|Year : 2022 | Volume
| Issue : 5 | Page : 440-446
Combination of hDPSCs and oxysterol in hyaluronic acid scaffolds for dental implant therapy: A narrative review
Imam S Azhar, Veda S A Nariswari, Devy P Kusumawardhani, Mohammad A Maksum
Department of Prosthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia
|Date of Submission||28-Oct-2021|
|Date of Decision||05-Aug-2022|
|Date of Acceptance||09-Aug-2022|
|Date of Web Publication||31-Oct-2022|
Mr. Imam S Azhar
Jl. Major General Prof. Dr. Moestopo No. 47, Surabaya 60132, East Java
Source of Support: None, Conflict of Interest: None
Aim: The latest development of a dental therapy implant is the tissue engineering triad; one of them applies a combination of hDPSCs (human dental pulp stem cells) and oxysterol in media hyaluronic acid scaffolds. hDPSCs can produce osteoblasts in the bone repair process. Basic fibroblast growth factors and vascular endothelial growth factors are found in hDPSCs, and they can help speed up the vascularity and bone development. Oxysterol is an oxidized cholesterol product that can be found naturally in humans and animals. Oxysterol is an osteogenic factor that affects osteogenic differentiation by activating the liver X receptors and the Hh pathway signaling. Hyaluronic acid is a nonsulfate linear polysaccharide made up of disaccharide units of D-glucuronic acid and N-acetyl-d-glucosamine that occur naturally, which are linked by β-glycosidic bonds 1–3 and β-1–4. The hyaluronic acid scaffolds can be used for bone regeneration by increasing osteogenesis, osseointegration, and mineralization. The study aimed to describe the potential for combining hDPSCs and oxysterol in media hyaluronic acid scaffolds for dental implant therapy. Materials and Methods: Ideas and innovations were obtained based on the literature in journals and textbooks in the last 5 years (2016–2021) from PubMed, Google Scholar, and Web of Science databases. The review used the technique to find the similarity of the literature with the same keywords and then made conclusions. The theories that have been obtained are then summarized into a continuous series; thus, readers can more easily understand the ideas and innovations offered. Results: Pertaining to various literatures, there were 30 journals from PubMed, Google Scholar, and Web of Science databases. The case reports analyzed patients with inclusion criteria for dental implants and osseointegration. From the results of the review, it was found that the combination of these three ingredients has ingredients that can induce osseointegration. Conclusion: The combination of hDPSCs and oxysterol in media hyaluronic acid scaffolds can potentially provide bone regeneration in dental implant treatment.
Keywords: hDPSCs, Hyaluronic Acid, Implant, Oxysterol, Scaffold
|How to cite this article:|
Azhar IS, Nariswari VS, Kusumawardhani DP, Maksum MA. Combination of hDPSCs and oxysterol in hyaluronic acid scaffolds for dental implant therapy: A narrative review. J Int Oral Health 2022;14:440-6
|How to cite this URL:|
Azhar IS, Nariswari VS, Kusumawardhani DP, Maksum MA. Combination of hDPSCs and oxysterol in hyaluronic acid scaffolds for dental implant therapy: A narrative review. J Int Oral Health [serial online] 2022 [cited 2022 Dec 6];14:440-6. Available from: https://www.jioh.org/text.asp?2022/14/5/440/359964
| Introduction|| |
Based on Basic Health Research (RISKESDAS) in 2018, the most common dental problems experienced by Indonesians are tooth decay or cavities; 45.3% and 7.9% of the Indonesian population received a treatment of tooth extraction. Tooth extraction will result in an alveolar defect that physiologically will undergo a healing process. Resorption alveolar ridge after a tooth extraction is a condition that must happen and be a challenge for dentists to manage the former revocation well so do advanced treatments such as the manufacture of dental implants.
Dental implant therapy is an alternative replacement for tooth loss that has many advantages over other prostheses. The success of dental implant treatment must be supported by osseointegration and good bone condition. Thus, the placement is recommended immediately after extraction to minimize bone loss and shorten the prosthodontic treatment process. The latest development of dental implant therapy is the tissue engineering triad, which applies a combination of hDPSCs (human dental pulp stem cells) and oxysterol in media hyaluronic acid (HA) scaffold.
Combination of hDPSCs and oxysterol in media HA scaffold
hDPSCs can produce osteoblasts in the bone repair process. hDPSCs contain basic fibroblast growth factor and vascular endothelial growth factor, accelerating the vascularity and bone formation. Oxysterol is an oxidized cholesterol product that can be found naturally in humans and animals. Oxysterol is an osteogenic factor that affects osteogenic differentiation by activating the liver X receptors (LXRs) and the Hh pathway signaling. HA is a linear polysaccharide nonnaturally occurring sulfate-1-disaccharide units that are composed of d-glucuronic acid and N-acetyl-D-glucosamine linked by a glycosidic bond of β-1–3 and β-1–4. The HA scaffold can be used for bone regeneration by increasing osteogenesis, osseointegration, and mineralization. The aim of this review is to describe the potential of the combination of hDPSCs and oxysterol in media HA scaffolds for dental implant therapy.
This review article provides an idea and innovation related to bone regeneration in dental implants. Ideas and innovations were obtained based on the literature review in journals and textbooks in the last 5 years (2016–2021) because the contents of journals were updated and carried out using academic literature search engines such as PubMed, Google Scholar, and Web of Science databases. The literature review used includes research results and article reviews to describe the theory and link it into a framework that became an idea and innovation. This review article can be used as the basis for further research to prove the truth of the theory that has been written. The literature review of this article used the technique to find the similarity of the literature with the same keywords and then made conclusions. The theories that have been obtained are then summarized into a continuous series; thus, readers can more easily understand the ideas and innovations offered.
| Materials and Methods|| |
This article uses the literature review method to provide an idea and innovation as shown in [Figure 1] related to bone regeneration in dental implants. Ideas and innovations are obtained based on the literature reviews in journals and textbooks in the last 5 years (2016–2021) because the journal’s contents are updated and carried out using academic literature search engines such as PubMed, Google Scholar, and Web of Science databases. The literature review includes research results and article reviews to describe theories and link them into a frame of mind that becomes an idea and innovation.
This review article can be used as the basis for further research to prove the truth of the theory. The literature review of this article uses the technique of finding similarities from several libraries with the exact keywords and then making conclusions. The theories that have been obtained are then summarized into a continuous series so that it is easier for readers to understand the ideas and innovations offered.
The inclusion criteria were as follows:
- Articles on mesenchymal stem cells (MSCs), especially hDPSCs
- Articles on bone regeneration
- Articles about oxysterol in the human body
- Articles on the development of HA scaffold
- Articles on the relationship between hDPSCs, oxysterol, and HA scaffold
The exclusion criteria were as follows: any article that is not updated, has no new research date, and is not related to bone regeneration.
Population (P): patients with alveolar bone resorption who are planning dental implant treatment with bone regeneration
Intervention (I): bone regeneration using a combination of hDPSCs, oxysterol, and HA scaffold
Comparison (C): patients treated with other bone graft materials
Outcome (O): international publication and that described the effectiveness and success of the combination of hDPSCs and oxysterol in HA scaffold media for implant therapy
Study design (S): narrative literature review.
| Result|| |
Based on the keywords used, many articles were excluded depending on the initial screening of the title and abstract as they did not qualify the objective of the present review. Finally, 36 relevant articles were found valid and were selected for the review. The review bias and comparison reviews are shown in [Table 1].
| Discussion|| |
Osseointegration is one of the keys to success in dental implant treatment. Osseointegration is the process of integrating alloplastic materials into a bone. The osseointegration process is linked to the postextraction tissue-healing process, which comprises four stages: hemostasis, inflammation, proliferation, and remodeling. Osseointegration can occur through two mechanisms, namely contact osteogenesis and distance osteogenesis. Immediately and up to several months after implant placement, takes place a series of inflammatory responses followed by angiogenesis and osteogenesis in peri-implant area to achieve osseointegration. The process of osteogenesis is regulated by osteocytes, osteoblasts, and osteoclasts, where osteocytes through the Wnt signaling pathway are able to induce bone formation even in cases of dominating fibrous encapsulation and regulating the proliferation and differentiation of osteoblasts.
Human dental pulp stem cells
hDPSCs are MSCs that can differentiate into osteoblasts, chondrocytes, myocytes, adipocytes, and neurocytes after being isolated from the dental pulp tissue., hDPSCs can be obtained from the teeth extracted and isolated using procedures of cryopreservation to maintain the proliferation and differentiation capabilities.
The presence of hDPSCs is indicated by the expression of CD90, CD146, CD73, and CD105, which are known as MSC markers. The addition of hDPSCs in postextraction treatment showed a bone growth and an increase in the higher bridging defects and accelerated the maturation of lamellar bone. hDPSCs show the same matrix markers and proteins with components that play a role in the formation of hard tissue, such as alkaline phosphate, osteocalcin, and osteopontin, and hDPSCs can proliferate into osteoblasts and osteoclasts that play a role in bone regeneration. hDPSCs have a higher rate of proliferation, clonogenic potential, and progenitor cell counts when compared with bone marrow mesenchymal stem cells (BMMSCs), thus increasing the mineralization potential.
Oxysterol consists of 27 carbon atoms derived from the oxidation of cholesterol by the enzymatic and nonenzymatic mechanisms found in humans and animals. These compounds are formed as a secondary product of lipid peroxidation or by the action of specific monooxygenases. Oxysterol acts as an endogenous modulator in lipid metabolism and osteogenic factors.
Oxysterol has an effect for osteogenic differentiation, which is activated by LXRs and Hh signaling directly with the binding smoothened receptor (Smo). LXRs activated by oxysterol interact alternately with Hh signaling during osteogenesis. Hh signaling exerts osteoinductive effects and regulates osteoblast differentiation, which is important during the bone development., Oxysterol increases the gene and protein expression of LXRα and LXRβ, Hh protein levels, Smos, and transcription factor Gli-1 during osteogenic differentiation. There is a linear relationship between LXRs and Hh signaling, namely the transfection of siRNA, LXRα, and LXRβ decreases Smo and Gli-1 proteins. The inhibition of Hh signaling reduces the levels of LXRα and LXRβ proteins and suppresses osteogenic activity. Oxysterol promotes bone formation through a mechanism of bone morphogenetic proteins (BMP)-2 and Wnt signaling. According to Montgomery’s research, endochondral ossification of oxysterol has a better quality microstructure than rhBMP-2.
The scaffold is a three-dimensional polymer framework that functions as an extracellular matrix that plays a role in facilitating stem cells and growth factors to adhere, proliferate, and differentiate cells and vascularity. HA is a naturally occurring glycosaminoglycan that offers numerous benefits as a biomaterial building element. HA is not immunogenic, can be enzymatically degraded, and is relatively not attached to cells and proteins. Chemically, HA is classified as a glycosaminoglycan and consists of repeating disaccharide units of (1–4-β-D-glucose pyranose rancid), (1–3)-N-acetyl-2-amino-2-deoxy-β-D-glucopyranose acid. HA can be found in soft connective tissue and is found in organisms with the highest concentration. HA is a moisturizing polymer with hydroxyl groups that may attach water molecules securely to chains via hydrogen bonding.
HA plays a key role as a material scaffold. HA has been widely applied as scaffold because of high biocompatibility and can enhance the biological properties of synthesis and the osteogenic effect of the scaffold., The scaffold HA base can be used as a delivery vehicle for osteoinductive chemicals or other mediators. Because of its viscosity and the chelate reaction between hyaluronate and Ca2+, the HA disseminated throughout the scaffold aids in maintaining the scaffold’s structure in a hydrated environment. This reaction also benefits the formation of the nucleus.
Combination of hDPSCs and oxysterol in HA scaffolds
Based on in vitro studies of stromal bone–producing cells taken from the dental pulp tissue, it shows that cultured cells are able to differentiate progenitor cells for osteoblasts characterized by CD44+, Runt-related transcription factor 2 (RUNX-2), and osteoblast cells or osteoclasts expression. On 3D media made from the extracellular matrix that has added with hDPSCs, it showed bone-related protein expression, such as osteopontin (OPN), bone-sialoprotein (BSP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX-2), osterix (OSX), alkaline phospate (ALP), and collagen type 1 (Col 1) on the seventh postculture day as shown in [Figure 2].
|Figure 2: Immunohistological examination of hDPSCs shows bone-related genes expression: (A) osteopontin, (B) bone sialoprotein, (C) osteocalcin, and (D) Col 1|
Click here to view
Under hypoxic conditions in the culture center will stimulate hDPSCs to differentiate to form osteoblasts, which in turn will produce Col 1, which is a bone-forming protein. Col 1 served as the framework for the hDPSCs architecture, which then underwent calcification. During the process of differentiation, osteoblasts are upregulated by RUNX-2 and OSX. RUNX-2 promotes MSCs to differentiate into immature osteoblasts, which in turn will form new immature bones. OSX promotes the differentiation of MSCs into osteoblasts. In addition, OSX also promotes the maturation of preosteoblast cells and the differentiation of osteoblasts into bone cells. The increase in the OSX expression will be followed by an increase in other bone proteins such as Col 1, OCN, OPN, and BSP. The expression of OPN and OCN is crucial in determining the size, shape, and strength of the bones.
Oxysterol acts on hDPSCs by activating LXRs and Hh signaling by binding directly with Smo. Hh signaling is a signaling pathway associated with bone metabolism. This signaling begins by binding the Smo to the transmembrane protein patch, eliminating the inhibitory effect on other transmembrane proteins. Smo activates the intracellular signaling cascade, resulting in the activation of the transcription factor Gli that transcribes the target Hh, Gli-1, and Ptch genes. This regulation of transcription involves transcription factors Ci/Gli and complex interactions among complex accessory molecular membranes including fused, suppressor of fused, and Rab 23 to regulate the localization and stability of Gli. Oxysterol can induce osteogenic differentiation through other pathways, namely Wnt signaling, HES-1 and HEY-1 activation, and LXRs activation.
Oxysterols stimulate osteogenic differentiation of hDPSCs via BMP-2 induction. Oxysterol can regulate MSC differentiation. Oxysterol stimulates ALP activity, osteocalcin gene expression, Gli-1 expression, and mineralization, which are indicative of increased differentiation into osteoblast phenotypes in hDPSCs. Oxysterol increases mRNA expression from osteogenic genes such as BSP, BMP-2, Col1A2, and RUNX-2, which are the main osteogenic hDPSCs genes to osteochondrogenic progenitor cells. RUNX-2 stimulates the differentiation of hDPSCs to preosteoblasts, inhibits the differentiation of adipogenic cells, and inhibits the differentiation of chondrogenic cells so that it will maintain the supply of immature osteoblasts to increase the expression of osteopontin.,
HA activates the CD44 cellular surface. HA promotes MSC migration and Ap8c3 cell motility by activating CD44. In addition, surface receptors such as ICAM-1 and RHAMM receptors also have a role in regulating cell motility by HA. HA increases the initial inflammation and cell migration in the granulation tissue formation by facilitating the generation of inflammatory factors through the CD44-mediated pathway. Besides that, the CD44-mediated release of interleukin (IL)-1β, IL-8, and tumor necrosis factors (TNF)-α in fibroblasts under HA stimulation showed a positive reciprocal relationship.
HA injected into the injury site has been shown to accelerate the bone formation process because angiogenesis and mesenchymal cell differentiation occur more rapidly, resulting from degraded HA, maintained in very viscous molecular weight HA. Not only that, but suitably sulfonated glycosaminoglycans can help bone production by enhancing the development of osteoblast precursors and early osteoblasts., Research shows that signaling pathways involving the Smad protein family HA can increase the effect of BMP-2 significantly. Several studies have also shown a link between HA and suppressed extracellular signal-regulated kinase (ERK) phosphorylation, as well as the downregulation of BMP-2 antagonists such as noggin and follistatin in MG63 cells when stimulated with BMP-2.
HA has a good cell adhesion as a material scaffold. The integrin ligand fibronectin binds to the HA hydrogel to increase cellular adhesion to the scaffold. In scaffold HA, the integrin-specific fibronectin α5β1 fragment was intended to improve cellular adhesion and osteogenesis. HA acts as a matrix and carrier for rhBMP-2, increasing stem cell adhesion and proliferation.
The drawback of this study is that there are no studies combining these materials into one study. The articles we got were combining oxysterol with hDPSCs, hDPSCs with HA, and oxysterol with HA that has a relationship with the bone regeneration.
| Conclusion|| |
A combination of hDPSCs and oxysterol cultured in HA scaffolds has the potential to be an osteoinductive material to accelerate bone regeneration in dental implant treatment. In some existing literature, it has been shown that the combination of hDPSCs, oxysterol, and HA scaffolds can accelerate osteogenesis, osseointegration, and mineralization after dental implant placement. It is hoped that more studies will test the effectiveness of the use of hDPSCs, oxysterol, and HA scaffolds in accelerating the bone regeneration process; thus in the future, the use of hDPSCs, oxysterol, and HA scaffolds in dental implants can be implemented by health workers in daily practice.
Thank you to Universitas Airlangga and Faculty of Dental Medicine Universitas Airlangga who have supported and facilitated us in the preparation of this research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Imam Safari Azhar (initiator of ideas, author, and supervisor); Veda Sahasika Nariswari (initiator of ideas, discussion and conclusion author); Devy Putri Kusumawardhani (initiator of ideas, discussion and methods author); Mohammad Ali Maksum (initiator of ideas, introduction and discussion author).
Ethical policy and institutional review board statement
Patient declaration of consent
There are no patient’s consent needed.
Data availability statement
There are no data availability statement.
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[Figure 1], [Figure 2]