A clinical study involves research using human volunteers (also called . Various Federal agencies, including the Office of Human Subjects Research Protection. Human Factors-Simulated Use Validation Studies. . combination product for review under an ANDA that may include HF studies should contact the CDER. included in the guidelines for direct food additives and color additives used in conduct human studies in support of the safety of direct food additives and.
studies Included human
When participants are healthy volunteers who receive financial incentives, the goals are different than when the participants are sick. During dosing periods, study subjects typically remain under supervision for one to 40 nights.
Usually pilot experiments are conducted to gain insights for design of the clinical trial to follow. There are two goals to testing medical treatments: Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition.
The benefits must outweigh the risks. Children and people with unrelated medical conditions are also frequently excluded. The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type s of patients might benefit.
If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment s and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs , concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs.
The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device:. While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo.
Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures that all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects.
As a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method , specifically the experimental step. The most common clinical trials evaluate new pharmaceutical products , medical devices such as a new catheter , biologics , psychological therapies , or other interventions.
Clinical trials may be required before a national regulatory authority  approves marketing of the innovation. Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket approval. An example of the former in the field of vascular surgery is the Open versus Endovascular Repair OVER trial for the treatment of abdominal aortic aneurysm , which compared the older open aortic repair technique to the newer endovascular aneurysm repair device.
Similarly to drugs, medical or surgical procedures may be subjected to clinical trials,  such as case-controlled studies for surgical interventions. The concepts behind clinical trials are ancient. The Book of Daniel chapter 1, verses 12 through 15, for instance, describes a planned experiment with both baseline and follow-up observations of two groups who either partook of, or did not partake of, "the King's meat" over a trial period of ten days.
Persian physician Avicenna , in The Canon of Medicine gave similar advice for determining the efficacy of medical drugs and substances. Although early medical experimentation was often performed, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy, was generally lacking. For instance, Lady Mary Wortley Montagu , who campaigned for the introduction of inoculation then called variolation to prevent smallpox , arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life.
Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed.
The first proper clinical trial was conducted by the physician James Lind. In , the catastrophic result of Anson 's circumnavigation attracted much attention in Europe; out of men, had died, most of them allegedly from having contracted scurvy. Lind conducted the first systematic clinical trial in He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol sulfuric acid , group three six spoonfuls of vinegar , group four half a pint of seawater, group five received two oranges and one lemon , and the last group a spicy paste plus a drink of barley water.
The treatment of group five stopped after six days when they ran out of fruit, but by that time one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. After , the discipline began to take its modern shape. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the s. Frederick Akbar Mahomed d. He also founded the Collective Investigation Record for the British Medical Association ; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials.
Fisher , while working for the Rothamsted experimental station in the field of agriculture, developed his Principles of experimental design in the s as an accurate methodology for the proper design of experiments. Among his major ideas, was the importance of randomization — the random assignment of individuals to different groups for the experiment;  replication — to reduce uncertainty , measurements should be repeated and experiments replicated to identify sources of variation;  blocking — to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of factorial experiments — efficient at evaluating the effects and possible interactions of several independent factors.
The British Medical Research Council officially recognized the importance of clinical trials from the s. The Council established the Therapeutic Trials Committee to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease.
The trial, carried out between —, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled. The methodology of clinical trials was further developed by Sir Austin Bradford Hill , who had been involved in the streptomycin trials.
From the s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson , among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in , which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of over 30, doctors over a period of several years.
His certificate for election to the Royal Society called him " International clinical trials day is celebrated on 20 May. Another way of classifying trials is by their purpose. A third classification is whether the trial design allows changes based on data accumulated during the trial. Finally, a common way of distinguishing trials is by phase, which in simple terms, relates to how close the drug is to being clinically proven both effective for its stated purpose and accepted by the regulatory authorities for use for that purpose.
Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial.
The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through phases 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population.
Before pharmaceutical companies start clinical trials on a drug, they will also have conducted extensive preclinical studies. Each phase has a different purpose and helps scientists answer a different question. A fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials.
A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. Currently, some phase 2 and most phase 3 drug trials are designed as randomized, double-blind , and placebo -controlled. Clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial.
In many cases, giving a placebo to a person suffering from a disease may be unethical. In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness.
In such studies, multiple experimental treatments are tested in a single trial. Genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug.
The first such approach targets squamous cell cancer , which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. A clinical trial protocol is a document used to define and manage the trial. It is prepared by a panel of experts.
All study investigators are expected to strictly observe the protocol. The protocol describes the scientific rationale, objective s , design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure. The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators.
The protocol also informs the study administrators often a contract research organization. The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance  issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH.
Journals such as Trials , encourage investigators to publish their protocols. Clinical trials recruit study subjects to sign a document representing their " informed consent ". The document is not a contract, as the participant can withdraw at any time without penalty. Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language.
Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. The number of subjects has a large impact on the ability to reliably detect and measure effects of the intervention.
This is described as its " power ". The larger the number of participants, the greater the statistical power and the greater the cost.
The statistical power estimates the ability of a trial to detect a difference of a particular size or larger between the treatment and control groups.
For example, a trial of a lipid -lowering drug versus placebo with patients in each group might have a power of 0. Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned randomly without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned.
Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment.
The Declaration of Helsinki provides guidelines on this issue. Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs in cell and animal studies before ever undergoing clinical trials.
In all, about 1, potential drugs are tested before just one reaches the point of being tested in a clinical trial. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public.
The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo.
Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low. For clinical trials involving potential for seasonal influences such as airborne allergies , seasonal affective disorder , influenza , and skin diseases , the study may be done during a limited part of the year such as spring for pollen allergies , when the drug can be tested.
Clinical trials that do not involve a new drug usually have a much shorter duration. Exceptions are epidemiological studies, such as the Nurses' Health Study. Clinical trials designed by a local investigator, and in the US federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company.
Clinical trials of new drugs are usually administered by a contract research organization CRO hired by the sponsoring company. The sponsor provides the drug and medical oversight. For help determining whether your study meets the definition of clinical trial, see the Clinical Trial Questionnaire below. Read your FOA carefully to determine whether clinical trials are allowed in your application.
If you are including multiple delayed onset studies in one delayed onset study entry, and you anticipate that any of these studies will be a clinical trial, check the "Anticipated Clinical Trial? Follow the standard instructions. Do not check the "Anticipated Clinical Trial? Fellowship FOAs do not allow independent clinical trials.
If you are including more than one delayed onset study in any given delayed onset study entry, address all the included studies in a single justification attachment.
Enter a brief title that describes the study the participants will be involved in. If there is more than one study i. The first characters will display in the bookmarks of the application image. When registering a clinical trial in ClinicalTrials. This field matches a ClinicalTrials. Indicate whether the study is exempt from Federal regulations for the Protection of Human Subjects. Select the appropriate exemption number s for this particular study.
Multiple selections are permitted. Regardless of whether these exemptions may apply to you in the future, you must fill out your application following the instructions below.
The categories of research that qualify for exemption are defined in the Common Rule for the Protection of Human Subjects. These regulations can be found at 45 CFR Note for basic and mechanistic studies involving human participants: The NIH definition of a clinical trial encompasses a broad range of studies, including studies using human participants that aim to understand fundamental aspects of phenomena, the pathophysiology of a disease, or the mechanism of action of an intervention.
Answer "Yes" or "No" to the following questions to determine whether this study involves a clinical trial. Answer the following questions based only on the study you are describing in this Study Record. If you answered "Yes" to all the questions in the Clinical Trial Questionnaire, this study meets the definition of a clinical trial.
Refer to the table below for information about what sections of this form are required, based on your answers to Question 1. Even if you answered "Yes" to all the questions in the Clinical Trial Questionnaire, only certain fields of the PHS Human Subjects and Clinical Trials Information form are required and other fields are not allowed because the study is not an independent clinical trial.
Inputting information into these sections will result in errors and will prevent your application from being accepted. If a clinical trial has already been entered into ClinicalTrials. If you are building on an existing study e. The number you enter in this field should match the ClinicalTrials. At least 1 entry is required, and up to 20 entries are allowed enter each entry on its own line. Each entry is limited to characters. Identify the name s of the disease s or condition s you are studying, or the focus of the study.
Include an entry for each condition. List the study's inclusion and exclusion criteria. To provide a bulleted list, use a dash or other character followed by a space "- " at the start of each bullet. Be sure to check the formatting in the assembled application image.
Further explanation or justification should be included in the Recruitment and Retention plan. Your text entry is limited to 15, characters but typically needs only characters.
Enter the numerical value for the minimum age a potential participant can be to be eligible for the study. Provide the relevant units of time i. Enter the numerical value for the maximum age a potential participant can be to be eligible for the study.
A new Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects policy takes effect for all applications submitted for due dates on or after January 25, Use the correct set of instructions according to your application due date. The Inclusion of Women, Minorities, and Children instructions will be changing, effective January 25, Please note that there are two sets of instructions below, based on the application due dates.
Organize your attachment into two sections, following the headings and specified order below, and discuss each of the points listed below. Start each section with the appropriate section heading - "Inclusion of Women and Minorities" and "Inclusion of Children.
Note that you may need to include multiple IERs for each study. Refer to the instructions for the IER below for more information. Existing Datasets or Resources. If you will use an existing dataset , resource, or samples that may have been collected as part of a different study, you must address inclusion, following the instructions above. This plan must include selection and discussion of one of the following analysis plans:. For the purposes of the Inclusion of Children, individuals under 18 are defined as a child ; however, exclusion of any specific age or age range group e.
In addition, address the following points:. For applications submitted for due dates on or after January 25, Describe how you will recruit and retain participants in your study. You should address both planned recruitment activities as well as proposed engagement strategies for retention. From the dropdown menu, select a single "Recruitment Status" that best describes the proposed study, based upon the status of the individual sites.
If any facility in a multi-site study has an individual site status of "recruiting," then choose "recruiting" for this question. Only one selection is allowed. Choose from the following options:. Provide a description or diagram describing the study timeline.
The timeline should be general e. Additional milestones or timelines may be requested as just-in-time information or post-award. The "Enrollment of First Subject" question is otherwise required unless the following applies to you:. From the dropdown menu, select whether this date is anticipated or actual. An Inclusion Enrollment Report is required for all human subjects studies unless, on Question 1.
However, more than one IER per study is allowed. These can be a combination of planned and cumulative reports. At a minimum, participants enrolled at non-U. It is important that the IER for a given study be associated with only one application and be provided only once in a given application e. If submitting individual application s as part of a network or set of linked applications, please provide the IER with the individual site applications unless otherwise directed by the FOA.
When preparing a renewal or resubmission of a renewal , investigators should provide a narrative description regarding the cumulative enrollment from the previous funding period s as part of the progress report section of the research strategy attachment in the application.
If a given study will continue with the same enrollment or additional enrollment, or if new studies are proposed, provide a new IER for each as described in the instructions below. If IERs were provided in the initial submission application, and if those studies will be part of the resubmission application, complete the IER and submit again with the resubmission application, regardless of whether the enrollment has changed or not.
Also, provide any new additional IERs. For multi-project applications with studies that are self-contained within a single component: Should the study span more than one component, include the IER with the Study Record in the Overall Component and insert a comment in the comment field of the IER to indicate what other components it is associated with. If the study involves analysis of an existing dataset or resource e.
If the study involves prospective recruitment or new contact with participants answer "No" to this question. Use separate IERs for studies involving use of existing datasets or resources only and for studies that involve prospective recruitment or new contact with study participants. Select whether the participants described in the IER are based at a U. Domestic or at a non-U.
For additional guidance on how to complete the IER if you will be working with non-U. Indicate the country or countries in which participants will be enrolled. Foreign countries can be reported together in one IER. However, you must use separate IERs for U. You can add up to countries per IER.
Indicate the type of enrollment location e. Enrollment locations are typically where the research is conducted, and can be different from the recruitment site. Enter information you wish to provide about this IER. This includes, but is not limited to, addressing information about distinctive subpopulations if relevant to the scientific hypotheses being studied.
If inclusion monitoring is conducted on another study or NIH grant e. Instead, provide a comment in this field to the effect that previous IER s are still applicable. If you are revising the IER s in your original grant application, provide a comment here to that effect. Should the study span more than one component, include the IER with the Study Record in the Overall Component and insert a comment here in the comment field to indicate what other components it is associated with.
All studies must enter planned enrollment counts unless your proposed study will use only an existing dataset or resource. Enter the expected number of females and males in the respective fields who are both Asian and Not Hispanic or Latino. Enter the expected number of females and males in the respective fields who are both Asian and Hispanic or Latino.
Enter the expected number of females and males in the respective fields who are both Native Hawaiian or Other Pacific Islander and Not Hispanic or Latino. Enter the expected number of females and males in the respective fields who are both Native Hawaiian or Other Pacific Islander and Hispanic or Latino. Enter the expected number of females and males in the respective fields who are both Black or African American and Not Hispanic or Latino.
Enter the expected number of females and males in the respective fields who are both Black or African American and Hispanic or Latino. Enter the expected number of females and males in the respective fields who are both White and Not Hispanic or Latino. Enter the expected number of females and males in the respective fields who are both White and Hispanic or Latino. The aetiology is not fully understood.
It was concluded in that study that the ankylotic areas in several cases could not be detected radiographically [ 57 ]. Association between ectopic eruption of maxillary canines and first molars has also been reported [ 55 ]. The explanation for this presumed association has not been given. In the primary dentition eruption arrests are often seen in molars [ 59 , 60 ].
Less severe infraposition of primary molars does not require treatment due to natural exfoliation [ 59 ]. More severe secondary retention of primary molars results in extraction [ 60 ] due to ankylosis. Every single permanent tooth can erupt ectopically.
The prevalence of ectopic eruption is different for individual teeth. Most common in this connection is ectopic eruption of the maxillary canines [ 36 , 61 — 72 ]. The aetiology behind this ectopic condition is intensively discussed. Becker and Chaushu [ 69 ] have in an extended study compared dental ages in patients with bucally displaced canines with a control group with normally located canines. Approximately half the subjects with palatal displacement exhibited a late-developing dentition while the timing in dental development in the remaining subjects was normal [ 69 ].
Buccal displacement of maxillary canines was not associated with a retarded dental development but demonstrated dental development similar to conditions seen in the control group. This study supports the idea that there are different aetiologies for the occurrence of buccal versus palatine canine ectopia [ 69 ]. It has also been described in the literature that an association exists between palatally ectopic canines and small malformed and missing teeth in the dentition [ 62 , 69 , 70 ].
Sacerdoti and Baccetti [ 71 ] analyzed a sample of subjects and found that the prevalence rate of palatally displaced canines was 2. Skeletally they reported a reduced vertical relationship in patients with palatally displaced canines. When they in that study [ 71 ] compared unilateral palatally displaced canines with bilateral palatally displaced canine cases they found that unilateral displacement was associated with agenesis of upper lateral incisors whereas bilateral displacement was associated with third molar agenesis [ 71 ].
This is again a finding which has not been explained. This was later confirmed by Artmann et al. Also deviations in the cranio-facio-skeleton have been reported in cases with ectopic maxillary canines [ 63 , 64 ]. Resorption of maxillary lateral incisors due to ectopic eruption of maxillary canines is a severe clinical problem, which is in focus in the literature on ectopic maxillary canines [ 61 ]. Transposition, which is an eruption deviation characterized by the shifting of place in the dental arch of single teeth causing treatment problems, is also a well-known eruption deviation in the permanent dentition [ 73 ].
In these dentitions craniofacial alterations in the maxillary skeleton have also been reported [ 66 ]. This specific type of eruption deviation is seemingly not described in the primary dentition. Ectopic eruption of other teeth such as mandibular canines and third molars [ 74 , 75 ] is described in the permanent dentition.
Transmigration of a mandibular canine is a rare condition with unknown aetiology [ 76 , 77 ]. With regards to aetiology, speculations behind these ectopic eruption courses are many.
Most often genetic conditions are defined as the cause of ectopia [ 68 , 75 , 78 ], but that is not always the case. Ectopia can also be caused by deviations in space that may be hereditary, just as seen in small jaws, but can also be acquired due to early tooth extraction or due to primary teeth that are not shed. Additionally, a correlation between morphological ectodermal deviations in dentitions and ectopia has been described [ 65 ].
The size, growth, and osseous maturity of the jaw are also parameters that play a role in the understanding of the aetiology behind ectopia [ 64 ]. The space condition and how to analyze space experimentally, especially for third mandibular molar eruption, have been in focus in several reports. When all these eruption aspects are comprised they provide a good insight into how tooth eruption progresses, when the teeth erupt, and where they erupt, but we have no coherent understanding of why the teeth erupt.
When we do not know the aetiology behind eruption and cannot explain the eruption mechanism, then we cannot perform aetiology-based treatment. We can attempt to guess a treatment as, for example, surgical exposure of a first permanent molar that has primarily arrested eruption, because we have experienced that this treatment encourages eruption, but we do not know whether it is the crown follicle or the overlying gingiva, the alveolar bone or perhaps other factors that cause the arrested eruption.
Several reviews from experienced researchers have, like the one from Marks and Schroeder [ 78 ], discussed the mechanism of tooth eruption, which is still not understood.
This review focuses on human and other mammalian teeth with a time- and spacewise limited period of eruption and analyzes recent observations and experimental data on dogs, rats, primates, and humans in a framework of basic biological parameters to formulate a guiding theory of tooth eruption. Acknowledging basic parameters i. We have critically analysed, summarized, and integrated recent findings associated with preeruptive movements of developing teeth, the intraosseous stage of premolar eruption in dogs, molar eruption in rodents, and premolar and molar eruption in primates.
The variable speeds of eruption are particularly important. In conclusion, the basic principles of tooth eruption depend on the type of signals generated by the dental follicle proper, the conditions under which teeth are moved, and the clinical understanding to be derived from this knowledge. If we look at the explanation and causes presented in the textbooks for the eruption process, we cannot find a clear answer either.
We can read that some authors suggest that the eruption force is connected with the force that occurs when the tooth root grows, that is, suggesting an association between eruption force and root extension [ 79 ]. Other important causes are cell proliferation, increased vascularity, and increased bone formation around the teeth.
Additional possible causative agents, which have been noted include: Probably all these factors have an influencing role but not necessarily independently of each other. Although all the factors associated with tooth eruption are not yet known, elongation of the root and modification of the alveolar bone and periodontal ligament are thought the most important factors. These events are coupled with the changes overlying the tooth that produce the eruption pathway.
A connection between pulpal and periodontal reactions has also been mentioned as a causal factor in eruption [ 79 , 80 ].
Thus, Bath-Balogh and Fehrenbach write in their textbook from on pages 84 and Each theory for eruption presents a problem in its conception. Root growth, existence of a temporary ligament, vascular pressure, contractile collagen, and hormonal signals genetic targets all have been used to explain eruption.
The dental follicle surrounding the tooth crown has also been described as a factor decisive for the eruption process. Koch and Paulsen state the question regarding eruption mechanism in their paediatric textbook from thus on page One of the most important local environmental factors is crowding among the developing and erupting teeth. Tooth eruption is a biological process, which is still not fully understood. The process is accompanied by multiple tissue changes, such as resorption and apposition of the alveolar bone, and development of the root and periodontium.
The problem is still how the tooth is elevated in the jaw. In general it can be concluded that the individual eruption pattern is inherited, that is, genetic, and that this pattern is also affected by local and general external factors. Many major textbooks do not mention the aetiology behind eruption and some only state that it is unknown [ 79 — 82 ]. Furthermore, Berkowitz et al. Whatever the system implicated in the eruptive mechanism, the evidence should be judged according to the following five criteria.
Animal experimental studies support the theory that the follicle is of importance for the eruption process [ 2 , 3 , 83 — 85 ] and have also shown that innervation plays a specific role in tooth eruption [ 4 , 86 — 90 ]. There is no doubt that the bone tissue surrounding the tooth and the general growth conditions in the body play a role [ 21 , 91 — 97 ].
In conditions with abnormal bone such as that observed in osteopetrosis then tooth eruption is affected [ 95 ], but the bone quality is not the only factor, which can explain the eruption process.
Human studies have suggested that there is no convincing correlation between early tooth formation before crown formation evaluated radiographically and the innervation pattern of the jaws [ 98 ]. Even though much is known about several aspects in the human tooth eruption we cannot explain what it is that causes a tooth to move in the jaw after crown formation and gradually erupt, often in a very long eruption path longer than the root of the tooth to its final place in the tooth row.
Considering that the phenomenon of tooth eruption and specifically pathological tooth eruption plays a major role in both clinical and theoretical dentistry there is surprisingly sparse literature on the subject. This is no doubt due to methodological difficulties. Experimental studies on animal tissue cannot uncritically be transferred to human conditions. Meanwhile, the eruption process cannot be studied on a molecular level sufficiently and furthermore not longitudinally in human tissues because teeth have to be extracted, which separates the teeth from the periodontal membrane and the surrounding bone.
As we cannot understand what causes a tooth to erupt and at the same time claim that the eruption process cannot be studied on animal experimental material and uncritically transferred to humans and secondarily that also human material have its methodological limitations, how can we then form a hypothesis for the eruption process?
This proposed hypothesis must be formed based on experience from human material. It is logical to turn to experiences from pathological and genetic material and to analyse what are the consequences of different diseases for different tissue types and for the eruption process. And then try to gather the information from pathological eruption processes and create a hypothesis for the eruption mechanism. It is not easy, but still it is more difficult based on observations of normal eruption courses to understand, for example, why the permanent first molars erupt at the same time in all four quadrants.
It can be registered, but it cannot be explained. Another way to approach the eruption problem is to combine knowledge from histological and histochemical studies of human teeth and jaws from different time before birth with similar studies of teeth including periodontium after birth.
Basic knowledge on tooth tissue and the tissue that surrounds teeth can thus be analyzed in normal foetuses and pathologically genetically deviant foetuses. When this knowledge on tissue and genetics is transferred to the postnatal dentition, a hypothesis can be proposed based on a scientific background. This latter method forms the basis for the presented theory. Before we try to understand what initiates, moves, lifts, and forms the path for a tooth primordium during eruption it is necessary to look at the early embryonic jaw formation and tooth formation.
The mandible and maxilla are formed in the early embryonic developmental stage from neural crest cells. These cells migrate from different areas on the neural crest of the neural tube with different molecular-biological origin. The cells with the different origins migrate to the different regions, also known as fields, to the jaws [ 49 ]. These fields are schematically marked on a panoramic radiograph, seen in Figure 1.
The fields are characterized by having a separate innervation and regionally specific ectomesoderm, which is shown in the regions in Figure 1. Figure 2 demonstrates the molecular-biological fields in the cranium [ 49 ].
These fields are different not just in the cranium and jaws but also in the dental arches [ 49 ]. The fields have different molecular origins and different innervations. They are shown in the dental arch and palate in Figure 3. The early tooth formation is comprised of an ectodermal epithelial bud surrounded by regionally specific ectomesenchyme [ 48 , 86 , 91 ].
The nerve supply to the early tooth primordium, which is under rapid development, goes through a complicated path-finding process to the tooth primordium and gathers to begin with around the apical part of the primordium [ 91 ]. Quickly, the primordium develops through the well-known cap and bell stages. During these stages the innervation spreads and surrounds both the apical and the coronal parts of the primordium.
Later, the reaction for nerve tissue is seen most strongly apically. The formation and tissue components in the early tooth formation are demonstrated in Figure 4. The innervation thus comprises a very important tissue component in the apical root sheet or root membrane that could also be designated the root follicle. There is no epithelium in the root follicle in contrast to the follicle around the tooth crown that has a pronounced inner layer of epithelium and only a light outer layer of innervation.
In summary, these are thus the tissue types:
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