Tenofovir Alafenamide for Pregnant Chinese Women With Active Chronic Hepatitis B: A Multicenter Prospective Study.

BACKGROUND & AIMS: Data on long-term tenofovir alafenamide (TAF) therapy for pregnant women with active chronic hepatitis B (CHB) (immune clearance and reactivation phases, currently and previously diagnosed) and their infants are lacking. METHODS: Pregnant women with active CHB treated with TAF and tenofovir disoproxil fumarate (TDF) were enrolled in this multicenter prospective study, and infants received immunoprophylaxis. The primary outcomes were rates of adverse (safety) events in pregnant women and defects in infants and fetuses. The secondary outcomes were virologic responses in pregnant women, infants' safety, hepatitis B surface antigen (HBsAg) status, and growth conditions. RESULTS: One hundred three and 104 pregnant women were enrolled and 102 and 104 infants were born in the TAF and TDF groups, respectively. In the TAF group, the mean age, gestational age, alanine aminotransferase level, and viral loads at treatment initiation were 29.3 years, 1.3 weeks, 122.2 U/L, and 5.1 log10 IU/mL, respectively. TAF was well-tolerated, and the most common adverse event was nausea (29.1%) during a mean of 2 years of treatment. Notably, 1 (1.0%) TAF-treated pregnant woman underwent induced abortion due to noncausal fetal cleft lip and palate. No infants in either group had birth defects. In the TAF group, the hepatitis B e antigen seroconversion rate was 20.7% at postpartum month 6, infants had normal growth parameters, and no infants were positive for HBsAg at 7 months. The TDF group had comparable safety and effectiveness profiles. CONCLUSIONS: TAF administered throughout or beginning in early pregnancy is generally safe and effective for pregnant women with active CHB and their infants.

p63 in corneal and epidermal differentiation.

The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.

Protective effect of folic acid on vulnerability to oxidative stress in dental pulp stem cells of deciduous teeth from children with orofacial clefts.

Orofacial clefts (OFCs) are among the most common congenital craniofacial malformations, including cleft lip with or without cleft palate as the core symptoms. Developmental or functional defects in neural crest cells (NCCs) that contribute to craniofacial morphogenesis are involved in OFC development. Previous studies have suggested that oxidative stress in NCCs is involved in the development of OFCs, suggesting that the anti-oxidative activity of folic acid (FA) could have protective effects. However, studies of human-derived NCCs are limited, as these cells are predominantly active during the embryonic stage. In this study, the effects of oxidative stress and FA were evaluated in human OFCs. In particular, NCC-derived stem cells from human exfoliated deciduous teeth (SHEDs) were obtained from 3 children with non-syndromic cleft lip with cleft palate (CLPs) and from 3 healthy children (CTRLs). Mitochondrial reactive oxygen species (ROS) levels were significantly higher in CLPs than in CTRLs and were associated with lower mRNA expression levels of superoxide dismutase 1 (SOD1) and decreased cell mobility. In addition, significantly greater vulnerability to pyocyanin-induced ROS, mimicking exogenous ROS, was observed in CLPs than in CTRLs. These vulnerabilities to endogenous and exogenous ROS in CLPs were significantly improved by FA. These results indicated that the transcriptional dysregulation of SOD1 in NCCs is an oxidative stress-related pathological factor in OFCs, providing novel evidence for the benefits of perinatal anti-oxidant supplementation, including FA, for the management of these common deformities.

Efficacy of rhBMP-2 in Cleft Lip and Palate Defects: Systematic Review and Meta-analysis.

The aim of this study was to analyze the efficacy of using rhBMP-2 (recombinant human morphogenetic protein-2) in the treatment of patients with cleft lip and palate defects (CLPD). Seven databases were screened: PubMed (Medline), Lilacs, Ibecs, Web of Science, BBO, Scopus, and The Cochrane Library. Clinical trials that evaluated the use of bioactive treatment with rhBMP-2 in the treatment of patients with CLPD were included. Statistical analyses were performed by comparing the standardized mean difference of bone formation volume and bone filling percentage (p = 0.05). Ten studies compared the use of rhBMP-2 and iliac crest bone graft (ICBG). The global analysis for bone formation volume and bone filling percentage showed that bioactive materials were similar to ICBG with a standardized mean difference of respectively 0.07 (95% CI - 0.41 to 0.56) and 0.24 (95% CI - 0.32 to 0.80). The available literature suggested that use of rhBMP-2 presented similar bone formation results to those of ICBG in secondary alveolar bone grafting for patients with CLPD.

Prenatal Treatment with Dexamethasone in Suspected Congenital Adrenal Hyperplasia and Orofacial Cleft: a Case Report and Review of the Literature.

Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency is a genetic disorder that leads to hypocortisolism, hyperandrogenism and, in the most severe forms, also to hypoaldosteronism. Girls with classic CAH are born with virilized external genitalia. Prenatal dexamethasone (DXM) treatment can reduce virilization but may have side effects for mother and fetus. We present the first case of a girl who was born with CAH and an orofacial cleft. She was treated with prenatal DXM to prevent virilization. Oral clefts have to be considered as a potential side effect of prenatal DXM treatment.

Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

Mutations in transforming growth factor beta (TGFß) receptor type II (TGFBR2) cause Loeys-Dietz syndrome, characterized by craniofacial and cardiovascular abnormalities. Mice with a deletion of Tgfbr2 in cranial neural crest cells (Tgfbr2(fl/fl);Wnt1-Cre mice) develop cleft palate as the result of abnormal TGFß signaling activation. However, little is known about metabolic processes downstream of TGFß signaling during palatogenesis. Here, we show that Tgfbr2 mutant palatal mesenchymal cells spontaneously accumulate lipid droplets, resulting from reduced lipolysis activity. Tgfbr2 mutant palatal mesenchymal cells failed to respond to the cell proliferation stimulator sonic hedgehog, derived from the palatal epithelium. Treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor or telmisartan, a modulator of p38 MAPK activation and lipid metabolism, blocked abnormal TGFß-mediated p38 MAPK activation, restoring lipid metabolism and cell proliferation activity both in vitro and in vivo. Our results highlight the influence of alternative TGFß signaling on lipid metabolic activities, as well as how lipid metabolic defects can affect cell proliferation and adversely impact palatogenesis. This discovery has broader implications for the understanding of metabolic defects and potential prevention of congenital birth defects.

High-Potency Topical Steroids: An Effective Therapy for Chronic Scalp Inflammation in Rapp-Hodgkin Ectodermal Dysplasia.

Chronic erosive pustular dermatitis with a predilection for the scalp is a hallmark of ectodermal dysplasias (EDs) caused by mutations in TP63, including Rapp-Hodgkin and Hay-Wells EDs. It is among the most troublesome and symptomatic complications and is typically refractory to classic wound care approaches. We report two cases of Rapp-Hodgkin ED with refractory scalp erosions that markedly improved with the use of potent topical steroids. We also note marked similarities between this scalp inflammation and "erosive pustular dermatosis of the scalp," a condition more typically found in elderly individuals with severe scalp sun damage, and speculate about possible shared pathogenetic mechanisms.

APR-246/PRIMA-1(MET) rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations.

p53 and p63 share extensive sequence and structure homology. p53 is frequently mutated in cancer, whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246/PRIMA-1(MET) (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities.

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.

Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18(+) cells but failed to further differentiate into K14(+) cells (epidermis/limbus) or K3/K12(+) cells (corneal epithelium). APR-246 (PRIMA-1(MET)), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.

Controlled release of injectable liposomal in situ gel loaded with recombinant human bone morphogenetic protein-2 for the repair of alveolar bone clefts in rabbits.

BACKGROUND AND OBJECTIVE: The aim of the present study was to develop and examine a new non-invasive injectable graft for the repair of alveolar bone clefts using recombinant human bone morphogenetic protein-2 (rhBMP-2) encapsulated within injectable liposomal in situ gel (LIG). METHOD: Different liposomal formulations loaded with rhBMP-2 were prepared, and the effects of the preparation methods and lipid content on the efficiency of rhBMP-2 encapsulation within the liposomes were studied. For the preparation of in situ gel, deacetylated gellan gum (DGG) was used, and the in vitro gelation characteristics of the gel were evaluated. In vivo pharmacokinetics and histology were also assessed. Critical size alveolar defects were surgically created in the maxillae of 30 New Zealand rabbits and treated with different injectable formulae, including rhBMP-2 liposomes and in situ gel (rhBMP-2-LIG). RESULTS: The results indicated that the prepared rhBMP-2-LIG prolonged the release and residence time of BMP-2 within rabbits for more than 7 days. Histomorphometric assessment showed 67% trabecular bone filling of the defects treated using this novel formula. CONCLUSION: BMP-2-LIG is a promising delivery device for the repair of alveolar bone defects associated with cleft deformities.

Bilateral suprazygomatic maxillary nerve block for cleft palate repair in children: a prospective, randomized, double-blind study versus placebo.

BACKGROUND: The authors investigated the efficacy of bilateral suprazygomatic maxillary nerve block (SMB) for postoperative pain relief in infants undergoing cleft palate repair. METHODS: In this prospective, double-blind, single-site, randomized, and parallel-arm controlled trial, 60 children were assigned to undergo bilateral SMB with general anesthesia with either 0.15 ml/kg of 0.2% ropivacaine (Ropi group) or 0.15 ml/kg of isotonic saline (Saline group) on each side. The primary endpoint was total postoperative morphine consumption at 48 h. Pain scores and respiratory- and SMB-related complications were noted. RESULTS: The overall dose of intravenous morphine after 48 h (mean [95% CI]) was lower in the Ropi group compared with that in the Saline group (104.3 [68.9 to 139.6] vs. 205.2 [130.7 to 279.7] µg/kg; P = 0.033). Continuous morphine infusion was less frequent in the Ropi group compared with that in the Saline group (1 patient [3.6%] vs. 9 patients [31%]; P = 0.006). Three patients in the Saline group had an episode of oxygen desaturation requiring oxygen therapy. There were no technical failures or immediate complications of the SMB. Intraoperative hemodynamic parameters, doses of sufentanil, pain scores, and postoperative hydroxyzine requirements were not different between the two groups. CONCLUSION: Bilateral SMB is an easy regional anesthesia technique that reduces total morphine consumption at 48 h after cleft palate repair in children and the use of continuous infusion of morphine and may decrease postoperative respiratory complications.

Relationship Between Amoxicillin Use in Pregnancy and Congenital Anomalies: A Systematic Review.

OBJECTIVE: Amoxicillin is among the most used antibiotics in the treatment of a wide spectrum of bacterial infections. Although amoxicillin is categorized as group B in pregnancy, the findings of studies regarding its effects on the fetus are controversial. The aim of this systematic review was to review the reported effects of amoxicillin administration in pregnancy on congenital anomalies. METHODS: Published articles in PubMed, Scopus, SID, and Magiran databases, as well as Google Scholar were searched till May 2021 based on a search strategy. Case-control and cohort studies in Persian or English language were included. Four studies, including two case-control and two cohort studies, with an overall sample size of 260491 pregnant mothers, were included in the review. RESULTS: A review of case-control studies revealed an increased risk for cleft palate in one study. Cohort studies did not reveal a significant relationship between amoxicillin use and major congenital anomalies. CONCLUSION: The findings of this systematic review showed that although no major congenital anomaly was reported for the administration of amoxicillin consumption with or without clavulanic acid, there is a possibility that amoxicillin administration in pregnancy might be related to some anomalies, including cleft palate. Amoxicillin should be administered with caution during pregnancy till more evidence is provided regarding its safety.

Descriptive epidemiology of external structural birth defects in Enugu State, Nigeria.

Objectives: To determine the birth prevalence, trend, and characteristics of external structural birth defects occurrence in Enugu Metropolis, Nigeria. Design: Cross-sectional study involving review of delivery records. Setting: The study was conducted at three tertiary hospitals, one public and two missionary, in Enugu Metropolis. Participants: Mothers and their babies delivered between 1 January 2009 and 31 December 2016 in the study facilities. Main outcome measures: Birth prevalence of defects presented as frequency/10,000 births. Other descriptive variables are presented as frequencies and percentages. Results: There were 21530 births with 133 birth defects (birth prevalence: 61.8/10,000 births) and 1176 stillbirths (stillbirth rate: 54.6/1000 births). The frequencies and birth prevalence (/10,000 births) of recorded defects were: Limb deformities 60(27.9), Neural tube defects (NTDs): 36(16.7), Urogenital system defects: 12(5.6), Gastrointestinal system defects 10(4.6) and Orofacial clefts 4(1.9). Birth defects occurrence showed a rising trend from 2009 to 2016. The mean (SD) age of mothers whose babies had Birth defects was 29.1(4.7) years. Only 62(46.6%) of 133 antenatal clinic folders of these women were traceable for further review. Eighteen (29.0%) had febrile illness in early pregnancy, 9(14.5%) had Malaria, 17(27.4%) had <4 antenatal clinic attendance, 7(11.3%) did not take folic acid and 6(9.7%) took herbal medications during pregnancy. Conclusions: Birth defects occurrence showed a rising trend with limb deformities and NTDs having the highest prevalence. Record keeping was poor at the facilities. Birth defects preventive interventions like folic acid supplementation for women-of-childbearing age should be promoted in Enugu Metropolis. Funding: This work was supported by the non-communicable disease Minigrant from the Task Force for Global Health, Decatur, Georgia, USA (TPN-FE-NCD-C2-IFO-9).

Addition of dexmedetomidine to bupivacaine for greater palatine nerve block prolongs postoperative analgesia after cleft palate repair.

BACKGROUND AND OBJECTIVE: The effect of dexmedetomidine on the duration of sensory blockade has not been studied in humans. We evaluated the effect of adding dexmedetomidine to bupivacaine on the duration of postoperative analgesia in children who underwent repair of a cleft palate. METHODS: Thirty children who were scheduled for repair of a complete cleft palate using a combination of general anaesthesia and greater palatine nerve block were allocated randomly into one of two equal groups (n = 15). In both groups, the greater palatine nerve block was performed bilaterally using 0.5 ml of solution on each side. The B group received bupivacaine 0.25%, whereas the BD group received bupivacaine 0.25% with 1 microg kg(-1) dexmedetomidine. Heart rate, systolic blood pressure, pain score, the time to the first request for analgesia, and the degree of sedation were recorded. RESULTS: There was no difference in haemodynamic variables between the two groups. The pain score was significantly higher in the B group as compared with the BD group. The time to the first request for analgesia was significantly longer in children in the BD group (mean 22 h, range 20.6-23.7 h) as compared with those who received bupivacaine alone (14.2 h, 13-15 h). Sedation scores in the postoperative period did not differ between the study groups. CONCLUSION: Greater palatine nerve block with a combination of dexmedetomidine and bupivacaine increased the duration of analgesia after repair of a cleft palate by 50% with no clinically relevant side effects.

Is it possible to antagonize 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin- induced cleft palate by prenatal administration of folic acid? An experimental study.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause a high percentage of cleft palate in fetuses when administered during organogenesis in certain strains of mice including C57BL/6J. In this study, folic acid (FA) was tested for antiteratogenic effects on TCDD-induced cleft palate in fetal mice. The pregnant C57BL/6J mice were dosed with 24 microg TCDD/kg and/or 5 mg, 10 mg, 20 mg, 40 mg FA/kg body weight on gestation day (GD) 10. The control group mice received 50 mL sesame oil/kg body weight on GD10. The mice were sacrificed on GD12.5, GD13.5, GD14.5, GD15.5, and GD16.5. The harvested embryos were examined to detect the incidence of cleft palate and the developing palatal shelves on different phases were investigated morphologically and histologically among different groups. Total frequency of clefts was 55.56% in TCDD group and 17.50% (5 mg), 42.85% (10 mg), 42.10% (20 mg), 28.26% (40 mg) in TCDD + FA groups. FA (5 mg) reduced the incidence of the cleft palate from 55.56% to 17.50% (p = 0.005). There were no significant differences between the TCDD group and 10 mg, 20 mg, 40 mg TCDD + FA groups. Based on the these results, the present study suggests that FA can reduce the incidence of 2,3,7,8-TCDD-induced cleft palate in mice.

Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses.

BACKGROUND: There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. METHODS: Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool. RESULTS: Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. CONCLUSIONS: The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.

A LCMS-based untargeted lipidomics analysis of cleft palate in mouse.

BACKGROUND: Recent studies have shown that lipid metabolism was abnormal during the formation of cleft palate. However, the composition of these lipid species remains unclear. OBJECTIVE: Aims of this study were to identify the lipid species components and reveal the key lipid metabolic disorders in cleft palate formation. METHODS: The pregnant mice were divided into experimental group exposed to all-trans retinoic acid (RA-treated group) (n = 12) and control group (n = 12) at embryonic gestation day 10.5 (E0.5). The component of the palatal tissue metabolome was analyzed using a LCMS-based nontargeted lipidomics approach. Multivariate statistical analysis was then carried out to assess the differences between the RA-treated group and the control group. RESULTS: Twenty-nine lipid species were found to discriminate between RA-treated and control embryos. Among them, 28 lipid species increased and 1 lipid species decreased in the RA-treated group. Among these lipids, 13 were triglycerides, 9 were PEs, 3 were PCs, 2 were PSs, 2 were DGs. Further analysis of the number of carbons and unsaturated bond of triglycerides showed that TGs with high unsaturated bonds constituted a higher fraction in the RA-treated group. A higher amount of triglycerides containing 52, 54, 56, 58, 60 carbons, and 1 to 8 unsaturated bonds. Of note, under RA treatment, TG 50:1, 52:2, 56:6and 60:8 became the most prominent. CONCLUSION: Lipid metabolism is significantly different in the formation of cleft palate induced by RA, and the unsaturated triglycerides increased in the RA-treated group may play an important role in the formation of cleft palate.

Anterior cleft palate due to Cbfb deficiency and its rescue by folic acid.

Core binding factor ß (Cbfb) is a cofactor of the Runx family of transcription factors. Among these transcription factors, Runx1 is a prerequisite for anterior-specific palatal fusion. It was previously unclear, however, whether Cbfb served as a modulator or as an obligatory factor in the Runx signaling process that regulates palatogenesis. Here, we report that Cbfb is essential and indispensable in mouse anterior palatogenesis. Palatal fusion in Cbfb mutants is disrupted owing to failed disintegration of the fusing epithelium specifically at the anterior portion, as observed in Runx1 mutants. In these mutants, expression of TGFB3 is disrupted in the area of failed palatal fusion, in which phosphorylation of Stat3 is also affected. TGFB3 protein has been shown to rescue palatal fusion in vitro TGFB3 also activated Stat3 phosphorylation. Strikingly, the anterior cleft palate in Cbfb mutants is further rescued by pharmaceutical application of folic acid, which activates suppressed Stat3 phosphorylation and Tgfb3 expression in vitro With these findings, we provide the first evidence that Cbfb is a prerequisite for anterior palatogenesis and acts as an obligatory cofactor in the Runx1/Cbfb-Stat3-Tgfb3 signaling axis. Furthermore, the rescue of the mutant cleft palate using folic acid might highlight potential therapeutic targets aimed at Stat3 modification for the prevention and pharmaceutical intervention of cleft palate.

Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study.

A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients.