The Risk of Medication-Related Osteonecrosis of the Jaw in Children: Guidance for Antiresorptive Use in Pediatric Patients.

BACKGROUND: Antiresorptive targeted cancer therapies, such as denosumab and bisphosphonates, are used in adults, but their application in pediatric cancer is more recent. Side effects such as osteonecrosis of the jaw (ONJ) observed in adults have curtailed use of these medications in the pediatric population. PURPOSE: This study assesses the frequency of ONJ, other side effects, and the indications for use of denosumab versus bisphosphonates in pediatric subjects. STUDY DESIGN, SETTING, SAMPLE: A retrospective cohort study of pediatric subjects who underwent bisphosphonate or denosumab therapy at our institution from 2007-2023 was conducted. Subjects aged ≥ 18 years at therapy initiation were excluded. INDEPENDENT VARIABLE: The independent variable was antiresorptive therapy divided into 2 groups, treatment with intravenous bisphosphonates or denosumab. MAIN OUTCOME VARIABLE(S): Primary outcomes were development of bisphosphonate-related and denosumab-related ONJ. Secondary outcomes included additional side effects. COVARIATES: ONJ risk factors, subject demographics, indications for use, timing, duration, and cumulative dose of antiresorptive therapy were abstracted. ANALYSES: Univariate and bivariate statistics were computed to describe the sample and measure associations between antiresorptive therapy and outcomes. P values < .05 conferred statistical significance. RESULTS: The sample was composed of 178 subjects with a mean age of 11.7 ± 6.1 years. There were 14 (7.9%) and 164 (92.1%) subjects treated with denosumab and bisphosphonate therapies, respectively. There were 0 cases of ONJ across all subjects. The most common indication for treatment was adjuvant targeted therapy for aggressive tumors and malignancy (39.3%) followed by osteoporosis (14.6%). Subjects treated with denosumab had higher frequencies of hypercalcemia and severe bone pain than subjects treated with bisphosphonates, 28.6% versus 1.2% (P < .001) and 14.3% versus 0.00% (P < .001), respectively. CONCLUSION AND RELEVANCE: While invasive dental procedures are ideally performed before antiresorptive treatment, our data suggest that bisphosphonates may be used safely in the pediatric population with low concern for ONJ. Our data also demonstrated bisphosphonates may have a more tolerable side effect profile than denosumab. If the perceived benefits are similar, we recommend using bisphosphonates as first-line therapy in children while reserving denosumab for refractory cases. Future studies will help determine long-term side effects and differences in efficacies of these medications.

Custom Endoprosthesis-Assisted Pediatric Microsurgical Jaw Reconstruction.

Surgical treatment of pediatric maxillary and mandibular tumors can cause significant postresection disfigurement, mastication, and speech dysfunction. The need to restore form and function without compromising growth at the recipient and donor sites poses a particular reconstructive dilemma. This study evaluates outcomes of the custom endoprosthesis (CE) compared with noncustom reconstruction (NCR) and introduces an algorithm using CE to optimize available soft tissue reconstructive options. An Institutional Review Board-approved retrospective review of all patients undergoing maxillary or mandibular reconstruction between 2016 and 2022 was completed. The independent variable of interest was CE utilization. Primary outcomes of interest included hardware failure/removal or exposure, major complications, and revision surgeries. Covariates of interest included patient demographics, medical comorbidities, tumor size, and pathologic diagnosis. Statistical analyses including independent t test, χ2 analyses, and univariate/multivariate logistic regression were performed using RStudio version 4.2.1. Fifty-one patients (37 mandible and 14 maxilla) underwent CE or NCR. Of patients, 37% (n = 19) received CE. Of patients who underwent mandibular reconstruction, there were significantly lower rates of hardware exposure (14.3% versus 47.8%, P = 0.018), failure (7.1% versus 43.5%, P = 0.048), major complications (28.6% versus 78.2%, P = 0.008), and revisions (11.1% versus 50.0%, P = 0.002) in the CE cohort compared with the NCR cohort. The rates of hardware failure, exposure, major complications, and revisions did not significantly differ in maxillary reconstructions, however, CE successfully reconstructed significantly larger defects (179.5 versus 74.6 cm3, P = 0.020) than NCRs. Deviating from NCR, the authors propose an algorithm considering anatomical location, extent of resection, and patient age for soft tissue selection. This algorithm yielded improved mandibular reconstructive outcomes and no increase in complications rate in maxillary reconstruction despite larger resection defects. Furthermore, the authors' initial findings demonstrate that CE is a safe option for pediatric maxillary and mandibular reconstruction that may, in addition, facilitate improved form and function.

Failure Rates Based on Alveolar Cleft Volume: An Analysis of the Critical-Sized Defect for Alveolar Bone Grafting.

BACKGROUND: Alveolar bone grafting (ABG) using iliac crest bone graft (ICBG) is best practice for children with complete cleft lip and palate. With the advent of recombinant human bone morphogenetic protein (rhBMP-2) and demineralized bone matrix (DBM), excellent results can still be achieved while avoiding donor-site morbidity. This study aims to determine the critical-sized defects by analyzing graft failure rates for ICBG and rhBMP-2/DBM to guide surgeons performing ABG. METHODS: A retrospective review was conducted evaluating patients who underwent ABG from 2016-2022. Patients with preoperative and postoperative cone beam computed tomography (CBCT) imaging were included. Volumetric defect sizes were calculated using preoperative imaging. Graft success criteria were based on both clinical and radiographic outcomes. Logistic regressions analyzed graft failure rates to identify an optimal cutoff, which defined the critical-sized defect. RESULTS: Ninety-three patients were included. Bone graft cohorts included ICBG (n=30) and rhBMP-2/DBM (n=63). The critical-sized defects were calculated to be 810 mm 3 and 885 mm 3 for ICBG and rhBMP-2/DBM, respectively. There were significantly higher graft failure rates beyond the critical size compared to below for both ICBG (71.4% vs. 0.0%; p<0.001) and rhBMP-2/DBM (65.0% vs. 14.0%; p<0.001). CONCLUSION: This study identified critical-sized defects based on alveolar cleft volume for ICBG or rhBMP-2/DBM with higher graft failure rates beyond the predicted thresholds. Distinct ranges in cleft volume were identified where patients might benefit from each select graft option.

A Single Institution 19 Year Comparison of Furlow and Straight Line Palatoplasty Techniques in Bilateral Cleft Lip and Palate.

OBJECTIVE: This study aims to compare patients' speech correcting surgery and fistula rates between the Furlow and Straight Line (SLR) palatoplasty techniques when combined with greater palatine flaps for complete bilateral cleft lip and palate (BCLP) repair. DESIGN: This was a single-center IRB approved retrospective cohort study. SETTING: This study took place at an urban tertiary academic center. PATIENTS, PARTICIPANTS: All patients with BCLP anomalies that underwent repair between January 2003 and August 2022 were included. Patients with index operations at an outside institution or incomplete medical charting were excluded. INTERVENTIONS: A total of 1552 patients underwent palatoplasty during the study period. Of these, 192 (12.4%) met inclusion criteria with a diagnosis of BCLP. MAIN OUTCOME MEASURES: Primary outcomes of this study included rate of fistula and incidence of speech correcting surgery. Secondary outcomes included rate of surgical fistula repair. RESULTS: One hundred patients underwent SLR (52.1%) and 92 Furlow repair (47.9%). There was no significant difference in fistula rates between the SLR and Furlow repair cohorts (20.7% vs. 15.0%; p = 0.403). However, SLR was associated with lower rates of speech correcting surgery when compared to the Furlow repair (12.5% vs. 29.6%; p = 0.011). CONCLUSIONS: This study compares the effect of Furlow and SLR on speech outcomes and fistula rates in patients with BCLP. Our findings suggest that SLR resulted in an almost three times lower rate of velopharyngeal dysfunction requiring surgical intervention in patients with BCLP, while fistula rates remained similar.

A 10-Year Nationwide Analysis of Risk Factors of Readmission and the Implications of Same-Day Discharge Following Velopharyngeal Insufficiency Correcting Surgery.

OBJECTIVE: To investigate risk factors for readmission and the implications of same-day discharge for surgical management of velopharyngeal insufficiency (VPI). DESIGN: Retrospective cohort. SETTING: Multi-institutional/national. PATIENTS AND PARTICIPANTS: Patients who underwent VPI-correcting surgery (n = 4479) were identified in the National Surgical Quality Improvement Program Pediatric database from 2012-2021. MAIN OUTCOMES MEASURE(S): 30-day unplanned readmission. RESULTS: A total of 3878 (86.6%) patients were admitted inpatient following surgical intervention, while 601 (13.4%) were discharged on the same day. Thirty-day readmission rate was 1.7% across all patients. Based on multivariate logistic regression, patient factors identified as significant predictors of 30-day readmission included ASA class 4 (OR 11.22 [95% CI 1.01-124.91]; p = 0.049), steroid use (OR 7.30 [95% CI 2.22-23.97]; p = 0.001), and gastrointestinal disease (OR 2.48 [95% CI 1.22-5.00]; p = 0.012). Upon interaction analysis, patients with cardiac or neuromuscular disease who were discharged on the same day of surgery were associated with a higher readmission rate than those admitted to the hospital (cardiac disease RR 6.72 [95% CI 1.41-32.06]; p = 0.017) and (neuromuscular disease RR 12.39 [95% CI 1.64-93.59]; p = 0.015). CONCLUSIONS: Approximately 90% of VPI-correcting procedures are completed inpatient nationwide. Cardiac and/or neuromuscular disease significantly increased the patients' readmission risk when discharged on the same day of surgery. The inpatient setting should remain the best practice as adequate resources are available to mitigate life-threatening complications.

Comparing Outcomes of Traditional Lip Repair Versus Early Cleft Lip Repair on a National Scale.

BACKGROUND: Cleft lip (CL) is one of the most common congenital anomalies and has traditionally been repaired surgically when the patient is between 3 and 6 months of age. However, recent single-institutional studies have demonstrated the efficacy and safety of early CL repairs (ECLRs) during the neonatal period. This study seeks to evaluate the outcomes of ECLR (repair <1 month) versus traditional lip repair (TLR) by comparing outcomes on a national scale. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Pediatric Date File was used to query patients who underwent CL repairs between 2012 and 2022. The main outcome measures were anesthesia times and perioperative complications. The main predictive variable was operative group (ECLR vs TLR). Patients were considered to be in the ECLR cohort if they were younger than 30 days after birth at the time of cleft repair. Student t test and χ2 analyses were used to evaluate categorical and continuous differences, respectively. Multiple logistic regression was performed to model the association of ECLR versus TLR with death within 30 days, overall complication rates, dehiscence rates, readmission within 30 days, and reoperation rates while controlling for various covariates. RESULTS: Multiple linear regression determined that the ECLR cohort had significantly shorter operative times when controlling for operative complications, sex, cardiac risk factors, and American Society of Anesthesiologists class (coefficient = -34.4; confidence interval, -47.8 to -20.9; P < 0.001). Similarly, multiple linear regression demonstrated ECLR patients to have significantly shorter time of exposure to anesthesia (coefficient = -35.0; 95% confidence interval, -50.3 to -19.7; P < 0.001). Multiple logistic regression demonstrated that ECLR was not significantly associated with an increased likelihood of any postoperative complication when controlling for sex, cardiac risk factors, and American Society of Anesthesiologists class (P = 0.26). CONCLUSIONS: The findings of this study provide nationwide evidence that ECLR does not lead to an increased risk of adverse outcomes or complications. In addition, ECLR patients have shorter surgeries and shorter exposure to anesthesia compared with TLR. The results provide further evidence that ECLR can be done safely where earlier intervention may result in better feeding/weight gain and subsequently improve cleft care. However, longer-term studies are warranted to further elucidate the effects of this protocol.

Immediate Nasal Reconstruction in Management of Infected Nasal Alloplast and Allografts: A Case Series.

BACKGROUND: The use of alloplastic and allogenic nasal implants is widely popular in rhinoplasty. However, the use of these materials is accompanied by a risk of infection and extrusion. Traditionally, management of these complications is performed in a dual-staged fashion. First, the implant is removed and infection is controlled, then a delayed reconstruction is performed. However, scarring and soft tissue contracture make a delayed reconstruction challenging, and optimal aesthetic outcomes are difficult to achieve. This study was designed to evaluate the outcomes of immediate nasal reconstruction following removal of an infected nasal implant. METHODS: A retrospective chart review was performed of all patients who had infected nasal implants and underwent simultaneous removal and immediate nasal reconstruction with autologous cartilages (n = 8). Data collected included patient age, race, pre-operative presentation, intraoperative surgical maneuvers, and post-operative outcomes and complications. Post-operative results were used to measure success of the single-staged method. RESULTS: Follow-up ranged from 12 to 156 months with mean 84.4 months of the eight patients who were evaluated in the study, none had any major post-operative complications that required revision or reconstruction. All of the patients had marked improvement in nasal form and function. Six of the eight (75%) patients reported excellent aesthetic outcomes; two (25%) requested revisional surgeries for aesthetic concerns. CONCLUSION: Low complication rates and excellent aesthetic outcomes are possible in immediate autologous reconstruction following removal of an infected nasal implant. This is an alternative approach that obviates the inherent problems of a traditional delayed reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ..

Lessons Learned from a Single Institution's Eight Years of Experience with Early Cleft Lip Repair.

Background and Objectives: The traditional approach in managing wide cleft lip deformities involves presurgical nasoalveolar molding (NAM) therapy followed by surgical cleft lip repair between three and six months of age. This institution has implemented an early cleft lip repair (ECLR) protocol where infants undergo primary cleft lip repair between two and five weeks of age without NAM. This study aims to present this institution's ECLR repair protocol over the past eight years from 188 consecutive patients with unilateral or bilateral CL/P deformity. Materials and Methods: Retrospective review was conducted at Children's Hospital Los Angeles evaluating patients who underwent ECLR before three months of age and were classified as American Society of Anesthesiologists (ASA) class I or II from 2015-2022. Anthropometric analysis was performed, and pre- and postoperative photographs were evaluated to assess nasal and lip symmetry. Results: The average age at cleft lip repair after correcting for gestational age was 1.0 ± 0.5 months. Mean operative and anesthetic times were 120.3 ± 33.0 min and 189.4 ± 35.4, respectively. Only 2.1% (4/188) of patients had postoperative complications. Lip revision rates were 11.4% (20/175) and 15.4% (2/13) for unilateral and bilateral repairs, respectively, most of which were minor in severity (16/22, 72.7%). Postoperative anthropometric measurements demonstrated significant improvements in nasal and lip symmetry (p < 0.001). Conclusions: This analysis demonstrates the safety and efficacy of ECLR in correcting all unilateral cleft lip and nasal deformities of patients who were ASA classes I or II. At this institution, ECLR has minimized the need for NAM, which is now reserved for patients with bilateral cleft lip, late presentation, or comorbidities that preclude them from early repair. ECLR serves as a valuable option for patients with a wide range of cleft severity while reducing the burden of care.

The Top 100 Cited Articles in the Microsurgical Treatment for Lymphedema.

BACKGROUND: Evidence-based medicine uses the current best evidence for decisions about patient care. Lymphedema is a chronic debilitating medical condition caused by a dysfunctional lymphatic system. This study analyzes the most cited articles, including the levels of evidence, for the surgical treatment of lymphedema. METHODS: The Web of Science Sci-Expanded Index was utilized to search for surgical treatment of lymphedema. Articles were examined by three independent reviewers and the top 100 articles were determined. The corresponding author, citation count, publication year, topic, study design, level of evidence, journal, country, and institution were analyzed. RESULTS: Since 1970, the top 100 articles have been cited 7,300 times. The average citation count was 68 and standard deviation was 55. The majority was case series (71), followed by retrospective cohort (8), prospective cohort (7), retrospective case-control (5), and randomized controlled trials (2). Based on the "Level of Evidence Pyramid," 71 articles were level IV, 13 articles were level III, and 9 articles were level II. On the Grading of Recommendations Assessment, Development, and Evaluation Scale, there were 71 articles with "very low," 20 articles with "low," and 2 articles with "moderate" quality of evidence. CONCLUSION: The top 100 cited articles were mostly case series and lacked high levels of evidence. Most studies are retrospective case series with short-term outcomes. However, low level evidence for new surgical procedures is to be expected. Current trends suggest the treatment and understanding of lymphedema will continue to improve.

Pediatric Orthognathic Surgery: A NSQIP-P Comparison of Peri-Operative Factors and Outcome Differences Between Cleft and Noncleft Patients.

OBJECTIVE: The present study aimed to investigate the risk factors, complication profiles, and clinical outcomes of cleft and noncleft patients undergoing single jaw (mandibular or LeFort 1) and bimaxillary (BSSO + LeFort 1). DESIGN: Retrospective Cross-sectional Study Setting: National Surgical Quality Improvement Program database 2018-2019. PATIENTS: Pediatric patients. INTERVENTIONS: Outcomes for mandibular, LeFort 1, and bimaxillary osteotomy were retrospectively evaluated for cleft and noncleft patients. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to determine the odds of complications and length of stay for cleft and noncleft patients undergoing single jaw and double jaw surgery. RESULTS: 669 pediatric patient underwent orthognathic surgery in the study period; the majority received LF1 only (n = 385; 58.3%), followed by mandible only (n = 179; 27.1%), and bimaxillary (n = 105; 15.9%%). Cleft differences were present in 56% of LFI patients, 32% of mandibular patients, and 22% of bimaxillary patients. After multivariate adjustment, ASA class III was associated with nearly 400% increased odds of any complication including readmission and reoperation (OR = 5.99; CI [[1.54-23.32]], p < 0.01, and 65% increased LOS (ß-coefficient = 1.65, CI [1.37-1.99], p < 0.01). Presence of cleft was not significantly associated with odds of any complication (p = 0.69) nor increased LOS (p = 0.46) in this population. CONCLUSION: Complications remained low between surgery types among cleft and noncleft patients. The most significant risk factor in pediatric orthognathic surgery was not the presence of cleft but rather increased ASA class. Though common in patients seeking orthognathic surgery, cleft differences did not cause additional risk after adjustment for other variables.

Computer-aided Surgical Planning and Osteosynthesis Plates for Bimaxillary Orthognathic Surgery: A Study of 14 Consecutive Patients.

Computer-aided surgical planning has become popular for planning orthognathic surgery (OS) as it saves surgeons' time and effort. A recent advancement has been the utilization of patient-specific cutting guides and osteosynthesis. The purpose of this study is to report the postoperative bimaxillary position utilizing custom plates for both jaws versus custom plates used in the maxilla only in 23 consecutive patients. Methods: All patients who underwent bimaxillary OS in 2017-2018 with preoperative computed tomography (CT) scan, postoperative day 1 CT scan, and at least 6 months follow-up were included in the study. Group 1 utilized maxillary preprinted plates (maxilla only). Group 2 utilized bimaxillary preprinted plates (maxillomandibular). Eight cephalometric landmarks to evaluate the movements were chosen. The ranges of the angle between the sella/nasion plane and the nasion/A plane (SNA), the angle between the sella/nasion plane and the nasion/B plane (SNB), and the angle created by the A point' nasion' and B point' which measures the relative position of maxilla to mandible, were analyzed to assess the angular change. Mean-squared displacement and the SD of the distances were used to assess movement in space. Results: Twenty-three patients (nine in group 1 and 14 in group 2) met the inclusion criteria. Results showed interarch relationships using custom plates for both jaws with ANB 0.4 compared to ANB 1.4 for maxillary custom plates only. Mandibular landmarks showed greater variation, and the t test study revealed the right mandibular first molar landmark showing the greatest variation (P = 0.03). Conclusions: Custom osteosynthesis plates for OS show good accuracy for the maxilla and higher variation in the mandible. Further studies will determine the margin of error that cannot be corrected with postoperative orthodontics.

Premaxillary Setback in Bilateral Cleft Lip and Palate Repair.

OBJECTIVE: The aim of this study is to evaluate surgical outcomes and maxillofacial growth in patients undergoing primary lip repair with or without premaxillary setback. DESIGN: Retrospective review. SETTING: Children's Hospital of Los Angeles, California. PATIENTS AND PARTICIPANTS: Patients with bilateral cleft lip ± palate (BCLP) who underwent lip repair with or without premaxillary setback from January 1975 to September 2021. INTERVENTIONS: No intervention was performed. MAIN OUTCOME MEASURE(S): Patient demographics, comorbidities, and syndromic status were obtained. Indications for premaxillary setback, incidence of midface hypoplasia, orthodontic and/or orthognathic treatments, follow-up, complications, and revisions were recorded and analyzed. Comparisons among long-term outcomes, particularly the development of midface hypoplasia were made between groups. RESULTS: Thirty-one patients who underwent BCLP repair with premaxillary setback (BCLP + PS) and 31 matched control patients who underwent BCLP repair without premaxillary setback (BCLP - PS) were included. Among the 2 groups, multiple logistic regression demonstrated that when controlling for comorbidities, syndromic status, timing of lip repair, and timing of palate repair, premaxillary setback was neither significantly associated with the development of midface hypoplasia (P = .076) nor the timing of midface hypoplasia development (P = .940) in those that ultimately acquired this facial dysmorphology. CONCLUSIONS: While a high incidence of midface hypoplasia was seen in both BCLP ± PS and BCLP - PS, our findings demonstrate no difference in midface hypoplasia irrespective of premaxillary setback in the setting of BCLP. Future prospective studies investigating the downstream ramifications of our suggested selection criteria for premaxillary setback are warranted.

Influence of Monobloc/Le Fort III Surgery on the Developing Posterior Maxillary Dentition and Its Resultant Effect on Orthognathic Surgery.

BACKGROUND: Timing of frontofacial surgery for the syndromic craniosynostosis as it relates to various surgical risks has not been adequately studied. The purpose of this study was to investigate posterior dental complications of midface advancement in patients with syndromic craniosynostosis undergoing surgery at different ages and the effects on subsequent orthognathic surgery. METHODS: A retrospective chart review of patients with syndromic craniosynostosis treated with midface advancement (monobloc or Le Fort III) from 1999 to 2018 was carried out. Patient demographics, records, and imaging studies were reviewed. A subanalysis of those patients who were also treated with orthognathic surgery from 2014 to 2018 with imaging studies available for analysis was also performed. RESULTS: Thirty-seven patients met the inclusion criteria. Sixty-four percent of the patients had radiographic evidence of maxillary molar dental abnormality. Older age at the time of surgery was significantly associated with a lower odds of sustaining dental injury (OR, 0.55; p = 0.034). The odds of damaging second or third maxillary molars was significantly higher with a younger age at the time of surgery (p = 0.021 and p = 0.034). The odds of sustaining dental injury increased moving posteriorly, showing the risk of abnormal pattern of M3 greater than M2 greater than M1. Advanced age at the time of surgery was significantly associated with decreased odds of dental injury (OR, 0.55; p = 0.034). CONCLUSIONS: Damage to the developing permanent maxillary molars may affect orthodontic management, mastication, and potentially maxillary development. Delaying frontofacial surgery until development of the permanent maxillary dentition should be considered if other indications do not mandate earlier intervention.

Gingiva-Derived Mesenchymal Stem Cell-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration.

IMPACT STATEMENT: Peripheral nerve injuries (PNIs) are common and debilitating, usually resulting in considerable long-term disability and remaining an unmet clinical need. Even though the combination of mesenchymal stem cells (MSCs) and the state-of-the-art tissue engineering technologies has shown promising therapeutic potentials for PNI, there is still not a single licensed stem cell-based product for peripheral nerve repair/regeneration. Emerging evidence indicates that MSC-derived extracellular vesicles (EVs) are comparably effective as MSCs in the therapy of a variety of disease models or pathological conditions. This report shows that local delivery of gingiva-derived mesenchymal stem cell (GMSC)-derived EVs could obviously promote axonal regeneration and functional recovery of injured mice sciatic nerves. Importantly, the findings suggest that GMSC-derived EVs promoted the expression of Schwann cell dedifferentiation/repair phenotype-related genes in vitro, particularly c-JUN, a key transcription factor that drives the activation of repair phenotype of Schwann cells during PNI and regeneration.

Applications of Mesenchymal Stem Cells in Oral and Craniofacial Regeneration.

The field of tissue engineering and regenerative medicine has been rapidly expanded through multidisciplinary integration of research and clinical practice in response to unmet clinical needs for reconstruction of dental, oral, and craniofacial structures. The significance of the various types of stem cells, specifically mesenchymal stem cells derived from the orofacial tissues, ranging from dental pulp stem cells to periodontal ligament stem cells to mucosa/gingiva has been thoroughly investigated and their applications in tissue regeneration are outlined in this article.