Intraoral Vacuum-Assisted Closure Therapy—A Pilot Study in Medication-Related Osteonecrosis of the Jaw

Accepted Manuscript Intraoral vacuum-assisted closure therapy – a pilot study in medication-related osteonecrosis of the jaw Johannes Laimer, MD, DMD, Otto Steinmassl, MD, DMD, Martin Hechenberger, MD, DMD, Michael Rasse, MD, DMD, PhD, Rajmond Pikula, MD, Emanuel Bruckmoser, MD, DMD PII:

S0278-2391(17)30307-5

DOI:

10.1016/j.joms.2017.02.033

Reference:

YJOMS 57696

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 27 January 2017 Revised Date:

27 February 2017

Accepted Date: 28 February 2017

Please cite this article as: Laimer J, Steinmassl O, Hechenberger M, Rasse M, Pikula R, Bruckmoser E, Intraoral vacuum-assisted closure therapy – a pilot study in medication-related osteonecrosis of the jaw, Journal of Oral and Maxillofacial Surgery (2017), doi: 10.1016/j.joms.2017.02.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title page

Intraoral vacuum-assisted closure therapy –

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a pilot study in medication-related osteonecrosis of the jaw

Author list: Johannes Laimer, MD, DMD1, Otto Steinmassl, MD, DMD2, Martin Hechenberger, MD,

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DMD3, Michael Rasse, MD, DMD, PhD4, Rajmond Pikula, MD5, and Emanuel Bruckmoser, MD, DMD6

1

Consultant, University Hospital for Craniomaxillofacial and Oral Surgery, Anichstrasse 35,

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A-6020 Innsbruck, Austria 2

Consultant, University Hospital for Craniomaxillofacial and Oral Surgery, Anichstrasse 35,

A-6020 Innsbruck, Austria 3

Consultant, University Hospital for Craniomaxillofacial and Oral Surgery, Anichstrasse 35,

4

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A-6020 Innsbruck, Austria

Professor and Head, University Hospital for Craniomaxillofacial and Oral Surgery, Anichstrasse 35,

A-6020 Innsbruck, Austria 5

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Consultant, University Hospital for Plastic, Reconstructive, and Aesthetic Surgery, Anichstrasse 35,

A-6020 Innsbruck, Austria 6

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Consultant, University Hospital for Craniomaxillofacial and Oral Surgery, Anichstrasse 35,

A-6020 Innsbruck, Austria

Corresponding author: Emanuel Bruckmoser, MD, DMD University Hospital for Craniomaxillofacial and Oral Surgery Anichstrasse 35 A-6020 Innsbruck Austria phone: +43-(0)688-9725132 [email protected]

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Intraoral vacuum-assisted closure therapy –

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a pilot study in medication-related osteonecrosis of the jaw

Abstract PURPOSE

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For about two decades vacuum-assisted closure (V.A.C.®) therapy has been widely used for the management of complex wounds and soft tissue defects on the external body surface. As yet, this technique has not been

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studied for intraoral wound management. It was therefore the aim of this study to evaluate the feasibility, safety, and effectiveness of intraoral V.A.C.® therapy in patients with medication-related osteonecrosis of the jaw (MRONJ). METHODS

Following successful construction of an intraoral device providing sufficient airtight sealing, the respective

the V.A.C.® therapy system. RESULTS

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individually manufactured appliances were used in a prospective clinical trial comprising three patients using

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It could be shown that intraoral V.A.C.® therapy is possible and does not have significant side effects. Positive effects of various extent, like formation of new granulation tissue, cessation of pain and pus suppuration were

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found. CONCLUSION

In this prospective proof-of-principle study it was demonstrated that intraoral V.A.C.® therapy is feasible and safe. It could potentially play a role in the management of MRONJ and other types of intraoral wounds (e.g. osteoradionecrosis, postoperative wound dehiscence, etc.).

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Introduction ®

Vacuum-assisted closure (V.A.C. ) therapy The principle of negative pressure wound therapy (NPWT) has already been described in 1986[1]. In the English literature it was first published by Argenta and Morykwas in the 1990s[2, 3] and introduced as a

V.A.C.® therapy system was used in all patients.

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commercial product (V.A.C.® therapy, KCI USA, Inc., San Antonio, TX) more than 20 years ago. In our study the

The mechanisms of NPWT mainly include four primary effects[4] promoting better wound healing:

wound dimension itself (macrodeformation)

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• the application of a special foam will bring the wound edges closer together reducing the size of the

proliferation[5] (microdeformation)

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• the deformation of the wound surface at a microscopic level will stretch cells and facilitate division and

• fluid from the extracellular space will be removed due to the effect of the negative pressure[6] • an insulated, warm and moist environment will be provided[7] leading to a faster wound healing compared to wounds solely exposed to air as already described by Winter[8] in 1962.

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Although side effects and complications of NPWT like bleeding, infection, pain, and even rupture of heart and death have been reported in the literature[9], V.A.C.® therapy has become an integral part for the management of complex wounds of the skin and soft tissues all over the body.

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Consequently, this widely-used technique for wound management has been successfully employed in various specialties and indications. In a recent prospective randomized controlled trial NPWT was shown to

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significantly reduce the incidence of superficial incision infections following open abdominal surgery when compared to the gauze-covering control group[10]. In another prospective randomized controlled trial negative pressure dressings with 80 mm Hg for 4 days were shown to improve graft take of split-thickness skin grafts in burns patients and could particularly be considered in non-ideal wound bed and grafting conditions[11]. Regarding burns, NPWT is not only associated with improved outcomes in smaller lesions but has also shown to be feasible in extensive burns concerning ≥15% of the total body surface area. NPWT appeared to improve graft take and to decrease infection risk, length of stay, and wound care associated pain[12]. In reconstructive surgery beneficial effects have been reported in attempts to rescue flaps with venous congestion not attributable to a mechanical etiology, thus, not being accessible for surgical salvage therapy[13]. Although 9 out of 12 patients with flap congestion after pedicle or free-flap reconstruction suffered partial flap loss, all 2

ACCEPTED MANUSCRIPT congested flaps survived and all patients presented complete coverage of the defects after postoperative NPWT application for 3 to 10 days. Medication-related osteonecrosis of the jaw (MRONJ) A particularly challenging intraoral condition is medication-related osteonecrosis of the jaw (MRONJ) not

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only affecting the upper and/or lower jaw bone but also the intraoral mucosal tissue[14, 15]. Considering this dual affection MRONJ can somehow be regarded as one of the most difficult scenarios for intraoral wound management.

MRONJ has to be considered as a potentially severe adverse effect secondary to the oral intake or

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intravenous application of bisphosphonates, or the subcutaneous application of the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab[16]. In recent years case reports regarding some

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antiangiogenic drugs used for the treatment of various tumors (mainly bevacizumab[17] and sunitinib[18]) have been published where these drugs were found to have similar side effects with regard to jaw bone and intraoral mucosal damage.

The risk of developing MRONJ significantly varies and is influenced by several factors. A common trigger is preceding tooth extraction or other minor oral surgery[19-21]. The risk in cancer patients receiving denosumab

one percent[23].

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ranges from 0.7 to 1.9%[22], whereas in studies with level one evidence the risk for zolendronate lies around

Clinically, the manifestations of MRONJ can be classified into four stages[16]. In stage 0, patients present

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with non-specific symptoms or clinical and radiographic findings, however, there is no intraoral bone exposure. In stage 1 the characteristic finding of exposed necrotic jaw bone can be seen. In addition to this feature,

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evidence of infection is noted in stage 2. Finally, stage 3 refers to severe cases showing complications like extraoral fistula, abscess, pathologic fracture, etc. The management of MRONJ has been the subject of vivid debate and is still discussed controversially. Conservative treatment options include antibacterial mouth rinse, antibiotics and analgesics[16]. Some authors favor surgical debridement with subsequent soft tissue closure[24, 25], and even partial maxillectomy or mandibular resection have been described as an ultimate resort[26]. To the best of our knowledge V.A.C.® therapy has not yet been used for proper intraoral wound management. It was therefore the aim of this pilot study to apply this technique in MRONJ patients suffering from complex intraoral wounds. 3

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Patients and Methods Legal and administrative formalities In order to evaluate the feasibility and safety of intraoral V.A.C.® therapy in MRONJ patients a prospective,

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non-randomized, non-controlled medical device clinical study was conceived which has been independently reviewed and approved by the respective local ethics committee (reference number: AN2014-0185 338/4.12). Following this positive decision, the compulsory application for risk assessment was made at the Austrian

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Medicines and Medical Devices Agency (www.basg.gv.at/en) which represents the responsible national regulatory body. Finally, the study was registered in the European Database on Medical Devices, i.e. EUDAMED

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(clinical trial registration number: CIV-(AT)-16-07-016226).

Study specific monitoring was provided by the Clinical Trial Center, Medical University of Innsbruck, Austria, during the whole project. Study protocol

For safety reasons patients were admitted to our ward in order to have full 24 hours’ surveillance and the

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possibility to intervene at any time in case of obvious or suspected adverse effects. The intraoral appliance was removed at least one time per day for cleaning and assessment of the intraoral situation to evaluate treatment progress as well as potential side effects. In case of pus suppuration this was noted, too. Additionally, a visual

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analogue scale (VAS) for intraoral pain ranging from zero (no pain) to ten (maximum pain) was recorded daily. All diagnostic and therapeutic procedures and interventions were undertaken with the understanding and

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written consent of each subject in full accordance with ethical principles, including the World Medical Association Declaration of Helsinki. Patient selection

The inclusion criteria referred to patients aged 18 years or older suffering from MRONJ stage 1 or 2 with a history of bisphosphonate or denosumab medication. Written informed consent was obtained from all patients prior to inclusion. The exclusion criteria were as follows: maxillary bone defects with open maxillary sinus, significantly reduced general condition, drug abuse/addiction, significant incompliance with regard to the study protocol, pregnant and breast feeding women 4

ACCEPTED MANUSCRIPT Intraoral suctioning device First an alginate impression was made in the upper or lower jaw according to the localization of the exposed necrotic bone. Then an ordinary plaster cast model was made serving as template for a vacuumformed deep drawn splint (figure 1) consisting of the pressure moulding material Durasoft® (SCHEU, Iserlohn,

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Germany). The inner surface of the Durasoft® splint was further covered with Ufi Gel® (VOCO, Cuxhaven, Germany) to achieve airtight sealing and enhance patient comfort (figure 2). A piece of variable size (corresponding to the area of exposed bone) of the so built splint was then cut out to provide sufficient room for the V.A.C.® GranuFoam™ Dressing. In order to cover this hole in the splint, a patch-like membrane was used

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in which also a small plastic tube was integrated serving as the connection between the intraoral appliance and the external tubing system of the vacuum pump. In our study the ActiV.A.C.® therapy unit (V.A.C.® Therapy, KCI

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USA, Inc., San Antonio, TX) was used to generate the required negative pressure. Study subjects

The first patient was a 66 years old male suffering from prostate cancer who had received 120 milligrams of denosumab subcutaneously one time per month for a total duration of almost three years. This medication was discontinued about three months before study entry when intraoral problems were noticed for the first time.

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At that point he had an operation aiming for soft tissue closure of the exposed necrotic jaw bone; however, the respective mucosa became dehiscent short time after surgery. The patient showed an extensive area of exposed bone in the maxillary front and premolar region bilaterally corresponding to MRONJ stage 1 (figure 3).

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The therapeutic negative pressure at the beginning was 75 mmHg and was increased to 100 mmHg on the third, and to 125 mmHg from the fourth day on. NPWT was applied for a total duration of 11 days.

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The second patient was a 78 years old woman suffering from breast, thyroid gland, and renal cancer who had received 120 milligrams of denosumab monthly over a period of two and a half years. Two and a half weeks before study entry she underwent an unsuccessful operation for intraoral soft tissue closure. The patient had exposed necrotic bone in the mandible bilaterally corresponding to MRONJ stage 1 (figures 4 and 5). Hence, an intraoral device with a double suctioning system had to be constructed in order to apply negative pressure on both sides (figure 6). A negative pressure of 125 mmHg was applied over a total duration of 13 days. The third patient was a 64 years old male suffering from pancreatic cancer and melanoma both of which he had been operated for. He had received zolendronic acid monthly for an unknown period of time. Over the 5

ACCEPTED MANUSCRIPT preceding eleven months the patient had been operated four times and developed dehiscence each time shortly after surgery. He did not show an obviously visible area of exposed jaw bone but only a several centimeters long gap of mucosal dehiscence in the right lower retromolar region where the necrotic bone could be probed. On hospital admission he indicated pain (VAS = 3), and pus suppuration was noted

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corresponding to MRONJ stage 2 (figure 7). As this patient was significantly incompliant in the first instance, NPWT was discontinued on the fourth day (“part 1”). He then stayed in hospital and was re-evaluated two days later. As he definitely wanted to recommence NPWT the importance of adequate compliance was explained to him and the treatment was re-

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initiated and continued for another five days (“part 2”).

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Results

The intraoral application of NPWT was well tolerated and did not show any side effects in our patients apart from a certain discomfort of having the suctioning device placed in the mouth and being obliged to carry the ActiV.A.C.® therapy unit around 24 hours a day. Also the plastic tube connecting the intraoral device with the

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external tubing system of the vacuum pump was much better tolerated than expected (figure 8). Regarding treatment effects some granulation in the first patient was noticed in one region after a couple of days when compared to the starting point (figure 9). The most significant finding, however, was the increasing

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degree of cleanliness which could be considered as an ideal condition in case of intended further surgery for soft tissue closure. The patient did not indicate any pain (VAS = 0), and there was no pus suppuration on any

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day of the inpatient treatment.

Treatment effects in patient two were certainly most impressive as it was possible to achieve formation of sufficient granulation tissue (figures 10 and 11) allowing for tension free soft tissue closure. Initially it was hoped that the approximated wound edges would grow together making any further surgery unnecessary. As th

this did not happen the left and the right sided dehiscences were sutured in local anesthesia on the 9 and 12

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days, respectively. The patient indicated some complaints as she reported severe itching of the lower lip on day five and six (VAS ranging from 3 to 7). However, objectively no obvious abnormality, like for example swelling, redness, erosion or ulceration was visible. The itching disappeared two days after the application of an overthe-counter lip cream. 6

ACCEPTED MANUSCRIPT Patient three did not show any area of visibly exposed bone which renders assessment of treatment success difficult. The most significant therapeutic progress was noted in the second part of his hospital stay after NPWT had been reinitiated. Not only the jaw pain already present before hospital admission (VAS = 3) disappeared one day after resumption of NPWT but also pus suppuration ceased at the same time. As pain and pus

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suppuration are indicative of MRONJ stage 2, this treatment success represents a transformation from stage 2 to stage 1 where no signs of inflammation were present any longer. Moreover, towards the end of the hospital stay some granulation was visible (figure 12) so that it was decided to close the dehiscence (which could still be

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probed) in local anesthesia.

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Discussion

Since many years NPWT has been widely used for the management of complex wounds and soft tissue defects of the external body surface. In contrast, we only found one case report in the international literature reporting the application of intraoral V.A.C.® therapy. However, the respective publication[27] does not refer to the use of vacuum-assisted closure therapy for proper actual wound management. The authors describe

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their efforts to treat a keratocystic odontogenic tumor in the mandible where the application of negative pressure was supposed to stimulate bone regeneration in order to reduce the cystic bone cavity in size and volume.

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The principal aim of our study was to evaluate the feasibility and safety of V.A.C.® therapy intraorally in MRONJ patients. As yet there is no worldwide consensus for the treatment of MRONJ which is primarily due to

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the fact that the currently existing treatment modalities not only have various shortcomings but also unpredictable success rates. Hence, there is need for additional or alternative treatment options, preferably with minimal invasiveness.

Regarding the feasibility of NPWT application intraorally, the crucial challenge to be solved (i.e. the airtight sealing of the intraoral appliance) could be achieved in all patients. Once the device had been manufactured on the plaster cast model, only slight modifications were necessary to achieve and maintain adequate sealing. This was mainly done by relining the splint with Ufi Gel®. In figures 13 and 14 it is shown how the patch-like membrane presses the foam towards the wound on activation of the vacuum pump.

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ACCEPTED MANUSCRIPT Regarding the safety of intraoral V.A.C.® therapy, there were no adverse effects considered to be related to the negative pressure application. As already mentioned above, the second patient reported itching of the lower lip during two days. However, we believe that this complaint appeared independently from the negative pressure therapy and should therefore not be classified as treatment related side effect. The general

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acceptance of having the suctioning device placed intraorally and the vacuum pump to carry around all the time was better than expected. Also the connecting plastic tube between both devices (from intra- to extraoral) was well tolerated.

With regard to the treatment results evaluated, it can be stated that positive effects have undoubtedly

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been shown. Especially in the second patient, significant formation of granulation tissue was noticed which eventually allowed for tension free closure of the wounds bilaterally in local anesthesia. Also, the treatment

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result in the third patient is remarkable because the cessation of pain and pus suppuration is to be regarded as “down-staging” from MRONJ stage 2 to MRONJ stage 1. In the first patient the massively contaminated appearing wound became more and more clean during treatment, and additionally some formation of granulation tissue was noted.

Although according to the protocol long term outcome was not a parameter to be evaluated in this proof-

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of-principle study we would like to mention that - following surgery for soft tissue closure - the operated areas became dehiscent again. However, patients one and two did not report any complaints nor were there any signs of infection at follow-up visits. Patient one deceased in January 2017 from his cancer and patient two was

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lost to follow-up several months after surgery. Also patient three did well until about two months after soft tissue closure when pus secretion reappeared. After several weeks of conservative treatment with regular

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application of disinfectant irrigations in clinic he was operated again and is doing fine since this intervention. Considering the existence of similar features in both MRONJ and osteradionecrosis patients (in particular intraorally exposed "dead" bone) NPWT could also prove useful in the latter indication. Regardless, if significant gain of soft tissue would be achieved or not, we believe that due to its incontestable cleaning effect, intraoral V.A.C.® therapy could in any way prove to be a valuable preparatory measure to create ideal preconditions if surgery for soft tissue closure is planned. It appears plausible that operative treatment results may be better if the operation field has undergone a thorough cleaning procedure beforehand as it can be achieved with NPWT. Furthermore in cases of postoperative dehiscence of intraoral wounds (e.g. after trauma surgery), NPWT could be considered an additional treatment option, even more since in this indication the underlying bone is usually 8

ACCEPTED MANUSCRIPT not compromised. Hence, it could be assumed that treatment outcome for soft tissue closure would be better under these circumstances. Another alternative or additional option would be the application of NPWT directly following soft tissue closure as there is evidence for beneficial effects of NPWT on closed incisional wounds[28]. Finally, NPWT with instillation could be considered as well since there is evidence that it provides

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better overall clinical outcomes than standard of care alone in various indications[29]. It has to be stressed, however, that all these conceivable applications and treatment modalities are highly speculative at current state.

We have to admit that the preliminary results of this small pilot study leave several questions open. It is for

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example not clear if application of negative pressure for a longer time (e.g. three or four weeks) would lead to improved treatment results, e.g. formation of more granulation tissue and/or conjunction of approximated

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wound edges. Once the safety of this treatment would be shown in a larger sample, hospital admission would not necessarily be required so that patients could be treated and followed on an outpatient basis. Besides, treatment results could potentially be improved by modifying the intensity of the negative pressure and/or the mode of action (intermittent instead of continuous negative pressure). Finally, in this study the intraoral device was removed at least once a day; however, maybe positive effects would be greater if the device was left in

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place for at least two or three days in a row.

Despite all these potential shortcomings and points of criticism, in this proof-of-principle study the feasibility and safety of V.A.C.® therapy for actual intraoral wound management in a small collective of MRONJ

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patients has been demonstrated for the first time. Positive effects have been shown which would justify further studies in larger patient collectives.

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With regard to a potential broad use of this technique in various indications, the manufacturing process is to be simplified and automatized to allow for efficient work flows and economical production of the intraoral devices. We are currently planning a follow-up study in which the appliances would be produced by aid of 3-D printing technology. Although initial costs for this procedure would be considerable, it is to be expected that this technique should pay off in the long term. Ideally the clinician would only have to take an impression, send it to the manufacturer (e.g. a dental lab specializing in 3-D printing technology), and shortly after, the readymade intraoral suctioning device would be returned. In view of these prospects we believe that intraoral V.A.C.® therapy could become a straightforward technique (outpatient setting imaginable) to improve wound

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ACCEPTED MANUSCRIPT management in the oral cavity, provided that both safety and effectiveness will be demonstrated in appropriately designed larger trials.

Acknowledgement We are indebted to our dental technician, Daniel Grimm, for his invaluable help in developing,

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manufacturing, and continuously improving the intraoral suctioning devices used in this study.

Conflict of Interest Statement

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None of the authors has any commercial associations that might create a duality of interest in connection with the submitted article. No institutional, private or corporate financial support has been received for the

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work within this manuscript. A potential conflict of interest is declared by J. Laimer and E. Bruckmoser since these authors are named as inventors of the intraoral suctioning device and the method for manufacturing this appliance for which a request for grant of a European patent has been submitted by the Medical University

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Innsbruck, Austria (reference number: EP16200331).

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References 1.

Kostiuchenok BM, Kolker, II, Karlov VA, Ignatenko SN, Muzykant LI: [Vacuum treatment in the surgical

management of suppurative wounds]. Vestnik khirurgii imeni I. I. Grekova 137:18, 1986 2.

Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W: Vacuum-assisted closure: a new method for

3.

Argenta LC, Morykwas MJ: Vacuum-assisted closure: a new method for wound control and treatment:

clinical experience. Annals of plastic surgery 38:563, 1997

Orgill DP, Bayer LR: Negative pressure wound therapy: past, present and future. International wound

SC

4.

journal 10 Suppl 1:15, 2013

Saxena V, Hwang CW, Huang S, Eichbaum Q, Ingber D, Orgill DP: Vacuum-assisted closure:

M AN U

5.

RI PT

wound control and treatment: animal studies and basic foundation. Annals of plastic surgery 38:553, 1997

microdeformations of wounds and cell proliferation. Plastic and reconstructive surgery 114:1086, 2004 6.

Morykwas MJ, Simpson J, Punger K, Argenta A, Kremers L, Argenta J: Vacuum-assisted closure: state of

basic research and physiologic foundation. Plastic and reconstructive surgery 117:121S, 2006 Scherer SS, Pietramaggiori G, Mathews JC, Prsa MJ, Huang S, Orgill DP: The mechanism of action of the

TE D

7.

vacuum-assisted closure device. Plastic and reconstructive surgery 122:786, 2008 8.

Winter GD: Formation of the scab and the rate of epithelization of superficial wounds in the skin of the

9.

EP

young domestic pig. Nature 193:293, 1962

Li Z, Yu A: Complications of negative pressure wound therapy: a mini review. Wound repair and

AC C

regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 22:457, 2014 10.

Li PY, Yang D, Liu D, Sun SJ, Zhang LY: Reducing Surgical Site Infection with Negative-Pressure Wound

Therapy After Open Abdominal Surgery: A Prospective Randomized Controlled Study. Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society, 2016 11.

Petkar KS, Dhanraj P, Kingsly PM, Sreekar H, Lakshmanarao A, Lamba S, Shetty R, Zachariah JR: A

prospective randomized controlled trial comparing negative pressure dressing and conventional dressing methods on split-thickness skin grafts in burned patients. Burns : journal of the International Society for Burn Injuries 37:925, 2011 11

ACCEPTED MANUSCRIPT 12.

Fischer S, Wall J, Pomahac B, Riviello R, Halvorson EG: Extra-large negative pressure wound therapy

dressings for burns - Initial experience with technique, fluid management, and outcomes. Burns : journal of the International Society for Burn Injuries 42:457, 2016 13.

Qiu SS, Hsu CC, Hanna SA, Chen SH, Cheong CF, Lin CH, Chang TN: Negative pressure wound therapy

14.

RI PT

for the management of flaps with venous congestion. Microsurgery 36:467, 2016 Landesberg R, Cozin M, Cremers S, Woo V, Kousteni S, Sinha S, Garrett-Sinha L, Raghavan S: Inhibition

of oral mucosal cell wound healing by bisphosphonates. Journal of oral and maxillofacial surgery : official

15.

SC

journal of the American Association of Oral and Maxillofacial Surgeons 66:839, 2008

Migliorati CA, Saunders D, Conlon MS, Ingstad HK, Vaagen P, Palazzolo MJ, Herlofson BB: Assessing the

the American Dental Association 144:406, 2013 16.

M AN U

association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. Journal of

Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F: American

Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and

17.

TE D

Maxillofacial Surgeons 72:1938, 2014

Guarneri V, Miles D, Robert N, Dieras V, Glaspy J, Smith I, Thomssen C, Biganzoli L, Taran T, Conte P:

Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three

18.

EP

large prospective trials in advanced breast cancer. Breast cancer research and treatment 122:181, 2010 Brunello A, Saia G, Bedogni A, Scaglione D, Basso U: Worsening of osteonecrosis of the jaw during

19.

AC C

treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44:173, 2009 Ferlito S, Puzzo S, Liardo C: Preventive protocol for tooth extractions in patients treated with

zoledronate: a case series. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 69:e1, 2011 20.

Lodi G, Sardella A, Salis A, Demarosi F, Tarozzi M, Carrassi A: Tooth extraction in patients taking

intravenous bisphosphonates: a preventive protocol and case series. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 68:107, 2010

12

ACCEPTED MANUSCRIPT 21.

Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, Nakayama T, Bessho K: Increased

incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. International journal of oral and maxillofacial surgery 41:1397, 2012 22.

Qi WX, Tang LN, He AN, Yao Y, Shen Z: Risk of osteonecrosis of the jaw in cancer patients receiving

RI PT

denosumab: a meta-analysis of seven randomized controlled trials. International journal of clinical oncology 19:403, 2014 23.

Coleman R, Woodward E, Brown J, Cameron D, Bell R, Dodwell D, Keane M, Gil M, Davies C,

Burkinshaw R, Houston SJ, Grieve RJ, Barrett-Lee PJ, Thorpe H: Safety of zoledronic acid and incidence of

SC

osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for

24.

M AN U

women with stage II/III breast cancer. Breast cancer research and treatment 127:429, 2011 Wutzl A, Biedermann E, Wanschitz F, Seemann R, Klug C, Baumann A, Watzinger F, Schicho K, Ewers R,

Millesi G: Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head & neck 30:1224, 2008 25.

Holzinger D, Seemann R, Klug C, Ewers R, Millesi G, Baumann A, Wutzl A: Long-term success of surgery

in bisphosphonate-related osteonecrosis of the jaws (BRONJs). Oral oncology 49:66, 2013 Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related

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26.

osteonecrosis of the jaws. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 67:85, 2009

Halama D, Hemprich A, Frerich B: [Intraoral application of vacuum-assisted closure in the treatment of

EP

27.

28.

AC C

an extended mandibular keratocyst]. Zentralblatt fur Chirurgie 129 Suppl 1:S53, 2004 De Vries FE, Wallert ED, Solomkin JS, Allegranzi B, Egger M, Dellinger EP, Boermeester MA: A

systematic review and meta-analysis including GRADE qualification of the risk of surgical site infections after prophylactic negative pressure wound therapy compared with conventional dressings in clean and contaminated surgery. Medicine 95:e4673, 2016 29.

Kim PJ, Attinger CE, Olawoye O, Crist BD, Gabriel A, Galiano RD, Gupta S, Lantis Ii JC, Lavery L, Lipsky

BA, Teot L: Negative Pressure Wound Therapy With Instillation: Review of Evidence and Recommendations. Wounds 27:S2, 2015

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Figure legends Figure 1: plaster cast model with vacuum-formed deep drawn splint (Durasoft®) Figure 2: Ufi Gel® layer to achieve airtight sealing and enhance patient comfort

Figure 4: exposed bone in the right mandible in patient 2 Figure 5: exposed bone in the left mandible in patient 2

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Figure 3: large area of exposed necrotic maxillary bone as starting point in patient 1

Figure 7: starting point in patient 3 presenting pus suppuration

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Figure 6: intraoral suctioning device for bilateral application of negative pressure in patient 2

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Figure 8: small plastic tube connecting the intraoral appliance to the extraoral tubing system of the vacuum pump

Figure 9: clean situation and some granulation tissue (see arrow) at the end of treatment in patient 1 Figure 10: significant gain of granulation tissue (right mandible) at the end of treatment in patient 2

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Figure 11: significant gain of granulation tissue (left mandible) at the end of treatment in patient 2 Figure 12: newly formed granulation tissue (right mandible) at the end of treatment in patient 3

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Figure 13: intraoral suctioning device in patient 3 prior to launching negative pressure

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Figure 14: launch of negative pressure in patient 3 presses membrane down onto the foam

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