-PRF was collected from the tubes using a syringe, keeping the needle just above the interface.
To make HA + i-PRF polymer, i-PRF in a syringe was transferred to a metal kidney tray and after five minutes, HA particles were added gradually. Within 15 minutes, the start of polymerization was observed and the material was ready for use in a total time of 20 minutes. [Figure 2]
Figure 2.
Method of forming HA + i-PRF polymer-a) Collection of i-PRF. (After centrifugation, the red blood cells remain at the bottom and the light yellow to orange color liquid in the tube above is i- PRF. The top layer was aspirated using a syringe by placing the tip of the syringe just above the junction of the 2 layers) b) The collected i-PRF emptied into a sterile metal kidney tray c) After 5 minutes, hydroxyapatite granules were added gradually d) Ready to use, cohesive mass or polymer of i-PRF and HAwas obtained in 15-20 minutes
Confounders, Variables, and Assessment
The patients were assessed for Age, Gender, Type of cyst/tumor, and Location of cyst/tumor as independent variables while clinical outcome variables were Pain (VAS score), edema, mucosal color (at postoperative day 01, 03, and 07) and Radiological outcome variables were the Volume of defect (cc), Density of new bone (HU) on NCCT (at 2nd and 4th month).
a) Volume of defect:
Using the VOI (volume of interest) tool on Siemens Syngo Via imaging software, the defect was outlined in all required sections of a plane to create 3D VOI, and volume was noted [Figure 3a]. Volume (in cc) measured on: a) Pre-operative CT b) Postoperative 2nd month CT and c) Postoperative 4th month CT. The healing ratio, which was the primary outcome variable, was calculated as follows[18]:
Figure 3.
a) Measuring 3-D volume (in cc) of defect on Siemens Syngo Via imaging software using VOI tool b) Measuring density (in HU) of new bone on Siemens Syngo Via imaging software using ROI tool
The healing ratio (HR) or percentage reduction in the volume of the defect (PRV) was calculated to be taken into analysis for 2nd month (HR2) and for 4th month (HR4)
b) Density of new bone forming at the periphery
Using the ROI tool (Region-of-interest) on Siemens Syngo Via imaging software, a small ROI circle was made at the most representative area on newly forming bone, and the Hounsfield unit (HU) value was noted [Figure 3b].
Statistical analysis
Statistical analysis was done using Jamovi software (version 2.3.18). For demographic analysis, frequency was calculated. For continuous variables, the assumptions of normality and homogeneity of variables were accessed. Normality assumes that the scores are normally distributed (bell-shaped), and we tested it using the one sample Shapiro Wilk test and visual inspection of the Q–Q plot. The homogeneity of variance assumes that both groups have equal variance and will be assessed using Levene’s test for equality of variances. If Levene’s test showed unequal variances, it indicates that equal variance cannot be assumed, then we used the Welch t-test instead of the student t-test which is more reliable when to sample has unequal variances. z test of proportion was conducted to compare categorical data
RESULTS
18 patients with 19 maxillomandibular cysts/tumors (n = 19) treated with surgical enucleation, bone grafting, and primary closure were taken in the final analysis [Figure 4]. The mean age of patients included in this study was 30.6 ± 7.41 years. An independent sample t-test was applied to test whether the mean age of group HA + i-PRF differs from the mean age of group HA. We observed a statistically non-significant difference in the mean age of both groups. (P value = 0.486). Amongst 19 cysts/tumors included in the study, 47.4% are male and 52.5% are female. In terms of Location, 52.63% of lesions were in the anterior maxilla, 36.84% of lesions were in the posterior mandible and 10.52% of lesions were in the anterior mandible [Table 1].
Figure 4.
CONSORT Diagram for the study
Table 1.
Details of Gender, age, type of cyst and location of lesion
| HA + i-PRF | HA | |
|---|---|---|
| Mean±SD | 29.7±7.47 | 32.1±7.25 |
| Total | 10 | 09 |
| Gender | ||
| Male | 6 (31.6%) | 3 (15.8%) |
| Female | 4 (21.1%) | 6 (31.6%) |
| Total | 10 | 09 |
| Type of cyst | ||
| Radicular cyst | 05 | 04 |
| OdontogenicKeratocyst | 02 | 02 |
| Residual cyst | 00 | 02 |
| Dentigerous cyst | 01 | 01 |
| Lateral periodontal cyst | 01 | 00 |
| Giant cell lesion | 01 | 00 |
| Total | 10 | 09 |
| Location of lesion | ||
| Anterior maxilla | 5 (26.3%) | 5 (26.3%) |
| Anterior mandible | 2 (10.5%) | 0 |
| Posterior mandible | 3 (15.8%) | 4 (21.1%) |
| Total | 10 | 09 |
The comparison of mean pain score (VAS Score) between group HA + i-PRF and group HA was not statistically significant at postoperative day 01(P value = 0.855) and day 03(P value = 0.720). The pain score was 0 in all 19 lesions on postoperative day 7.
Edema and abnormal mucosal color were present in all 19 lesions on day 01 while both were absent in all 19 lesions on day 07 [Table 2].
Table 2.
Details of clinical outcome parameters
| HA + i-PRF | HA | Test of significance | |
|---|---|---|---|
| Pain | |||
| Mean±SD at day 1 | 3.60±0.51 | 3.56±0.52 | t=0.186, P=0.855 |
| Mean±SD at day 3 | 1.70±0.48 | 1.78±0.44 | t=0.365, P=0.720 |
| Mean±SD at day 7 | 00 | 00 | ---- |
| Edema | |||
| Edema Present at day 1 | 10 (100%) | 9 (100%) | z=0, P=1 |
| Edema Present at day 3 | 4 | 5 | z=0.678, P=0.498 |
| Edema Present at day 7 | 0 | 0 | ---- |
| Mucosal colour | |||
| Abnormal mucosal colour present at day 1 | 10 (100%) | 9 (100%) | z=0, P=1 |
| Abnormal mucosal colour present at day 3 | 3 | 5 | z=1.13, P=0.26 |
| Abnormal mucosal colour present at day 7 | 00 | 00 | ---- |
A z-test for proportion was conducted to compare the presence/absence of edema and abnormal mucosal color at postoperative day 03 across groups. The result was not statistically significant (P < 0.05) with z-value = 0.678 and P value = 0.498. Even the result for mucosal color was not statistically significant (P < 0.05) with z-value = 1.13 and P value = 0.26 [Table 2].
Welch t-test was used to compare the mean healing ratios at postoperative 2nd month across groups. There was a statistically significant difference (P value: 0.007) with a mean difference of 6.27% more in the HA + i-PRF. Similarly, the test showed a statistically significant difference (P value: 0.005) in 4th month, with a mean difference of 9.52% more in the HA + i-PRF [Table 3].
Table 3.
Details of Radiological outcome parameters
| HA + i-PRF | HA | Test of significance | |
|---|---|---|---|
| Healing ratio/percentage reduction in volume of defect (in %) | |||
| Mean±SD at post operative 2 months | 63.5±2.34 | 57.2±5.21 | t=3.32, P=0.007 |
| Mean±SD at post operative 4 months | 90.3±7.32 | 80.8±5.33 | t=3.21, P=0.005 |
| Density of new bone (in HU) | |||
| Mean±SD at post operative 2 months | 623±42.9 | 528±96.5 | t=2.73, P=0.020 |
| Mean±SD at post operative 4 months | 685±56.6 | 592±119.1 | t=2.14, P=0.056 |
Welch t-test was used to compare the mean density of new bone at the postoperative 2nd month across groups. There was a statistically significant difference (P value: 0.020) with a mean difference of 95.2 HU more in the HA + i-PRF. Even At 4th month, the difference in the mean density of new bone across groups was seen but the relation was not significant (P value: 0.056) [Table 3]
DISCUSSION
The most preferred surgical management of odontogenic cysts is enucleation followed by watertight closure, originally described by Partsch in 1910 as ‘cystectomy’ (Partsch II). This procedure was well accepted for lesions up to 2 cm, wherein osteogenic and angiogenic cells from the surrounding bone and periosteum could reach blood clots in the defect and promote bone regeneration.[19] But in larger cysts the blood clot in the defect might get disintegrated and retracted due to separation from the bony wall and thus can easily lead to infection.[19]
Unlike other tissues, bone has an intrinsic capacity to regenerate and repair itself by the process of primary or secondary healing. However, this action is dependent on adequate vascularity, and avascularity may lead to the pathogenesis of such defects.[20] Also, the collapse of surrounding tissue into such defects would lead to contour defects.[21] Grafting of such large bony defects not only reduces the risk of infection but also accelerates bone regeneration. Furthermore, it would also prevent wound dehiscence by providing a strong base against which mucosa can rest, thus eliminating the dead space between the flap and bony defect.[22]
There are numerous literature available focusing on the use of autogenous grafts, allogenous grafts, xenografts, or alloplastic and synthetic grafts as bone grafts.[11,21,22,23,24] In recent times, PRF has shown promising results on various oral pathologies due to its growth-promoting and regenerating properties.[25] Thus, we performed the study with a research question of whether adding i-PRF to a previously well-known synthetic bone graft i.e. HA, will have any marked effect on bone healing.
Different types of HA are Bovine HA and Synthetic HA, derived from different origins for various uses. A study was conducted by Kattimani et al.[23] 2014, to evaluate and compare bovine HA and synthetic HA as a bone graft in maxillary cystic bony defects. They concluded that both grafts are biocompatible for filling bone defects, both grafts exhibited less bone resorption and enhanced bone formation with similar efficacy. We have utilized synthetic HA.
Regarding radiological assessment, a study has shown the maximum radiographic density of grafted cystic bone defects at 24 weeks (6 months) but the mean density at the 3rd-month interval and the 6-month interval was statistically not significant suggesting not much difference between the 3rd and 6 months. Considering these facts had assessed the grafted cystic bone till 4th month. In contradictory to our study, Kamel HM et al.[26] 2020, had evaluated bone density on CBCT in the 9th month.
Our study has shown better density of the new bone in the HA + i-PRF group compared to the HA group in 2nd month and the relation was statistically significant. This is in accordance with another study where biphasic bone graft material along with PRF has shown statistically significantly higher mean bone density than biphasic bone graft material without PRF.[26]
In their study, Tiwari UO et al. 2020[27] concluded that the periapical bone healing after periapical surgery is enhanced after placing bone regenerative materials, and PRF with hydroxyapatite seems to be better than PRF with alendronate. A similar is with this study.
Nanohydroxyapatite and Platelet-rich Fibrin combination has shown faster periapical bone regeneration in the first 3 months than hydroxyapatite or Nanohydroxyapatite alone. Thus the studies favor adding PRF with other bone graft material to enhance bone regeneration.[28]
The combination of PRF and Hydroxyapatite Graft when used in three–wall intrabony defects, has shown significant improvements compared to PRF alone. Both PRF and HA increase the regenerative effects resulting in better overall healing patterns, per our study.[29]
Limitations
The primary limitations of this study were its limited sample size and short follow-up period. To address these issues, future studies should be designed with a larger sample size and a longer follow-up duration. Additionally, this was a single-center trial, which further restricts the generalizability of the findings. The authors recommend conducting multicentric trials and incorporating intergroup comparisons with variables such as maxillary versus mandibular and anterior versus posterior regions.
CONCLUSION
i-PRF (injectable platelet-rich fibrin) recently has been recognized as an emerging modality in the treatment of various maxillofacial pathologies due to its regenerating properties. The novelty of the study was to evaluate whether polymer of i-PRF and hydroxyapatite as bone graft substitute may have better healing and hence can be a potent alternative to hydroxyapatite alone. The polymer of i-PRF and HA prepared as the sticky bone yields faster and better bone healing in post-enucleation maxillomandibular bony defects as compared to hydroxyapatite alone based on radiological findings till 4 months. Thus, our study favors the utilization of i-PRF in conjunction with other bone grafts like hydroxyapatite. The author highly recommends further study in combination with i-PRF and other bone graft material to enhance its evidence.
Ethical approval
Ethics approval was obtained from the ethical review committee of the institution with IRC reference no. IRC-AIIMS/Pat/IEC/PGTh/July20/43 on 20/09/2021.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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