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Distraction Sugosteogenesis: Its Biologic Bases and Therapeutic Principles

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 ORIGINAL ARTICLE
Distraction Sugosteogenesis: Its Biologic Bases and
Therapeutic Principles
Jaime Castro-Núñez, DMDy
Purpose: Recently, the terms sugosteogenesis and distraction
sugosteogenesis have been introduced to the scientific literature.
While the former describes a biologic phenomenon, the latter refers
Downloaded from http://journals.lww.com/jcraniofacialsurgery by pcUzqATA5iBL9bzZ7Ker2HOoIdxnC7gVLFGs1U1q1T3XSQjjcLl2/G19s/XtFRxzY/SChE7q6BnukjoQ+5/ACXRgy8YwSlKkuecTwePwDwpfS6pq5Kffs0SRXyCqHdmr on 11/05/2018
to the clinical technique which relies on the accelerated normal
bone healing process that takes place at the osseous walls surround-
ing a cystic cavity when active negative pressure is applied. The
purpose of this study is to provide the biologic bases and the
therapeutic principles of this emerging technique. Employing
well-stablished biologic principles, clinical evidence from analo-
gous techniques, emerging experimental data, and circumstantial
evidence, this study presents the possible mechanism of action of
the evacuator for odontogenic cysts (Evocyst), a closed, vacuum-
like drain system intended to treat cystic conditions using negative
pressure.
Methods: A review of the literature was done. Keywords for the
Medline search were: marsupialization, decompression,
odontogenic cysts, effects of negative pressure on bone, and
negative pressure wound therapy. In addition, relevant
publications from the reference list of the retrieved studies were
considered. The matches were evaluated for relevance and analyzed
accordingly. Clinical reports used to illustrate the concept of
distraction sugosteogenesis were performed following the
Declaration of Helsinki on medical protocol and ethics.
Results: Currently, the standard of care to manage odontogenic
cystic lesions includes marsupialization, enucleation and curettage,
decompression, and surgical resection. However, there is a need for
an alternative option in which the entity could be treated while
promoting bone formation. With large odontogenic cystic
conditions treated in a short period of time, distraction
sugosteogenesis appears to be a choice.
Conclusion: The application of negative pressure to osseous cells
produces a stretching that creates mechanical cues that trigger
signaling pathways, promotes fluid flow, and enhances
angiogenesis. All of them, combined, may explain
sugosteogenesis. The clinical application of such parameters may
explain the good clinical results obtained with the Evocyst.
From the Institución Universitaria Colegios de Colombia, Bogota,
Colombia; and yOral and Maxillofacial Surgery Department, University
of Kentucky Lexington, KY.
Received March 4, 2018.
Accepted for publication July 9, 2018.
Address correspondence and reprint requests to Dr Jaime Castro-Núñez,
DMD, Research Department, Institución Universitaria Colegios de
Colombia, Autopista Norte Km 20 via a Chı́a, Bogota, Colombia;
E-mail: jacastron@hotmail.com
The author reports no conflicts of interest.
Copyright # 2018 by Mutaz B. Habal, MD
ISSN: 1049-2275
DOI: 10.1097/SCS.0000000000004892
2088 The Journal of Craniofacial Surgery  Volume 29, Number 8, November 2018
Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Key Words: Active negative pressure, decompression,
marsupialization, odontogenesis, odontogenic cysts
(J Craniofac Surg 2018;29: 2088–2095)
O dontogenesis is a complex process by means of which a tooth
is developed from cells from both the ectoderm of the first
pharyngeal arch and the ectomesenchyme of the neural crest.
Together, the enamel organ, the dental papilla, and the dental
follicle (tooth germ) form a tooth. Eventually, it erupts into the
oral cavity to play an important role in life.1 Upon completion of the
process, occasionally epithelial cells from the dental lamina,
reduced enamel epithelium, or the Hertwig’s epithelial root sheath
persist in the surrounding tissues as remnants.2 Usually, such
residual cells (rests of Serres, rests of the reduced enamel epithe-
lium, and rests of Malassez) linger dormant without causing any
inconvenience to the patient.1,2
Nevertheless, certain stimuli have the potential to activate those
remains, which may respond by proliferating. As cells proliferate,
the center of the growing epithelial nest degenerates, mainly due to
the lack of irrigation, hence forming a cyst, that is, a pathologic
cavity containing liquid or semisolid material and lined with
epithelium.3–11 The fluid secreted by the epithelial cells exerts
an expansive hydrostatic pressure against the surrounding bone,
thus partially explaining the resorption of bone and the enlargement
of the entity, which takes place along the lines of least resistance,
that is, the cancellous bone.8– 12
The biomechanical theory, the cellular aspects of cystic
growth, and the biochemistry of bone destruction contribute to
the understanding of the cyst’s behavior.13 During the 1970s
investigators discovered that the wall produced collagenases
(including matrix metalloproteinases), prostaglandins, and leuko-
trienes.14 – 22 The presence of interleukin-1a (IL-1a) and IL-612–13,23
and glycosaminoglycans24–26 inside odontogenic cysts was also
documented. Taken altogether, the mechanism explaining cystic
enlargement includes hydrostatic pressure, release of ILs by the
epithelial cells, and subepithelial layer of fibroblast, which lead to
osteolytic interactions, thanks in part to the cystic wall’s ability to
recruit osteoclasts.12 IL-1, for example, has the potential to stimulate
osteoclastogenesis27,28 and to trigger connective tissue cells to pro-
duce collagenases (involved in the destruction of bone matrix) and
prostaglandins (responsible for osteoclast activation and increase in
the permeability of the capillaries in the wall).12,29–31
In the late 1880s, Partsch discovered that opening a cyst into the
oral cavity halted its growing potential; this technique was called
cystostomy.32,33 In 1942, Neuschmidt34 described an alternative to
cystostomy (Partsch I) in large mandibular cysts by keeping them
open using a rubber tube (drainierungs-Methode), today known as
decompression. In 1947, Thomas35 introduced the technique to the
United States. Currently, it is accepted that Partsch I, Partsch II, and
decompression are different procedures sharing the same princi-
ples.36 In 2015, Delgado-Rueda et al.37 introduced the concept of
double decompression. Later, a 2-way decompression device was
reported.38 Recently, the use of active intracystic negative pressure
The Journal of Craniofacial Surgery  Volume 29, Number 8, November 2018
has been linked to osteogenesis.39 To define this negative pressure-
induced osteogenesis concept, the terms sugosteogenesis and
distraction sugosteogenesis (DS) were coined.40
Employing established biologic concepts, circumstantial evi-
dence, and clinical and experimental data, the author reasoned that
the application of intracystic negative pressure had the potential to
remove the cystic epithelium while transmitting physiologic
forces to the surrounding bone capable of inducing a faster
osteogenic response through cell stretching. The aim of this study
is to provide the biologic foundations of DS and its therapeutic
principles.
METHODS
A review of the literature was performed. Keywords for the Medline
search included the following terms: marsupialization, decompres-
sion, odontogenic cysts, negative pressure, bone, negative pressure
wound therapy (NPWT), and distraction osteogenesis (DO). Pub-
lications from the reference list of the retrieved articles were
considered and analyzed accordingly. Clinical reports are presented
and discussed to illustrate and demonstrate the principles governing
DS. This protocol was approved by Ethics Committee/Institutional
Review Boards and was designed following the Declaration of
Helsinki on medical protocol and ethics.
RESULTS
This study presents the clinical results obtained with the evacuator
for odontogenic cysts (Evocyst) and the pertinent literature
reviewed to explain and support the possible mechanisms by means
of which the Evocyst is thought to exert its function. Regarding
clinical data, 60% of treated patients were males and 40% females,
with a mean age of 18 years (range 11–34 years). All treated cystic
conditions affected the mandible, with 80% of them occurring in the
posterior zone (mandibular body, angle, and ramus) and 1 condition
affecting the symphysis.
From the radiographic point of view, 40% of lesions were
multilocular and 60% unilocular. While 80% of the entities were
relatively common odontogenic cystic conditions such as kerato-
cystic odontogenic tumors, dentigerous, and residual cysts, 20%
represented uncommon histopathologic findings such as calcifying
epithelial cyst. The main complaint of patients was the size of the
intraoral unit, which 60% considered uncomfortable. Adherence to
treatment protocol was accomplished by all patients. Upon removal
of the intraoral unit (4–5 weeks after placement), 1 patient devel-
oped a fistula at the site of the tube, which was successfully closed
with a local flap. No major complications were reported.
All patients reported that during the first 48 to 72 hours after the
activation of the extraoral unit, the reservoir was filled with
abundant sanguinolent fluid, which was no longer present after
the 4th day. After that period of time, the reservoir contained a
colorless fluid, which most probably was a combination of normal
saline solution 0.9% and tissue exudates. All patients were
instructed to return for a follow-up visit 4 to 5 weeks after surgery
with a recent panoramic X-ray. In 100% of patients, newly formed
bone had filled the osseous defects. This means that a fast osteo-
genic response (sugosteogenesis) took place as soon as the device
was activated. As it will be presented and discussed later in
this study, one egregious osseous defect affecting the symphysis
was filled with new bone in <2 weeks. Thanks to the benefits of
this emerging technique, aggressive surgical procedures were
avoided.
In the following paragraphs, pertinent literature will be analyzed
and discussed in an attempt to provide a biologic explanation for the
accelerated osseous healing observed in our patients when active
negative pressure was applied to odontogenic cystic conditions.
# 2018 Mutaz B. Habal, MD
Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Distraction Sugosteogenesis
DISCUSSION
Distraction Sugosteogenesis: An emerging
Technique Using the Evocyst
Could it be possible to design a conservative method to treat
odontogenic cysts in such a way that it deals with the pathology
while promoting osteogenesis? Taking as starting point a previous
tubing design38– 40 and based on the principles of cystic decom-
pression,41,42 DO,43,44 NPWT,45 and experimental data suggesting
that negative pressure could promote osteogenesis,46– 48 the author
designed and implemented the Evocyst.39 Figure 1A-B, for exam-
ple, depict a multilocular lesion which resolved after 1 month using
the Evocyst. More interesting, another osteolytic lesion initially
measuring 10.5  4.5 cm (Fig. 1C) was reduced by more than 50%
after only 11 days employing the device (Fig. 1D).
Decompression: A Reliable Technique
Decompression of large odontogenic cysts has become a more
popular treatment over the last 15 years.12,31,36,41,49 –64 The method,
which is based on the rationale that releasing the intraluminal
pressure causes cystic reduction by gradual bone growth from
the periphery, causes minimal surgical 0morbidity, changes the
malignancy’s environment, avoids the reestablishment of its inter-
nal pressure, decreases/inhibits the amount of IL-1a and IL-6,
maintains pulp vitality, preserves anatomical structures, prevents
pathologic fractures, thickens the cystic lining, and it is associated
with a relatively low risk of recurrence.35,50,55 In infants, other
benefits are preservation of the tooth buds, minimal impairment of
skeletal growth, and social adaptation.31
Fluid pressure in odontogenic jaw cysts is thought to be higher
than atmospheric’s.65,66 Intracystic pressure may change as the
pathology enlarges, since it is regulated by the permeability and the
blood pressure of the wall’s capillaries; lymphatic drainage; venous
return from the cavity; osmotic tension of the fluid; and the
elasticity of the wall.10,65 Marsupialization/decompression periods
range from 255 to 8051 months, with an average of 6 to 14.59 Degrees
of shrinkage are between 19.1% after 1 month and 81% after 17.5
months.52 Kubota et al12 reported that a minimum decompression
time of 12 months was required for dentigerous cysts to decrease
50% of their original size. Park et al60 reported a 39% shrinkage rate
in 7 months, while Lizio et al63 noted a 70.5% reduction after
8 months of treatment (Table 1). Decompression decreases the size
from 50% to 81% over periods ranging from 7 to 44 months.61 The
speed of shrinkage depends on the initial volume of the lesion.62
Long treatment time is the main disadvantage of the technique.
Since most of the times the reduced lesion requires enucleation, it is
accepted that neither marsupialization, nor decompression are
definitive methods of treatment.55,61,63
Distraction Sugosteogenesis: A Superior
Technique?
The Evocyst, on the contrary, is believed to perform a dual
function, that is, to evacuate or suck up the entire cyst (epithelial
lining, fibrous capsule, and their products) while inducing sugos-
teogenesis. Since DS is able to shorten treatment time considerably,
the drawbacks of marsupialization/decompression such as tube
dislodgement, tissue irritation, overgrowth around the tube, long
treatment times, and patient compliance are minimized or elimi-
nated.67 Of note, the physical forces exerted by the extraoral unit
indeed maximize the tendency of peripheral bone to centripetally
grow into the cavity center after the relief of the internal hydrostatic
pressure caused by the cystic content.31 Therefore, DS eliminates
the morbidity and costs associated to bone grafting procedures.
2089
Castro-Núñez The Journal of Craniofacial Surgery  Volume 29, Number 8, November 2018

TABLE 1. Some Characteristics Related to Marsupialization/Decompression

Feature Study

Intracystic fluid pressure

KCOT 337.6 mm Hg Kubota et al12
Dentigerous cyst 258.2 mm Hg
Radicular cyst 254.0 mm Hg
Periodontal cyst 47 mm Hg Skaug65
Follicular cyst 44 mm Hg
Residual cyst 38 mm Hg
Mean decompression time
KCOT 8.32 months Gao et al36
Radicular cyst 2.75 months
Unicystic ameloblastoma 9.14 months
KCOT 11 months Pogrel and Jordan51
KCOT 10 months Brøndum and Jensen64
Odontogenic cystic lesions in general Anavi et al55
Mandible 9.1 months
Maxilla 9.3 months
Mean relative speed of shrinkage
KCOT 2.87 cm2/month Gao et al36
Radicular cyst 3.37 cm2/month
Unicystic ameloblastoma 2.71 cm2/month

KCOT, keratocystic odontogenic tumor.

promoting osteogenesis? To tackle this question, the odontogenic

FIGURE 1. (A) A radiopaque multilocular lesion at presentation. (B) 1-month
postoperative radiograph showing resolution of the entity and woven bone. (C)
An osteolytic lesion of the symphysis measuring 10.5  4.5 cm. (D) 11 days after
using the Evocyst, a new radiography showed that the lesion reduced more than
50% of its original size. Sugosteogenesis around the anterior lower teeth and the
basal bone is remarkable. (E) Proposed mechanism by means of which the
Evocyst is believed to function. 1. Interstitial fluid flow. Normal saline solution
0.9% is used to irrigate the cavity. This solution enhances interstitial fluid flow,
which is the primary mechanism used by bone cells perceive changes in their
mechanical environment. Strain-induced fluid flow regulates the anabolic
response of bone cells to mechanical cues. Evocyst-induced fluid flow may
contribute to the stimulation of osteoprogenitor cells. 2. Evacuation of cystic
epithelium/capsule and their products. The negative pressure exerted by the
extraoral unit has the potential to both remove the entity’s epithelium/capsule
and their biochemical products and to promote cellular responses leading to
angiogenesis and osteogenesis. 3. Tension to surrounding bone. While
removing the cyst, negative pressure also creates a line of tension along the
surrounding bone, which results in the transmission of mechanical forces that
generate cell stretching. Other effects of mechanical stress on bone cells include
regulation of the proliferation and differentiation of mesenchymal stem cells
and osteogenic precursors, induction of signaling pathways promoting
osteogenesis, modulation of the expression of osteonectin and collagen type I,
and increase in alkaline phosphatase activity. 4. Increased vascularization.
Negative pressure stimulates angiogenesis by inducing and directing fast
migration of pre-existing blood vessels. 5. Short-term hypoxia. Bone and
angiogenic cells in the cystic cavity may be under low oxygen tension.
Activating the hypoxia-inducible factor-1 regulatory pathway may play a role
in both angiogenesis and osteogenesis. All those interactions occur at the
same time and have been separated here only for academic purposes.
If the advantages of DS are summed up, this protocol stands up as a
more clinical and biologic effective approach if the patient can be
closely monitored and adheres to the therapy. Disadvantages of the
method are the size of the intraoral unit and the lack of data regarding
long-term results. Several studies indicate that around 70% of
recurrences take place within the first 5 years of initial treatment.68,69
But the initial question remains: what if a conservative method is
designed in such a way that it deals with the pathology while
epithelium must be understood as the source of the problem.70,71 In
fact, recurrence is mostly attributed to either incomplete removal of
the epithelial lining or growth of a new entity from small satellite
cysts or odontogenic epithelial rests left behind during the initial
treatment.72,73
Removing the Epithelial Lining by Using Active
Intracystic Negative Pressure
Surgical drains are used to remove bodily fluids and to improve
wound healing.74 They are open or closed, with the latter subdivided
into passive or active (Table 2). The first surgeons who applied negative
pressure to odontogenic cysts were Rud,75 Heidsieck,76 and Hjørting-
Hansen et al,77 based on the technique described by Mandal78 for
primary wound healing (Table 3). While they must be credited for the
application of negative pressure to odontogenic cysts, there are,
however, substantial conceptual and therapeutic differences from
DS. Rud75 and Heidsieck76 reported good results, but only immediate
postoperative findings were described. Moreover, their therapeutic
goal was to drain the cystic contents, not to remove the epithelial lining
or to induce osteogenesis. Heidsieck76 used a Redon, which did not
allow irrigation. In the early 1990s, Hjørting-Hansen et al77 drained 42
patients as part of the surgical treatment for odontogenic cysts. They
reported primary healing with complete closure of the incision in 90%
of patients after using the drain for 3.6 days in average. Total osseous
regeneration was reported in 57% of patients.
Those studies share the following: the therapeutic goal was to
drain the cystic contents, the cyst needed to be enucleated at a
second surgical time, daily irrigation was impossible, some patients
needed bone grafts after enucleation, and removal of the system,
usually within a week, was dictated by the amount of fluid
evacuated in a 24-hour period.75–77 The Evocyst, on the contrary,
exerts a negative pressure force believed to suck the epithelial lining
and the fibrous capsule into the extraoral unit. This, in turn, takes
out of the scene prostaglandins, collagenases, and proteinases that
stimulate osteoclastic activity. Additionally, removal of the Evocyst
is dictated by the complete filling of the defect with new bone.

2090 # 2018 Mutaz B. Habal, MD

Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery  Volume 29, Number 8, November 2018 Distraction Sugosteogenesis

TABLE 2. Classification of Surgical Drains

Type Definition Example

Open The contents are exposed to the atmosphere. Drain fluid collects in gauze pad or stroma bag Penrose, corrugated drain
Closed The contents are not exposed to the atmosphere. The tubes drain into a bag, reservoir, or bottle
Not driven by negative pressure (channels the fluids)
Passive Driven by negative pressure (suction or vacuum) Robinson drain, T-tube
Active Redivac, VAC

Inducing Osteogenesis by Means of Active
Negative Pressure (Sugosteogenesis)
The physiologic responses of tissues to applied mechanical
forces are known since Wolff.79 Hence, for more than a century,
clinicians have implemented them in several techniques, including
orthodontics, DO, soft-tissue expansion, and NPWT. The clinical
and experimental evidence supporting the fact that mechanical
forces stimulate angiogenesis, osteogenesis, and wound healing
is overwhelming.80–110 In the following paragraphs, the author will
discuss, first, studies supporting the effects of mechanical forces on
angiogenesis and then investigations supporting the effects of such
forces on osteogenesis to theorize, at the end, on the possible
mechanisms by means of which the Evocyst in thought to
induce sugosteogenesis.
Osteogenesis and angiogenesis are intimately related.107 There-
fore, to understand the effects of negative pressure on osteogenesis,
the role of angiogenesis must be discussed first. Mechanical stress
has a direct effect on angiogenesis82; hence, local negative pressure
that can trigger angiogenesis and local blood flow is used to treat
wounds.103 Therefore, the cell’s physical environment can be
manipulated to promote specific tissue healing responses.101 Stud-
ies have demonstrated that mechanical stimulation or the applica-
tion of stress to soft tissues:
1. Stretches cells to encourage proliferation and differentiation by
regulating the extracellular matrix via cell-mediated mechani-
cal-signaling pathways. Said forces are within the physiologic
margins known to foment cell proliferation and differentia-
tion.95 Cells react to stretching by regulating specific genes and/
or the induction of pathways leading to tissue-specific cell
differentiation and angiogenesis.80,81
2. Transmits signals that are necessary for the cells to respond to
biochemical cues.80 In fact, there are reports describing a
transcriptional mechanism sensitive to mechanical and chemi-
cal signals that control angiogenesis.105
3. Increases the expression of vascular endothelial growth factor
(VEGF) and fibroblast growth factor.103
Bone, on the contrary, is also known to respond to a variety of
mechanical stimuli, which regulate the proliferation and differenti-
ation of mesenchymal stem cells (MSCs) and osteogenic precur-
sors. Various stimuli have shown to act through numerous signaling
pathways to induce osteogenic differentiation of bone-marrow-
derived stroma cells (BMSCs) and osteoblast activities.93 Mechan-
ical stimulation or the application of stress on bone:
1. Promotes the expression of collagen type I and osteonectin in
MSCs.102
2. Decreases osteoclastogenesis through osteoprotegerin (OPG)
and OPG-ligand (OPGL) signaling.86,98
3. Stimulates the proliferation and differentiation of osteopro-
genitor cells.90,91,96 In fact, they induce osteoblasts to both
proliferate and increase osteogenic growth factor production,
extracellular matrix deposition, and enhance VEGF production.90
4. Augments fluid flow, which is thought to be the main
mechanism used by bone cells to perceive alterations in their
surroundings. Tension-induced fluid flow regulates bone cell
anabolic response to mechanical cues.89,94,97 Experimental
studies have shown that MSCs could be stimulated to proliferate
and differentiate along osteoblastic pathways through fluid-
flow-induced mechanisms, thus suggesting a regulation of both
osteoblast and mesenchymal precursors via shared signaling
pathway.97
5. Activates tissue-specific progenitor cell pathways that unfold to
stimulate bone even after the period of mechanostimulation.101
6. Promotes the secretion of factors and matrix molecules inherent
to osteoblastic differentiation.91
Few researchers have investigated the effects of negative pres-
sure on bone.46,47,111,112 In 2009, Yang et al46 presumed that
intermittent negative pressure could promote osteogenesis in human
BMSCs in vitro. After isolating BMSCs, they were allocated into

TABLE 3. Historical Summary of Conservative Techniques

Technique Designer Year Notes

32
Cystostomy Carl Partsch 1892 Partsch I
Cystectomy Carl Partsch33 1910 Partsch II
Decompression Von Neuschmidt34 1942 Used a rubber tube
Decompression Earle Thomas35 1947 Introduced the technique to the United States. If he was aware of Neuschmidt’s study is unknown
Decompression Kurt H. Thoma6 1958 Thoma, who popularized decompression in his book Oral Surgery, attributed the method to Thomas
Negative Pressure Jørgen Rud75 1967 Reported the successful treatment of a KCOT
Negative Pressure Carl Heidsieck76 1968 Expanded on the subject
Negative Pressure Erik Hjørting-Hansen et al77 1993 Reported the largest series
Double Decompression Javier Delgado-Rueda et al37 2015 Introduced the concept of double decompression
Distraction Sugosteogenesis Jaime Castro-Núñez et al39 2017 Presented the technique

KCOT, keratocystic odontogenic tumor.

# 2018 Mutaz B. Habal, MD 2091

Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Castro-Núñez The Journal of Craniofacial Surgery
negative pressure treatment group (pressure: 50 kPa, 30 min/times,
twice daily) and control group (cultured in conventional condi-
tions). Researchers examined the osteogenesis of BMSCs using
phase-contrast microscope, determined alkaline phosphatase (ALP)
activity, and the immunohistochemistry of collagen type I. Employ-
ing real-time polymerase chain reaction, they evaluated mRNA
expressions of OPG and OPGL.
The OPG, also known as osteoclastogenesis inhibitory factor
and tumor necrosis factor (TNF) receptor superfamily member 11B
(TNFRSF11B), is a cytokine receptor that inhibits both differentia-
tion and function of osteoclasts. It is the receptor for receptor
activator of nuclear factor kappa-B ligand (RANKL). The RANKL,
an osteoclast differentiation factor (ODF), is also known as OPGL,
TNF ligand superfamily member 11, TNF-related activation-
induced cytokine, and ODF. It is a transmembrane ligand that
functions as a key factor for osteoclast differentiation and activa-
tion. Receptor activator of nuclear factor k B (RANK), also known
as TRANCE receptor or TNFRSF11A, is the receptor for RANKL
and part of the RANK/RANKL/OPG signaling pathway that coor-
dinates osteoclast differentiation and activation. Osteoclast activity,
therefore, is modulated by the OPGL/OPG ratio.
What Yang et al46 found was that after 2 weeks of intermittent
negative pressure BMSCs had a typical appearance of osteoblasts,
positive expression of collagen type I, and increased ALP activity.
When compared to the control group, the mRNA expression of OPG
was increased significantly and the mRNA expression of OPGL
decreased substantially. They concluded that intermittent negative
pressure could promote osteogenesis in human BMSCs in vitro. In
2013, Swain et al47 experimented on male, skeletally mature New
Zealand White rabbits by creating a 15-mm-diameter defect and
placing a calcium phosphate scaffold over it. In the experimental
group, negative pressure was delivered for 1, 4, 6, or 10 days. No
negative pressure was applied to the control group. Twelve weeks
after creating the defect, experimental animals exhibited greater
defect bridging and bone within the scaffolds. They documented an
extracellular matrix densely populated with cells and capillaries.
The experimental group had greatly increased vascularity after the
application of negative pressure. In addition to angiogenesis, vas-
cular invasion of the scaffold by pre-existing vessels took place.
The study suggested that negative pressure activated within mature
dura a natural healing cascade that resulted in osteogenesis.
More recently, Sun et al112 compared the osteogenic differenti-
ation of orofacial bone marrow stromal cells before and after
marsupialization in subjects with odontogenic cysts. They showed
that decompression could promote the stemness and osteogenic
potential of BMSCs, which have the characteristics of self-prolif-
eration and multi-differentiation (adipogenic, chondrogenic, osteo-
genic) potential. Activation of the extracellular-signal-regulated
kinase/c-Jun N-terminal kinase (ERK/JNK) signaling pathway
was proposed as an important mechanism for decompression. They
concluded that decompression might participate in the modulation
of proliferation, stemness, and differentiation through regulating
ERK and JNK pathways in orofacial BMSCs. That is supported by
Ninomiya et al50 who demonstrated that decompression dramati-
cally decreased the expression of IL-1a in the epithelial cells of
keratocystic odontogenic tumor.
How is the Evocyst Thought to Induce
Sugosteogenesis?
The benefits of local negative pressure are edema reduction,
interstitial fluid flow and exudate management, stimulation of
angiogenesis, enhancement of blood flow, and local effects on
wound perfusion, growth factor, cytokine expression, and cellular
activity. Such properties lead to an enhanced formation of
2092
Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
 Volume 29, Number 8, November 2018
granulation tissue, thus improving wound healing parameters.113
Ideally, what is required for the treatment of odontogenic cystic
conditions is a reliable method for removing the lesion while
predictably stimulating, in situ, progenitor cells to launch the
osteogenic healing pathway without the requirement of exogenous
factors or cells.
Although the exact mechanisms by means of which the Evocyst
is believed to perform its dual function have not been elucidated,
this author hypothesizes that the delivered negative pressure is
capable of removing the entity’s epithelium/capsule and their
biochemical products. Such negative pressure, at the same time,
creates a line of tension along the surrounding bone, which results in
the transmission of mechanical forces that generate cell stretching,
hence inducing sugosteogenesis. Such theoretical assumption is
supported by emerging experimental data.46,47,112 This section is an
attempt to translate such experimental findings into the therapy we
are proposing.
The question to be answered is: what are the mechanisms by
means of which the Evocyst is thought to induce osteogenesis/
angiogenesis in the absence of added exogenous factors and/or
cells? The Evocyst is a device composed of several parts, all of
which could individually play a role in evacuating the cyst while
modulating bone healing. These elements are a 2-way (irrigation
and decompression) intraoral unit and an extraoral reservoir capable
of applying forces of typically 45 mm Hg.
Taken all experimental studies together and our evidence, it is
possible that the stretch/mechanical stress exerted by the extraoral
unit:
1. Promotes sugosteogenesis by:
 Regulating the proliferation and differentiation of MSCs
and osteogenic precursors.47
 Inducing signaling pathways that promote osteogenic
differentiation of BMSCs and osteoblast activities.93,100
 Enhancing the expression of osteonectin and collagen
type I, which is the major organic component of the
extracellular bone matrix.46,102
 Increasing ALP activity. This enzyme hydrolyzes the ester
bond of organic phosphate compounds under alkaline
conditions to promote calcification.46
 Decreasing osteoclastogenesis via OPGL and OPG
signaling.46,86,98 Intermittent negative pressure could
promote OPG expression while inhibiting OPGL expres-
sion. A drop in OPGL/OPG mRNA ratio is lost with time
after the cessation of negative pressure.46 The ERK/JNK
signaling pathway might be involved.112
2. Stimulates angiogenesis by:
 Inducing and directing migration of pre-existing blood
vessels.106,113
 Enhancing granulation tissue formation and wound
healing.45,106
 Changing the OPGL/OPG mRNA ratio.
 Activating the hypoxia-inducible factor (HIF)-1 regula-
tory pathway, which is believed to directly influence
angiogenesis.46 The HIF-1 is a transcription factor
important for the maintenance of cellular oxygen
homeostasis.46 Increased vascularization, in turn, leads
to an intensified delivery of osseous stem cells.107
 Regulating cellular pathways or specific genes governing
angiogenesis.80,81
3. Creates short-term hypoxia:
 Bone cells in the cystic cavity may be under low oxygen
tension. Lennon et al114 reported that cultures of rat MSCs
at low oxygen tension had more cells and generated more
osseous tissue when compared to cells under 21% oxygen.
# 2018 Mutaz B. Habal, MD
The Journal of Craniofacial Surgery  Volume 29, Number 8, November 2018
Hypoxia in cells subjected to negative pressure may be a
major stimulus for the expression of HIF-1.46
 Activation of the HIF pathway by negative pressure
triggers hypoxia-responsive gene expression like VEGF,
which plays a critical role in angiogenesis.46
4. Exerts forces capable of removing the cyst and its contents:
 By actively removing the cystic epithelium/capsule and
their products, the extraoral unit breaks down the harmful
interactions between them. The interruption of the
epithelium-capsule-osteoclasts relationship halts their
destructive behavior. Through the decompression tube,
the extraoral unit reduces to 0 mm Hg the intracystic
pressure. This reduction in pressure, in conjunction with
the progressive evacuation of the cystic components,
perhaps inhibit the expression of inflammatory factors
such as IL-1a and prostaglandin E2, responsible for
triggering osteoclast-like cells and collagenase synthe-
sis.21,50,112
The intraoral unit, on the contrary, plays a significant role
through its double tubing system. The decompression tube: serves
as a conduit through which the cystic contents exit and transmits the
forces exerted by the negative pressure chamber directly into the
cystic cavity. The irrigation tube, at the same time, allows lavage,
which is an integral part of the therapy.35 It also acts in conjunction
with the extraoral unit to promote fluid flow, which recently has
been linked to increased osseous healing.47
According to Jiang et al89 and others,94,97 interstitial fluid flow is
the primary mechanism by which bone cells perceive changes in
their mechanical environment and strain-induced fluid flow reg-
ulates the anabolic response of bone cells to mechanical cues. In this
regards, there is no doubt that the Evocyst enhances such fluid flow
inside the lesion. In this context, fluid flow induced by the Evocyst
may contribute to the stimulation of osteoprogenitor cells. This may
explain, at least in part, the enhanced osseous healing observed in
our patients. In summary, the application of negative pressure to
osseous cells produces a stretching that creates mechanical cues that
trigger signaling pathways, promotes fluid flow, and enhances
angiogenesis. All of them, combined, may explain sugosteogenesis
(Fig. 1E).
FUTURE RESEARCH AND DIRECTIONS FOR
INVESTIGATORS AND CLINICIANS
To better understand this technique and to elucidate the biomolec-
ular mechanisms behind it, other types of studies must be con-
ducted. Future research should focus on the optimal intensity of
negative pressure; frequency of treatment; recurrence rates; quality
of the newly formed bone; implications for tissue engineering;
molecular pathways; and the clinical applications in other lesions
such as cranial defects, periodontal bone loss, and cysts/osseous
defects in large bones.
This study provided the therapeutic principles of DS and theo-
rized on its biologic bases. The experimental researcher will find in
this study questions requiring answers which will allow a better
understanding of the biologic, molecular, and biomolecular mech-
anisms behind sugosteogenesis and DS. The clinician, on the
contrary, will have another tool to treat odontogenic cystic condi-
tions. Advantages of this new approach are: conservative; elimina-
tion of cystic lining/capsule and the harmful substances they
produce; increased vascularity with concomitant enhanced bone
formation around the cyst; no need for aggressive surgical proce-
dures with associated extensive and expensive reconstructive sur-
gery; elimination of bone grafting procedures; low costs; and faster
recovery. Disadvantages are: unknown recurrence rates; patient
# 2018 Mutaz B. Habal, MD
Copyright © 2018 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Distraction Sugosteogenesis
commitment; several follow-up visits; uncomfortable intraoral unit;
and challenge to keep outstanding oral hygiene. Surgeons dealing
with odontogenic cystic entities should be able to implement the
technique without major complications.
ACKNOWLEDGMENT
The author thanks his wife Lyda and his kids Sara, Isaac, and
Danna. He thanks Drs David Rey, Alfonso Ayala, César Torres, and
Pedro Moreno for their enthusiastic support. The author thanks
Joseph van Sickels and Larry Cunningham and librarian Tagalie
Heister and her team at the University of Kentucky. Lastly, the
author also thanks his oral pathology professor Jairo Bustillo and
Alejandro Hoyos for the fantastic job with figure design.
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