Mesenchymal Stem Cell Secretome as Novel Regenerative Approach in Oral Ulcerative Lesions Management: A Review

Satutya Wicaksono¹, Jola Rahmahani², Diah Savitri Ernawati³, Fedik Abdul Rantam³,

Theresia Indah Budhy^4,5, Alexander Patera Nugraha^6,7, Reyhan Mahendra Nur⁶,

Nuraini Indrastie, Nastiti Faradilla Ramadhani^7,8,

Tengku Natasha Eleenabinti Tengku Ahmad Noor^9,10

¹Graduate Student of Immunology, Postgraduate School, Universitas Airlangga, Surabaya, Indonesia.

²Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Universitas Airlangga,

Surabaya, Indonesia.

³Department of Oral Medicine, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

⁴Immunology Study Program, Postgraduate School, Universitas Airlangga, Surabaya, Indonesia.

⁵Department of Oral and Maxillofacial Pathology, Universitas Airlangga, Surabaya, Indonesia.

⁶Department of Orthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

⁷Graduate Student of Dental Health Science, Faculty of Dental Medicine,

Universitas Airlangga, Surabaya, Indonesia.

⁸Department of Dentomaxillofacial Radiology, Faculty of Dental Medicine,

Universitas Airlangga, Surabaya, Indonesia.

⁹Membership of Faculty of Dental Surgery, Royal Collage of Surgeon, Edinburgh University, United Kingdom.

¹⁰Malaysian Armed Forces Dental Officer, 609 Armed Forces Dental Clinic, Kem Semenggo,

Kuching, Sarawak, Malaysia.

*Corresponding Author E-mail: alexander.patera.nugraha@fkg.unair.ac.id

ABSTRACT:

Introduction: Paracrine effects exerted by trophic factors secreted by the mesenchymal stem cell (MSCs) are now considered the primary mechanism of regenerative abilities. These trophic factors, comprised of various growth factors, cytokines, microvesicles, and exosomes, are collectively called MSC secretome (MSC-S). MCS-S is thought to be a promising means of regenerative therapy. Architectural and functional oral epithelial loss in oral ulcerative lesions (OUL) may become the proper target for MSC-S regenerative therapy. Several pre-clinical studies have been conducted to assess the potential of MSC-S to facilitate OUL healing. Aim: Thus, this article attempts to review current relevant studies regarding the applicability of MSC-S for OUL management. Method: This review was based on a literature search on several sites (PubMed, Scopus, ScienceDirect) with specific keywords "MSC secretome", “regenerative therapy”, "oral ulcer", and "regenerative therapy", "wound healing". Results: A total of 37 articles were included in this review. Conclusion: Based on the results, we concluded that MSC-S could improve oral mucosa regeneration and repair. Thus MSC-S would be a promising therapy for OUL therapy.

KEYWORDS: Dentistry, Medicine, Conditioned medium, Mesenchymal stem cells, Regenerative medicine.

INTRODUCTION: 

Oral ulcerative lesions (OUL) are the most common lesions in the oral mucosa. These conditions may arise from various local or systemic factors, such as trauma, immune-mediated disease, infection, and neoplasm.¹ The presence of pain in OUL disrupts the stomatognathic system's homeostasis, which leads to the decline of oral-health related quality of life (OH-QoL).² Proper management of OUL is mandatory to limit their debilitating consequences, especially in the case of complex OUL cases (i.e. chronic ulceration in diabetes mellitus patients, geriatric population, and vascular diseases). Frequently, these types of cases do not resolve by conventional therapy.³ Novel treatments are needed to overcome this problem. Architectural epithelial defects reaching the lamina propria are the characteristic of the ulcerative lesion. Inducing total restoration of lost tissue is pivotal in OUL management.⁴ Regenerative therapy is a promising novel paradigm to resolve this issue due to its therapeutical aim to replace defective tissue. One of the most prominent means of regenerative therapy is mesenchymal stem cell (MSCs) therapy.⁵

MSCs are non-hematopoietic multipotent stem cells that can be isolated from various adult and perinatal tissues. The regenerative ability of MSCs is played by the ability of the MSCs to differentiate into mature cells and replace damaged host cells.⁶ However, several studies reported that direct transplantation of MSCs showed low cell survival and engraftment rates which compromised the treatment success. Unwanted side effects such as tumorigenicity, cellular rejection, embolism formation, unwanted differentiation, and infection transmission have also been reported.^5-7 MSCs' ability to induce regeneration is also mediated by their ability to secrete a plethora of trophic factors responsible for tissue regeneration and repair that work in a paracrine manner. This collection of secreted trophic factors is called MSCs secretome (MSC-S). MSC-S can induce the nearby cells' regenerative cellular and molecular activities by paracrine mechanisms.^8-9 This article attempt to review current relevant knowledge about the applicability of MSC-S in the regenerative management of OUL.

METHOD:

This research conducted an independent literature search utilizing various databases, including PubMed, NCBI, Scopus, ScienceDirect, and ResearchGate, using keywords like "MSC secretome," "regenerative therapy," "oral ulcer," and "regenerative therapy," "wound healing." Data was collected using the following criteria: 1) observational in vitro/in vivo studies and clinical trials; 2) English texts; 3) publications from 2007 to 2022; and 4) open-access and full-texts available. Similar research were looked at to support the primary study.

RESULTS AND DISCUSSION:

Mesenchymal Stromal Cell Secretome (MSC-S):

The first step of obtaining MSC-S is isolating MSCs from various adult tissues, such as the bone marrow, adipose tissue, dental pulp or others. The donor tissue was then processed into cell culture. Based on Sagaradze et al. (2019), MSC culture is carried out by seeding MSC at a density of 3x103 cells/cm2 on uncoated culture plastic and cultivated to 70–80 percent confluence in 100mm culture dishes at fourth–fifth passages. MSC was then washed three times in 10 mL HBSS without Ca2+ and Mg2+ and supplemented with MSC NutriStem XF Basal Medium (Biological Industries, Beit-Haemek, Israel) or DMEM with low glucose (DMEM-LG, HyClone). Cells were grown in conventional conditions (5% CO₂; 37°C). The conditioned medium samples were then collected, centrifuged for 10 minutes at 4°C at 3000rpm to remove cell debris, and frozen in aliquots at 70°C.¹⁰

The characterisation of MSC-S is pivotal to determining its therapeutic benefit. The bioactive molecules of MSC-S proteins can be detected and measured using antigen-antibody binding assays, such as enzyme-linked immunosorbent assay (ELISA), Luminex bead-based array, microarray, western blotting, and cytokine antibody array.¹¹ Soluble molecules from MSC-S have been reported to contain various growth factors, cytokines, chemokines, adipokines, antioxidant molecules, pro-angiogenic factors, and anti-apoptotic factors.¹² Based on Vizoso et al. (2017), MSC-S contain several immunomodulatory factors, including TGF-B, hepatic growth factor (HGF), indoleamine 2,3 dioxygenase-1 (IDO-1), IL-10, IL-1 receptor antagonist (IL-1Ra) and prostaglandin E2 (PGE2).¹³ Dabrowsky et al. (2017) stated that stem cell metabolites contain various growth factors, such as hepatocyte growth factor (HGF), insulin growth factor-1 (IGF-1), and VEGF, which play an essential role in the angiogenesis process in the wound healing process. In addition, AMSCM contains extracellular vesicles, also known as exosomes. Exosomes are small vesicles (40–200nm) covered by a lipid bilayer membrane.¹¹ Exosomes have an essential role in intercellular communication caused by their contents, such as nucleic acids, messenger RNA (mRNA), microRNA (miRNA), transfer RNA (tRNA), and other non-coding RNAs.^14,15

MSC-S also contains various molecules that act as resolution-associated molecular patterns (RAMPs). RAMPs (e.g. HSP10, aB-crystallin (aBC), HSP27 and binding immunoglobulin Protein (BiP)) are molecules released by cells in the event of cellular stress and serve to offset the inflammatory and immune response-induced effects of the pathogen-associated molecular pattern (PAMPs) or damage-associated molecular pattern (DAMPs).^16,17 RAMP is a multifunctional, constitutively produced protein whose immunoregulatory activity is dependent on the fast disintegration of the intracellular milieu, either actively (in response to cell stress) or passively (in response to necrotic cell death). RAMPs aid in the restoration of immunological homeostasis by giving regulatory and anti-inflammatory signals to wounded tissue and by inactivating immune cells.¹⁸ RAMPs also play a role in inducing the polarisation of M1 to M2 macrophages. This process is called the resolution mechanism, where RAMP binds to TLR-2/4 on the macrophage cell surface and induces transcription factors and enzymatic processes for M2 macrophages.^19,20 Polarization of M1 macrophage to M2 macrophage is pivotal in wound healing due to M2 macrophage's capability to release various growth factors and anti-inflammatory cytokines. These factors will limit the inflammatory phase, thus allowing the following phase of wound healing. Several studies showed that impairment of this mechanism is the underlying pathogenic mechanism of non-healing wounds.^2,20

Oral Ulcerative Lesions (OUL):

OUL is defined as structural and functional loss of the oral epithelial layer, which exposes its underlying connective tissue. This pathology is the manifestation of various diseases with different etiologies, such as trauma (mechanical, chemical, thermal), infection, immune-mediated diseases, drug reactions, and neoplasm.¹ Furthermore, OUL can be caused by a variety of processes and etiopathogenic mechanisms, including ruptured bullae/vesicles, external forces, host-related variables, or epithelial proliferation and differentiation changes.^1,4 The duration of OUL can be self-limited, which usually takes 10-14 days to heal.^21,22

However, several local (i.e. ulcer size) or systemic conditions may mediate the impairment of healing processes. Large OUL, such as in major recurrent aphthous stomatitis (Maj RAS) and traumatic ulcer with granulomatous eosinophilia (TUGSE), may be challenging to treat. This type of OUL requires a more complex management technique.^1,4,24 Moreover, it takes a longer time to heal, thus prolonging the pain sensation and the morbidity of the patients. OUL accompanied by degenerative systemic conditions, such as diabetes mellitus and physiologic ageing, may lead to the development of a chronic ulcer.²⁵ Several physiological alterations in the wound healing process include growth factor production, angiogenic response, macrophage, collagen formation, granulation tissue amount, fibroblast migration and proliferation, and the balance between ECM component and remodelling by the Matrix Metalloproteinase (MMPs), have been identified in diabetic patients.²⁵ Physiologic ageing may also manifest similar pathological conditions seen in diabetic patients.Conventional therapy using topical pharmacological approaches, such as benzydamine hydrochloride 0,15%, Aloe vera extract gel, and steroids topical drugs, have been proven inadequate in such conditions.^3,25 A novel therapeutic approach that can address the current therapeutical shortfall is needed.

Wound Healing Process:

Wound healing is a complex process that aims to restore tissue structure and function of damaged tissue.²⁶ This process involves synergistic activity between multiple cellular and molecular components in the four main phases of wound healing, namely hemostasis, inflammation, proliferation, and remodelling. Hemostasis is the first step in the wound healing process. At this stage, the formation of blood clots that function to close the wound, which occurs immediately after exposure to injury and resolves within a few hours.^27-29 At the same time, platelets will trigger vasoconstriction in the blood vessels exposed to injury, which serves to stop bleeding, filling the tissue with blood clots consisting of cytokines and growth factors. Blood clots contain the molecules of fibrin, fibronectin, vitronectin, and thrombospondin molecules, which will form a temporary matrix as a medium for migration of leukocytes, keratinocytes, fibroblasts, and endothelial cells and as a reservoir of growth factors. Platelets secrete chemotactic factors that will affect leukocyte infiltration. Platelets and leukocytes will activate the inflammatory process by releasing cytokines and growth factors.²⁸

The inflammatory phase is when cellular and molecular mechanisms occur to eliminate various debris, necrotic tissue, and pathogenic microorganisms in the wound area, which play a role in creating an ideal microenvironment for wound healing. The goal of the proliferative stage is to reduce the area of the lesional tissue with contraction and fibroplasia, establishing an active epithelial barrier to activate keratinocytes. This proliferative phase lasts 48 hours after exposure to injury and can occur up to day 14. The proliferative phase is responsible for lesion closure, including angiogenesis, fibroplasia and reepithelialisation.²⁹ Several mechanisms are essential for forming granulation tissue in the proliferative phase, namely reepithelialisation, angiogenesis and fibroplasia.³⁰ The final stages of wound healing are contraction and remodelling. Fibroblasts increase the expression of smooth muscle actin in response to mechanical tension and cytokines like TGF-B, converting into myofibroblasts, which compress wounds by contacting integrin receptors on extracellular matrix components like fibronectin and collagen. When fibroblasts boost the expression of type I collagen and matrix metalloproteinases break down old collagen, typically type III collagen, remodeling occurs (MMP).³¹

The oral mucosa is a tissue composed of cells such as keratinocytes, endothelial cells, fibroblasts, and others and belongs to the labile (continuously dividing) tissue group. This type of tissue can repair itself through the proliferative activity of local stem cells or the proliferation of adult cells.⁴ The nature of this tissue can be an engineering target to create a therapy that can improve wound healing activity. Wound healing in the oral mucosa is influenced mainly by growth factors. Growth factors are soluble factors that can be seen by macrophages, epithelial cells, and stem cells that can work in paracrine manners to stimulate cell regenerative activities.^30,32 Study by Nugraha et al. using a scratch test assay, reported that the migration of human gingival somatic cells is increased 12 hours after the application of medicinal signalling cell metabolites oral-based (MSCM oral-based/gingival mesenchymal stem cell secretome). This study also stated the potential role of CXC motif chemokine ligand 12 and stromal-derived factor-1 in the secretome that induced cell migration.³³ Similar results are also shown in other studies using different cells, such as human immortalised keratinocytes (HaCaTs).^34,35, human dermal fibroblast (HDFs)^36,37, human endothelial cells (HECs)¹⁰and human dermal microvascular endothelial cells (HDMECs)³⁵ as shown in Table 1. Research by Walter et al. also stated that human bone marrow MSC-S could accelerate cellular migration of HaCaTs by using scratch wound assay. This study also analyses the bioactive protein in their MSC-S using ELISA multi arrays and found that it contains TGF-B1, IL-6, IL-8, MCP-1, RANTES, collagen type I, fibronectin, SPARC, and IGFBP-7. These growth factors are postulated as the mediator of the regenerative activities. 

Table 1: Collected in vitro studies based on our independent literature search.

No	Sample study	Source of Secretome	Bioactive molecules	Types of Study and method	Result	Reference
1.	Gingival mesenchymal cells (GMSCs)	Rabbit gingival mesenchymal stem cell	Not identified	In vitro (MTT assay and Scratch test)	No reduction of cells (biocompatible, viable), Increased cellular migration after 12 hrs of application	Nugraha et al., 2019.^33
2.	Human immortalised keratinocytes (HaCaTs) & L929 fibroblast	Human bone marrow mesenchymal stem cell	TGF-b1, IL-6, IL-8, MCP-1, RANTES, collagen type I, fibronectin, SPARC, IGFBP-7	In vitro (Scratch wound assay, MTS assay)	Accelerated cellular migration	Walter et al., 2010.^34
3.	Human endothelial cells (HECs)	Subcutaneous adipose mesenchymal stem cell	VEGF, HGF, Angpt-1, PEDF.	In vitro (Scratch wound assay)	Accelerated cellular migration	Sagaradze et al., 2019.^10
4.	Human dermal fibroblasts (HDFs)	Human bone marrow mesenchymal stem cell	Not identified	In vitro (Scratch assay, MTT assay, gene expression analysis)	Higher cell viability/proliferation, accelerated cell migration, upregulated bFGF and EGF expression	Saheli et al., 2020.^36
5.	Human dermal microvascular endothelial cells (HMECs), HaCaTs, Human foreskin fibroblasts (HFFs)	Human multipotent adult progenitor cell	Not identified	In vitro (MTT assay, scratch test assay, angiogenesis assay)	Increased cellular proliferation, accelerated cellular migration, induced capillary tube formation (HMEC)	Ahangar et al., 2020.^35
6.	Dermal fibroblast, keratinocytes, vascular endothelial cell	Human bone marrow mesenchymal stem cell	HGF, EGF, bFGF	In vitro (scratch wound assay, MTT assay, and MMP-2, MMP-9 and Ki-67 expression)	Accelerated cellular migration, Higher cell viability and proliferation, increased MMP-2/9 expression, increased Ki-67 expression	Park et al., 2020.^37

CONCLUSION:

MSC-S comprises a plethora of trophic factors, including growth factors, cytokines, chemokines, and other molecules. The identified molecules of the MSC-S are considered relevant in facilitating the regeneration and repair of the cells in the oral mucosa. The application of MSC-S has been proven effective in inducing regenerative activities of keratinocytes, fibroblast, and endothelial cells in limited in vitro studies. Moreover, the immunomodulatory effect of MSC-S is regarded as a crucial feature of MSC-S in enhancing wound healing. These theories implicate the applicability of MSC-S as the novel therapeutical approach in OUL management. However, the preclinical studies' promising potency of MSC-S, particularly in vivo studies, is still very limited. Future studies regarding its application in the management of OUL are highly required.

REFERENCES:

1. Farah CS, Balasubramaniam R, McCullough MJ, editors. Contemporary oral medicine: A comprehensive approach to clinical practice. Springer International Publishing; 2019.

2. Gottrup F, Apelqvist J, Bjarnsholt T, Cooper R, Moore Z, Peters EJ, Probst S. Antimicrobials and Non-Healing Wounds. Evidence, controversies and suggestions—key messages. J Wound Care. 2014; 23(10): 477-482. https://doi.org/10.12968/jowc.2014.23.10.477.

3. Karavana SY, Sezer B, Güneri P, Veral A, Boyacioğlu H, Ertan G, Epstein JB. Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: an in vivo animal study. Inter J OralMax Sur. 2011; 40(9): 973-978. https://doi.org/10.1016/j.ijom.2011.02.034.

4. Kumar A, Abbas AK, Jon C. Aster, Robbins SL,Cotran RS. Robbins and Cotran pathologic basis of disease 10th ed. USA: Philadelphia Elseviers Saunders., 2005. pp. 71-110.

5. Rantam FA, Nugraha AP, Ferdiansyah, Purwati, Bumi C, Susilowati H, Hendrianto E, Utomo DN, Suroto H, Sumartono C, Seiawati R, Prakoeswa CR, Indramaya DM. A Potential Differentiation of Adipose and Hair Follicle-derived Mesenchymal Stem Cells to Generate Neurons Induced with EGF, FGF, PDGF and Forskolin. Research J. Pharm. and Tech. 2020; 13(1): 275-281

6. Nugraha AP, Rantam FA, Narmada IB, Ernawati DS, Ihsan IS. Gingival-Derived Mesenchymal Stem Cell from Rabbit (Oryctolaguscuniculus): Isolation, Culture, and Characterization. Eur J Dent. 2021; 15(2): 332-339.

7. Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Inter J Mol Sci. 2020; 21(19): 7038. https://doi.org/10.3390/ijms21197038.

8. Dabrowski FA, Burdzinska A, Kulesza A, Sladowska A, Zolocinska A, Gala K, Paczek L, Wielgos M. Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. J ObsGyn Res. 2017; 43(11): 1758-68. https://doi.org/10.1111/jog.13432.

9. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, Marbán E. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010; 106(5): 971-80. https://doi.org/10.1161/CIRCRESAHA.109.210682.

10. Sagaradze G, Grigorieva O, Nimiritsky P, Basalova N, Kalinina N, Akopyan Z, Efimenko A. Conditioned medium from human mesenchymal stromal cells: towards the clinical translation. Inter JMol Sci. 2019;20(7):1656. https://doi.org/10.3390/ijms20071656.

11. Bunnell BA. Adipose Tissue-Derived Mesenchymal Stem Cells. Cells. 2021;10(12): 3433. https://doi.org/10.3390/cells10123433.

12. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Inter JMol Sci. 2017; 18(9): 1852. https://doi.org/10.3390/ijms18091852.

13. Hsu PJ, Liu KJ, Chao YY, Sytwu HK, Yen BL. Assessment of the immunomodulatory properties of human mesenchymal stem cells (MSCs). JoVE (Journal of Visualized Experiments). 2015; (106): e53265. doi: 10.3791/53265

14. Soleymaninejadian E, Pramanik K, Samadian E. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Am JRepro Immunol. 2012; 67(1): 1-8. https://doi.org/10.1111/j.1600-0897.2011.01069.x

15. Anjo SI, Lourenço AS, Melo MN, Santa C, Manadas B. Unraveling mesenchymal stem cells’ dynamic secretome through nontargeted proteomics profiling. InMesenchymal Stem Cells 2016 (pp. 521-549). Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3584-0_32.

16. Shields AM, Panayi GS, Corrigall VM. Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis?.ClinExperImmunol. 2011; 165(3): 292-300. https://doi.org/10.1111/j.1365-2249.2011.04433.x.

17. Wenzel TJ, Kwong E, Bajwa E, Klegeris A. Resolution-associated molecular patterns (RAMPs) as endogenous regulators of glia functions in neuroinflammatory disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2020; 19(7): 483-94. https://doi.org/10.2174/1871527319666200702143719.

18. Lee WJ, Tateya S, Cheng AM, Rizzo-DeLeon N, Wang NF, Handa P, Wilson CL, Clowes AW, Sweet IR, Bomsztyk K, Schwartz MW. M2 macrophage polarization mediates anti-inflammatory effects of endothelial nitric oxide signaling. Diabetes. 2015; 64(8): 2836-46.  https://doi.org/10.2337/db14-1668.

19. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nature Immunol. 2011; 12(11): 1035-44. https://doi.org/10.1038/ni.2109.

20. Li M, Hou Q, Zhong L, Zhao Y, Fu X. Macrophage related chronic inflammation in non-healing wounds. FrontImmunol. 2021; 12: 2289. https://doi.org/10.3389/fimmu.2021.681710.

21. Mortazavi H, Safi Y, Baharvand M, Rahmani S. Diagnostic features of common oral ulcerative lesions: an updated decision tree. Inter J Dent. 2016; 2016. https://doi.org/10.1155/2016/7278925

22. Hanum F, Ernawati DS, Jusri M. Effectiveness of Probolinggo blue grape (Vitis vinifera) extract on fibroblasts proliferation in traumatic ulcer of Rattusnovergicus albino. Oral Med Dent J. 2013; 4(2): 103-12.

23. Larasati AR, Soesilawati P, Arundina I. Effect of Stichopushermanii extract to increase re-epithelization in healing process of traumatic ulcer in wistar rat’s oral mucous. Or Bio Jour. 2013; 5(2): 41-46.

24. Ernawati DS, Puspa A. Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in Apismellifera Lawangpropolis extract gel-treated traumatic ulcers in diabetic rats. Vet World. 2018; 11(3): 304. https://dx.doi.org/10.14202%2Fvetworld.2018.304-309

25. Ganesha R, Hernawan I, Hendarti HT, Radithia D, Hadi P, Ayuningtyas NF, Ernawati DS. Expression of FGF-2 and fibronectin in citrus limon fruit peel malang essential oil gel treated traumatic ulcer in diabetic wistar rats (Rattusnovergicus). Res J Pharm Tech. 2019; 12(7): 3350-4.

26. Nugraha AP, Rezkita F, Puspitaningrum MS, Luthfimaidah S, Narmada IB, Prahasanti C, Ernawati DS, Rantam FA. Gingival Mesenchymal Stem Cells and Chitosan Scaffold to Accelerate Alveolar Bone Remodelling in Periodontitis: A Narrative Review. Research J. Pharm. and Tech 2020; 13(5):2502-2506.

27. Suciadi SP, Nugraha AP, Ernawati DS, Ayuningtyas NF, Narmada IB, Prahasanti C, Dinaryanti A, Ihsan IS, Hendrianto E, Susilowati H, Rantam FA.The Efficacy of Human Dental Pulp Stem Cells in regenerating Submandibular Gland Defects in Diabetic Wistar Rats (Rattusnovergicus). Research J. Pharm. and Tech. 2019; 12(4): 1573-1579.

28. Saputra G, Nugraha AP, Budhy TI, Rosari FS, Lestari NAI, Sari AA, Gheasani A, Valensia T, Ramadhani NF, Noor TNEBTA, Nugraha AP, Nugraha AP, Sosiawan A. Nanohydroxyapatite-Chitosan Hydrogel Scaffold with Platelet Rich Fibrin and Buccal Fat Pad derived Stem Cell for Aggressive Periodontitis Treatment: A Narrative Review. Research Journal of Pharmacy and Technology. 2022; 15(12):5903-8.

29. Yahya C, Rohman MS, Hidayat M, Nugraha AP, Rantam F. Resveratrol maintain Human Iliac Bone Marrow Mesenchymal Stem Cells Stemness through Sirtuin 1 Mediated Regulation of SRY-Box Transcription Factor 2: an in vitro and in silico study. Research Journal of Pharmacy and Technology. 2022; 15(5):2313-9.

30. Rezkita F, Wibawa KGP, Nugraha AP. Curcumin loaded Chitosan Nanoparticle for Accelerating the Post Extraction Wound Healing in Diabetes Mellitus Patient: A Review. Research Journal of Pharmacy and Technology, 2020, 13(2): 1039–1042.

31. Inayati F, Narmada IB, Ardani IGAW, Nugraha AP, Rahmawati D. Post Oral Administration of Epigallocatechin Gallate from Camelia sinensis Extract Enhances Vascular Endothelial Growth Factor and Fibroblast Growth Factor Expression during Orthodontic Tooth Movement in Wistar Rats. JKIMSU 2020; 9(1): 58-65.

32. Nareswari RAAR, Narmada IB, Djaharu’ddin I, Rahmawati D, Putranti NAR, Nugraha AP. Effect of vitamin D administration on vascular endothelial growth factor expression and angiogenesis number in orthodontic tooth movement of pregnant Wistar rats. 2019; 33(3): 182-8.

33. Nugraha AP, Susilowati H, Hendrianto E, Karsari D, Ertanti N, Dinaryanti A, Ihsan IS, Narmada IB, Ernawati DS, Rantam FA. Medicinal signaling cells metabolite oral based as a potential biocompatible biomaterial accelerating oral ulcer healing (in vitro study). Eur J Dent. 2019; 13(3): 432-6. doi:10.1055/s-0039-1693923.

34. Walter MN, Wright KT, Fuller HR, MacNeil S, Johnson WE. Mesenchymal stem cell-conditioned medium accelerates skin wound healing: an in vitro study of fibroblast and keratinocyte scratch assays. Exper Cell Res. 2010; 316(7): 1271-81. https://doi.org/10.1016/j.yexcr.2010.02.026.

35. Ahangar P, Mills SJ, Smith LE, Strudwick XL, Ting AE, Vaes B, Cowin AJ. Human multipotent adult progenitor cell-conditioned medium improves wound healing through modulating inflammation and angiogenesis in mice. Stem Cell Res Ther. 2020; 11(1): 1-6. https://doi.org/10.1186/s13287-020-01819-z.

36. Saheli M, Bayat M, Ganji R, Hendudari F, Kheirjou R, Pakzad M, Najar B, Piryaei A. Human mesenchymal stem cells-conditioned medium improves diabetic wound healing mainly through modulating fibroblast behaviors. Arch Dermatol Res. 2020; 312(5): 325-36. https://doi.org/10.1007/s00403-019-02016-6.

37. Park SR, Kim JW, Jun HS, Roh JY, Lee HY, Hong IS. Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol Ther. 2018; 26(2): 606-17. https://doi.org/10.1016/j.ymthe.2017.09.023.

Received on 04.01.2023            Modified on 08.05.2023

Accepted on 12.07.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(3):1408-1413.

DOI: 10.52711/0974-360X.2024.00223