Professional Documents
Culture Documents
Edward Ellis
PII: S0278-2391(13)01437-7
DOI: 10.1016/j.joms.2013.11.026
Reference: YJOMS 56144
Please cite this article as: Ellis III E, An Algorithm for the Treatment of Non-Condylar Mandibular
Fractures, Journal of Oral and Maxillofacial Surgery (2013), doi: 10.1016/j.joms.2013.11.026.
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Mail Code 7908
San Antonio, TX 78229
Ellise3@uthscsa.edu
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Phone: 210-567-3470
Fax: 210-567-2995
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Abstract
An algorithm for the treatment of non-condylar mandibular fractures is presented based
on outcomes from studies that have been performed over the past 30 years. It is designed
to assist clinicians in formulating a treatment plan that can be expected to provide the
patient with a predictable outcome.
INTRODUCTION
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Mandibular fractures are common facial injuries, constituting either the most prevalent or
the second most prevalent (after nasal) facial fracture.1,2 Treatment of mandibular
fractures varies considerably among regions, countries, and practitioners. This should not
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be surprising given the differences in health care availability, quality and delivery
strategies in different locations.
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The advent of stable internal fixation over the past 40 years has considerably changed
how mandibular fractures are treated, but not all locations have this technology available.
There have been many studies published on the outcomes of various treatment strategies
for mandibular fractures treated with stable internal fixation. Interestingly, even in those
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locations that do have or apply stable internal fixation devices, different fixation schemes
are applied to the same fracture by various practitioners. The reason treatment varies so
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considerably is that most surgeons tend to treat patients according to their training and
past experience rather than scientific data. It is therefore not surprising that patients
receive different treatments for similar mandibular fractures.
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The purpose of this paper is to present an algorithm for the treatment of non-condylar
fractures of the mandible using available evidence as a guide. Condylar fractures have not
been included because they present unique considerations that complicate a treatment
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algorithm, such as the ability to treat without reduction and/or fixation of the fracture.
The algorithm to be presented will assess several factors about the mandibular fracture(s)
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that have an effect on the treatment (Figure 1). The algorithm also will take into account
confounders that directly affect treatment choices.
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ALGORITHM (Figure 1)
The assumption that is made with the algorithm presented (Figure 1) is that any fractures
that the surgeon chooses to treat with open reduction and internal fixation (ORIF) will
have ample fixation applied so that no postoperative intermaxillary fixation (IMF) will be
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necessary. Thus, the fixation requirements for the fractures may be more than would be
required if one were to employ a period of IMF after ORIF.
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When a patient presents with a fractured mandible, there are several conditions or factors
that should be considered to help define appropriate treatment.
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arch bar, they can be treated according to the Dentulous Algorithm. If not, they are placed
into the Edentulous Algorithm.
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often be unsuccessful because there is nothing to stabilize the fragment that contains no
teeth. This situation is most common with fractures through the angle, but also occurs
with body fractures when no teeth are present distal to the fracture line. Most of these
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fractures are “unfavorable,” meaning that the direction and/or bevel of the fracture line
offers no resistance to the pull of the elevator muscles, allowing the ramus to rotate and
the fracture to displace (Figure 2). For purposes of the algorithm, it will be assumed that
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fractures that do not have teeth on both sides of the fracture will be “unfavorable”
fractures, meaning that they cannot be satisfactorily treated closed with IMF. However,
there may be an occasional patient whose fracture is “favorable” and such a patient could
be treated closed. In practice, however, these are uncommon.
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The presence of stable teeth on both sides of a fracture line is of paramount importance
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for two reasons. First, it is what will determine whether or not the patient can be treated
closed, i.e. with a period of IMF. Simple linear (Figure 3) and comminuted (Figure 4)
fractures can be treated closed as long as there are stable teeth on each side of the fracture
(and of course teeth in the maxilla). Similarly, the presence of acute or chronic infection
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at the fracture site does not obviate the possibility of treating such fractures closed.
Additional treatment for the infection may also be required (eg. incision and drainage,
antibiotics, etc.).
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The second reason that the presence of teeth on both sides of the fracture is important is
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because if the surgeon chooses open reduction and internal fixation for the fracture, the
dentition can be used as a second point of fixation. In fact, when treating a fracture
through the body of the mandible, the application of an arch bar to the mandibular teeth
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When teeth are not present on both sides of the fracture, for instance fractures through the
angle (Figure 6A) and some fractures through the body (Figure 6B), open treatment
becomes necessary to prevent rotation of the ramus from the pull of the elevator muscles.
A single miniplate applied along the superior border is adequate fixation in such cases
when this is the only fracture of the mandible, or when other fractures have been made
“rigid” by application of rigid internal fixation devices (see below).5 A single miniplate
applied in this location neutralizes the functional forces generated from elevation of the
ramus and depression of the symphysis from the attached muscles by sharing the loads
with the bone along the fracture and compressing them together.6
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Summarizing, when teeth are present on both sides of the fracture, the surgeon has the
choice of treating the fracture closed or open. However, when teeth are present on only
one side of the fracture, the only choice is to treat the fracture open unless the fracture
line happens to be “favorable.”
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If Open Treatment is Chosen, Does the Fracture Require Load-Bearing or Load-Sharing
Fixation?
Load-bearing fixation, a form of rigid fixation, is the application of internal fixation
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devices that are of sufficient strength that they can bear all the loads of mastication
transmitted across the fractured area.7 The bone does not have to share any of the loads.
In practice, this is most often accomplished by application of a reconstruction bone plate
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with a minimum of three screws on each side of the fracture. Any mandibular fracture can
be treated with load-bearing fixation. When the surgeon is not sure what fixation to apply
to a given fracture, they will never be wrong by applying load-bearing fixation.
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Load-sharing fixation is the application of internal fixation devices that require that the
bone fragments participate in transferring functional loads across the fractured area.7
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Examples are the application of miniplates, compression plates, lag screws, etc. across a
fracture (Figures 5 and 6). All of these techniques load the bony interfaces during
mandibular function so the broader the area of bone contact, the more stable the fixation
provided.
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The character of the fracture determines what type of fixation is required. Simple linear
fractures can undergo either load-bearing or load-sharing fixation (Figures 5 and 6),
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whereas comminuted or defect fractures must undergo only load-bearing fixation (Figures
7 and 8). Chronically-infected fractures should also have load-bearing fixation applied
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when treated open because the bony interfaces may have become demineralized and will
not provide a stable interface for load-sharing fixation. Infections present for a week or
two (acute infections) can be treated with either load-sharing or load-bearing fixation
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because their bony fragments have not yet undergone demineralization and provide a
stable interface for load-sharing fixation.8-14
Summarizing, load-sharing fixation can only be applied to fractures that have broad areas
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of healthy bone contact. Whenever this is not the case, for example in comminuted,
defect, chronically-infected, or atrophic fractures, load-bearing fixation should be used.
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Unlike load-bearing fixation that can be applied to any fracture, load-sharing fixation can
only be applied to some fractures. When in doubt, use load-bearing fixation
(reconstruction bone plate)!
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States is a fracture through the angle combined with a contralateral fracture through the
symphysis or body fracture.
As in isolated fractures, in cases where more than one fracture exists and there are usable
teeth in all fragments, the surgeon has a choice of either closed or open treatment. Such
fractures can be treated closed whether or not they are infected and/or comminuted
(Figure 9). If open treatment is selected, the choice of internal fixation hardware becomes
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more complicated because the biomechanics of the multiply-fractured mandible is more
complex than in an isolated fracture of the mandible.5
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If the surgeon selects load-sharing fixation for the fractures, it is important to consider
what hardware is applied. Within the category of load-sharing fixation, there are many
internal fixation schemes--some more stable than others. For instance, the Champy
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technique of applying a single miniplate for mandibular body and/or angle fractures is not
“rigid” fixation, but instead allows some motion between the bone fragments during
function (i.e. the fixation is non-rigid). This choice of fixation functions well when
applied to an isolated fracture of the mandible.18,19 However, when applied to bilateral
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fractures of the mandible, a single miniplate in both locations is associated with more
complications then when at least one of the fractures is treated with “rigid” fixation.5
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“Rigid” fixation can be applied by use of a reconstruction bone plate (load-bearing
fixation) or the application of lag screws, two miniplates, compression plates, two
locking plates, etc. (i.e. load-sharing fixation)(Figure 10). Therefore, a general principle
is that when multiple mandibular fractures are present, only one of the fractures can be
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treated with non-rigid fixation—all the others must be treated with rigid fixation.
When teeth are not present, closed techniques are of limited success. Several studies have
shown that using splints, dentures, or external pin fixation are associated with higher
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rates of complication than is open reduction and stable internal fixation.20-27 Thus, when
teeth are not present, ORIF is the only choice that one can usually employ.
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provide bone-buttressing. For instance, an edentulous mandible like the one shown in
Figure 11A can be treated with load-sharing fixation because there is a large volume of
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bone in the area of the fracture whereas the one shown in Figure 11B requires load-
bearing fixation. The key to the decision on the amount of fixation required for the
treatment of a fractured edentulous mandible is the vertical height of bone at the fracture
site. When the vertical height of bone is great, load-bearing fixation can be used,
assuming no comminution, defect or chronic infection is present. The reason that this is
possible is because when fixation is applied in a biomechanically-favorable location, such
as the superior border of the mandible, the fracture is neutralized during function by
compression of the bone fragments below the point of fixation (Figure 12A).
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On the other hand, when a fracture occurs through an atrophic mandible (Figure 12B), it
usually fractures in the thinnest area with the least bone height. A plate applied across
this fracture will have to bear all the functional loads transferred across the fracture
because there is too little bone for load-sharing. Thus, load-bearing fixation must be used
in atrophic mandibles. Thus the adage, the smaller the mandible, the bigger the bone
plate must be!28
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Unlike fractures in the dentate mandible, one should also consider the addition of
autogenous bone or products that promote bone formation when dealing with fractures
through the atrophic mandible. These mandibles have little endosteum or periosteum with
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osteocompetent cells to promote osseous union.27 Without the addition of bone or bone-
promoting products, atrophic mandibles may not heal and instead a “titanium union”
maintains the reduction. In time, the plate can fail and the non-healed fracture becomes
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obvious. Alternatively, the bone plate may be electively removed to facilitate prosthetic
reconstruction and a non-union then becomes apparent.
DISCUSSION
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The purpose of the algorithm presented is to help clinicians prescribe treatment for a
given fracture. As with all algorithms, other variables must also be considered because
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each patient and each injury has its own unique personality and character. For instance,
when there is doubt about whether or not a patient may come back for follow-up care,
one might wish to use ORIF rather than closed techniques. When choosing fixation
schemes for these patients, it might be prudent to apply rigid internal fixation rather than
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non-rigid functionally-stable fixation. Similarly, the use of load-bearing fixation even
when the fracture would otherwise be treatable with load-sharing fixation is added
insurance. Doing either will allow the clinician to either not use or to remove the arch
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bars immediately after the internal fixation is applied. The lower arch bar will then not be
available as another point of fixation for a fracture that has teeth on both sides but if
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enough fixation is applied directly on the bone, it becomes unnecessary. This should be
considered when it is doubtful a patient may return for follow-up. In such cases, the arch
bar can become a liability to the patient because it facilitates the development of
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periodontitis when left in place for long periods of time in patients with poor oral
hygiene.
One might wonder why an algorithm presented in 2014 includes the use of closed
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treatment for fractures of the mandible. The reason for its inclusion is because closed
treatment works very well when applied to the appropriate fracture. When a fracture
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occurs in the dentate portion of the mandible where there are sound teeth on each side
and in the maxilla, the application of IMF not only restores the occlusion, but helps
reduce the fracture and also provides fixation to allow healing to progress. When there
are areas of comminution, open treatment becomes more complicated because a long
reconstruction bone plate must be adapted to the mandible that spans the area of
comminution. If there are good teeth on each side of a comminuted fracture, closed
treatment can be very easy treatment for this otherwise difficult fracture.
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Treatment may also be prescribed based on convenience. Often, patients will show up in
the oral and maxillofacial surgeon’s office with a fractured mandible being self-referred
or referred from a local hospital. If the fracture lends itself to closed treatment, this can be
performed readily in the surgeon’s office with little cost or effort. If open treatment is
chosen, it requires more inconvenience for the surgeon and the patient because the patient
usually must be admitted to the hospital for treatment. Thus, closed treatment is still
being successfully used by many practitioners and it definitely has a place in the
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management of mandibular fractures.
The surgical approaches for those fractures treated open were not mentioned in the
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algorithm. The choice of surgical approaches does not affect the fixation requirements
and can be determined by the experience and desires of the surgeon. In general, the vast
majority of mandibular fractures in the dentate mandible can be treated using an intraoral
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surgical approach. This is especially so for simple (linear) fractures from the angle
forward. When comminution occurs, especially in the posterior mandible, it will be more
difficult to adapt and secure a reconstruction bone plate through a transoral approach. The
surgeon might choose a transfacial approach in such cases. In the edentulous and
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especially the atrophic mandible, a transfacial approach certainly facilitates open
treatment. Such fractures are easier to instrument through a transfacial approach,
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simplifying the reduction and the application of internal fixation devices.
This algorithm does not include fractures of the condylar process. The reason for not
including them is that these fractures are unique among facial fractures in that they can be
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treated open or closed without IMF. When treated closed, condylar process fractures can
be treated with or without immobilization of the mandible. All other mandibular fractures
treated closed require a period of IMF. This makes them unique. Because condylar
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process fractures are often, if not mostly, associated with other mandibular fractures,
including them would greatly complicate a treatment algorithm. Although not included,
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condylar process fractures follow similar rules as discussed above. For instance, in the
case where there are fractures of the mandibular angle, body, and/or symphysis as well
as the condylar process, if ORIF is chosen, non-rigid fixation can only be applied to one
of them.5 That means that if the condylar process fracture will be treated closed, all the
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SUMMARY
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The algorithm for the treatment of non-condylar mandibular fractures presented here can
help the clinician decide on a reasonable treatment plan. Certainly, the treatment for each
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case must be individualized, but the principles presented should be considered because
they are based on sound scientific outcomes.
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Figure Legends
Figure 2. A, “favorable” fracture from the standpoint of preventing the mandibular ramus
from rotating when using IMF to treat the fracture. B, “unfavorable” fracture from the
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standpoint of preventing the mandibular ramus from rotating when using IMF to treat the
fracture. C, Panoramic radiograph taken 3 weeks after a patient with an unfavorable
fracture through the right mandibular angle was treated closed. Note the anterosuperior
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rotation of the mandibular ramus secondary to the uninhibited pull of the elevator
muscles because of lack of teeth on the proximal segment which might have prevented
this.
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Figure 3. Fracture of the mandibular body with teeth on both sides of the fracture treated
closed. This treatment could be employed whether or not there was infection present,
whether or not there was comminution, and whether or not there were other mandibular
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fractures, as long as all fractures had teeth on both sides to provide reduction and fixation
by IMF. Obviously, sufficient maxillary teeth would also be necessary to facilitate IMF.
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Figure 4. Comminuted fracture of the mandibular body with teeth on both sides of the
fracture treated closed. This treatment could be employed whether or not there was
infection present, and whether or not there were other mandibular fractures, as long as all
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fractures had teeth on both sides to provide reduction and fixation by IMF. Obviously,
sufficient maxillary teeth would also be necessary to facilitate IMF.
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Figure 5. Fracture of the mandibular body with teeth on both sides of the fracture treated
open. The use of an arch-bar and a miniplate placed either above the mental nerve (A) or
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below it (B) is all that is required for an isolated fracture of the body/symphysis region.
This treatment could also be applied to an acutely-infected fracture but NOT to a
chronically-infected fracture or a comminuted fracture. When ORIF is chosen as the
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treatment in such cases, the fixation requirements call for load-bearing fixation and a
reconstruction bone plate would be indicated. If there were bilateral fractures and ORIF
was selected as the treatment, at least one of the fractures should be treated with load-
sharing or load-bearing rigid fixation; the other could be treated with load-sharing non-
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Figure 6. Fracture of the angle (A) or body (B) of the mandible with teeth on only one
side treated open. Closed treatment will not be reliable in such instances because of the
tendency for the mandibular ramus to rotate from the pull of the elevator muscles. A
single miniplate placed at the superior border is adequate fixation if this is the only
fracture present. When the plate is placed along the lateral surface of the mandible (B),
one should consider a stronger bone plate because standard miniplates can deform under
function from the torqueing of the segments.
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Figure 7. Comminuted fracture of the mandibular body with teeth on both sides of the
fracture treated open. This fracture requires load-bearing fixation so a reconstruction
bone plate is employed. This treatment could be employed whether or not infection was
present. Maintenance of an arch bar in this case is not necessary from the standpoint of
providing additional fixation across the fracture. The reconstruction bone plate alone is
ample fixation.
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Figure 8. Comminuted fracture of the angle or body of the mandible when there are teeth
on only one side treated open. This fracture requires load-bearing fixation so a
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reconstruction bone plate is employed. This treatment could be employed whether or not
infection was present.
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Figure 9. Bilateral fractures in the tooth-bearing region of the mandible treated closed.
This treatment could be employed whether or not there was infection present, whether or
not there was comminution, and whether or not there were other mandibular fractures, as
long as all fractures had teeth on both sides to provide reduction and fixation by IMF.
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Obviously, sufficient maxillary teeth would also be necessary to facilitate IMF.
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Figure 10. Bilateral fracture of the mandible treated open. This fracture could not be
treated closed because of there are no teeth behind the angle fracture to prevent rotation
of the ramus. With open treatment, only one of the fractures can be treated with non-rigid
fixation. In practice, it is easier to make the more anterior fracture rigid by the application
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of two miniplates, a stronger, thicker bone plate, etc. The angle fracture can then be
treated with non-rigid fixation (single miniplate).
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requirements are very different. The atrophic mandible requires more fixation than the
non-atrophic mandible.
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the small bone plate at the superior surface of the fractured mandible by compressing the
bone along the inferior border. When there is atrophy (B), there is inadequate bone to
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form a fulcrum point so the plate must take on all the loads generated across the fracture.
Figure 13. Illustration showing use of a single miniplate at the superior border of an
edentulous but not atrophic mandibular fracture. This fixation scheme works on fractures
that are located through an area of the mandible with a large vertical dimension.
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References
1. Costello BJ, Papadopoulos H, Ruiz R: Pediatric craniomaxillofacial trauma. Clin
Pediatr Emerg Med 6:32-40, 2001
2. Hwang K, You SH: Analysis of facial bone fractures: an 11-year study of 2,094
patients. Indian J Plast Surg 43:42-48, 2010
3. Pauwels F: Grundriss einer biomechanik der frakturheilung. Verh Dtsch Orthop Ges
34:62, 1940.
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4. Spiessl B, Schargus G: Das Okklusionsproblem bei der funktionsstabilen
Osteosynthese des bezahnten Unterkiefers. (The problem of occlusion in functionally
stable osteosynthesis of the dentulous mandible). Dtsch Zahn- Mund u Kieferheilk,
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57:293-6, 1971
5. Ellis E: Open reduction and internal fixation of combined angle and body/symphysis
fractures of the mandible: How much fixation is enough? J Oral Maxillofac Surg
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71:726-733, 2013
6. Champy M, Lodde JP, Schmitt R, et al. Mandibular osteosynthesis by miniature
screwed plates via a buccal approach. J Maxillofacial Surg 6:14-9, 1978
7. Sugar A, Bentley R: Biomechanics of the bone-implant-unit. Chapter 1.5.5 in:
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Principles of Internal Fixation of the Craniomaxillofacial Skeleton – Trauma and
Orthognathic Surgery, Ehrenfeld M, Manson PN, Prein J (eds), Thieme, Stuttgart,
2012, pp. 91-93 AN
8. Friedrich B, Klaue P: Mechanical stability and post-traumatic osteitis: An
experimental evaluation of the relation between infection of bone and internal
fixation. Injury 9:23-29, 1977
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9. Beckers HL: Treatment of initially infected mandible fractures with bone plates. J
Oral Surg 37:310, 1979
10. Johansson B, Krekmanov L, Thomasson M: Miniplate osteosynthesis of infected
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20. Bruce RA, Strachan DS: Fractures of the edentulous mandible: The Chalmers J.
Lyons Academy study. J Oral Surg 34:973, 1976
21. Bruce RA, Ellis E: The second Chalmers J. Lyons Academy study of fractures of the
edentulous mandible. J Oral Maxillofac Surg 51:904, 1993
22. Buchbinder D: Treatment of fractures of the edentulous mandible, 1943 to 1993: A
review of the literature. J Oral Maxillofac Surg 51:1174, 1993
23. Luhr HG, Reidick T, Merten HA: Results of treatment of fractures of the atrophic
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edentulous mandible by compression plating. J Oral Maxillofac Surg 54:250, 1996
24. Eyrich GK, Gratz KW, Sailer HF: Surgical treatment of fractures of the edentulous
mandible. J Oral Maxillofac Surg 55:1081, 1997
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25. Iatrou I, Samaras C, Lygidakis NT: Miniplate osteosynthesis for fractures of the
edentulous mandible: A clinical study, 1989–1996. J Craniomaxillofac Surg 26:400,
1998
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26. Kunz C, Hammer B, Prein J: Fractures of the edentulous atrophic mandible:
Management and complications [in German]. Mund Kiefer Gesichtschir 5:227, 2001
27. Ellis E, Price C: Treatment protocol for fractures of the atrophic mandible. J Oral
Maxillofac Surg 66:421-435, 2008
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28. Schilli W, Stoll P, Bahr W, Prein J: Mandibular Fractures. Chapter 3 in: Manual of
Internal Fixation in the Cranio-Facial Skeleton, Prein J (ed), Springer, Berlin, 1998,
p. 87 AN
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Simple (linear) Fx(s) Non-Rigid Load
(+/- Acute Infection) Sharing Fixation OK
on only one fx: RIF
on any others
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Load Bearing
Teeth Missing Fixation Required
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on at least one
side of any Fx Comminuted Fx(s)
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Dentate
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Closed Redn + IMF
Teeth on Both
choice (+/- Infxn or
Sides of Fx(s)
Comminution
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Mandible
Fracture
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Load Bearing
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Atrophic Fixation Required
Edentulous
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Comminuted Fx(s)
ORIF
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