INTRODUCTION

Researchers have isolated stem cells from various sources, including bone marrow, adipose tissue, skin, and umbilical cord, and studied them for their potential to proliferate and differentiate into other cell types, thereby regenerating damaged tissues. Mesenchymal stem cells (MSCs) isolated from dental tissues have also been studied extensively recently due to their relatively easy availability. In 2000 [1], human dental pulp stem cells (hDPSCs) were first isolated. The stem cells from human exfoliated deciduous teeth (SHED) were isolated in the subsequent three years. Additionally, apical papilla and periodontal ligament stem cells were isolated and characterized [2]. Among them are SHED, derived from the pulp of deciduous teeth, tissues typically thrown away for clinical and biological reasons. As a result, SHED is a readily available and potentially effective cell source for tissue regeneration [3].

A cleft lip or palate is the most frequent congenital orofacial anomaly. Most patients will need alveolar bone grafting before beginning orthodontic treatment and again during treatment. Autogenous iliac bone grafting is the traditional method for closing bone defects at the alveolar cleft. However, the extensive surgical invasion creates severe hypoesthesia and pain at the donor site following surgery. Also reported are iliac bone fractures, infections, and hematomas [4]. Illiac bone harvesting is a major surgical procedure, even for young patients. This has led to the hopeful expectation of the eventual development of a less invasive technique. In this respect, the researchers have been working on improving a method for regenerating alveolar bone in patients with cleft lip and palate utilizing mesenchymal stem cells isolated from human bone marrow (hBMSCs). Dogs with an artificial alveolar cleft had their bone regrown after receiving hBMSC transplants, allowing for the orthodontic migration of teeth into the newly formed bone [5]. However, patients are still forced to undergo invasion since puncturing the iliac bone is required to harvest cells. Thus, it is necessary to investigate a different cell source for alveolar bone rebuilding [6].

In cell therapy, stem cells are injected into a patient, whereas stem cells are embedded in scaffolds in tissue engineering. Stem cells are helpful in a variety of contexts because they differ from differentiated cells in several key ways: (1) they can be harvested in more significant numbers; (2) they have a much higher proliferation capacity; (3) they can be cultured for a long time; (4) they can go through senescence and then differentiate into a variety of desired cell phenotypes; and (5) they can support the vascularization of scaffolds. Although current clinical stem cell techniques have the potential to cure a variety of illnesses, including organ failure, congenital structural defects, tissue loss, and organ transplantation or autologous tissue transfer [7], they also have significant limitations, such as immune rejection, organ shortages, allergic responses, and damage to healthy tissues after therapy [8]. Therefore, modern regenerative treatments have centered on stem cell utilization for tissue regeneration and organ replacement [9].

MATERIALS AND METHODS

A systematic literature review from 2010 to 2022 was performed using PubMed, Medline, and ScienceDirect databases. The keywords used were "cleft lip," "cleft palate," "and stem cells," and "alveolar reconstruction." In addition, the PRISMA flowchart was used to describe the selection process of searched articles.

Risk of Bias Assessment

The Cochrane risk of bias assessment method was used to assess the quality of the studies included.

RESULTS AND DISCUSSION

Alamoudi et al. (2017) [10] investigated that MSCs are an essential and potent tool in regenerative medicine. Tissue engineering uses a combination of stem cells, appropriate scaffolds, and tissue regeneration to give an appealing alternative for facilitating both hard and soft tissue recovery. AT-MSCs have gained popularity and luster in regenerative medicine owing to their angiogenic characteristics, the production of different cytokines with immunomodulatory properties, and wound-healing powers. Furthermore, a high cell count results in adipose tissue aspirate with decreased discomfort and donor site morbidity. MSCs extracted from bone aspirate at a volume of 10-40 ml of marrow, on the other hand, resulted in a low number of cells with significant discomfort and donor site morbidity.

In a study by Stepanova et al. (2017) [11], six individuals were chosen to evaluate the influence of MSCs on bone tissue development in young patients with diverse kinds of cleft palate, using autologous MSCs, 3–4 weeks before the scheduled operation. All six patients who were treated with MSCs had positive outcomes. The oral and nasal cavities were separated. The palatopharyngeal ring's function was maintained. The continuity of the upper jaw's alveolar process was repaired, and the mouth vestibule fissure was removed in young patients with unilateral and bilateral cleft palates. At the follow-up X-ray examination following the operation, new tissue was discovered in the location of the bone defect after the application of cellular technologies, comparable to the bone tissue based on density. The density varied from 65 to 110 HU on the Hounsfield scale. Stepanova et al. studied the short-term and long-term treatment outcomes of young children with congenital cleft palates. During the postoperative phase, there were no significant variations in the wound healing time.

Tanikawa et al. (2020) [12] analyzed the effect of deciduous dental pulp stem cells on maxillary alveolar reconstruction in patients with cleft lip and palate. Six patients, ranging in age from 8 to 12, were examined. For bone healing assessment, a computed tomography (CT) was performed. There were no surgical complications among DDPSC patients. In group one, 37.5% had substantial edema in the early postoperative period, whereas 87.5% experienced severe donor site aches by week two. Preoperative and postoperative exams demonstrated that all six patients who received bone tissue engineering alveolar bone grafts had a progressive alveolar bone union. No patients received DDPSC with 250 mg Bio-Oss Collagen and had partial or whole graft loss, wound disintegration, or ectopic bone growth.

Vatankhah et al. (2018) [13] obtained MSSCs cultivated from the human umbilical cord and intermittently injected them into ten newborns. Specimens are tested with an inverted microscope. After a year, this condition had much healed, the space between the two lips had closed, and the cleft palate of these newborns was improving with continued therapy. According to tests and research, extracting and cultivating mesenchymal stem cells from the cord takes less time. Furthermore, this procedure treats up to 90% of the cells generated in this manner with no adverse effects.

In the research by Toyota et al. (2021) [14], surgical procedures are undertaken from infancy through childhood to achieve bone bridge development and continuous structure between alveolar clefts. Human umbilical cords were taken after permission from five healthy full-term pregnant women aged 25 to 38 who had had a cesarean section at a maternity clinic. Micro-computed tomography and histological staining revealed that UC-MACS cells infused with HA Col generated more abundant bone growth between the experimental alveolar clefts than HA Col implantation alone. Cells immunopositive for osteopontin collected along the bone surface, with some becoming lodged in the bone. Immunopositive cells for human-specific mitochondria were aligned along the newly created bone surface and inside the new bone, suggesting that UC-MACS cells contributed to the development of bone bridges across alveolar clefts. These results suggest that human umbilical cords constitute a dependable bioresource and that UC-MACS cells may help with alveolar cleft restoration.

The investigation by Martín-del-Campo et al. (2019) [15] in which adipocyte stem cells (ADSCs) appeal to musculoskeletal tissue engineering applications such as cleft lip and palate. The secondary alveolar cleft osteoplasty performed during the mixed dentition stage is the standard treatment for repairing alveolar cleft defects. Martín-del-Campo et recommended using fatty tissue in maxillary alveolar cleft abnormalities because of its differentiation potential, ease of access to this source of cells, and capacity to grow in vitro quickly. In addition, the authors investigated the ability of ADSCs seeded in biphasic hydroxyapatite/calcium triphosphate (HA/TCP) bone substitutes to repair maxillofacial bone defects, concluding that they were a practical option for the reconstruction of human maxillofacial bone defects in the case of limited autograft availability or morbidity in the donor site.

The research was done by Bueno et al. (2011) [16], in which the primary goal of the work was to see whether there were any persistent changes in gene expression profiles between mesenchymal stem cells from NSCL/P patients and controls. Bueno et al. got the mRNA from DPSC was used to validate the microarray expression data by qRT-PCR for a more significant number of genes. In addition, 16 more healthy controls and 13 people with NSCL/P had cultures taken. The transcriptomes of six dental pulp stem cell (DPSC) cultures from NSCL/P patients and six controls were compared in this study. Most of the cell cultures (>90%) showed positive labeling for cell adhesion (CD29, CD90) and mesenchymal stem cell markers (SH2, SH3, SH4) but were negative for endothelial and hematopoietic cell markers. Furthermore, the microarray studies included two NSCL/P patients and three control cell cultures previously proven to differentiate into bone, muscle, cartilage, and fat following in vitro stimulation. As a result, the cell populations employed in this investigation had the characteristics of stem cells.

Arango et al. (2014) [17] determined in their research that using SCs and the optimal scaffold for cleft lip patients is little known. Research has focused chiefly on utilizing SCs and scaffolds for alveolar crest rebuilding to replace the more invasive iliac bone marrow transplant surgery. The child was five months old at the time of surgery and had the following test findings. The aim of utilizing SCs on these individuals is to reduce donor site movement and postoperative problems. To our knowledge, the use of SCs as a coadjutant in cleft lip surgery has not been documented in the scientific literature. The goal of the research was to describe a case of a cleft lip patient in whom Arango et al. employed SCs as a surgical coadjutant. The patient's lip usually healed, with minimal irritation around the surgery site lasting a few days and dissipating. There was no infection or excessive edema.

Schreurs et al. (2020) [18] analyzed in the study that fibrosis and scarring often impede cleft palate surgery's functional and cosmetic results. Schreurs et al. addressed emerging tissue engineering technologies for promoting muscle and skin regeneration while reducing scarring. Umbilical cord blood stem cells are a potential, safe, and noninvasive source of stem cells that can be coupled with anti-inflammatory and antifibrotic compounds in a scaffold. Preconditioning stem cells with cytoprotective chemicals before applying them to the wound region may boost stem cell survival and contribute to a regeneration milieu. This unique method is expected to promote muscle and skin regeneration after cleft repair, resulting in a superior functional and cosmetic outcome.