StemCell Therapy

Dental considerations in patients with liver disease 2015 Oral health in patients with liver cirrhosis. Eur J Gastroenterol Hepatol.2015 Jul;27(7):834-9. doi: 10.1097/MEG.0000000000000356. Grnkjr LL1,Vilstrup H. Abstract OBJECTIVE:The aim of this study was to describe the oral care habits and self-perceived oral health in patients with liver cirrhosis, as well as to evaluate the impact of oral health on well-being and the relation to nutritional status.

PARTICIPANTS AND METHODS:From October 2012 to May 2013, we carried out a prospective study on patients with liver cirrhosis. Questions on oral care habits and self-perceived oral health were answered, and the Oral Health Impact Profile questionnaire (OHIP-14) provided information on oral conditions. The findings were compared with The Danish Institute for Health Services Research report on the Danish population's dental status.

RESULTS:One hundred and seven patients participated. Their oral care habits and self-perceived oral health were poorer than the Danish population; the patients had fewer teeth (on average 19 vs. 26, P = 0.0001), attended the dentist less frequently (P = 0.001), more rarely brushed teeth (P = 0.001) and had problems with oral dryness (68 vs. 14%, P = 0.0001). The patients' mean OHIP score was 5.21 7.2, with the most commonly reported problems being related to taste and food intake. An association was observed between the OHIP score and the patients' nutritional risk score (P = 0.01).

CONCLUSION:Our results showed that cirrhosis patients cared less for oral health than the background population. Their resulting problems may be contributing factors to their nutritional risk and decreased well-being. Oral health problems may thus have adverse prognostic importance. Our results emphasize the need for measures to protect and improve the oral health of cirrhosis patients.

Aug 18 2014 Getting Dental Work with Hepatitis C and Cirrhosis Getting Dental Work withHepatitis Cand Cirrhosis is important. A good dentist ..

2014 Oral Conditions Might Cause Severe Outcomes in Patients With Viral Hepatitis Infection Nima Mahboobi 1, * ; and Seyed Moayed Alavian 2 1 Department of Oral and Maxillofacial Surgery, Tehran University of Medical Sciences, Tehran, IR Iran2 Middle East Liver Diseases Center (MELD Center), Tehran, IR Iran *Corresponding Author: Nima Mahboobi, Department of Oral and Maxillofacial Surgery, Tehran University of Medical Sciences, Tehran, IR Iran. Tel: +98-2188989161, E-mail: nima.mahboobi@gmail.com. Hepatitis Monthly. 14(12): e25866 , DOI: 10.5812/hepatmon.25866 Article Type: Editorial; Received: Dec 8, 2014; Revised: Dec 8, 2014; Accepted: Nov 13, 2014; epub: Dec 25, 2014; collection: Dec 2014 Keywords: Health; Infection; Hepatitis

The world health organization (WHO) has defined health as a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity. It is easy to express that complete health and wellness is merely impossible without oral health (1). After tooth decay in humans known as the most common infectious disease in the globe, periodontal diseases including gingivitis and periodontitis are among the most common oral diseases. The periodontal diseases are a group of chronic inflammatory diseases, involving the soft tissue and bone surrounding the teeth in the jaws, known as periodontium. Periodontal diseases are mainly caused by bacterial infection (2, 3). Although a review article published in 2008 showed a possible trend of a lower prevalence of periodontitis in the last 30 years, the authors of the paper recommended more research in the area to approve the evidence (4). To date, the association of various conditions and periodontal diseases has been acknowledged. A long list including overweight/obesity, hypertension, metabolic syndrome, diabetes mellitus, child preterm birth and low birth weight, rheumatoid arthritis and chronic obstructive pulmonary disease can be mentioned (5-7). Therefore, a hypothesis of association between either viral hepatitis infection or its progression and periodontal diseases seems quite close to mind. Previously, the association of several oral diseases including oral lichen planus, Sjogrens syndrome and pemphigus vulgaris with viral hepatitis infection was documented (8, 9).

A study performed by Nagao et al. (10) and published in the current issue is noteworthy from different aspects. Little has been dedicated to reveal the association between periodontal diseases and outcomes of viral hepatitis infection. According to their self-claimed statement of being the first study evaluating periodontal disease and patients with liver diseases resulting from viral hepatitis infection, the results were shocking. The conclusion states that periodontitis might be associated with progression of liver disease in patients with viral hepatitis, hence, control of oral diseases is essential for the prevention and management of liver fibrosis. This conclusion draws the attention of researchers to possible confounding factors never focused before. While performing different research projects on various links between hepatitis and dental setting in the past years, we reflected lack of data experience repeatedly. The conditions that made us urge researchers to develop research on oral fluid and viral hepatitis, viral hepatitis transmission risk during dental treatments and now the role of oral diseases on viral hepatitis have never been acknowledged. However, there are inconsistencies that must be noted before establishing new research. The methodology for studies on periodontal diseases remains elusive. A fundamental prerequisite for any epidemiological study is an accurate definition of the disease under investigation. Unfortunately in periodontal research, uniform criteria have not been established so far. Because of methodological problems the data used to assess treatment needs for periodontal diseases have been of questionable value and are not comparable (11). References and source

2012 Sept2012 Dental and Orofacial Health and Hepatitis CPrior to treating HCV it is important that any active dentaldisease be managed. Non-urgent dental treatment may need to be postponeduntil HCV treatment has ceased. Unfortunately, dental problems areknown to delay the onset of treatment for HCV. Dentaltreatment during anti-HCV therapy should be undertaken following consultation withmedical specialists. Blood tests and further investigations may beappropriate and in some cases in-patient care may be required. Immunocompromised patients, particularly those with neutropaenia, are at risk ofsepsis. If emergency dental treatment is necessary, consultation withmedical specialists is recommended. If the patient is anaemic, coagulopathic or thrombocytopaenic precautions may be needed. Pre-treatment optimisation and comprehensive post-operative care may berequired. Particular attention must be given to haemostasis....Download PDF Here..

Received:23/06/2010 Accepted: 16/01/2011

Abstract Introduction: Liver diseases are very common, and the main underlying causes are viralinfections, alcohol abuse and lipid and carbohydrate metabolic disorders. The liver has a broad range of functions inmaintaining homeos- tasis andhealth, and moreover metabolizes many drug substances. Objective: An update is provided on the oral manifestationsseen in patients with viral hepatitis, alcoholic and non-alcoholic liverdisease, cirrhosis and hepa-tocellular carcinoma, and on the dental management of such patients. Material and methods:

A Medline-PubMed search was conducted of the literature over the last 15 years using the keywords: hepatitis, alcoholic hepatitis, fatty liver, cirrhosis and hepatocellular carcinoma. A total of 28 articles were reviewed, comprising 20 lite- rature reviews,a clinical guide, three clinical trials and four case series.

Results: Oral clinical manifestations can be observed reflecting liver dysfunction, such as bleeding disorders, jaundice, foetorhepaticus, cheilitis, smooth tongue,xerostomia, bruxism and crusted perioral rash. In the case of infection causedby hepatitis C virus (HCV), the most frequent extrahepatic manifestations mostly affect the oral region in the form of lichen planus, xerostomia, Sjgrens syndrome and sialadenitis. The main complications of the patient with liverdisease are risk of contagion (for healthcarepersonnel and other patients), the risk of bleeding and the risk of toxicitydue to alteration of the metabolism of certain drugs.

Keywords: Hepatitis, alcoholic hepatitis, fatty liver, cirrosis, hepatocellular carcinoma. Cruz-Pamplona M,Margaix-Muoz M, Gracia Sarrin-Prez MG.Dentalconsiderations in patients with liver disease. J Clin Exp Dent. 2011;3(2):e127-34.

http://www.medicinaoral.com/odo/volumenes/v3i2/jcedv3i2p127.pdf Article Number: 50340 http://www.medicinaoral.com/odo/indice.htm Medicina Oral S. L. C.I.F. B 96689336 - eISSN: 1989-5488 eMail: jced@jced.es Introduction Liver diseases are very common and can beclassified as acute (characterized by rapid resolution andcomplete restitution of organ structure and function once theun-derlying cause has been eliminated) or chronic (charac- terized by persistent damage, with progressivelyimpai-red organ function secondary to the increase in livercell damage). Based on the extent and origin of thedamage, chronic liver disease ranges from steatosis or fatty liver to hepatocellular carcinoma, and includes hepatitis, fi-brosis and cirrhosis. Liver diseases can also beclassified as infectious (hepatitis A, B, C, D and E viruses, infec-tious mononucleosis, or secondary syphilis andtubercu- losis) or non-infectious (substance abuse such asalcohol and drugs, e.g., paracetamol, halothane, ketoconazole, methyldopa and methotrexate) (1).

The liver has a broad range of functions inmaintaining homeostasis and health: it synthesizes mostessential serum proteins (albumin, transporter proteins,blood coagulation factors V, VII, IX and X, prothrombin and fibrinogen (1), as well as many hormone and growth factors), produces bile and its transporters (bile acids, cholesterol, lecithin, phospholipids), intervenes in the regulation of nutrients (glucose, glycogen, lipids, cho- lesterol, amino acids), and metabolizes and conjugates lipophilic compounds (bilirubin, cations, drugs) to faci- litate their excretion in bile or urine.

Liverdysfunction alters the metabolism of carbohydrates, lipids,proteins, drugs, bilirubin and hormones (2). Accordingly, liver di- sease is characterized by a series of aspects that mustbe taken into account in the context of medical and dental care (3).

Since many drug substances are metabolized in the liver, it is essential for the clinician to compile a complete me- dical history, evaluating all body systems and themedi-cation used by the patient. The patient drug metabolizing capacity can be evaluated based on the analysis ofenzy-mes such as alanine aminotransferase (ALT) oraspartate aminotransferase (AST), and other liver functiontests (2, 4).

In situations of advanced liver disease, the vitamin K le-vels can be significantly lowered, thus giving rise to a re- duction in the production of blood coagulation factors. In addition, portal hypertension can scavenge platelets for- med in the spleen, thus giving rise to thrombocytopenia.This in turn can lead to an excessive bleeding tendency, which is one of the main adverse effects seen during the treatment of patients with impaired liver function (4). Dentists are particularly at risk of hepatitis B and Ccon- tagion, due to the transmission routes of these viruses, since these professionals are exposed to the bloodand oral secretions of potentially infected individuals (5) particularly in the case of accidents with sharp or cutting instruments.

VIRAL HEPATITIS Hepatitis of viral origin comprises aheterogeneous group of diseases caused by at least 6 different types of viruses: A, B, C, D, E and G (2).

Five million new cases of viral hepatitis are documented each year throughout the world, and a study published by Chandler-Gutirrez et al. (6) estimates the prevalence in Spain to be 3.7%. - Hepatitis A Hepatitis A is caused by the hepatitis A virus(HAV), an RNA picornavirus (3) endemic in many developing countries. Its estimated prevalence is 1.1% (6). This vi- rus is transmitted via the enteral (oral-fecal) route (5), as a result of the ingestion of contaminated water or food (mollusks), though intrafamilial contagion has also been described, as well as contagion in closed institutions and secondary to sexual intercourse.

The disease is typically mild and self-limiting, and is cha- racterized by the sudden onset of nonspecific symptoms. There is no carrier state. In children or young indivi- duals the disease tends to be asymptomatic, while adults typically present fever, fatigue, abdominal discomfort, diarrhea, nausea and/or jaundice. The patient is able to transmit the infection during the incubation period (2-6 weeks) and until the appearance of symptoms. The diagnosis is based on the signs and symptoms and on serological testing for anti-HAV IgM and IgG anti- bodies (3). Host response in the form of anti-HAV anti- bodies affords lifelong immunity, protecting the patient against future HAV infection.

The risk of nosocomial contagion among healthcare per- sonnel is quite low (3). Vaccines are available that offer immunity against HAV (Havrix, Vaqta) for people at risk (i.e., subjects traveling to endemic areas, drug abusers, patients with chronic liver disease and subjects with occupational risk factors) (2, 3). - Hepatitis B The hepatitis B virus (HBV) is an encapsulatedDNA virus that replicates within the hepatocyte (3). Hepatitis B is a worldwide health problem, with an estimated 400 million carriers of the virus (5). It has been calculated that 1.53% of all patients reporting to the dental clinic are HBV carriers (6). The transmission routes comprise sexual contact, intra- venous drug use and blood transfusions. In Asia perinatal transmission is common (3). An important consideration among dental professionals is the risk of percutaneous transmission through punctures or cuts with instruments infected from HBV-positive patients, or absorption through the mucosal surfaces (eyes, oral cavity). Trans- mission through saliva can occur as a result of absorp- tion from mucosal surfaces (2). Some studies have re- ported the presence of HBsAg in saliva and crevicular fluid of HBV-positive patients. Dental professionals, particularly those dedicated to oral surgery (7), have athree- to four-fold greater risk of HBV infection than the general population (3), though vaccines and barrier methods have contributed to lessen the risk (2, 7). Fo- llowing inoculation, the seroconversion risk is 30% (8). The incubation period lasts 2-6 months. Over 50% of all infections are subclinical and are not associated with jaundice. In this context, since the disease may prove asymptomatic, many people are unaware that they have suffered the infection in the past (5). Approximately 90% of all HBV-infected adults show complete healing, but 5-10% develop chronic hepatitis with complications in the form of cirrhosis and hepatocellular carcinoma (3, 4), resulting in 5000-6000 deaths a year due to liver fa- ilure (4).

The disease is diagnosed by quantifying the levels of HBV DNA, HBsAg and the antigen / antibody ratio. Vaccines have been developed that induce an effective immune response against the virus in most patients. If a non-immunized individual becomes exposed to HBV, immunoglobulincan be administered to afford protec-tion afterexposure. The current management protocols include HBV immunization as part of the pediatric vac-cinationprogram (3)

HepatitisC Hepatitis C virus (HCV) infection is the main cause of chronic liverdisease (9, 10) and of liver-related morbi-dity and mortality worldwide (9). It has been estimated that 8000 to10,000 deaths a year are attributable to HCV (4), and thelatter represents the main indication for li- ver transplantation in Europe and the United States (9).The estimatedglobal prevalence of the disease is 2.2%, representing approximately 130 million infected indivi-duals in the world (10). Great geographical variabilityis observed(9), possibly as a result of immunogenetic factors. Thelowest prevalences are found in the Uni- ted Kingdom and Scandinavia, and the highest in Egypt (11). HCV is an RNA virus mainly transmitted via the paren- teral routefrom infected blood (3, 9, 12). The sources of contagion include blood transfusion (although the risk has beenminimized since donor blood tests and controls are made (12)), percutaneous exposure through contami- natedinstruments, and occupational exposure to blood (9). The individuals at greatest risk are hemophiliacs,patients ondialysis and parenteral drug abusers.

Other transmission routes are sexual contact and perinatal and idiopathiccontagion (3). The prevalence of the infection among dentalprofessionals is similar to that found in the generalpopulation, though epidemiological studies suggest that dentists constitute a risk group for HCV in- fection (12). Following inoculation, the estimated seroconversion risk is 1.8% (8). The incubation period is long (up to three months), and 85% of all patients with HCV in- fection developchronic hepatitis. In those cases wheresymptoms areobserved, these tend to be mild, and most subjects remain relatively asymptomatic during the first two decades after infection with the virus (4). The morbidity associated to HCV infection is due not only to theconsequences of chronic liver disease but also to the extrahepatic manifestations (11). The best documented condition associated to hepatitis C is cryo- glubulinemia, a multisystemic disorder often characte- rized bypurpura, weakness and joint pain, and which may precede thedevelopment of B-cell non-Hodgkin lymphoma or membrane proliferative glomerulonephri- tis (12).

Otherrelated disorders are porphyria cutanea tarda, lichenplanus, sialadenitis, thyroid gland dys-function, diabetes mellitus and peripheral neuropathy (11). Over 74% of all HCV-infected patients ultimately developextrahepatic manifestations in the course of theinfection (10).

Different enzyme-linked immunosorbent assay (ELISA) and recombinant immunoblot assay (RIBA) techniques have been developed for the diagnosis of HCV infection, though thediagnostic gold standard remains detection of the viral genome using real time polymerase chain reaction (RT-PCR) technology (3, 12). No effective vaccine against HCV has yet been deve- loped, and spontaneous resolution is unusual (12). The existing therapy comprises combination treatment with interferon and ribavirin, which offers a sustained res- ponse rate of 30-40% (3). CHRONIC HEPATITIS Chronic hepatitis is a diffuse inflammatory disorder of the liver witha duration of over 6 months in which the underlying cause can be infectious (mainly hepatitis C virus and, to a lesser extent, hepatitis B and D viruses), pharmacological or immunological. The disease can develop in the absence of symptoms or withnonspecific manifestations such as fatigue, nausea or abdominal pain. The course is normally slow and pro- gressive, and symptoms typically do not manifest until years after the initial causal event (e.g., infection). Some patientsdevelop the disorder without significant liver damage, while others rapidly progress towards cirrhosis and possible hepatocarcinoma. Chronic hepatitis due to HCV infection is the principal cause of cirrhosis and he- patocellular carcinoma (3).

ALCOHOLIC LIVER DISEASE Alcoholic liver disease is one of the 10 most common causes of death in the industrialized world, and is res- ponsible for 3% of all fatalities. The epidemiological data indicate a threshold of 80 g of alcohol in males and 20 g infemales, consumed on a daily basis during 10-12 years, in order to cause the corresponding liver damage. Ten grams of pure ethanol are equivalent to a glass of wine or a beer,while a glass of whiskey doubles that amount. Factors such as chronic hepatitis C infection, obesity andgenetic factors can accelerate the develop

NON-ALCOHOLIC FATTY LIVER Non-alcoholic fatty liver is defined as the accumulation of fat (mainly triglycerides) in the liver, representing over 5% of the weight of the organ (5), in the absence of alcohol consumption in excess of 10 g a day (15).The observedliver damage ranges greatly from simple steatosis (accumulation of fat in the liver) to steatohepatitis(fat accumulation with added inflammation), advan- ced fibrosisand cirrhosis (16). This disorder is mainly associated to obesity, diabetes, hyperlipidemia and insulin resistance. There is a strong correlation between insulin resistance and excessive triglyceride accumulation within the liver cells (15). However, 16.4% of all patients with non-alcoholic fatty liver presentnone of these predisposing factors (17) The condition ispotentially reversible after eliminating or minimizingthe aforementioned causal factors (14). No clear treatments have been established to date for non-alcoholic fatty liver, though interventions such as bariatricsurgery (in the case of obese individuals) and oral antidiabetic drugs (glitazones) in patients with type 2 diabetes have shown encouraging results (15).

CIRRHOSIS Liver cirrhosis is very common in our setting, with well defined morphopathological characteristics that lead to destruction of the liver parenchyma. The disease is accompanied by a series of extrahepatic manifestations in other body organs and system (18). Liver cirrhosis is irreversible, and is characterized by the formation of fibrous scarring in the liver, with the formation of rege-neration nodules that increase resistance to blood flow through theorgan. The resulting deficient liver perfu- sion damages vital structures in the organ and adversely affects its physiological functions (19). The main cau-ses of liver cirrhosis are hepatitis B and C infection and alcohol abuse.Other potential causes are non-alcoholic steatohepatitis, genetic alterations and autoimmune di-sorders (3). The maincomplications of cirrhosis are portal hyperten- sion,hepatocellular carcinoma and organ function loss. Cirrhosis in itself constitutes a risk factor for the develo- pment of hepatocellular carcinoma (16). The treatment options comprise suppression of the cau- sal stimulus, antiviral therapy and liver transplantation in the endstages of cirrhotic disease (3).

HEPATOCELLULAR CARCINOMA Hepatocellularcarcinoma is the fifth most frequent can-cer worldwide (16). As such, it constitutes an important public health problem, and is one of the most common and life-threatening malignancies in the world with a survival rate after two years of only about 2% (3). It has been estimated that HBV and HCV are responsible for over 80% of all hepatocarcinomas. The other cau- ses are alcoholic and non-alcoholic steatohepatitis. Most patients with hepatocellular carcinoma have a history of cirrhosis, which in itself constitutes a preneoplastic con- dition (12, 16). Liver cirrhosis has a prolonged natural course, and pro- duces symptoms only in the advanced stages of the di-sease, when no healing treatment options are available. The main treatment for hepatocellular carcinoma is sur- gery (in thosecases where the tumor proves resectable), though unfortunately many cases are non-operable due to theproximity of vital structures, the presence of me- tastases, or other comorbidities (3). Objectives The present study offers a literature review of the oral manifestations that can be found in patients with viral hepatitis, alcoholic and non-alcoholic liver disease, cirr- hosis and hepatocellular carcinoma, and the dental ma-nagement of patients with these liver disorders.

Material and Methods A literature search was made of the articles indexed in the PubMed Medline database, using the following MeSH validated key words: hepatitis, alcoholic hepati- tis, fatty liver, cirrhosis and hepatocellular carcinoma. The search was limited to articles in English or Spanish published overthe last 15 years. A total of 28 articles were reviewed, comprising 20 literature reviews, a clini- cal guide, three clinical trials and four case series.

Results 1. ORALCLINICAL MANIFESTATIONS The oral cavity can reflect liver dysfunction in the form of mucosal membrane jaundice, bleeding disorders, pe-techiae, increased vulnerability to bruising, gingivitis, gingival bleeding (even in response to minimum trau-ma) (3, 19),foetor hepaticus (a characteristic odor of advanced liver disease), cheilitis, smooth and atrophic tongue, xerostomia, bruxism and crusted perioral rash (1).

In these patients, chronic periodontal disease is a common finding. Patients with alcoholic hepatitis can present glossitis, angle cheilitis and gingivitis, particularly in combination withnutritional deficiencies (3, 20). Some patients who consume largeamounts of alcohol for prolonged periods of time can develop sialadenosis. As commented by Frie- dlander (20), this is believed to be the result of ethanol- induced peripheral autonomic neuropathy giving rise to alterations insalivary metabolism and secretion.

Patients with advanced cirrhosis tend to present defi-cient oral hygiene, particularly in those cases where the liver impairment is associated to alcohol abuse. Bagn et al. (18) reported worsened dental conditions in patients with livercirrhosis, in coincidence with other authors such as Novacek et al. (21), who considered that due to the severity and characteristics of cirrhosis, patients tend to neglect care of the oral cavity (18). In a recent study, Grossmann et al (9). found many patients with HCV infection to present poor dental health a situation that contributes to worsen their quality of life. Extrahepatic manifestations have been reported in 74% of all HCV-infected individuals (19), and some of these conditions predominantly or exclusively affect the oral region (10). The main disorders associated with HCV infection are xerostomia, Sjgrens syndrome (SS), sia-ladenitis and particularly lichen planus (LP) (9). Xerostomia increases patient vulnerability to caries andoral softtissue disorders (9) which, in combination with deficient hygiene, in turn facilitate the development of candidiasis. It has not yet been demonstrated whether HCV infection causes disease similar to primary Sjgrens syndrome or whether itis directly responsible for development of Sjgrens syndrome in certain types of patients. Howe-ver, it isnotorious that some subjects can present a triple association of HCV infection, Sjgrens syndrome and sialadenitis orsalivary gland lymphoma (10).

Although bacteria are the main cause of sialadenitis, vi- ruses such as HCV have been implicated as causes of sialadenitis associated to xerostomia (19). Epidemiological evidence suggests that lichen planus may be significantly associated to HCV infection, though the existing data are controversial (22). This association appears to be dependent upon the geographical setting, being more common in Mediterranean countries and in Japan (22). Bagn et al. (23) found the prevalence of HCV infection to be greater in patients with oral lichen planus (OLP) than in the control group. Although further studies are needed, recent data suggest that patients are most likely first infected with HCV and posteriorly de- velop lichen planus (24) though the way in which this

2. DENTAL MANAGEMENT

Liver disease has important implications for patients receiving dental treatment (3). The most frequent pro-blems associated with liver disease in clinical practice refer to the risk of viral contagion on the part of the den-tal professionals and rest of patients (cross-infection),the risk of bleeding in patients with serious liver disease,and alterations in the metabolism of certain drug subs-tances (1) which increases the risk of toxicity. HCV has been detected on different surfaces within the dental clinic after treating patients with hepatitis C, and the virus moreover is able to remain stable at room tem-perature for over 5 days (12). Strict sterilization mea-sures are therefore required, since deficient sterilizationcan expose both the dentist and other patients to hepa-titis infection (5). The universal protective measures areapplicable in order to prevent cross-infection, i.e., theuse of barrier methods, with correct sterilization and di-sinfection measures (1). It has been demonstrated thatconventional sterilization techniques eliminate specificproteins and nucleic acids (HBV DNA and HCV RNA)from dental instruments previously infected with HBVand HCV.

x

Although there are no data confirming theirefficacy in lessening the risk of contagion, the measuresre commended in the case of accidental perforation of the skin with instruments or needles comprise careful was-hing of the wound (without rubbing, as this may inocula-te the virus into deeper tissues) for several minutes withsoap and water, or using a disinfectant of established efficacy against the virus (iodine solutions or chlorine formulations). In turn, pressure should be applied benea-th the level of the wound in order to induce bleeding and thus help evacuate any possible infectious material.If exposure through some mucosal membrane has oc-curred, abundant irrigation with tap water, sterile saline solution or sterile water is advised, for several minutes. The rationale behind these measures is to reduce the number of viral units to below the threshold count nee-ded to cause infection (i.e., the infectious dose). In this sense, dilution with water may lower the viral count to below this threshold (8). Whenever possible, the hepa-titis antigen status of the patient should be determined.In the event of parenteral exposure to hepatitis virus-positive antigens, the dentist should receive treatment with anti-hepatitis B immunoglobulin (5). Table 1 offers a schematic description of the steps to be followed. The compilation of a detailed clinical history is essen-tial before dental treatment in order to identify patientsposing possible risks (5), together with a thorough oralexploration. Interconsultation with the patient physicianor specialist is advisable in order to establish a safe andadequate treatment plan adapted to the medical condi-tion of the patient (3), considering the degree of liver functional impairment involved (1).

Table 1

x

Exploration of the oral cavity should assess any signs alerting to the exis-tence of systemic disease. The patient should receive an explanation of the risks associated with treatment, and informed consent is to be obtained.In patients with acute-phase viral hepatitis, only emer-gency treatment should be considered. In subjects with chronic hepatitis it is important to determine the pos-sible existence of associated disorders (autoimmuneprocesses, diabetes, etc.) in order to prevent their direct complications and problems derived from specific me-dication use (corticosteroids and/or immune suppres-sors). Evaluation is also required of the possible medical conditions associated to HCV contagion, fundamentally blood transmitted infections (HIV, HBV).It also must be taken into account that liver disease is often associated with a decrease in plasma coagulation factor concentrations (2, 3). In a patient with liver di-sease, the surgical risk is related to the severity of the disease, the type of surgery planned, and the presence of comorbidities. Surgery is contraindicated in patients with certain conditions such as acute hepatitis, acute li-ver failure or alcoholic hepatitis (25). If invasive mea-sures are required, prior coagulation and hemostasistests are required: complete blood count, bleeding time,prothrombin time / international normalized ratio (INR),thrombin time, thromboplastin time and liver bioche-mistry (GOT, GPT and GGT) (1, 26). Table 2 reports the normal coagulation test values. In the event altered test values are detected, the hematologist or liver spe-cialist should be consulted (3), with the postponement of elective treatment. Any emergency treatments should be provided in the hospital setting.

In the event of surgery, trauma should be minimized (3) in order to optimize hemostasis, with a careful surgical technique,applying pressure to control bleeding and using hemos-tatic agents (2). Based on the laboratory test findings and the treatment to be carried out, local hemostatic agents may be advisable (oxidized and regenerated cellulose),as well as antifibrinolytic agents (tranexamic acid), fresh plasma, platelets and vitamin K (1, 26). Antibiotic pro-phylaxis is suggested, since liver dysfunction is associa-ted to diminished immune competence (2).Liver disease may result in alterations in the metabolism of certain drugs. The physician treating the patient the-refore should be consulted in order to establish which drugs are used, their doses and possible interactions(3). The administration of certain analgesics, antibioticsand local anesthetics is generally well tolerated by pa-tients with mild to moderate liver dysfunction, though modifications may prove necessary in individuals with advanced stage liver disease (2). In this context, drugs metabolized in the liver may have to be used with cau-tion or their doses reduced (1, 26) (Table 3), and certain substances such as erythromycin, metronidazole or te-tracyclines must be avoided entirely (3). Most of the an-tibiotics prescribed for oral and maxillofacial infections can be used in patients with chronic liver disease, and in general the beta-lactams can be administered. Amino-glycosides can increase the risk of liver toxicity in pa-tients with liver disease, and so should be avoided. Themetabolism of clindamycin in turn is prolonged in suchpatients, and different studies suggest that it contribu-tes to liver degeneration (27).

Nonsteroidal antiinflam-matory drugs (NSAIDs) should be used with caution oravoided, due to the risk of gastrointestinal bleeding andgastritis usually associated to liver disease. Prophylaxiscan be provided in the form of antacids or histamine re-ceptor antagonists (2, 3). Acetaminophen (paracetamol)is to be avoided in patients with serious liver disease (4),and aspirin and NSAIDs are not indicated in patientswith altered hemostasis (4). Authors such as Douglas etal. (27) describe acetaminophen as a safe alternative toaspirin or NSAIDs that can be administered at doses ofup to 4 g/day during two weeks without adverse liver effects, warning patients to avoid alcohol consumption while receiving treatment with the drug. In patients using benzodiazepines, the dose should be lowered, withprolongation of the interval between doses. Local anes-thetics are generally safe provided the total dosage doesnot exceed 7 mg/kg, combined with epinephrine (27).Table 4 shows the drugs that are contraindicated and those that can be used with caution. Although some of these substances are metabolized in the liver, the doses at which they are used in dental practice are considered to be acceptable unless the patient suffers very severe liver dysfunction.

Table 4 shows the drugs that are contraindicated and those that can be used withcaution.

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Dental considerations in patients with liver disease ...

Understanding Cancer -- Diagnosis and Treatment How Is Cancer Diagnosed?

The earlier cancer is diagnosed and treated, the better the chance of its being cured. Some types of cancer -- such as those of the skin, breast, mouth, testicles, prostate, and rectum -- may be detected by routine self-exam or other screening measures before the symptoms become serious. Most cases of cancer are detected and diagnosed after a tumor can be felt or when other symptoms develop. In a few cases, cancer is diagnosed incidentally as a result of evaluating or treating other medical conditions.

Cancer diagnosis begins with a thorough physical exam and a complete medical history. Laboratory studies of blood, urine, and stool can detect abnormalities that may indicate cancer. When a tumor is suspected, imaging tests such as X-rays, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and fiber-optic endoscopy examinations help doctors determine the cancer's location and size. To confirm the diagnosis of most cancers , a biopsy needs to be performed in which a tissue sample is removed from the suspected tumor and studied under a microscope to check for cancer cells.

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Cancer Center: Types, Symptoms, Causes, Tests, and ...

(Image source: allthingsstemcell.com)

Dental pulp is the soft live tissue inside a tooth. Dental pulp contains stem cells, known as Dental Pulp Stem Cells. The finest Dental Pulp Stem Cells are found in a baby teeth or milk teeth. The stem cells from the milk teeth are 'mesenchymal' type of cells i.e. cells that have the ability to generate a wide variety of cell types like chondrocytes, osteoblasts and adipocytes. Chondrocytes are cells that have the ability to generate cartilage, which can play an important role in the treatment of arthritis and joint injuries. Osteoblasts are cells that have the ability to generate bones. Adipocytes are cells that have the ability to compose adipose tissue, specialized in storing energy as fat. In essence, dental stem cells can generate solid structures of the body such as bone, new dental tissue, cartilage and muscle. New research suggests the potential (currently under experimental research)to regenerate nerves. This is being studied further for use in dentistry and medicine. With these properties of dental stem cells, you can well imagine the sheer confidence with which the next generation can face a host of life-threatening situations later in life, since they will be equipped with the means to rectify and regenerate parts of their own bodies.

Dentition

The following table lists the age-span during which milk teeth and permanent teeth start appearing.

Baby Teeth (Primary)

Upper Teeth

Eruption of Teeth

Loss of Teeth

Central incisor

8 to 12 months

6 to 7 years

Lateral incisor

9 to 13 months

7 to 8 years

Canine

16 to 22 months

10 to 12 years

First molar

13 to 19 months

9 to 11 years

Second molar

25 to 33 months

10 to 12 years

Lower Teeth

Eruption of Teeth

Loss of Teeth

Central incisor

6 to 10 months

6 to 7 years

Lateral incisor

10 to 16 months

7 to 8 years

Canine

17 to 23 months

9 to 12 years

First molar

14 to 18 months

9 to 11 years

Second molar

23 to 31 months

10 to 12 years

Permanent Teeth

Upper Teeth

Eruption of Teeth

Central incisor

7 to 8 years

Lateral incisor

8 to 9 years

Canine

11 to 12 years

First premolar

10 to 11 years

Second premolar

10 to 12 years

First molar

6 to 7 years

Second molar

12 to 13 years

Lower Teeth

Eruption of Teeth

Central incisor

6 to 7 years

Lateral incisor

7 to 8 years

Canine

9 to 10 years

First premolar

10 to 12 years

Second premolar

11 to 12 years

First molar

6 to 7 years

Second molar

11 to 13 years

Third molar (Wisdom Teeth)

17 to 21 years

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Dental Stem Cells - Stemade Biotech

Stem cells from wisdom teeth could help repair corneas

Stem cells inside your teeth could one day help repair eye scratches that cause blindness, scientists report February 23 in Stem Cells Translational Medicine. Read article >

Corneal disease causes nearly 10 percent of blindness cases worldwide, and the condition is typically treated with donor corneas. But researchers at the University of Pittsburgh have discovered that stem cells from the dental pulp of wisdom teeth can be manipulated to form cells of the eyes cornea a finding that may provide an easier procedure to repair corneal scarring. Read article >

Stem cells from the dental pulp of wisdom teeth can be coaxed to turn into cells of the eye's cornea and could one day be used to repair corneal scarring due to infection or injury, according to researchers at the University of Pittsburgh School of Medicine. The findings, published online today in STEM CELLS Translational Medicine, indicate they also could become a new source of corneal transplant tissue made from the patient's own cells. Read article >

Recent research aimed at finding a treatment for a common form of blindness could give new meaning to the term "eye teeth." In a study in mice published in STEM CELLS Translational Medicine, researchers at the University of Pittsburgh show how stem cells harvested from teeth extracted during routine dental procedures can potentially be used to restore sight in those suffering from corneal blindness. Read article >

Today Shows Chief Medical Editor, Dr. Nancy Snyderman discusses dental stem cells - click here to view the Today Show Health segment.

We are thrilled to report an exciting development in stem cell research: the first human study using dental stem cells was published November 12th in the European Cells and Materials journal! This is great news for National Dental Pulp Laboratory, which stores dental stem cells and has long believed in their potential for future medical use.

In the study, patients had wisdom teeth that were impacted, which caused bone loss (resorption) at the site of impaction. Because the bone defect would not repair on its own after the wisdom teeth were removed, the researchers used a mixture of dental pulp stem cells harvested from the patient's non-impacted, upper wisdom teeth and placed them onto a "scaffold" made of collagen sponge. This mixture was then used to fill in the injured areas that were left when the impacted teeth were removed from the lower jaw. (The upper jaw area served as a control, or comparison, area-no dental stem cells were used there).

Three months after treatment, bone had completely regenerated at the injury site and the periodontal tissue had been restored. Optimal bone regeneration was seen in the seven patients who returned for the one year follow up. The investigators concluded that this clinical study demonstrates that dental stem cells and a collagen sponge scaffold can completely restore bone defects in the human jaw and indicates that these cells have the potential to repair and/or regenerate tissues and organs.

Previously, jaw defects had been repaired using dental stem cells in an animal model only-never in humans. In fact, no dental stem cell therapies have ever been shown in humans. As you can guess, this bone grafting study is very exciting for all of us who believe in the future promise of dental stem cell therapies-whether a dental stem cell banking facility like our own NDPL, or individuals who want to preserve their own or their children's pulp in order to have a source of stem cells that they might be able to put to use for future medical needs.

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National Dental Pulp Laboratory | Stem Cell News

Corneal blindness afflicts millions of individuals worldwide and is currently treated by grafting with cadaveric tissues; however, there are worldwide donor tissue shortages, and many allogeneic grafts are eventually rejected. Autologous stem cells present a prospect for personalized regenerative medicine and an alternative to cadaveric tissue grafts. Dental pulp contains a population of adult stem cells and, similar to corneal stroma, develops embryonically from the cranial neural crest. We report that adult dental pulp cells (DPCs) isolated from third molars have the capability to differentiate into keratocytes, cells of the corneal stoma. After inducing differentiation in vitro, DPCs expressed molecules characteristic of keratocytes, keratocan, and keratan sulfate proteoglycans at both the gene and the protein levels. DPCs cultured on aligned nanofiber substrates generated tissue-engineered, corneal stromal-like constructs, recapitulating the tightly packed, aligned, parallel fibrillar collagen of native stromal tissue. After injection in vivo into mouse corneal stroma, human DPCs produced corneal stromal extracellular matrix containing human type I collagen and keratocan and did not affect corneal transparency or induce immunological rejection. These findings demonstrate a potential for the clinical application of DPCs in cellular or tissue engineering therapies for corneal stromal blindness.

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Dental Pulp Stem Cells: A New Cellular Resource for ...

Developing wisdom teeth have many adult stem cells. They share some of the same characteristics as embryonic stem cells, but:

Because wisdom teeth stem cells are adult, the ethical, religious, and political issues associated with using embryonic stem cells are avoided.

Having your own banked stem cells is like having a back-up insurance policy. They are on hand when:

Adult stem cells are unique cells that maintain, after birth, the ability to multiply and to differentiate into other types of cells and tissues. Present in small numbers in almost all adult tissues, they heal damage caused by illness, injury and normal aging. Some adult tissues, including developing wisdom teeth, contain a large number of a special type of stem cells, called mesenchymal stem cells.

Stem cells are found in immature pulp (dental papilla) inside developing wisdom teeth and in the soft-tissue sac (follicle) covering its crown. The pulps of deciduous (baby) teeth and periodontal ligament (PL) also contain stem cells but they are fewer in number. Dental stem cells are derived directly from the developmental cells, which form teeth.

Yes! Bruce A. Fraser, D.D.S., M.S. and Gregory C. Michaels, D.D.S., M.S. merely need to place your freshly removed wisdom teeth into vials containing a preservative solution and ship them over-night to Biodontos FDA-certified tissue bank. Trained technicians at the tissue bank isolate the cells and perform the rest of the banking process.

Yes! Each tooth usually provides a million or more stem cells, four teeth supply 4 million or more. With modern laboratory technology, the number of stem cells can be multiplied (expanded) numerous times. The potential number of stem cells is significantly greater than the number found in banked cord-blood, for example.

Any time! Your dentist, physician or other medical specialist can request your cells whenever you have a condition that will benefit from their use. Currently, stem cells are being used to treat many medical problems and are being assessed in numerous clinical trials. More uses will be established in the coming years. Upon arrival at our tissue bank, we assess your stem cells for viability. Cells that are not viable cannot be banked. We will notify you through your surgeon. Viable stem cells are cryogenically preserved and can be banked (stored) indefinitely.

No. Banked stem cells are stored for their donors own (autologous) use. They can only be used by someone else for example, another family member if you specifically authorize it and if tissue matching tests confirm they are a suitable recipient.

Stem cells regenerate and produced specialized type cells. Stem cells heal and restore skin, bones, cartilage, muscles, nerves and other tissues. Contemporary medicine currently deems many diseases untreatable, but with the help of stem cells these diseases can, in fact, be treated. Some of these diseases are:

We recommend that you discuss your desire to harvest and bank your dental stem cells with Drs. Fraser and Michaels at your consultation appointment. They will review the entire procedure and explain the enrollment process, discuss banking fees and payment options, and provide answers to many of your questions.

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Stem Cells From Wisdom Teeth - Dental Implants Gahanna

Finding humor in dental stem cell collection and storage

Yes, the search included looking for frozen peas or sausage by KAREN DAVIS , RDH, BSDH As I listened to a presentation by Provia Labs about the potential to use dental stem cells from extracted teeth to treat various medical conditions, I got a bit teary eyed. My daughter, Madeline, has Crohn's disease, and she was scheduled to have her wisdom teeth extracted. My heart raced as I watched a video about advances in the field of stem cell research for many conditions, including Crohn's disease. The idea of preserving Madeline's dental stem cells from extracted wisdom teeth through the Store-A-Tooth company resonated with me. I didn't know a lot about dental stem cell research at that point, but I knew I didn't want to miss an opportunity should future research provide a pathway to a cure. I contacted the company to learn more about dental stem cell preservation and banking, and made arrangements for Madeline's extracted wisdom teeth not to end up in the trash. The Store-A-Tooth website by Provia Labs is a great resource to learn more about dental stem cells and ongoing research, and it answered my questions about getting the extracted teeth to the lab. The process almost seemed too easy. However, I managed to complicate things, which at this point I can only laugh about. My first wrong step was in not listening to my daughter, who repeatedly tried to convince me that she really wanted to be put to sleep for her extractions. Upon reviewing her X-rays and consulting with the dentist, I was convinced these would be simple extractions that could be handled with a mild tranquilizer and nitrous oxide. We orchestrated the extraction date immediately following completion of her college semester, and before she was to leave town 10 days later for a wedding. All arrangements with Provia Labs had been made, and they explained that a box would be shipped to me with the Store-A-Tooth container necessary to ship the extracted teeth to the company. They provided cool packs that I needed to freeze the night before her extractions so that the wisdom teeth could be placed in a secure container for transport. This was to help preserve the integrity of the dental stem cells inside the pulp of the wisdom teeth. I was arriving back in town the night before her appointment, and I felt confident that once I was home I would be able to unpack the box and freeze the cold packs so that I could carry them to the office for the extraction procedure. However, I forgot. It didn't occur to me that I had completely forgotten my role until 10 minutes before we were to leave for the dental office. Madeline was already groggy from the tranquilizer she had taken, and I transformed into a panicked dental hygienist mom. I searched my freezer for frozen peas, frozen sausage, anything that could keep the dental stem cells cool enough to ship them to Store-A-Tooth. In route to the dental office I received a calm phone call from Store-A-Tooth wanting to know if I had any questions before the procedure. I was relieved to hear her voice and confessed my mistake about the cold packs. She reassured me that I would have plenty of time to freeze the packs at the dental office since the courier pick-up was a few hours after the extractions. My daughter proceeded to the treatment room to undergo nitrous oxide while I slipped the cold packs into the freezer. It wasn't too long before the dentist emerged with what I thought must have been the fastest extractions in history, but he informed me that strangely enough, the tranquilizer coupled with my daughter's high anxiety and lack of sleep the night before created a situation in which she had become combative when they tried to give her an injection. Oh my. He recommended we reschedule the extractions with an oral surgeon and IV sedation. I should have listened to my daughter! I removed the cold packs from the freezer while Madeline inhaled oxygen, and I analyzed my calendar in an attempt to find another time to squeeze in her extractions before she attended the wedding. I remembered what she told me: "Mom, I don't want to look like a chipmunk at the wedding." Almost miraculously, I found an opening that day with an oral surgeon we trusted, so I filled out the registration forms online and gathered up my daughter to drive her to the next office. Before walking out the door, I remembered the cold packs that I had removed from the freezer after the failed extraction attempt. I grabbed the unfrozen cold packs and my daughter, and I called Store-A-Tooth on the way to the next office to ask them to change the courier pick-up to the oral surgeon's office. Unfazed, they got the new address for pick-up, reassured me that I could freeze the cold packs at the new office during the extractions, and that by the time the courier came, they would be cold enough to safely transport the wisdom teeth, preserving the precious stem cells. While waiting for my daughter during her extractions, it occurred to me that in my haste and panic that morning, I had inadvertently discarded the customized shipping box from Store-A-Tooth to return the container holding the wisdom teeth, cold packs, and Styrofoam container. I checked my watch. The timely recycling service had surely come and retrieved all trash, including the customized items I had thoughtlessly discarded. I knew Madeline would be finishing her procedure within minutes, and I didn't have time to go shopping for a shipping box, so I did what most stressed out dental hygienist moms would do I called her dad. I instructed him to get to the nearest FedEx office immediately to buy a shipping box and bring it to us ASAP. While I was listening to the assistant give careful postop instructions, her dad called to inform me that the first place he went to didn't have the right size boxes, but with my encouragement he broke speed limits to the next FedEx office, and just as groggy Madeline was being wheeled out to my car, her dad pulled up with five box choices. The next day, I received a call from Store-A-Tooth that the teeth had arrived sufficiently cooled, and that the team would begin the process of extracting the dental stem cells from the pulp and cryogenically freezing them in safe storage until they may be needed. I was relieved that all of my mistakes did not spoil the opportunity to bank Madeline's stem cells, and that the company was well prepared to handle consumer errors. I was fortunate to learn about the service. But patients need to learn about it from their dental professionals. Presently the majority of extracted wisdom teeth and primary teeth are discarded. Take a few moments to visit the website at http://www.storeatooth.com , and be sure to visit the page that lists current dental stem cell research. As dental professionals, we have a huge opportunity and even obligation to be the liaison between emerging dental research and clinical application for our patients. Who knows what the future holds for dental stem cells, but based upon the speed at which research is taking place, the future looks promising. RDH Karen Davis , RDH, BSDH, is the founder of Cutting Edge Concepts, an international continuing education company. She practices dental hygiene in Dallas, and is an independent consultant to the Philips Corporation. She can be reached at Karen@Karendavis.net . Here are a few facts related to dental stem cells Stem cells come from two sources embryonic cells from embryos, and adult stem cells from bone marrow, umbilical cord blood, dental pulp, and adipose tissue. Even though there are niches of dental stem cells present in periodontal ligaments and in apical papilla, those easiest to retrieve and bank are found in exfoliating primary teeth, teeth extracted for orthodontic reasons, and extracted wisdom teeth. Patient education about the ability to bank stem cells is essential prior to extraction. The distinctive difference between stem cells compared to other cells of the body is the capacity to develop into many different cell types, and under certain conditions can be induced to become a tissue-specific or an organ-specific cell. Regenerative medicine is the term used to describe the emerging field of using stem cells to repair, replace, or enhance biological function lost to injury, disease, congenital abnormalities, or aging. Adult stem cells from bone marrow have been used clinically for over 50 years and provide a valuable pathway for researching, understanding, and using dental stem cells for various functions. Cryopreservation is the process of using very low temperatures, typically around -300 degrees, to store cells for future use. In human clinical studies, dental stem cells have demonstrated the ability to regenerate alveolar bone. In animal studies, dental stem cells have shown the potential to repair damaged corneas, treat liver disease, repair myocardial infarction, treat muscular dystrophy and spinal cord injury, regenerate damaged pulp, reconstruct craniofacial defects, engineer new teeth, and treat diabetes. More RDH Articles Past RDH Issues

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Dental Stem Cell Articles - DentistryIQ

University of Adelaide researchers have discovered that stem cells taken from teeth can grow to resemble brain cells, suggesting they could one day be used in the brain as a therapy for stroke.

In the University's Centre for Stem Cell Research, laboratory studies have shown that stem cells from teeth can develop and form complex networks of brain-like cells. Although these cells haven't developed into fully fledged neurons, researchers believe it's just a matter of time and the right conditions for it to happen.

"Stem cells from teeth have great potential to grow into new brain or nerve cells, and this could potentially assist with treatments of brain disorders, such as stroke," says Dr Kylie Ellis, Commercial Development Manager with the University's commercial arm, Adelaide Research & Innovation (ARI).

Dr Ellis conducted this research as part of her Physiology PhD studies at the University, before making the step into commercialisation. The results of her work have been published in the journal Stem Cell Research & Therapy.

"The reality is, treatment options available to the thousands of stroke patients every year are limited," Dr Ellis says. "The primary drug treatment available must be administered within hours of a stroke and many people don't have access within that timeframe, because they often can't seek help for some time after the attack.

"Ultimately, we want to be able to use a patient's own stem cells for tailor-made brain therapy that doesn't have the host rejection issues commonly associated with cell-based therapies. Another advantage is that dental pulp stem cell therapy may provide a treatment option available months or even years after the stroke has occurred," she says.

Dr Ellis and her colleagues, Professors Simon Koblar, David O'Carroll and Stan Gronthos, have been working on a laboratory-based model for actual treatment in humans. As part of this research Dr Ellis found that stem cells derived from teeth developed into cells that closely resembled neurons.

"We can do this by providing an environment for the cells that is as close to a normal brain environment as possible, so that instead of becoming cells for teeth they become brain cells," Dr Ellis says.

"What we developed wasn't identical to normal neurons, but the new cells shared very similar properties to neurons. They also formed complex networks and communicated through simple electrical activity, like you might see between cells in the developing brain."

This work with dental pulp stem cells opens up the potential for modelling many more common brain disorders in the laboratory, which could help in developing new treatments and techniques for patients.

Story Source:

The above post is reprinted from materials provided by University of Adelaide. Note: Materials may be edited for content and length.

The rest is here:
Stem cells from teeth can make brain-like cells ...

Abstract

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration.

Key words:Dental stem cells, regenerative dentistry, mesenchymal stem cells, tissue engineering, stem cells.

The formation of the tooth is determined by the cells of which it is composed, the buccal epithelial cells that form the enamel organ and the mesenchymal cells that form the dental papilla. The enamel is formed by the enamel organ, and the dentin is formed by the dental papilla. Cells from the neural crest also take part in tooth formation. These cells originate in the nervous system and later migrate to the maxilla and mandible, where they interact with mesenchymal cells to form the enamel organ and the dental papilla (1,2).

The tooth has two anatomical parts. The crown is the part of the tooth which is covered with enamel and it is the part usually visible in the mouth. The root is the part embedded in the jaw. It anchors the tooth in its bony socket and is normally not visible. The tissues of tooth are enamel, dentin, cementum and pulp. The pulp contains blood vessels and nerves that enter the tooth from a hole at the apex of the root and cementum (Fig.). Around of tooth the periodontal ligament attaches the cementum to the alveolar (3).

-Dental Pulp Tissue

Dental pulp is a loose connective tissue that occupies the pulp chamber of the tooth and originates in the embryonic dental papilla (ectomesenchymal tissue); it is the mature form of the papilla and the only smooth tissue of the tooth. The principal cell of this tissue is the odontoblast, also referred to as the dentinoblast. The dental pulp also contains fibroblasts, undifferentiated mesenchymal cells or stem cells, macrophages, and lymphocytes (4).

-Periodontal ligament (PDL)

The periodontal ligament (PDL) is a vascularised, cellular soft connective tissue that surrounds the teeth and joins the root cementum with the hard sheet of the alveolar bone (5). Most of the cells in the PDL are fibroblasts, which primarily function to synthesise and maintain the extracellular matrix. These fibroblasts contain a developed cytoskeleton of microtubules and actin microfilaments that has been implicated in cellular motility processes. In addition to fibroblasts, the PDL contains osteoblasts, osteoclasts, cementoblasts, macrophages, and stem cells that are capable of generating fibroblasts, cementoblasts, and osteoblasts (6,7).

The term stem cell was proposed for scientific use by Russian histologist Alexander Maksimov in 1909. Alexander Maximov was the first to suggest the existence of hematopoietic stem cells (HSC) with the morphological appearance of a lymphocyte, capable of migrating throughout the blood to microecological niches that would allow them to proliferate and differentiate along specific (8). While research on stem cells grew out of findings by Canadian scientists in the 1960s (8,9). Based on their origin, there are two main types of stem cells: embryonic stem cells (ES cells) and postnatal or adult stem cells (AS cells). Embryonic stem cells were harvested from embryos, they are cells derived from the inner cell mass of the blastocyst (early stage embryo, 4-5 days old, consist of 50-150 cells) of earlier morula stage embryo. In other words these are the cells that form the three germ layers, and are capable of developing more than 200 cell types. In 1998 the first human embryonic stem cell line was derived at university of Wisconsin-Madison (10).

Stem cells can be classified according to their abilities to differentiate as totipotent, pluripotent, or multipotent. Totipotent stem cells are those that can be implanted in the uterus of a living animal and give rise to a full organism. Pluripotent stem cells are those that can give rise to every cell of an organism except its extra-embryonic tissues, such as the placenta. This limitation re-stricts pluripotent stem cells from developing into a full organism. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are pluripotent stem cells. Multipotent stem cells are adult stem cells which only generate specific lineages of cells (11,12).

Embryonic stem cells have both moral and technical problems; because these cells will later develop into a human being, taking these cells will require destruction of an embryo. Technically these cells are difficult to control and grow and they might as well form tumors after their injection (13). Differentiating embryonic stem cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face. And after ten years of research, there are no approved treatments or human trials using embryonic stem cells; but because of the combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source of regenerative medicine and tissue replacement after injury or disease (14).

A very recent development, with potentially a profound significance for clinical therapy has been the generation of induced pluri-potent stem (iPS) cells from somatic cells. The method for iPS cell induction is ground-breaking because somatic cells are converted directly into pluripotent cells through introduction of four genes: Oct-4, Sox2, c-Myc and Klf4 (15). iPS cells have been shown to be similar to ES cells in morphology, proliferation and differentiation capacity and genomic and epigenomic states (16).

To date, AS cells provide a promising tool for clinical applications in the near future due to their accessibility, despite their reduced plasticity (11). Although limited in their capability to differentiate, they can still develop into a number of cell lineages. The possibility of harvesting postnatal stem cells for later use in the same patient eliminates immunological difficulties and the risk of pathogen transmission. Adult stem cells from autologous origin are an appealing, and practical source for cell-based regenerative therapies that hold realistic clinical potential (11).

-Mesenchymal Stem Cells

Alexander Friedenstein was the first to evidence the presence of a population of nonhematopoietic cells that were capable of autorenovation and bone differentiation in the bone marrow (17). Subsequently, others showed the bone-marrow-derived cells isolated according to Friedensteins technique, also possessed high potency of proliferation and pluripotency of differentiation into mesenchymal tissues, and therefore Caplan used the term mesenchymal stem cell (MSC) to describe them (18). Further studies have established mesenchymal stem cells as a heterogeneous cell population in which each individual cell varies in its gene expression, differentiative capacity, expansion potential and phenotype (19,20). Moreover, all of them do not seem to fulfill the stem cell criteria. Therefore, they are preferred to be called multipotent stromal cell with the same acronym MSC (20). Several studies have demonstrated that MSCs can be isolated from multiple tissues, such as bone marrow, peripheral blood, umbilical cord blood, adult connective tissue, dental tissues, placenta, and amniotic membrane (21-24).

At present, any cell population which meets the following characteristics, irrespective of its tissue source, is generally referred as MSC: morphologically, they adhere to plastic and have a fibroblast-like appearance; functionally, they have the ability of self-renewal and could differentiate into cells of the mesenchymal lineage (osteocyte, chondrocyte and adipocyte), also into cells of the endoderm (hepatocytes) and ectoderm (neurons) lineages under proper cell culture conditions; phenotypically, they express more than 95% of the population express the CD105, CD73,CD90 surface antigens and that less than 2% of the population ex-press the pan-leukocyte marker CD45, the primitive hematopoietic progenitor and endothelial cell marker CD34, the monocyte and macrophage markers CD14 and CD11, the B cell markers CD79 and CD19, or HLA class II (25).

-Tissue Engineering in Dentistry with Mesenchymal dental stem cells

Tissue engineering is an interdisciplinary field of study that applies the principles of engineering to biology and medicine toward the development of biological substitutes that restore, maintain, and improve normal function (26). The emerging discipline of tissue engineering and regenerative medicine endeavors to use a rational approach based on morphogenetic signals for tissue induction, responding stem/progenitor cells and the scaffold to maintain and preserve the microenvironment (26).

Growth factors

Growth factors and signaling molecules have the ability to stimulate cellular proliferation and cellular differentiation. Bone morphogenetic proteins (BMPs) family members are used sequentially and repeatedly throughout embryonic tooth development, initiation, morphogenesis, cytodifferentiation and matrix secretion (26). Six different Bmps (Bmp2Bmp7) are coexpressed tem-porally and spatially Bmp6 were identified in human primary culture of dental pulp cells (27). BMPs have been successfully ap-plied for the regeneration of periodontal tissue (28), and other factors, such as PDGF, IGF-1, FGF-2, TGF-, and BMPs (29), have utility in tooth tissue engineering. Dentin matrix protein-1, a non-collagenous protein involved in the mineralization process, induced cytodifferentiation, collagen production and calcified deposits in dental pulp in a rat model (27). Other investigations have been demonstrated the effect of dexamethasone in cultures with dental stem cells, where these cells in combination with dexa-methasone can differentiate into osteoblasts, adipocytes or chondrocytes (30). Recently has been comproved the role of 17-estradiol on cementoblast activity. An in vitro study with PDL fibroblasts showed enhanced alkaline phosphatase activity and mineralized nodule formation when 17-estradiol was added to the cell-culture medium (31).

Cell Source: Mesenchymal dental stem cells (MDSCs)

To date, several types of adult stem cells have been isolated from teeth, including dental pulp stem cells (DPSCs) (32), stem cells from human exfoliated deciduous teeth (SHEDs) (33), periodontal ligament stem cells (PDLSCs) (34), dental follicle progenitor stem cells (DFPCs) (35), and stem cells from apical papilla (SCAPs) (36).

MDSCs are multipotent cells that proliferate extensively (maintained for at least 25 passages), can be safely cryopreserved, pos-sess immunosuppressive properties, and express mesenchymal markers. MSDSCs can be isolated using explant cultures or enzy-matic digestion. In addition, the stem cells derived from teeth are large spindle-shaped cells with a large central nucleus abundant cytoplasm, and cytoplasmic extensions in culture (Fig. ). These adherent cells are morphologically identical to the mesenchymal stem cells obtained from bone marrow (BMMSCs) (32). MDSCs can differentiate in vitro into cells of all of the germinal layers, including ectoderm (neural cells), mesoderm (myocytes, osteo-blasts, chondrocytes, adipocytes, and cardiomyocytes), and endo-derm (hepatic cells) (37).

Spindle shaped dental stem cells in culture media. Phase contrast microscopy, original magnification: X100.

In 2000, Gronthos et al. (32) discovered a new type of stem cells from adult human dental pulp that have the ability to differentiate into odontoblasts/osteoblasts, adypocites and neural cells. These were termed dental pulp stem cells (DPSC) (32). Transplanted ex vivo expanted DPSC mixed with hydroxyapatite/ tricalcium phosphate form ectopic dentin/pulp-like complexes in immunocompromised mice (32). These polls of heterogeneous DPSC form vascularizad pulp like tissue and are surrounded by a layer of odontoblast-like cells expressing factors that produce dentin containing tubules similar those found in natural dentin (32). In addition, DPSCs express mesenchymal markers as CD73, CD90 and CD105 (37). Stem cells from human exfoliated deciduous teeth (SHEDs), also termed immature, are MDSCs from dental pulp tissue of human deciduous teeth with the capacity to differentiate into osteogenic and odontogenic cells, adipocytes, and neural cells (32). As neural crest cell-associated postnatal stem cells, SHED express a variety of neural cell markers including nestin, beta III tubulin, GAD, NeuN, GFAP, NFM, and CNPase (33). Also, SHED are able to form bone when transplanted in vivo and may be an appropriate stem cell resource for treating immune disorders via improved immunomodulatory properties (33). Periodontal ligament stem cells (PDLSCs) isolated from human periodontal ligament also express mesenchymal markers. In vitro, PDLSCs have the ability to differentiate in vitro into adipogenic, osteogenic and chondrogenic cells (34). PDLSCs represent a novel stem cell population in terms of in vivo capacity to differentiate into cells similar to cementoblasts and collagen-forming cells, as evidenced positively en preclinical studies (34). Dental follicle progenitor stem cells (DFPCs) obtained from a mesenchymal tissue that surrounds the developing tooth germ are multipotent stem cells that have immunomodulatory properties, high proliferation potential and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth (35). Furthemore, are able to re-create a new periodontal ligament (PDL) after in vivo implantation (37). Finally, the stem cells from apical papilla (SCAPs) isolated from a precursor of radicular pulp, express mesenchymal markers and can differentiate into odontoblast-like cells and produce dentin-like tissue in both in vitro and in vivo study systems (36). SCAP together with PDLSCs are able to form a root-like structure when seeded onto the hydroxyapatite-based scaffold and implanted in pig jaws (37).

Scaffold

Actually, investigators search the ideal scaffold to facilitate the growth, integration and differentiation of stem cells. The scaffold should be biocompatible, non-toxic and have optimal physical features and mechanical properties. Experiments with cell-free scaffolds are especially attractive because of an easier handling process that eliminates the issues associated with the use of stem cells and their expansion in vitro, with storage and shelf-life, cost aspects, immunoresponse of the host and transmission of diseases (38). However there are some disvantages in this method: first, the cells may have low survival rates. Second, the cells might migrate to different locations within the body, possibly leading to aberrant patterns to mineralization. A solution for this problem may be to apply the cells together with a scaffold. This would help to position and maintain cell localization (39).

Many materials have been designed and constructed for tissue engineering approaches, namely natural and synthetic polymers or inorganic materials and composites, which have been fabricated into porous scaffolds, nanofibrous materials, microparticles and hydrogels. Natural materials include collagen, elastin, fibrin, alginate, silk, glycosaminoglycans such as hyaluronan, and chitosan (40). They offer a high degree of structural strength, are compatible with cells and tissues and biodegradable, but are often difficult to process and afflicted with the risk of transmitting animal-associated pathogens or provoking an immunoresponse. Synthetic polymers as poly lactic acid (PLA), poly glycolic acid (PGA), and their copolymer, poly lactic-co-glycolic acid (PLGA) provide excellent chemical and mechanical properties and allow high control over the physicochemical characteristics, such as molecular weight, configuration of polymer chains, or the presence of functional groups. Recently, hydrogels have been explored for tissue engineering applications in more detail. Hydrogels offer numerous interesting properties including high biocompatibility, a tissue-like water content and mechanical characteristics similar to those of native tissue (40).

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Mesenchymal dental stem cells in regenerative dentistry

Tooth Banking, what is it?

Tooth Banking is the storing of dental stem cells that have the ability to regenerate into various cell types. When your child's tooth or your own tooth falls out or is extracted, dental stem cells are harvested from the dental pulp within the tooth. Baby teeth and wisdom teeth are rich in dental stem cells. These cells within the pulp are a valuable source of highly regenerative stem cells. These dental stem cells are preserved indefinitely by being cryogenically frozen.

Why do we save money for our children's education? So that they can have the best possibilities for a successful career. Why do we spend money on our children's extracurricular activities? So that they can do what they love and experience lifetime memories and accomplishments. So why would we bank our children's teeth? So that they can have the best possible chance at a healthy future. Banking dental stem cells gives your children the ability to take advantage of stem cell therapies of today and those that emerge in the future. No parent wants their children to get sick or become disease stricken. So take advantage of medical benefits today that can provide cutting edge treatments for tomorrow.

An extremely rich source for mesenchymal stem cells is the developing tooth bud of the mandibular third molar (wisdom tooth) and baby teeth. While considered multipotent, they have proven to be pluripotent. The stem cells eventually form enamel, dentin, blood vessels, dental pulp, and nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection in younger years of age before calcification, and minimal to no morbidity, they constitute a major source for personal banking, research, and multiple therapies. These stem cells have also shown capable of producing hepatocytes, a potential cure for diabetes in the future.

Mesenchymal stem cells have already proven to be a powerful and potent platform for developing treatments. As you are reading this, scientists are studying the role of these amazing cells in treating conditions such as type 1 diabetes, spinal cord injury, stroke, myocardial infarction (heart attack), corneal damage and neurological diseases like Parkinson's, to name just a few.

For the past 22 years doctors have been using stem cells to treat over 78 diseases and blood oriented diseases. As of date there are over 2000 clinical trials that have been completed or are under way, demonstrating the use of stem cells to treat diseases, heal injuries, and grow replacement tissues like bone, cartilage, nerve, skin, muscles, and blood vessels.

Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function. This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues or organs.

By storing your own teeth or your childs teeth you are helping insure their future. Wisdom teeth are one of the most viable sources of stem cells. By banking, it adds peace of mind.

Storing dental stem cells is very similar to storing umbilical cord stem cells. Now you have another chance to store these viable stem cells. And unlike the hematopoietic stem cells derived from umbilical cord that can only develop in the blood and immune related cells, MSCs derived from teeth have unlimited potential due to their pluripotency (ability to differentiate in the several cell types).

Please contact The Tooth Bank to learn more about storing your dental stem cells. We look forward to talking to you.

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The Tooth Bank - Why Bank

Abstract Objectives

Stem cells have the ability to rescue and/or repair injured tissue. In humans, it is possible to isolate different types of stem cells from the body. Among these, dental pulp stem cells (DPSCs) are relatively easily obtainable and exhibit high plasticity and multipotential capabilities. In particular they represent a gold standard for neural-crest-derived bone reconstruction in humans and can be used for the repair of body defects in low-risk autologous therapeutic strategies.

An electronic search was conducted on PubMed databases and supplemented with a manual study of relevant references.

All research described in this review highlight that DPSCs are mesenchymal stem cells that could be used in clinical applications. Unfortunately, very few clinical trials have been reported. Major obstacles imposed on researchers are hindering the translation of potentially effective therapies to the clinic. Both researchers and regulatory institutions need to develop a new approach to this problem, drawing up a new policy for good manufacturing practice (GMP) procedures. We strongly suggest that only general rules be standardized rather than everything. Importantly, this would not have an effect on the safety of patients, but may very well affect the results, which cannot be identical for all patients, due to physiological diversity in the biology of each patient. Alternatively, it would be important to study the role of specific molecules that recruit endogenous stem cells for tissue regeneration. In this way, the clinical use of stem cells could be successfully developed.

DPSCs are mesenchymal stem cells that differentiate into different tissues, maintain their characteristics after cryopreservation, differentiate into bone-like tissues when loaded on scaffolds in animal models, and regenerate bone in human grafts. In summary, all data reported up to now should encourage the development of clinical procedures using DPSCs.

The stem cell field represents an area of particular interest for scientific research. The results so far obtained give good expectations for the use of stem cells in clinical trials. New therapeutic strategies have been made possible thanks to great advancements in stem cell biology, with the aim of regenerating tissues injured by disease.1and2 Based on their ability to rescue and/or repair injured tissue and partially restore organ function, multiple types of stem/progenitor cells have been speculated. A primary goal is to identify how different tissues and organs can arise from undifferentiated stem cells.

Stemness is the capability of undifferentiated cells to undergo an indefinite number of replications (self-renewal) and give rise to specialized cells (differentiation). Therefore, stem cells differ from other types of cells in the body because they are capable of sustaining self-renewal, are unspecialized, and can give rise to differentiated cell types. Differentiation can be recognized by a change in the morphology of the cell and by the detection of tissue-specific proteins.3 Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a physiological need for more cells to maintain tissues, by disease, or by tissue injury. Thus, the primary role of adult stem cells is to maintain and repair the tissue in which they are found. They are thought to reside in specific areas termed stem cell niches.4 Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis.5 Among these tissues, dental pulp is considered a rich source of mesenchymal stem cells suitable for tissue engineering applications and, for this reason, many studies are performed with the final aim of obtaining new bone.6, 7and8

Tissue engineering is a multidisciplinary field that combines biology, engineering, and clinical science in order to generate new tissues and organs. This science involves different steps, such as the identification of appropriate cells, the development of scaffolds, and the study of morphogenic signals required to induce cells to regenerate a tissue or organ.9 After having discussed the state of the art in the field of dental pulp stem cells research and their potential use in bone engineering, here we try to suggest how to overcome the problems limiting the translationability of research, with the aim of improving the health of patients.

Dental pulp, a soft connective tissue within the dental crown, is an interesting source of adult stem cells because of the large amount of cells present and the non invasiveness of the isolation methods compared to other adult tissue sources.8, 10and11 Dental pulp contains mesenchymal stem cells defined as dental pulp stem cells (DPSCs). DPSCs are obtained from human permanent and primary teeth, human wisdom teeth, human exfoliated deciduous teeth (SHEDs), and apical papilla.7, 12, 13and14 Moreover, DPSCs can be also isolated from supernumerary teeth, which are generally discarded.15 Other sources of dental stem cells are the periodontal ligament, which houses periodontal ligament stem cells (PDLSCs),16 and the dental follicle, which contains dental follicle progenitor cells (DFPCs).17and18 DPSCs have been isolated from different organisms, including humans, mouse, rat, sheep, chimpanzee, and pig.19, 21, 22and23

DPSCs differentiate into different kinds of cells and tissues24, 25, 26, 27and28 and their multipotency has been compared to those of bone marrow stem cells (BMSCs). It has been demonstrated that proliferation, availability, and cell number of DPSCs are greater than BMSCs.20

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Dental pulp stem cells: State of the art and suggestions ...

In recent years, stem cell research has grown exponentially owing to the recognition that stem cell-based therapies have the potential to improve the life of patients with conditions that range from Alzheimer's disease to cardiac ischemia and regenerative medicine, like bone or tooth loss. Based on their ability to rescue and/or repair injured tissue and partially restore organ function, multiple types of stem/progenitor cells have been speculated. Growing evidence demonstrates that stem cells are primarily found in niches and that certain tissues contain more stem cells than others. Among these tissues, the dental tissues are considered a rich source of mesenchymal stem cells that are suitable for tissue engineering applications. It is known that these stem cells have the potential to differentiate into several cell types, including odontoblasts, neural progenitors, osteoblasts, chondrocytes, and adipocytes. In dentistry, stem cell biology and tissue engineering are of great interest since may provide an innovative for generation of clinical material and/or tissue regeneration. Mesenchymal stem cells were demonstrated in dental tissues, including dental pulp, periodontal ligament, dental papilla, and dental follicle. These stem cells can be isolated and grown under defined tissue culture conditions, and are potential cells for use in tissue engineering, including, dental tissue, nerves and bone regeneration. More recently, another source of stem cell has been successfully generated from human somatic cells into a pluripotent stage, the induced pluripotent stem cells (iPS cells), allowing creation of patient- and disease-specific stem cells. Collectively, the multipotency, high proliferation rates, and accessibility make the dental stem cell an attractive source of mesenchymal stem cells for tissue regeneration. This review describes new findings in the field of dental stem cell research and on their potential use in the tissue regeneration.

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Mesenchymal stem cells in the dental tissues: perspectives ...

Dentinal repair in the postnatal organism occurs through the activity of specialized cells, odontoblasts, that are thought to be maintained by an as yet undefined precursor population associated with pulp tissue. In this study, we isolated a clonogenic, rapidly proliferative population of cells from adult human dental pulp. These DPSCs were then compared with human bone marrow stromal cells (BMSCs), known precursors of osteoblasts. Although they share a similar immunophenotype in vitro, functional studies showed that DPSCs produced only sporadic, but densely calcified nodules, and did not form adipocytes, whereas BMSCs routinely calcified throughout the adherent cell layer with clusters of lipid-laden adipocytes. When DPSCs were transplanted into immunocompromised mice, they generated a dentin-like structure lined with human odontoblast-like cells that surrounded a pulp-like interstitial tissue. In contrast, BMSCs formed lamellar bone containing osteocytes and surface-lining osteoblasts, surrounding a fibrous vascular tissue with active hematopoiesis and adipocytes. This study isolates postnatal human DPSCs that have the ability to form a dentin/pulp-like complex.

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Postnatal human dental pulp stem cells (DPSCs) in vitro ...

July 7, 2016 11:30 AM

Dental checkup. (Photo by Philippe Huguen/AFP/Getty Images)

CAMBRIDGE (CBS) Could root canals one day become a thing of the past?

That might just happen if a new treatment developed by scientists at Harvard University and the University of Nottingham catches on.

The freshapproach by researchers that was just awarded a Royal Society of Chemistry prize works to stimulate native stem cells inside teeth, triggering repair and regeneration of pulp tissue.

Dental fillings in their current state dont do anything to help heal teeth and are actually toxic to cells, Dr. Adam Celiz of the University of Nottingham says.

In cases of dental pulp disease and injury a root canal is typically performed to remove the infected tissues, Celiz said in a statement. The new treatment can be used similarly to dental fillings but can be placed in direct contact with pulp tissue to stimulate the native stem cell population for repair and regeneration of pulp tissue and the surrounding dentin.

The breakthrough could potentially impact millions of dental patients every year, the scientists say.

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Goodbye Root Canals? New Treatment Uses Dental Stem Cells ...

We investigated the potential of human dental pulp stem cells (hDPSCs) to differentiate into dopaminergic neurons in vitro as an autologous stem cell source for Parkinson's disease treatment. The hDPSCs were expanded in knockout-embryonic stem cell (KO-ES) medium containing leukemia inhibitory factor (LIF) on gelatin-coated plates for 3-4 days. Then, the medium was replaced with KO-ES medium without LIF to allow the formation of the neurosphere for 4 days. The neurosphere was transferred into ITS medium, containing ITS (human insulin-transferrin-sodium) and fibronectin, to select for Nestin-positive cells for 6-8 days. The cells were then cultured in N-2 medium containing basic fibroblast growth factor (FGF), FGF-8b, sonic hedgehog-N, and ascorbic acid on poly-l-ornithine/fibronectin-coated plates to expand the Nestin-positive cells for up to 2 weeks. Finally, the cells were transferred into N-2/ascorbic acid medium to allow for their differentiation into dopaminergic neurons for 10-15 days. The differentiation stages were confirmed by morphological, immunocytochemical, flow cytometric, real-time PCR, and ELISA analyses. The expressions of mesenchymal stem cell markers were observed at the early stages. The expressions of early neuronal markers were maintained throughout the differentiation stages. The mature neural markers showed increased expression from stage 3 onwards. The percentage of cells positive for tyrosine hydroxylase was 14.49%, and the amount was 0.526 0.033 ng/mL at the last stage. hDPSCs can differentiate into dopaminergic neural cells under experimental cell differentiation conditions, showing potential as an autologous cell source for the treatment of Parkinson's disease.

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Differentiation of Human Dental Pulp Stem Cells into ...

Protect your family's future health.

Secure their stem cells today.

Bank the valuable stem cells found in

baby teeth and wisdom teeth.

Researchers at the National Institutes of Health (NIH) discovered a rich source of adult stem cells in teeth the stem cells that naturally repair your body. Scientists aredirecting stem cells so they grow into almost any type of human cell, including heart, brain, nerve, cartilage, bone, liver and insulin producing pancreatic beta cells.

AAOMS - American Association of Oral and Maxillofacial Surgeons

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Doctors recommend StemSave stem cell banking for the cryopreservation of powerful adult stem cells from deciduous teeth (baby teeth), wisdom teeth or permanent teethwith healthy dentalpulp.

Easy OnlineEnrollment

StemSave Stem Cell Banking exclusively recovers and stores non-embryonic stem cells. Dental Stem Cells are also known asDSC, DASC, DPSC, or SHED cellsand are classified as atype of adult stem cells.

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Storing Stem Cells In Teeth For Your Familys Future Health

Dental tooth loss and consequences -- an update Compiled by Walter Sorochan

Posted August 24, 2012 Updated September 24, 2012; updated September 30, 2015; Disclaimer

Update Sept 30, 2015: Oral health is the most overlooked health issue in conventional and integrative medicine:

"The issue of bone loss after tooth loss has been ignored in the past by traditional dentistry. [according to Skinner] This is so because dentistry had no treatment to stop or prevent the process of bone loss and its consequences. As a result, doctors had to ignore the inevitable bone loss after tooth extraction. Today, the profession knows about bone loss and that implants [ if done at proper time ] can stop bone loss because implants stimulate the bone, similar to the way the tooth did prior to its loss." Skinner: effects of tooth loss 2008

The statistics on tooth loss are a bit staggering: 7 out of 10 adults age 35 to 44 have lost at least one tooth and a quarter of those aged 65 or older [or about 20 million people] have lost all their permanent teeth.Hill: stem cells grow new teeth 2012 There are numerous dental controversies, for example --- whether fluoridation is really effective in preventing dental caries. Many other issues about dentistry are not discussed. Fortunately, there are new developments in dentistry that may help all of us to deal with our dental problems.

"The next stem cell advance I expect is the availability of regenerative dental kits, which will give dentists the ability to deliver stem cell therapies in their own office. The delivery of stem cell therapies by the dentist is complicated, and these kits will simplify the process and make the treatment more affordable." Murray: latest dental stem cell 2012

Many dentists are not explainingthe silent issues in dentistry todayto their patients! Some dentists are not up to date on the new developments in dentistry. Even though all the hype about how brushing, flossing and cleaning teeth every six months to stop dental caries is good, it does not replace the information you need to know about missing teeth, how your jaw bones work and how to keep your teeth and jaw bones healthy. The new info about dentistry today is how teeth and implants can keep your jaw bones healthy!

The author decided to research about the consequences of missing teeth. Here is what your dentist may not share with you about teeth in general.

Normal jaw bone function: Teeth stimulate the jaw bone to maintain good health. Keeping your jaw bones healthy is probably more important than keeping your teeth clean.

When a tooth is lost, the lack of stimulation causes loss of the jaw bone. Whenever a tooth is extracted, nature will remove the bone that used to surround it. Teeth on either side will shift or tip into the empty space.[ orange rectangle around upper molar teeth in diagram ] If there is a tooth directly above or below the space it will over erupt, as there will not be anything to prevent it from coming out of the gum tissue. The majority of bone degeneration will occur within the first six months but will slowly continue for years. The movement of the adjacent teeth will not occur immediately; rather it will become noticeable after three to five years. How fast it occurs will depend on the density of bone in the area, your bite and how well your teeth occlude or interlock with each other. If you have missing teeth and you do not replace them, these movements will occur.

These movements may create gum problems and /or decay and could lead to the loss of other teeth. As you lose more teeth, you will be forced to chew in other areas, and this often leads to tooth fracture from overloading, excessive wear and/or TMJ (jaw joint) problems. Eventually more extensive and expensive dentistry may be required in the future. Bhanumathi: consquences missing teeth

Thus, when a tooth is extracted from a young person, by the time that person is middle aged, a great deal of bone will be missing. Did your dentist tell you this?

Have your dentist discuss your 'fix' options when you have a sore tooth: e.g.

Toothaches: Common dental causes of toothaches include dental cavities, dental abscess, gum disease, irritation of the tooth root, cracked tooth syndrome, temporomandibular joint [TMJ] disorders, impaction, and eruption.

The most common cause of a toothache is a dental cavity or carie. [ Refer to above diagram ] Dental cavities or caries are holes in the two outer layers of a tooth called the enamel and the dentin. Small, shallow cavities may not cause pain and may be unnoticed by the patient. The larger deeper cavities can be painful and collect food debris. The inner living pulp of the affected tooth can become irritated by bacterial toxins or by foods and liquids that are cold, hot, sour, or sweet, thereby causing toothaches. Severe injury to the pulp can lead to the death of pulp tissue, resulting in tooth infection, also referred to as dental abscess.

A tooth abscess, also known as root abscess, is a collection of pus that results from bacterial infection. The infection starts with the soft pulp of the tooth and becomes more severe finally leading to pus formation at the bottom of the tooth root.

Saving teeth with crowns and root canals: Saving teeth is what a dentist does best!Treatment of a small and shallow cavity usually involves a dental filling. Treatment of a larger cavity involves an onlay or crown. Treatment for a cavity that has penetrated and injured the pulp or for an infected tooth is either a root canal procedure or extraction of the affected tooth. The root canal procedure may involve draining the pus, removing the dying pulp tissue and replacing it with an inert filling material. The procedure is used in an attempt to save the dying tooth from extraction. You should be aware that root canals may not last a long time.

The only alternative to a root canal procedure is having the tooth extracted and replaced with a bridge, implant, or removable partial denture to restore chewing function and prevent adjacent teeth from shifting. WebMD: root canals

Fixing cavities and infected teeth requires that a dentist use a local anesthetic to numb your tooth and jaw bone. There is now controversy about the safety of local anesthetics like novocaine or provaine. Nickel: toxicities from local anestheics Stockton: 2004

It is normal procedure for a dentist to numb the jaw - tooth area before working on a painful tooth. He injects a local anesthetic that numbs the jaw-tooth area. The numbness normally wears off in about two to three hours. Sometimes the numbness can last for several days and even months. This prolonged numbness can occur when the needle passes through a nerve in the area of injection and damages a nerve. This complication of numbness is referred to as paresthesia. Garisto: Paresthesia 2011

Bone Resorption: Missing teeth cause changes in the jaw bone structure. The bone that supported the missing teeth begins to shrink or thin away. There is a loss of width and height of the jaw bone. The process is referred to as bone resorption. This is a natural process of your body saving bone nutrients and structure it is no longer using. Jaw bone loss happens most rapidly during the first year of tooth loss and is four times greater in the lower jaw than in the upper. Uditsky: fixing loss teeth lower jaw 2012 The images below help to illustrate this process:

"Both skulls above are real. The one on the right belonged to an elderly person who lost his teeth many years before he died. When he was young and he had teeth, his skull used to look like the one on the left. The first thing that jumps out at you is how thin the bone of his lower jaw is in comparison to the bone on the lower jaw of the skull on the left. But another thing that is not so apparent is the loss of the bone in the upper jaw.

Notice that both skulls are positioned with their lower jaws mounted so that the bone of the lower jaw is about parallel with the bone of the upper jaws. This tells you that the teeth are together. Even the skull on the right---if it had teeth. This gives you an idea of the amount of bone that that has been lost since this man had all his teeth extracted." Spiller: Bone Resorption

Most of us, 70%, have at least one tooth missing and have never had it replaced. Misch: consequences losing teeth 2011Spiller: index 2000 A vast majority do not suffer major problems like eating, speaking or the way they look. On the other hand, a few, especially some women, tend to develop the joint problems, headaches, neck aches or ear aches typical of jaw joint or TemporoMandibular Joint [TMJ]. When a tooth is lost, the lack of stimulation causes loss of the jaw bone. There is a 25% decrease in width of jaw bone during the first year after tooth loss and an overall 4 millimeters decrease in height over the next few years. Misch: consequences losing teeth 2011

One Lost Tooth Causes a Chain Reaction: The loss of a single tooth starts a chain reaction in the jaw bone. After a back molar tooth is lost, a series of destructive events occur including the shifting of other teeth, decay, tilt, drift and gum pocket formation. Eventually, bone loss and periodontal disease will cause further destruction. If you fail to replace a lost tooth in the back of your jaw, you could eventually lose all your teeth. Dentist Steinbergexplains how this can happen in his article: Replacing lost teeth 2011

Without chewing pressure to stimulate the bone, the jawbone begins to dissolve away immediately after extraction and continues forever unless an implant is placed. This is a very important piece of information that you need to be aware of!

Consequences of lost teeth: Skinner: effects of tooth loss 2008 Spiller: Bone Resorption Steinberg: Replacing lost teeth 2011 Misch: consequences losing teeth 2011

Facial changes naturally occur in relation to the aging process. When the teeth are lost, this process is grossly accelerated with more rapid facial aging. The loss of teeth can add 10 or more years to a person's face. A decrease in face height occurs as a result of the collapse of bone height when teeth are lost. Skinner: effects of tooth loss 2008 Patients are often unaware that bone, gum and facial changes are due to the loss of teeth. Instead, they blame these problems on aging, weight loss, or the dentist for making a poor denture. Besides several facial changes, there are other consequences of losing teeth and not replacing them:

Many people, who lost teeth, upon later wanting to repair the damage caused by the loss of the tooth find that repair is much more expensive because of the movement in the adjacent and opposing teeth.Spiller: index 2000 Indeed, the changes to the jaw may be so great that fixing the damage may be very difficult or impossible .... and expensive!

Ways to deal with missing teeth:

What are dental implants?

Dental implants [ illustration above ] are replacements for the roots of teeth, the parts that are below the gumline and anchored in bone. They are usually covered with a crown that shows above the line of the gums. Uditsky: fixing loss teeth lower jaw 2012 Spiller: index 2000 A primary reason to consider dental implants to replace missing teeth is the maintenance of jaw bone. As you may recall, bone needs stimulation to stay healthy. The implant takes the place of the missing tooth and stimulates the jaw bone to work normally.Misch: consequences losing teeth 2011 Bone resorption can be prevented by replacing natural teeth with dental implants soon after they are extracted. Key is soon!

Most importantly, implants reduce the amount of bone resorption. Studies have shown about 75% less resorption in parts of the jaw with implants compared to areas without them. Since most of the bone loss occurs within the first year after tooth loss, it is important to place implants within this time period. Uditsky: fixing loss teeth lower jaw 2012

Fixed bridge:

"Up until now, the most common but not necessarily the best option for replacing a single back tooth has been a three-unit fixed partial denture (FPD), also called a fixed bridge. In this case, the two teeth on either side of the gap, known as abutment teeth, are crowned and the two crowns together support a pontic a false tooth in the middle [from the French word for bridge].

This type of prosthesis [false replacement] can be fabricated within one to two weeks and provides normal shape, function [eating, talking and smiling], comfort, aesthetics and health. Because of these benefits, FPDs have been the treatment of choice. Misch: consequences losing teeth 2011

The bad side of doing a fixed bridge is that this procedure requires cutting down the healthy teeth on either side of the missing tooth. Tooth preparation of the adjacent teeth is irreversible and involves destroying quite a bit of tooth structure. Appleton: replacing missing teeth 2012 You and your dentist-orthodontist need to have a really good reason to do this procedure!

A well made fixed bridge can look natural, function well, and potentially last a lifetime. However, 75% of fixed bridges fail within 7 years. The fixed bridge is at least three teeth connected together with the false tooth (the replacement tooth) in the middle. Because the teeth are connected, you cannot pop dental floss between them. Instead you must thread the floss through underneath where the teeth are connected or use a special small brush to get under the connectors. People tend to neglect to perform this inconvenient extra step in their oral hygiene routine. This contributes to the relative high rate of failure of fixed bridges. Also, the extra stress on the teeth supporting the fixed bridge can lead to mechanical breakdown and thus adds to the failure rate. In spite of these potential problems, the fixed bridge is still the treatment of choice for many patients. Appleton: replacing missing teeth 2012

How Implants Stop Bone Loss: Dental implants fused and integrated into the jaw-bone serve as anchors to support teeth. They function the same as natural teeth in that the implant provides pressure stimulus on the opposite side tooth. As you may recall, bone needs stimulation to stay healthy. An implant-supported tooth, or teeth, allow for normal function of the whole jaw including the nerves, muscles and jaw joints. Moreover dental implants fuse to the bone, stabilizing and stimulating it to maintain its dimension and density.Misch: consequences losing teeth 2011

Missing teeth may cause sinus problems

Patients are often not quite clear that sinus problems may be related to missing teeth in the upper jaw and that these can be a very expensive fix.

Image courtesy Young: Sinus Lift

The maxillary sinuses are behind your cheeks and on top of the upper teeth [ upper diagram ]. These sinuses are cavities with empty, air-filled spaces. Some of the roots of the natural upper teeth extend up into the maxillary sinuses. When teeth in the upper jaw are removed and not replaced, the jaw bone can shrivel up and the sinus will expandfurther down toward the jaw ridge from the inside of the jaw bone. This often causes a thin wall of bone separating the maxillary sinus and the mouth, making it difficult or impossible to place dental implants in the jaw bone. Young: Sinus Lift Gougaloff: Sinus Lift Procedure 2008

However, the thin jaw bone can be regrown and the thin sinus wall can be restored by a procedure known as "sinus lifting." This procedure strengthens the growing bone in the upper jaw, allowing dental implants to be placed in the new bone growth. This restores the missing teeth. For more detailed information on bone grafts see bone graft post or link to Robert Gougaloff s website.

Finally, dental implants are now available in different sizes and length, making it more easy than in the past, to fix missing teeth in the jaw bones. You need to consult with your dental specialist for more information.

Is jaw bone loss reversible? Yes!

In cases where there is not enough bone to support a successful implant, the surgeon may perform a bone graft. A synthetic bone grafting compound may be used that is easier and more successful than bone on bone grafting. It can usually be done at the time of the implant surgery, allowing everything to heal into place together, which ultimately makes for a more solid implant.

Your dental health future is in dental stem cells:

Dentists are optimistic that stem cells will allow them to deliver more miraculous therapies that will benefit their patients and improve patient quality of life. The hope is that these dental stem cells could be used to heal the patients when they need it in the future. Research is now taking place about growing a bio-tooth, made from self-generated or self-produced [autogenous] Dental Pulp Stem Cells or DPSCs to regenerate lost teeth. DPSCs can be used in the same individual without the danger of an immune rejection response.

A dental study in 2009 used stem cells to heal jaw bone tissue.Nat Dental Pulp Lab: dental stem cells The stem cells come from a substance called dental pulp from within the interior chamber of our teeth. This pulp is made up of living soft tissue and stem cells.Dental stem cells are adult stem cells present in both baby (deciduous) teeth, and adult teeth. The stem cells consist of dental mesenchymal stem cells and dental epithelial cells. Dental epithelial cells give rise to enamel, while dental mesenchymal stem cells give rise to all of the other tissues of the tooth, including pulp, dentin, cementum, periodontal ligament, and surrounding alveolar bone. The ability to harvest cells from extracted wisdom teeth and supernumerary teeth that would otherwise be discarded as waste makes these tissues unique and valuable stem cell sources. Murray: latest dental stem cell 2012

A three month study, the first in dentistry, used dental stem cells to completely regenerate the injury site in the jaw and restore periodontal tissue. dAquino: stem cell healing in dentistry 2009 This study demonstrated that stem cells have great promise in helping to fix dental problems.

More recently in 2012, endodontics professor Dr. Peter Murray and colleagues from the College of Dental Medicine at Nova Southeastern University (NSU) have developed methods to control adult stem cell growth toward generating dental tissue and real replacement teeth. "Teeth can be grown separately, then inserted into a patients mouth, or the stem cells can be grown within the mouth, reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen." Hill: stem cells grow new teeth 2012

Why stem cells may be better than durable implants such as titanium dental implants? A short answer to this question is that stem cells lead to the regeneration of teeth with periodontal ligament that can remodel with the host. Mao: stem cells & future dental care 2008 Mao elaborates on this concept of stem cell use:

"Stem cells can be seeded in biocompatible scaffolds in the shape of the anatomical structure that is to be replaced. Stem cells may elaborate and organize tissues in vivo, especially in the presence of vasculature. Finally, stem cells may regulate local and systemic immune reactions of the host in ways that favor tissue regeneration.

Much of what dentists know is evolving into a new dentistry in which dental care is delivered increasingly by biologically based approaches. For example, biomolecules will be used for periodontal regeneration; stem cells will be used in the regeneration of dentin and/or dental pulp; biologically viable scaffolds will be used to replace orofacial bone and cartilage; and the defective salivary gland will be partially or completed regenerated." Mao: stem cells & future dental care 2008 Hill: stem cells grow new teeth 2012

So .... what do you do?

Using stem cells to safely regenerate missing teeth may be a few years in the future.Dentists predict that the technology should be available within the next decade. Hill: stem cells grow new teeth 2012 Meanwhile you should do the following:

1. Continue taking good care of your teeth == brushing and flossing regularly.

2. Pay immediate attention to missing teeth! Missing teeth are an overlooked item and need much more priority than brushing teeth because replacing lost teeth can prevent jaw bone loss and thereby keep your teeth and jaw bones healthy when you get older.

3. Be aware that dentistry is a business. Some dentists and prosthodontists may be more eager to have your money than fix your missing teeth!

4. Consider getting dental insurance if you have not done so. Today's available dental insurance coverage is better than none at all! Check to find out whether you have dental insurance coverage through your employer.

Some dental insurance plans may have an annual maximum benefit limit. Thus, once the annual maximum benefit is exhausted and additional treatments may become the patient's responsibility. Each year that annual maximum is reissued.

The problem with dental insurance is that companies selling dental insurance coverage have ceilings on how much dental insurance companies will cover, the kind of dental problems covered and so on; a form of rationing dental services. Many dental problems that occur in middle and senior stages of life; like replacing lost teeth, are expenses that the elderly cannot pay for and insurance companies place a limit on the amount they will pay.Unable to afford expensive fixes for loss of teeth, many elderly end up with continuing eating and jaw problems. It is the opinion of this author that we need a massive overhaul of the dental insurance system.

5. Make a partnership with your dentist so your dentist works for your health and that the partnership is a two-way street.This may be the new way of dentistry. In the past, many patients came to the dentist in pain and in need for immediate dental care. This 'one-way street' placed the patient in an uncompromising position of needing immediate dental care over dental information. Challenge your dentist!

6. Update your dentist with the information in this article .... to make him aware that you are an informed patient.

7. Check the references for some surprises.

Questions to ask:

Though one can easily find first-class experienced implant surgeons in some of the respected institutions, it is important to check the qualification, experience, profile and percentage of successful implant procedures of the implant surgeon you choose. You should never hesitate to ask any sort of questions related to your dental well-being in your next meeting:

What are your dental fix options? Have your dentist outline ALL of your options! For example, lose a tooth or save a tooth?

What kind of anesthetic will your dentist use: novocaine = trade name procaine Wiki: Procaine, lipocaine, mepivicane, lidocaine, bupiricane, demerol, other?

How big a dose will the anesthetic be? Is it related to body size?

How long will it take for the anesthetic to detoxify?

Are you allergic to the anesthetic? How does the dentist know?

What could potential side-effects be from the anesthetic? Nickel: toxicities from local anesthetics

What are the risks of a dental implant? or a root canal?

Why didn't your dentist prescribe a probiotic along with the antibiotic --- to restore the desirable good bacteria killed off by the antibiotic?

When was the last time your dentist went to a dental seminar or conference to update his background and skills?

Is there enough jaw bone to consider a dental implant? For example, it is important that you know everything related to the implant procedure much earlier than it happens.

Is your dentist going to get certified in dental stem cell surgery?

The author confesses that doing this article research about what should be new priorities in dentistry was not just informative but totally revealing.This author needed this information to be able to make better decisions about his own dental wellbeing. Sharing all this information in one location is done for your convenience. Hopefully you have become a little more informed about your dental health. Your feedback is most appreciated:

Your feedback is most appreciated: E-mail to: Author Walter Sorochan

To return to: web-site main page

References:

American Academy of Peredontonology [AAP], "Dental Implant Placement Options," Perio.org. AAP: Implant options

Appleton Richard, "What's the best way to replace a missing tooth or teeth?" HubPages, Explore Health (33,263) Oral Health (472), January 26, 2012. Appleton: replacing missing teeth 2012

Bubalo Marija, Zoran Lazi, Radomir Milovi, Anika ukovi, "Rehabilitation of Severely Resorbed Mandible Treated With Mini Dental Implants and Iliac Crest Bone Grafts: Case Report," Scientific Journal of the Faculty of Medicine in Ni 2011;28(3):183-188. Bubalo: rehab resorbed mandible 2011

Bhanumathi C.K, "Consequences Of Missing Teeth," WherincityMedical, October 22, 2009. Bhanumathi: consquences missing teeth

Changes in the Jaw Bones, Teeth and Face after Tooth Loss, Images. Images of bone-dental changes

Cosmetic dentistry grants, Free dental implants. Dental Grants

dAquino R, A De Rosa, V Lanza, V Tirino, L Laino, A Graziano, V Desiderio, G Laino, G Papaccio, "Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes," European Cells and Materials journal, November 12, 2009, Volume No 18 pages 75-83. dAquino: stem cell healing in dentistry 2009 The first human study using dental stem cells in dentistry.

Dental Lab Direct, "Temporary Bridge," Temporary Bridge or TempoBridge is now available for individuals that are in need of a false tooth for a short period of time. If you have a missing tooth, a bridge will be custom made to fill in the space with a false tooth; in the meantime, you may use a temporary bridge. This false tooth is attached within a clear retainer - bridging them together, sometimes called a flipper. The TempoBridge is designed for a short amount of time (5 months or less), cannot be used while eating, and can have only one, possibly two teeth. A better solution is the FLEXIBLE PARTIAL, it's well worth the additional dollars. Dental Lab Direct: Temp dental bridges

Gougaloff Robert, "Sinus Augmentation or Sinus Lift Procedure," Implant Laser Dentistry, September 10, 2008. Gougaloff: Sinus Lift Procedure 2008

Gougaloff Robert, "Stem Cells in Dentistry?" Implant Laser Dentistry, November 25, 2008. Gougaloff: stem cells 2008

Garisto Gabriella A., Andrew Gaffen, Herenia Lawrence, Howard Tenenbaum and Daniel Haas, Occurrence of Paresthesia After Dental Local Anesthetic Administration in the United States, Journal of American Dental Association, July 2010;141(7):836-844. Garisto: Paresthesia 2011

Hill David J., "Toothless No More Researchers Using Stem Cells to Grow New Teeth," Singularity Hub, May 10th, 2012. Hill: stem cells grow new teeth 2012

Mao Jeremy J., "Stem Cells and the Future of Dental Care," NYSDJ, March, 2008. Mao: stem cells & future dental care 2008

Here is the original post:
Dental tooth loss and consequences - an update - Freegrab

2.1. Stem cell sources

Many different types of stem cells have been used in the research, testing and treatment of diabetes mellitus, including stem cells that can be used to regenerate pancreatic islets, e.g. embryonic stem cells, adult stem cells and infant stem cells (umbilical cord stem cells isolated from umbilical cord blood).

Human embryonic stem cells (ESCs) were first isolated at the University of Wisconsin-Madison in 1998 by James Thomson (Thomson et al., 1998). These cells were established as immortal pluripotent cell lines that are still in existence today. The ESCs were derived from blastocysts donated by couples undergoing treatment for infertility using methodology developed 17 years earlier to obtain mouse ESCs. Briefly, the trophectoderm is first removed from the blastocyst by immunosurgery and the inner cell mass is plated onto a feeder layer of mouse embryonic broblasts (Trounson et al., 2001; 2002). However, cells can also be derived from early human embryos at the morula stage (Strelchenko et al. 2004) after the removal of the zona pellucida using an acidified solution, or by enzymatic digestion by pronase (Verlinsky et al., 2005). Nowadays, ESCs can be isolated from many different sources (Fig. 1).

ESCs are pluripotent, which means that they can differentiate into any of the functional cells derived from the three germ layers, including beta cells or insulin-producing cells (IPCs). The differentiation of ESCs into IPCs is prerequisite for their use as a diabetes mellitus treatment, and may occur either in vivo (after transplantation) or in vitro (before transplantation). In vivo differentiation is based on micro environmental conditions at the graft site, whereas in vitro differentiation requires various external factors that induce the phenotypic changes required to produce IPCs. This means that diabetes mellitus can be treated either by direct transplantation of ESCs, or by indirect transplantation of IPCs that have been differentiated from ESCs. However, Naujok et al. (2009) showed that ESCs could modify gene expression and exhibit a phenotype similar to that of islet cells when transplanted into the pancreas only if they are first differentiated in vitro, and that in vitro differentiation is a prerequisite for successful in vivo differentiation (Naujok et al., 2009). Moreover, using ESCs for pancreatic regeneration carries with it the risk of tumour formation after transplantation.

Therefore, the in vitro differentiation of ESCs into IPCs is necessary before they can be used to treat diabetes mellitus. Studies looking at the in vitro differentiation of ESCs into IPCs were first performed in 2001 using mouse cells (Lumelsky et al., 2001). However, the results could not be repeated in subsequent studies (Rajagopal et al., 2003; Hansson et al., 2004; Sipione et al., 2004). Researchers then developed a strategy for selecting ESCs expressing genes related to pancreatic cells (e.g. nestin), and successfully generated IPCs from these ESCs (Soria et al., 2000; Leon-Quinto et al., 2004). Other workers succeeded in creating IPCs from ESCs using gene transfer (Blyszczuk et al., 2003; Schroeder et al., 2006), or phosphoinositol-3 kinase inhibitors (Hori et al., 2002). The differentiation of ESCs into IPCs usually involves differentiation into embryoid bodies. This relatively long process comprises two phases: the embryoid body stage (45 days) and the differentiation stage (3040 days). In 2005, Shi et al. decreased the time taken for this differentiation process to 15 days (Shi et al., 2005).

ESC sources. ESCs can be isolated from fresh, frozen, dead, excess and genetically deficient embryos, by parthenogenesis and somatic nucleus transfer, from biopsies, and from pluripotent stem cells obtained from adult tissues.

In 2001, Assady et al. reported that IPCs could be generated by spontaneous differentiation of human ESCs. Although the IPC number and insulin content of these cells was low, this was the first proof-of-principle experiment indicating that human ESCs were a potential source of -like cells. Recent reports from D'Amour et al. and Kroon et al. described the differentiation of pancreatic lineage cells from human ESCs in vitro. To date, many groups have reported the in vitro generation of IPCs from human ESCs (D'Amour et al., 2006; Jiang et al., 2007; Jiang et al., 2007).

First created by Takahashi et al. (2007) and Yu et al. (2007), induced pluripotent stem cells (IPSCs) are a new source of embryonic-like stem cells, and are considered a technical breakthrough in stem cell research. IPSCs have several advantages over ESCs. One major advantage is that IPSCs can be created from any cell-type; thus, creating patient-specific stem cells (Park et al., 2008; Dimos et al., 2008). Similar to ESCs, IPSCs can differentiate into many different cell types, including neurons (Dimos et al., 2008; Chambers et al., 2008), heart muscle cells (Zhang et al., 2009) and insulin-secreting cells (Tateishi et al., 2008; Zhang et al., 2009).

IPSCs can be created from many different cell types via a simple process. First-generation IPSCs are obtained by transferring four genes (Oct-3/4, Sox-2, c-Myc and Klf4; Shinya Yamanaka et al., 2006) or Oct-3 / 4, Sox-2, Nanog and LIN28 into mice. Second-generation IPSCs are derived using only Oct-3/4, Sox-2 and Klf4, because c-Myc is an oncogene (Nakagawa et al., 2008). Third-generation IPSCs are generated using only two genes, Oct-3/4 and Sox-2, and the histone deacetylase inhibitor, valproic acid (VPA) (Danwei Huangfu et al., 2008).

A recent study shows that IPSCs can be successfully created from adult fibroblasts derived from type 1 diabetic patients (Rene'Maehr et al., 2009). These cells were differentiated into IPCs and used to successfully treat diabetic rats (Alipio et al., 2010).

A recent report by Harry Heimbergs group (Heimberg et al., 2008) describes the existence of pancreatic stem cells in mice. In their most recent study, Heimberg's group ligated the ducts that secrete pancreatic enzymes in adult mice. The result was a doubling in the number of beta cells within two weeks. Also, the pancreases of the experimental animals began to produce more insulin; evidence that the newly generated beta cells were functional (Xu et al., 2008). Another research team showed that the production of new beta cells was dependent on the gene neurogenin 3 (Ngn3), which plays a role in the pancreas during embryonic development, and successfully isolated and established a murine pancreatic stem cell line (Noguchi et al., 2008; 2009).

Human pancreatic stem cells have also been successfully differentiated into IPCs (Noguchi et al., 2010). Islet cells were isolated from the pancreases of human donors using the Ricordi technique modified by the Edmonton protocol. The isolated cells were then cultured in media specifically designed for mouse or human pancreatic embryonic stem cell culture. The cells were differentiated for 2 weeks in induction media containing exendin-4, nicotinamide, keratinocyte growth factor, PDX-1 protein, or protein BETA2/NeuroD. However, according to Davani et al. (2007), human islet precursor cells derived from human pancreases exhibit the properties of mesenchymal stem cells (MSCs) in that they adhere to plastic, express CD73, CD90 and CD105, and differentiate in vitro into adipocytes, chondrocytes, and osteocytes. Davani et al. also identified a rare population of CD105+/CD73+/CD90+ cells in adult human islets that express low levels of insulin mRNA (Davani et al., 2007).

MSCs are multipotent stem cells that can differentiate into a variety of cell types, such as osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells) (Anna et al., 2008). This cell type was first discovered in 1924 by the cell morphologist Alexander A. Maximo, who described a type of cell within the mesenchyme that develops into various types of blood cell. Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in 1963 (Becker et al., 1963; Siminovitch et al., 1963). Subsequently, ex vivo clonogenic assays were used to examine the potential of multipotent marrow cells (Friedenstein et al., 1974, 1976). In these assays, stromal cells or MSCs were used as colony-forming unit-fibroblasts (CFU-f). The characteristics of MSCs are as follows: they adhere to culture vessels; they have a fibroblast-like shape; they express Stro-1, CD133, CD29, CD44, CD90, CD105 (SH2), SH3, SH4 (CD73), c-kit, CD71, and CD106; and they can differentiate into specialised cells, e.g. bone, cartilage and fat.

MSCs have been isolated from many different tissues, including bone marrow (Oyajobi et al.. 1999; Majumdar et al., 2000; Prockop et al., 2001; Smith et al., 2004; Titorencu et al., 2007; Wolfe et al., 2008; Gronthos and Zannettino et al., 2008; Phadnis et al., 2011; Bao et al., 2011), adipose tissue (Katz et al., 2005; Baptista et al., 2009; Caviggioli et al., 2009; Baer et al., 2010; Bruyn et al., 2010; Estes et al., 2010; Tucker, Bunnell, 2011), peripheral blood (Kassis et al., 2006), umbilical cord blood (Erices et al., 2000; Rosada et al., 2003; Hutson et al., 2005; Reinisch et al., 2007; Bieback and Klter et al., 2007; Perdikogianni et al., 2008; Zhang et al., 2011), banked umbilical cord blood (Phuc et al., 2011), umbilical cords (Cutler et al., 2010; Farias et al., 2011), umbilical cord membranes (Deuse et al., 2010; Kita et al., 2010), umbilical cord veins (Santos et al., 2010), Wharton's jelly from the umbilical cord (Zeddou et al., 2010; Peng et al., 2011), placenta (Miao et al., 2006; Battula et al., 2007; Huang et al., 2009; Semenov et al., 2010; Pilz et al., 2011), decidua basalis (Macias et al., 2010; Lu et al., 2011), the ligamentum flavum (Chen et al., 2011), amniotic fluid (Feng et al., 2009; Choi et al., 2011, Shuang-Zhi et al., 2010), amniotic membrane (Chang et al., 2010; Marongiu et al., 2010), dental pulp (Agha-Hosseini et al., 2010; Karaz et al., 2010; Yalvac et al., 2010; Spath et al., 2010), chorionic villi from human placenta (Poloni et al., 2008), foetal membranes (Soncini et al., 2007), menstrual blood (Meng et al., 2007; Hida et al., 2008; Musina et al., 2008; Kyurkchiev et al., 2010), and breast milk (Patki et al., 2010) (Fig. 2).

Sources of MSCs. MSCs can be derived from several adult or infant tissues.

MSCs have been successfully differentiated into IPCs in vitro and can reduce blood glucose levels in both animals and humans after transplantation. The in vitro differentiation of MSCs into IPCs requires certain substances combined with medium stress. Most successful protocols for the differentiation of MSCs into IPCs used nicotinamide and/or exendin-4 inducers. Changes in the glucose concentration within the culture medium are necessary to trigger this process. MSCs are commonly cultured in low glucose medium to initiate differentiation before they can be induced to differentiate into IPCs by nicotinamide. In some studies, epidermal growth factor (EGF) was added to the culture medium during the IPC maturation phase in addition to nicotinamide. Currently, IPCs can be generated from MSCs obtained from human umbilical cord blood (Gao et al., 2008; Parekh et al., 2009; Wang et al., 2010), banked human umbilical cord blood (Phuc et al., 2011), placenta (Kadam et al., 2010), bone marrow (Sun et al., 2007; Xie et al., 2009; Phadnis et al., 2011), menstrual blood (Li et al., 2010), amniotic fluid (Trovato et al., 2009), Whartons jelly (Chao et al., 2008; Wu et al., 2009), amnion (Kadam et al., 2010), and adipose tissue (Chandra et al., 2009). Other studies report the successful use of transgenesis to differentiate MSCs into IPCs, or up-regulation of genes (mainly PDX-1 or betacellulin) related to signalling pathways that trigger this process (Karnieli et al., 2007; Li et al., 2007; Li et al., 2008; Hisanaga et al., 2008; Limbert and Seufert., 2009; Yuan et al., 2010; Paz et al., 2011). Moreover, coating the tissue culture flasks with substrates such as fibronectin or laminin can also induce MSCs to differentiate into IPCS (Moriscot et al., 2005; Chang et al., 2008; Gao et al., 2008; Lin et al., 2010; Lin et al., 2011).

Recent reports suggest that pancreatic duct cells, liver cells, spleen cells, and other cell types have the ability to differentiate into islet cells. Although it is difficult to differentiate adult cells into insulin-producing pancreatic cells, some researchers have shown evidence of pancreatic duct regeneration in mouse models. When gastrin was injected into mice to induce acinar cells to differentiate into duct cells, these cells became a cellular substrate for the formation of new beta cells, similar to the effects seen in rats receiving glucose injections (Weir and Bonner-Weir et al., 2004).

Liver cells originating from the endothelium may also be candidates for this specialised insulin-secreting role (Meivar-Levy et al., 2006). Yang et al. (2002) reported that exposure to high glucose concentrations caused oval cells in the liver to differentiate into cells with a phenotype similar to that of pancreatic islet cells (Yang et al., 2002). Another strategy involves the in vivo gene transfer of the pdx-1 gene into liver cells using an adenovirus vector to induce endogenous pdx-1 gene expression. Pdx-1, along with other beta cell genes, is associated with insulin secretion (Zalzman et al., 2005; Sapir et al., 2005; Shternhall-Ron et al., 2007; Aviv et al., 2009; Gefen-Halevi et al., 2010; Meivar-Levy and Ferber, 2010). Similar to pdx-1, betacellulin and neuro-D expression by liver cells yielded sufficient insulin-producing cells in a streptozocin (STZ)-induced diabetic mouse model. These techniques not only induce liver cells to differentiate into beta cells, but also create new islets within the liver itself (Kojima et al., 2003). Other studies showed that human foetal liver cells transfected with telomerase and pdx-1 can produce insulin and release it into the body. These cells cured diabetes mellitus when transplanted into immuno-deficient diabetic mice.

Fibroblasts are a relatively new source of islets and are easily isolated from skin. In a recent study, 61 single-cell-derived dermal fibroblast clones were established from human foreskin using a limiting dilution technique. These cells were able to differentiate into islet-like clusters when induced using pancreatic-inducing medium and several hormones, including insulin, glucagon and somatostatin, were detectable at both the mRNA and protein levels after induction. Moreover, transplantation of these islet-like clusters resulted in the release insulin in response to glucose in vitro (Bi et al. 2010).

Transplantation of stem cells/IPCs to treat diabetes mellitus has been investigated in both animal models and humans. Many different types of stem cells have been tested using different methods. Cells can be grafted underneath the kidney capsule (Rackham et al., 2011; Figliuzzi et al., 2009; Ito et al., 2010; Lin et al., 2009; Kodama et al., 2009; Kodama et al., 2008; Zhang et al., 2010; Ohmura et al., 2010; Xiao et al., 2008; Berman et al., 2010), delivered via intra-peritoneal injection (Boroujeni et al., 2011; Chandra et al., 2009; Koya et al., 2008; Shao et al., 2011; Kadam et al., 2010; Phuc et al., 2011; Lin et al., 2009) or intra-portally (Shyu et al., 2011; Trivedi et al., 2008; Li et al., 2010; Wu et al., 2007; Longoni et al., 2010; Itakura et al., 2007), grafted into the liver (Chao et al., 2008; Zhu et al., 2009; Xu et al., 2007; Chen et al., 2009; Wang et al., 2010) or injected into the tail vein (Dinarvand et al., 2010; Koblas et al., 2009; Kajiyama et al., 2010; Jurewicz et al., 2010) (Fig. 3). However, there is little research comparing the efficiency of these methods. Chen et al. (2009) showed that transplantation of stem cells into the liver produces better results than transplantation into the renal capsule. Although diabetes mellitus is caused by destruction of the beta cells within the pancreatic islets, no studies have attempted transplantation directly into the pancreas. This is because the pancreas is very sensitive organ and is vulnerable to mechanical intervention.

Methods of stem cell/IPC transplantation. Stem cells or IPCs can be transplanted via the tail vein, intraperitoneally, under the kidney capsule, into the liver, or via the portal vein.

Unlike IPC transplantation, the mechanisms underlying islet regeneration and the reductions in blood glucose levels seen in diabetic patients require further study. The main questions that need to be answered are: 1) what role do grafted stem cells play in the regeneration of pancreatic islets? 2) How will stem cells behave when grafted into the body rather than the pancreas?

One type of stem cell that has been used to treat diabetes mellitus and investigated extensively in animal models is MSCs. Almost all research on MSC transplantation shows that in vitro or in vivo transplantation of MSCs results in a reduction of blood glucose levels, weight gain and increased longevity. However, MSCs can play multiple roles. Grafted stem cells can move into the pancreatic islets and differentiate into IPCs (Sorvi et al., 2005; Sordi, 2009). In an in vitro model using MSCs derived from human bone marrow and pancreatic islets, Sorvi et al. (2005) demonstrated crosstalk between MSCs and pancreatic cells mediated by various chemokines and their receptors. A minority of BM-MSCs (225%) express chemokine receptors (CXC receptor 4 [CXCR4], CX3C receptor 1 [CX3CR1], CXCR6, CC chemokine receptor 1 [CCR1], and CCR7) and, accordingly, show chemotactic migration in response to chemokine CXC ligand 12 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3), and CCL19. These factors, released from the islets, were then able to attract MSCs. Moreover, MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)-positive MSCs (Sorvi et al., 2005). This result was subsequently confirmed in 2009 by Sordi, who hypothesised that the crosstalk between MSCs and pancreatic islets was driven by the CXCR4-CXCL12 and CX3CR1-CX3CL1 axes (Sordi, 2009). Movement of MSCs into the pancreas after transplantation was also confirmed by Lin et al. (2009) and Phadnis et al. (2011). Using bone marrow-derived MSC transplantation coupled with down-regulation of neurogenin 3 (Ngn3) induced by a recombinant lentivirus encoding two different small hairpin RNAs (shRNAs) for specific interference, they showed the successful engraftment of MSCs. In addition, they found that the endogenous pancreatic stem cells differentiated into IPCs and played a major role in reversing hyperglycaemia (Lin et al., 2009). However, there are cases in which stem cells derived from human umbilical cord blood also move into the pancreas and differentiate into IPCs in immunocompromised diabetic animals without improving hyperglycaemia (Koblas et al., 2009). Hasegawa et al. (2007) used Nos3 (-/-) mice as a model of impaired bone marrow-derived cell mobilisation and showed that the hyperglycaemia-improving effects of bone marrow transplantation were inversely correlated with the severity of myelo-suppression and delays in peripheral white blood cell recovery. Thus, stem cell mobilisation is critical for bone marrow transplantation-induced beta cell regeneration after injury. Therefore, they suggested that, during bone marrow transplantation, grafted cells first move into the recipients bone marrow and, subsequently, into the injured periphery to regenerate the recipients pancreatic beta cells (Hasegawa et al., 2007).

Another study showed that MSCs display immunomodulatory functions. MSCs prevented beta-cell destruction and development of diabetes mellitus by inducing regulatory T cells (Madec et al., 2009). Thus, MSC transplantation may prevent islet cell destruction by the immune system seen in type 1 diabetes mellitus and the pancreatic islets can be gradually restored. The result was a decrease in blood sugar levels and weight gain. While in a more recent study, it is said that MSCs protected islets from hypoxia/reoxygenation (H/R)-induced injury by decreasing apoptosis and increasing the expression of HIF-1, HO-1, and COX-2 mRNA. The MSCs induced the expression of anti-apoptotic genes, thereby enhancing resistance to H/R-induced apoptosis and dysfunction (Lu et al., 2010).

The use of ESCs for treating diabetes mellitus is limited because of high levels of tumour formation. So there were a few researches using the ESCs for treating diabetes mellitus. In one study, pancreatic cell ontogeny within ESCs transplanted into the renal capsule of STZ-induced mice resulted in pancreatogenesis in situ or beta cell neogenesis. Immunohistochemistry was performed on excised pancreatic tissues using antibodies against stage- and lineage-specific pancreatic markers. Twenty-one days post-transplantation, PDX-1+ pancreatic foci appeared in the renal capsule, which expressed exocrine enzymes (amylase) and endocrine hormones (insulin, glucagon, and somatostatin). These multi-hormonal endocrine cells, a characteristic of beta cell regeneration, suggested possible divergence from embryonic islet cell development (Kodama et al., 2008). In another study, Kodama et al. (2009) showed that transplanted ESCs could migrate into the injured pancreas. Cell tracing analysis showed that significant beta cell neogenesis occurred 2 to 3 weeks after injury. Importantly, whereas pancreas-localised ESC or their derivatives were found adjacent to the sites of regeneration, neogenic pancreatic epithelia, including Ngn3+ cells, were endogenous. Transplantation efficiency was confirmed by enhanced endogenous regeneration and increased beta cell differentiation from endogenous progenitor cells (Kodama et al., 2009).

Based on the successful transplantation of beta cells, or pancreatic islets, for the treatment of diabetes mellitus (Ris et al., 2011; Wahoff et al., 1995; 1996), transplantation of IPCs differentiated from stem cells is seen as a promising therapy for diabetic patients, particularly in light of the lack of tissue donors and the many side effects of insulin injections. Unlike stem cells, transplanted IPCs produce insulin directly. IPC transplantation using different grafting methods has been studied in mouse models. Routes of administration include the portal vein, intra-peritoneal injection, the liver, the tail vein, and the kidney capsule. IPCs, differentiated from bone marrow-derived MSCs, were successfully allografted into the portal vein in a rat model of diabetes mellitus. After transplantation, the IPCs migrated into the liver where they expressed islet hormones, resulting in reduced glucose levels between Days 6 and 20 post-injection (Wu et al., 2007). Xenotransplantation of IPCs derived from fresh or banked human umbilical cord blood into diabetic mice also showed positive results. These IPCs, transplanted via the portal vein (Wang et al., 2010) or intraperitoneally (Phuc et al., 2011), reduced the blood glucose levels in diabetic mice. When IPCs were grafted into the portal vein, human C-peptides were detected in the mouse livers by immunohistochemistry (Wang et al., 2010). Similar to these results, xenotransplantation of IPCs differentiated from the Whartons jelly from human umbilical cords restored normoglycaemia, body weight and a normal glucose tolerance test, indicating that the cells are functional when grafted via the portal vein (Kadam et al., 2010) or liver (Chao et al., 2008).

Zhang et al. (2010) injected IPCs differentiated from human islet-derived progenitor cells under the renal capsule of immunodeficient mice. One month later, 19/28 mice transplanted with progenitor cells and 4/14 mice transplanted with IPCs produced human C-peptide that was detectable in the blood. This indicates that the in vivo environment further facilitates the maturation of progenitor cells. Moreover, 9/19 mice transplanted with progenitor cells, and 2/4 mice transplanted with IPCs, secreted C-peptide in response to glucose (Zhang et al., 2010). Allotransplantation of IPCs differentiated from islet progenitor cells produced similar results (Shyu et al. 2011). In this study, progenitor cells cultured in matrigel differentiated into IPCs following transplantation into diabetic mice.

ESCs were also differentiated into IPCs and used to treat diabetes mellitus in animal models. After transplantation, these cells did not induce teratoma formation in STZ-induced mice and treatment reduced blood glucose levels to almost normal levels (Kim et al., 2003). Another study indicated that ESCs could differentiate into IPCs; however, transplantation of these pancreatic progenitor clusters into STZ-induced mice failed to reverse the hyperglycaemic state. This indicates that ESCs can differentiate into pancreatic progenitor cells and commit to a pancreatic islet cell fate, but are unable to perform the normal functions of beta cells (Chen et al., 2008). While most studies have focused on experimental treatments using IPC transplantation, another study used liver cells (rather than IPCs) to treat diabetes mellitus. Hepatic cells were differentiated from bone marrow-derived MSCs. Transplantation of syngeneic hepatic cells into STZ-induced mice cured their diabetes mellitus. Treatment of mice with hyperglycaemia and islet cell destruction resulted in repair of the pancreatic islets. Blood glucose levels, intra-peritoneal glucose tolerance tests, and serum insulin levels recovered significantly in the treated group. In addition, both body weight and the number of islets were significantly increased (Dinarvand et al., 2010).

Due to their properties of self-renewal and capacity for multipotent differentiation, stem cells are thought to be the best vector for delivering genes and therapeutic gene-coded proteins into the body. Gene transfer experiments that cause stem cells to differentiate into beta cells, or that transfer specific genes coding for insulin, have also been conducted in recent years. There are several possible reasons why the use of stem cell gene therapies can be used to treat diabetes mellitus. However, no study has compared the difference between IPCs produced by chemical induction and those derived from gene transfer. Some researchers hypothesise that the key is the genetic transfer of the signalling pathways related to differentiation from stem cells into IPCs, which will create IPCs more similar to stem cells in vivo. Others argue that genetic modifications, e.g. PDX-1, betacellulin, or Neuro-D transfer, induce cells to differentiate into beta cells, while yet others suggest that the efficiency of IPC transplantation is low because IPCs are mature, specialised cells. For long-term effectiveness, a source of insulin with a long-term regenerative capacity is needed. Early studies by Xu et al. (2007), looking at transferring insulin into MSCs, showed that the resulting MSCs did express human insulin. The body weight of diabetic mice treated with these MSCs increased by 6% within 6 weeks of treatment, and average blood glucose levels were 10.40 +/- 2.80 mmol/l (Day 7) and 6.50 +/- 0.89 mmol/l (Day 42), compared with 26.80 +/- 2.49 mmol/l (Day 7) and 25.40 +/- 4.10 mmol/l (Day 42) in untreated animals (p < 0.05). Experimental diabetes mellitus was effectively relieved for up to 6 weeks after intrahepatic transplantation of murine MSCs expressing human insulin (Xu et al., 2007). In other studies, STZ-treated mice transplanted with Pdx1-transduced adipose tissue-derived MSCs (Pdx1-MSCs) showed significant decreases in blood glucose levels and increased survival compared with control mice (Lin et al., 2009; Kajiyama et al., 2010).

Transplantation IPCs offers a potential cell replacement therapy for patients with type 1 diabetes mellitus. However, because of the inadequate number of cells obtained from donors, other stem cell sources have drawn significant attention from many research groups. The efficacy of these approaches is limited because they typically necessitate the administration of immunosuppressive agents to prevent rejection of transplanted cells. The use immunosuppressive drugs can have deleterious side effects, such as increased susceptibility to infection, liver and kidney damage, and an increased risk of cancer. In addition, immunosuppressive drugs may have unexpected effects on the transplanted tissues. For example, some reports have shown that cyclosporine can inhibit insulin secretion by pancreatic cells.

Immuno-isolation is a promising technique that protects the implanted tissues from rejection. One of the most common immuno-isolation techniques is to encapsulate cells within a semi-permeable membrane, such as alginate, that physically protects the grafts from the hosts immune cells while simultaneously allowing nutrients and metabolic products to diffuse into or out of the capsule. To achieve this, the cells are encapsulated within a hydrogel or alginate membrane using gravity, electrostatic forces, or coaxial airflow to form the capsule. Allogeneic and xenogeneic transplantation of encapsulated islets of Langerhans restores normal blood glucose levels in mice (Dufrane et al., 2006; Fan et al., 1990; Omer et al., 2003), dogs (Soon-Shiong et al., 1992a,b; 1993) and non-human primates (Sun et al., 1996) with diabetes mellitus induced by autoimmune diseases or chemical injury, without on the need for immunosuppressive agents. In most of these studies, transplantation was via intraperitoneal injection of islet cells. However, Dufrane et al. (2006) recently reported the generation of encapsulated porcine islets using a Ca-alginate material. These capsules were implanted under the kidney capsule of nondiabetic Cynomolgus monkeys. The implanted porcine islets survived for up to 6 months after implantation without immunosuppression, even in animals injected with porcine IgG. Moreover, C-peptide was detected in 71% of the animals. After 135 and 180 days, the explanted capsules still synthesised insulin and responded to glucose stimulation (Dufrane et al., 2006).

In another study, transplantation of alginate-encapsulated IPCs from an embryo-derived mouse embryo progenitor-derived insulin-producing-1 (MEPI-1) cell line lowered hyperglycaemia in immuno-competent, allogeneic diabetic mice. After transplantation, hyperglycaemia was reversed and was followed by a 2.5-month period of normal to moderate hypoglycaemia before relapse. Relapse occurred within 2 weeks in mice transplanted with non-encapsulated MEPI-1 cells. Blood glucose levels, insulin levels, and the results of an oral glucose tolerance test all correlated directly with the number of viable cells remaining in the capsules in the transplanted animals (Shao et al., 2011). Moreover, encapsulation of IPCs differentiated from amnion-derived MSCs, or adipose tissue-derived MSCs in polyurethane-polyvinyl pyrrolidone macrocapsules, or IPCs in calcium alginate, resulted in the restoration of normoglycaemia without immunorejection (Chandra et al., 2009; Kadam et al., 2010) in diabetic rats

Allogeneic islet/IPC transplantation is an efficient method for maintaining normal glucose levels and for the treatment of diabetes mellitus. However, limited sources of islets/IPCs, high rates of islet/IPC graft failure and the need for long-term immunosuppression are major obstacles to the widespread application of these therapies. To overcome these problems, co-transplantation of pancreatic islets/IPCs and adult stem cells is considered as a potential target for the near future. In fact, new results suggest that co-transplantation of stem/precursor cells, particularly MSCs, and islets/IPCs promotes tissue engraftment and beta cell/IPC survival. This theory proposes that stem cells also act as "feeder" cells for the islets, supporting graft protection, tissue revascularisation, and immune acceptance (Sordi et al., 2010).

Overcoming the loss of islet mass is important for successful islet transplantation. Adipose tissue-derived stem cells (ADSCs; referred to as MSCs by some authors) have angiogenic and anti-inflammatory properties. Co-transplantation of ADSCs and islets into mice promotes survival, improves insulin secretion by the graft, and reduces the islet mass required for treatment (Ohmura et al., 2010). In another study, MSCs derived from adipose tissue were differentiated into IPCs and co-transplanted with cultured bone marrow cells into 11 diabetic patients (7 male, 4 female; disease duration, 124 years; age range, 1343 years). Their mean exogenous insulin requirements were 1.14 units/kg BW/day, the mean glycosylated haemoglobin (Hb1Ac) level was 8.47%, and the mean c-peptide level was 0.1 ng/mL. All the patients received successful transplants and the mean follow-up period was 23 months. The results showed a decreased mean exogenous insulin requirement of 0.63 units/kgBW/day, a reduced Hb1Ac of 7.39%, and raised serum c-peptide levels (0.38 ng/mL). The patients reported no diabetic ketoacidosis events and a mean weight gain of 2.5 kg on a normal vegetarian diet and physical activity (Vanikar et al., 2010). However, a previous report indicated that similar results were obtained with undifferentiated MSC-derived adipose tissue co-transplanted with cultured bone marrow. In this study, human adipose tissue-derived MSCs were transfused along with unfractionated cultured bone marrow into five insulinopenic diabetic patients (2 male, 3 female; age range, 1428 years; disease duration, 0.6 to 10 years) being treated with human insulin (1470 U/d). The patients had postprandial blood sugar levels between 156 and 470 mg%, Hb1Ac levels of 6.8% to 9.9%, and c-peptide levels of 0.02 to 0.2 ng/mL. After successful transplantation, all patients showed a 30% to 50% reduction in their insulin requirements along with a 426-fold increase in serum c-peptide levels during a mean follow-up period of 2.9 months (Trivedi et al., 2008).

After transplantation, MSCs appear to play an immunomodulatory role, thereby promoting graft acceptance. In a cynomolgus monkey model, allogeneic MSCs were co-transplanted with islets intra-portally on postoperative Day 0 and intravenously with donor marrow on postoperative Days 5 and 11. Increased co-transplantation efficiency was associated with increased numbers of regulatory T-cells in the peripheral blood, indicating that co-transplantation of MSCs and islets may be an important method of enhancing islet engraftment and, thereby, decreasing the number of islets required (Berman et al., 2010). Co-transplantation may also downregulate the production of pro-inflammatory cytokines. These results also suggest that MSCs may prevent acute rejection and improve graft function after portal vein pancreatic islet transplantation (Longoni et al., 2010), or that they may induce haematopoietic chimerism and subsequent immune tolerance without causing graft-versus-host disease (Itakura et al., 2007). Moreover, MSC-stimulated graft vascularisation and improved islet graft function are both associated with co-transplanted islets (Figliuzzi et al. 2009; Ito et al. 2010). In addition, interleukin (IL)-6, IL-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC culture medium. These are trophic factors secreted by human MSCs that enhance the survival and function of the islets after transplantation (Park et al., 2010).

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Stem Cell Therapy for Islet Regeneration | InTechOpen

J Nat Sci Biol Med. 2015 Jan-Jun; 6(1): 2934.

Department of Conservative Dentistry and Endodontics, Institute of Dental Sciences, Sehora, Jammu and Kashmir, India

1Department of Physiology, Government Medical College, Patiala, Punjab, India

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Teeth are the most natural, noninvasive source of stem cells. Dental stem cells, which are easy, convenient, and affordable to collect, hold promise for a range of very potential therapeutic applications. We have reviewed the ever-growing literature on dental stem cells archived in Medline using the following key words: Regenerative dentistry, dental stem cells, dental stem cells banking, and stem cells from human exfoliated deciduous teeth. Relevant articles covering topics related to dental stem cells were shortlisted and the facts are compiled. The objective of this review article is to discuss the history of stem cells, different stem cells relevant for dentistry, their isolation approaches, collection, and preservation of dental stem cells along with the current status of dental and medical applications.

Keywords: Cell culture techniques, stem cells, stem cell research, tissue banks, tissue engineering

Regenerative capacity of the dental pulp is well-known and has been recently attributed to function of dental stem cells. Dental stem cells offer a very promising therapeutic approach to restore structural defects and this concept is extensively explored by several researchers, which is evident by the rapidly growing literature in this field. For this review article a literature research covering topics related to dental stem cells was made and the facts are compiled.

A web-based research on Medline (www.pubmed.gov) was done. To limit our research to relevant articles, the search was filtered using terms review, published in the last 10 years and dental journals. Various keywords used for research were regenerative dentistry (128 articles found), dental stem cells (111 articles found), dental stem cells banking (2 articles found), stem cells from human exfoliated deciduous teeth (SHED) (11 articles found). For each heading in the review, relevant articles were chosen and arranged in chronological order of publication date so as to follow the development of the research topic. This review screened about 250 articles to get the required knowledge update. Relevant data were then compiled with aim of providing basic information as well as latest updates on dental stem cells.

Stem cells also known as progenitor or precursor cells are defined as clonogenic cells capable of both self-renewal and multi-lineage differentiation.[1] In 1868, the term stem cell for the first time appeared in the works of German biologist Haeckel.[2] Wilson coined the term stem cell.[3] In 1908, Russian histologist, Alexander Maksimov, postulated existence of hematopoietic stem cells at congress of hematologic society in Berlin.[4] There term stem cell was proposed for scientific use.

Stem cells have manifold applications and have contributed to the establishment of regenerative medicine. Regenerative medicine is the process of replacing or regenerating human cells, tissues or organs for therapeutic applications.[5] The concept of regeneration in the medical field although not new has significantly advanced post the discovery of stem cells and in recent times have found its application in dentistry following identification of dental stem cells. Although, the concept of tooth regeneration was initially not accepted the ground-breaking work by stomatologist G. L. Feldman (1932) showed evidence of regeneration of dental pulp under certain optimal biological conditions. This work introduced the biological-aseptic principle of tooth therapy to achieve pulp regeneration using dentine fillings as building material for stimulating pulp regeneration.[6] Nevertheless subsequent researchers further improved this work.[6] Major breakthrough in dental history was achieved in year 2000 when Gronthos et al. identified and isolated odontogenic progenitor population in adult dental pulp.[7] These cells were referred to as dental pulp stem cells (DPSCs). Since this discovery several researchers have reported varieties of dental stem cells, which are described below:

Human dental stem cells that have been isolated and characterized are:

Stem cells from various sources and their features studied by various researchers are presented in .[7,8,11,12,13,14,15,16,17,18]

Stem cells and their features studied by various researchers (at full page width)

DPSCs are mesenchymal type of stem cells inside dental pulp.[19] DPSCs have osteogenic and chondrogenic potential in vitro and can differentiate into dentin, in vivo and also differentiate into dentin-pulp-like complex.[7] Recently, immature dental pulp stem cells[20] were identified which are a pluripotent sub-population of DPSC generated using dental pulp organ culture.

DPSCs are putative candidate for dental tissue engineering due to:[21]

Easy surgical access to the collection site and very low morbidity after extraction of the dental pulp.

DPSCs can generate much more typical dentin tissues within a short period than nondental stem cells.

Can be safely cryopreserved and recombined with many scaffolds.

Possess immuno-privilege and anti-inflammatory abilities favorable for the allotransplantation experiments.

Four commonly used stem cell identification techniques[22] are:

Fluorescent antibody cell sorting: Stem cells can be identified and isolated from mixed cell populations by staining the cells with specific antibody markers and using a flow cytometer.

Immunomagnetic bead selection.

Immunohistochemical staining.

Physiological and histological criteria, including phenotype, proliferation, chemotaxis, mineralizing activity and differentiation.

Various conventional methods to isolate stem cells from dental pulp are listed below:

Enzymatic digestion of whole dental pulp tissue in solution of 3% collagenase Type I for 1 h at 37C is done. Through process of filtering and seeding, cells with diameter between 3 and 20 m are obtained for further culture and amplification. Based on this approach, small-sized cell populations containing a high percent of stem cells can be isolated.

Enzymatic digestion of the dental pulp tissue is done to prepare single cell suspension cells of which are used for colony formation containing 50 or more cells that is further amplified for experiments.

Is an immune-magnetic method used for separation of stem cell populations based on their surface antigens (CD271, STRO-1, CD34, CD45, and c-Kit). MACS is technically simple, inexpensive and capable of handling large numbers of cells but the degree of stem cell purity is low.

Is convenient and efficient method that can effectively isolate stem cells from cell suspension based on cell size and fluorescence. Demerits of this technique are a requirement of expensive equipment, highly-skilled personnel, decreased viability of FACS-sorted cells and this method is not appropriate for processing bulk quantities of cells.

Dr. Songtao Shi discovered SHED in 2003. Miura et al.[8] confirmed that SHED were able to differentiate into a variety of cell types to a greater extent than DPSCs, including osteoblast-like, odontoblast-like cells, adipocytes, and neural cells. Abbas et al.[23] investigated the possible neural crest origin of SHED. The main task of these cells seems to be the formation of mineralized tissue, which can be used to enhance orofacial bone regeneration.

Types of stem cells present in human exfoliated deciduous teeth are

Advantages of banking SHED cells[25] include: It's a simple painless technique to isolate them and being an autologous transplant they dont possess any risk of immune reaction or tissue rejection and hence immunosuppressive therapy is not required. SHED may also be useful for close relatives of the donor such as grandparents, parents and siblings. Apart from these, SHED banking is more economical when compared to cord blood and may be complementary to cord cell banking. The most important of all these cells are not subjected to same ethical concerns as embryonic stem cells.

Step 1: Tooth collection

Freshly-extracted tooth is transferred into vial containing hypotonic phosphate buffered saline solution (up to four teeth in one vial). Vial is then carefully sealed and placed into thermette, after which the carrier is placed into an insulated metal transport vessel. Thermette along with insulated transport vessel maintains the sample in a hypothermic state during transportation. This procedure is described as sustentation. The time from harvesting to arrival at processing storage facility should not exceed 40 h.

Step 2: Stem cell isolation

Tooth surface is cleaned by washing three times with Dulbecco's phosphate buffered saline without Ca2+ and Mg2+. Disinfection is done and again washed with PBSA. Pulp tissue is isolated from the pulp chamber and is placed in a sterile petri dish, washed at least three times with PBSA. The tissue digestion is done with collagenase Type I and dispase for 1 h at 37C. Isolated cells are passed through a 70 um filter to obtain single cell suspensions. Then the cells are cultured in a MSC medium. Usually isolated colonies are visible after 24 h.

Step 3: Stem cell storage.

The approaches used for stem cell storage are: (a) Cryopreservation (b) magnetic freezing.

It is the process of preserving cells or whole tissues by cooling them to sub-zero temperatures. Cells harvested near end of log phase growth (approximately. 8090% confluent) are best for cryopreservation. Liquid nitrogen vapour is used to preserve cells at a temperature of <150C. In a vial 1.5 ml of freezing medium is optimum for 12 106 cells.

This technology is referred to as cells alive system (CAS), which works on principle of applying a weak magnetic field to water or cell tissue which will lower the freezing point of that body by up to 67C. Using CAS, Hiroshima University (first proposed this technology) claims that it can increase the cell survival rate in teeth to 83%. CAS system is a lot cheaper than cryogenics and more reliable.

Primary incisors and canines with no pathology and at least one third of root left can be used for SHED banking. Primary molar roots are not recommended for sampling as they take longer time to resorb, which may result in an obliterated pulp chamber that contains no pulp, and thus, no stem cells.[26] However in some cases where deciduous molars are removed early for orthodontic reasons, it may present an opportunity to use these teeth for stem cell banking.

MSCs residing in the apical papilla of permanent teeth with immature roots are known as SCAP. These were discovered by Sonoyama et al.[9] SCAP are capable of forming odontoblast-like cells, producing dentin in vivo, and are likely cell source of primary odontoblasts for the formation of root dentin. SCAP supports apexogenesis, which can occur in infected immature permanent teeth with periradicular periodontitis or abscess. SCAP residing in the apical papilla survive such pulp necrosis because of their proximity to the periapical tissue vasculature. Hence even after endodontic disinfection, SCAP can generate primary odontoblasts, which complete root formation under the influence of the surviving epithelial root sheath of Hertwig.[9]

Seo et al.[11] described the presence of multipotent postnatal stem cells in the human periodontal ligament (PDLSCs). When transplanted into rodents, PDLSCs had the capacity to generate a cementum/periodontal ligament-like structure and contributed to periodontal tissue repair. These cells can also be isolated from cryopreserved periodontal ligaments while retaining their stem cell characteristics, including single-colony strain generation, cementum/periodontal-ligament-like tissue regeneration, expression of MSC surface markers, multipotential differentiation and hence providing a ready source of MSCs.[27]

Using a mini pig model, autologous SCAP and PDLSCs were loaded onto hydroxyapatite/tricalcium phosphate and gelfoam scaffolds, and implanted into sockets in the lower jaw, where they formed a bioroot encircled with the periodontal ligament tissue and in a natural relationship with the surrounding bone.[28] Trubiani et al.[29] suggested that PDLSCs had regenerative potential when seeded onto three dimensional biocompatible scaffold, thus encouraging their use in graft biomaterials for bone tissue engineering in regenerative dentistry, whereas Li et al.[30] have reported cementum and periodontal ligament-like tissue formation when PDLSCs are seeded on bioengineered dentin.

Although tooth banking is currently not very popular the trend is gaining acceptance mainly in the developed countries. BioEden (Austin, Texas, USA), has international laboratories in UK (serving Europe) and Thailand (serving South East Asia) with global expansion plans. Stem cell banking companies like Store A- Tooth (Provia Laboratories, Littleton, Massachusetts, USA) and StemSave (Stemsave Inc, New York, USA) are also expanding their horizon internationally. In Japan, the first tooth bank was established in Hiroshima University and the company was named as Three Brackets (Suri Buraketto) in 2005. Nagoya University (Kyodo, Japan) also came up with a tooth bank in 2007. Taipei Medical University in collaboration with Hiroshima University opened the nation's first tooth bank in September, 2008. The Norwegian Tooth Bank (a collaborative project between the Norwegian Institute of Public Health and the University of Bergen) set up in 2008 is collecting exfoliated primary teeth from 1,00,000 children in Norway. Not last but the least, Stemade introduced the concept of dental stem cells banking in India recently by launching its operations in Mumbai and Delhi.

Most research is directed toward regeneration of damaged dentin, pulp, resorbed root, periodontal regeneration and repair perforations. Whole tooth regeneration to replace the traditional dental implants is also in pipeline. Tissue-engineering applications using dental stem cells that may promote more rapid healing of oral wounds and ulcers as well as the use of gene-transfer methods to manipulate salivary proteins and oral microbial colonization patterns are promising and possible.[31]

Adult MSCs recently identified in the gingival connective tissues (gingival mesenchymal stem cells [GMSCs]) have osteogenic potential and are capable of bone regeneration in mandibular defects. GMSCs also suppress the inflammatory response by inhibiting lymphocyte proliferation and inflammatory cytokines and by promoting the recruitment of regulatory T-cells and anti-inflammatory cytokines. Thus, GMSCs potentially promote the right environment for osseous regeneration and is currently being therapeutically explored.[32]

Researchers of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell Biology and Regenerative Medicine, reported a possible method for growing teeth from stem cells obtained in urine.[33] In this study, pluripotent stem cells derived from human urine were induced to generate tooth-like structures in a group of mice with a success rates of up to 30%. The generated teeth had physical properties similar to that of normal human teeth except hardness (about one-third less in hardness of human teeth). The reported advantages to such an approach were being noninvasive technique, low cost, and use of somatic cells (instead of embryonic) that are wasted anyways. Interestingly urine-derived stem cells do not form tumors when transplanted in the body unlike other stem cells; more over autologous sourcing of these cells reduces the likelihood of rejection.

Dental stem cells have the potential to be utilized for medical applications like heart therapies,[34] regenerating brain tissue,[35] for muscular dystrophy therapies[36] and for bone regeneration.[37,38] SHED can be used to generate cartilage[39] as well as adipose tissue.[40] In 2008 first advanced animal study for bone grafting was announced resulting in reconstruction of large size cranial bone defects in rats with human DPSCs.[41]

Researchers have observed promising results in several preclinical animal studies and numerous clinical trials are now on-going globally to further validate these findings. The Obama administration has made stem cell research one of the pillars of his health program. The U.S. Army is investing over $250 million in stem cell research to treat injured soldiers in a project called Armed Forces Institute for Regenerative Medicine. It is likely that the next stem cell advance is the availability of regenerative dental kits, which will enable the dentists the ability to deliver stem cell therapies locally as part of routine dental practice. An innovative method that holds promising future is to generate induced stem cells from harvested human dental stem cells. This approach reprograms dental stem cells into an embryonic state, thus expanding their potential to differentiate into a much wider range of tissue types. Researchers have so far succeeded in making specific dental tissues or tooth like structures although in animal studies but future advances in dental stem cell research will be the regeneration of functional tooth in humans.

As human stem cell research is a relatively new area, companies developing cell therapies face several types of risks as well, and some are not able to manage them thus pushing this venture into a highly speculative enterprise. Present clinical trials are being performed on recombinant human fibroblast growth factor-2, human platelet-derived growth factor, and tricalcium phosphate (GEM-21). Looking at the ongoing clinical trials, it is too early to speculate whether all therapies based on stem cells will prove to be clinically effective.[42]

Stem cells of dental origin have multiple applications nevertheless there are certain limitations as well. The oncogenic potential of these cells is still to be determined in long-term clinical studies. Moreover, the research is mainly confined to animal models and their extensive clinical application is yet to be tested. Other major limitations are the difficulty to identify, isolate, purify and grow these cells consistently in labs. Immune rejection is also one of the issues, which require a thorough consideration; nevertheless use of autologous cells can overcome this. Lastly, stem/progenitor cells are comparatively less potent than embryonic stem cells. Teeth-like structures cannot replace actual teeth, thus a considerable research research and development efforts is required to advance the dental regenerative therapeutics. Researchers still need to grow blood and nerve supply of teeth to make them fully functional. Although not currently available, these approaches may one day be used as biological alternatives to the synthetic materials currently used. Like other powerful technologies, dental stem cell research poses challenges as well as risks. If we are to realize the benefits, meet the challenges, and avoid the risks, stem cell research must be conducted under effective, accountable systems of social-responsible oversight and control, at both the national and international levels.[43]

Source of Support: Nil.

Conflict of Interest: None declared.

3. Wilson EB. 1st ed. New York: Macmillan Company; 1996. The Cell in Development and Inheritance.

4. Maximow A. The lymphocyte as a stem cell, common to different blood elements in embryonic development and during the post-fetal life of mammals. Folia Haematol. 1909;8:12334.

6. Polezhaev LV. 1st ed. Jerusalem: Keterpress; 1972. Restoration of lost regenerative capacity of dental tissues. In: Loss and Restoration of Regenerative Capacity in Tissues and Organs of Animals; pp. 14152.

23. Abbas, Diakonov I, Sharpe P. Neural crest origin of dental stem cells. Pan European Federation of the International Association for Dental Research (PEF IADR) Seq #96-Oral. Stem Cells. 2008 Abs, 0917.

26. Reznick JB. Continuing education: Stem cells: Emerging medical and dental therapies for the dental professional. Dentaltown Mag. 2008;Oct:4253.

31. Jain A, Bansal R. Regenerative medicine: Biological solutions to biological problems. Indian J Med Spec. 2013;4:416.

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Current overview on dental stem cells applications in ...

Dental Pulp Stem Cells were primarily derived from the pulp tissues of exfoliated deciduous teeth, primary incisors and permanent third molar teeth. The dental pulp, third molars in particular, have been shown to be a significant stem cell source due to greater numbers of stem cells residing in the pulp. DPSCs from third molars have been shown to express developmentally important transcription factors, such as oct4, sox2, klf4, nanog and c-myc, which is an indicator of their pluri-potency. Flow-cytometry analysis revealed DPSCs were positive for CD73, CD90, CD105 and CD166, but negative for CD34, CD45 and CD133, suggesting that these cells are mesenchymal-like stem cells. Under specific culture conditions, DPSCs differentiated into osteogenic, adipogenic and neurogenic cells, as well as formed tube-like structures in Matrigel assay.

Stem Cells From Human Exfoliated Deciduous Teeth (SHED) are considered to be the most immature of the Dental Stem Cells and show the highest proliferative capacity when grown in culture. Similar to the DPSCs from third molars, SHED are very durable in culture and have been passaged over 80 times with no detectable signs of senescence or telomere shortening. SHED express the embryonic stem (ES) cell markers Oct4, Nanog, stage-specific embryonic antigens (SSEA-3, SSEA-4), and tumor recognition antigens (TRA-1-60 and TRA-1-81). When cultured in neurogenic medium, SHED form sphere-like clusters which adhere to the culture dish or float freely in the culture medium.

Dental Follicle Stem Cells is an ectomesenchymal tissue surrounding the enamel organ and the dental papilla of the developing tooth germ prior to eruption. The tissue contains the progenitor cells that form the periodontium, (cementum, PDL, and alveolar bone). In culture DFSC adhere to plastic, proliferate well and like other mesenchymal stem cells show a typical fibroblast-like morphology. DFSCs express the embryonic marker OCT4 and the neural progenitor markers Notch-1 and nestin.

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Dental Pulp Stem Cells, Human Dental Pulp Stem Cells ...