Treatment of osteoradionecrosis of mandible with

bone marrow concentrate and with dental pulp

stem cells
Abstract
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INTRODUCTION
Osteoradionecrosis (ORN) is one of the redundant complications of radiotherapy
characterized by necrosis of irradiated bone. It develops due to progressive hypoxia, hypo-
vascularization, and hypo-cellularity of the affected bone. Radiation causes inflammation of
small blood vessels (endarteritis) resulting in the development of thrombi and occlusion of
the vascular lumen. It also causes altered collagen synthesis. Compromised tissue perfusion
and impaired repair and remodeling capacity make the bone vulnerable to necrosis, even
with mild provocation.[1] The mandible is the most commonly affected site following head
and neck radiation therapy. Trauma, dental extraction or other surgical manipulations, poor
oral hygiene, irritation from ill-fitting denture, usage of tobacco and alcohol are considered
to be the precipitating factors.
Clinically, ORN may manifest as mild discomfort when the lesion is small and localized, as
the lesion progresses, patient may experience pain, swelling, trismus, sequestrum
formation, and pathological fracture. Various treatment modalities are available and are
practiced according to the individuality of the lesion. Small and asymptomatic lesions are
managed conservatively while reserving more invasive surgical management for
progressive and symptomatic lesions.[2] The aim of this article is to present two cases of
ORN of mandible that developed following irradiation for squamous cell carcinoma for
which adult stem cell therapy alone with surgery was tried following failure of
conventional treatment methods. The first case was treated by autologous bone marrow
concentrate, and the second case was treated with allogeneic dental pulp stem cells (DPSC).
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CASE REPORTS

Case 1
A 48-year-old male reported to our Dental Clinic in March 2010 with the complaint of
severe pain and unhealed extraction socket. Past medical history revealed that he had
undergone radiotherapy for the management of carcinoma of the soft palate 3 years back. A
year after radiotherapy, the tooth on the lower right side was extracted, and the socket had
not healed for more than 6 months.
Clinical examination revealed unhealed socket in lower right second molar area with
exposure of underlying bone. The extracted socket had apparently developed ORN. The
patient was treated by us for nearly 1 year through conventional methods such as wound
debridement, warm saline irrigation, socket dressing with zinc oxide eugenol, and antibiotic
dressing. Since the complications recurred between periods of conservative treatment and
there was no sign of clinical improvement, it was decided to treat the case using stem cell
therapy. Detailed and specific informed consent was obtained from the patient and
institutional ethical committee approval obtained. Panoramic radiograph taken before
current therapy showed an area of bone destruction in right 2nd molar region with irregular
margins. Both radiolucency and radio-opacities were observed within the lesion suggestive
of chronic osteomyelitis. There was a suspicion of a hairline pathologic fracture (arrow) in
the radiograph [Figure 1].

Figure 1

Preoperative radiograph showing necrosed bone with suspected hairline fracture

Bone marrow aspiration and stem cell delivery

The patient was thoroughly assessed for spinal anesthesia and physician's opinion taken for
bone marrow aspiration. Under strict aseptic conditions, an Orthopedic surgeon aspirated
bone marrow from left superior posterior iliac crest as published previously.[3] About 60
ml of blood was aspirated using three 20 ml syringes each containing 0.3 ml of heparin.
From this 60 ml, 6 ml of concentrated bone marrow cells (BMCs) was prepared using
Harvest smart prep machine (R) (Harvest Technologies Corporation, 40 Grissom Road,
Suite 100 Plymouth, MA 02360 USA).
Under local anesthesia, the socket was curetted, necrotic bone was trimmed to reduce the
height of the socket and to induce fresh bleeding. Of 6 ml concentrate, 3 ml of BMCs was
injected around the socket and into the periosteum. The remaining 3 ml was mixed with
commercially available β-tricalcium phosphate/hydroxyapatite forming a bioactive matrix.
This stem cell matrix was spread inside the socket, and gingivovestibular flap was sutured.
The material is seen in the X-ray of the patient [Figure 2].

Figure 2

Stem cell matrix in place

Clinical outcome
The patient responded well with a gradual reduction in pain, and there was no discharge
from intraoral lesion after 2 months. The radiograph showed signs of early bone formation
at 2nd month [Figure 3] and evidence of consolidated bone formation after 6 months with
resolution of suspected fracture line [Figure 4]. The patient remained asymptomatic and
complete bone remodeling was noticed after 1 year. The patient was followed for more than
2 years and was symptom-free. There were no untoward effects noted related to this
treatment.

Figure 3

Bone formation 2 months postoperative

Figure 4

Six months postoperative showing bone formation

Case 2
A 47-year-old male reported to our department with the complaints of pus discharge on the
left side cheek for 1 year [Figure 5].

Figure 5

Extraoral sinus

The history revealed post-surgical radiotherapy and chemotherapy for squamous cell
carcinoma in left tonsillar region. Clinical examination showed nonhealing wound in the
36, 37 region and multiple grossly decayed teeth in the left mandibular quadrant with pus
discharge communicating extraorally through a sinus. Orthopantomogram revealed mixed
radiolucency and multiple dental caries in left side body of the mandible [Figure 6].
Eventually, the condition was diagnosed as ORN of mandible.
Figure 6

Preoperative OPG

Initially, the patient was treated with a broad spectrum antibiotics and clindamycin. Patient
was also prescribed pentoxyphylline (trentol) 500 mg and Vitamin E (evion) twice daily for
6 weeks to improve circulation. It was then decided to complete the treatment with stem
cell therapy.

Management and outcome

The allogeneic DPSC were obtained from teeth extracted for orthodontic management with
prior consent.
Surgical curettage was done followed by placement of stem cell graft. The graft consisted
of platelet-rich plasma (PRP) as a medium and alloplastic graft (tricalcium phosphate) as a
scaffold. DPSC were mixed with these, and the matrix was inserted into the defect. Primary
closure was given. Stem cells with PRP were also injected into the surrounding soft tissues.
The extraoral sinus was excised, and healing was uneventful without recurrence [Figure 7].
Periodic panoramic radiographs revealed an appreciable bone formation from the 2nd month
onward and is clearly noted at 6th month after procedure [Figure 8].

Figure 7

Six months postoperative healed sinus area

Figure 8

Six months postoperative OPG

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DISCUSSION
Mesenchymal stem cells derived from dental pulp differentiate into osteoblasts capable of
producing bone. Evidences exist showing that mesenchymal stem cells can be seeded on
scaffolds and used to repair human mandibular defects.[4,5,6] According to Ito et al.[7] a
gel made with DPSC and PRP showed excellent osteogenic characteristics and significant
new bone formation. The DPSC used in this case were cultured in a GMP lab and obtained
from the 2nd passage.
The therapeutic application of bone marrow-derived cells for human bone lesions is not
new. Adult stem cells have been the subject of many in vitro and animal experiments,
demonstrating significant potential in the management of bone lesions. Stimulation with
granulocyte colony-stimulating factor, blood aphaeresis, and expanded bone marrow in
autologous and homologous procedures have been attempted.[8] There is substantial
evidence that human bone marrow supplies the patient with not only hematopoietic cells
but also a significant number of mesenchymal stem cells.[9] Bone Marrow harvested stem
cells and progenitor cells (BMSC) may be capable of solid organ repair and it has been
demonstrated that adult human mesenchymal stem cells from bone marrow can represent a
promising source of skeletal regeneration.[10]
The authors use of bone marrow aspirate concentrate (BMAC) for the treatment of ORN of
mandible is first of its kind and the authors are not aware of any earlier reports published on
the above said procedure for ORN of mandible. There are significant data supporting the
clinical efficacy of BMAC stem cells. An immediate autologous transplantation of BMAC
can prevent complications of transplanted cells such as pre-aging (telomere shortening),
reduced viability, or dedifferentiation/reprogramming that is associated with in-
vitro cultivation.[11]
Recently, images of neo-angiogenesis following stem cell therapy in ORN of mandible
have been demonstrated by gadolinium-enhanced magnetic resonance scan. Vascular
growth is the basis for regeneration in all tissues, delivering oxygen, nutrients, chemical
signaling, migrating cells, and immunity. Good blood supply with sufficient viable cells are
required for osteogenesis.[8]
Earlier Ficoll-hypaque centrifugation procedures were used for isolation and cellular
expansion in-vitro.[10] The cellular composition of concentrate prepared by BMAC system
differs from Ficoll method with respect to the number of colony forming unit cells
(mesenchymal cells).[11]
The volume reduction protocol of the closed centrifuge allows for the highest concentrate
of the mesenchymal stem cells and therefore is a promising candidate for instant stem cell
therapy.[12] Sauerbier et al. have shown hard tissue regeneration in vitro by using both
Ficoll method and BMAC method.[11] Another major concern in stem cell therapy is
safety. To our knowledge, there have been no reports of adverse reactions or complications.
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CONCLUSION
Authors have successfully treated two cases of ORN with BMAC and DPSC and PRP,
respectively. More experience is required to arrive at a definitive conclusion regarding the
benefits of the stem cell therapy for mandibular ORN of the bone due to various etiological
factors.
Stem cell-based reconstruction may be attempted in unresponsive ORN cases before other
major deformative procedures are planned.
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Footnotes
Source of Support: Nil

Conflict of Interest: None declared.

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REFERENCES
1. Silvestre-Rangil J, Silvestre FJ. Clinico-therapeutic management of osteoradionecrosis: A
literature review and update. Med Oral Patol Oral Cir Bucal. 2011;16:e900–4. [PubMed]

2. Vanderpuye V, Goldson A. Osteoradionecrosis of the mandible. J Natl Med Assoc. 2000;92:579–

84.[PMC free article] [PubMed]

3. Turan RG, Bozdag-Turan I, Ortak J, Akin I, Kische S, Schneider H, et al. Improvement of cardiac
function by intracoronary freshly isolated bone marrow cells transplantation in patients with acute
myocardial infarction. Circ J. 2011;75:683–91. [PubMed]

4. Giuliani A, Manescu A, Langer M, Rustichelli F, Desiderio V, Paino F, et al. Three years after
transplants in human mandibles, histological and in-line holotomography revealed that stem cells
regenerated a compact rather than a spongy bone: Biological and clinical implications. Stem Cells
Transl Med. 2013;2:316–24.[PMC free article] [PubMed]

5. Wolff J, Sándor GK, Miettinen A, Tuovinen VJ, Mannerström B, Patrikoski M, et al. GMP-level
adipose stem cells combined with computer-aided manufacturing to reconstruct mandibular
ameloblastoma resection defects: Experience with three cases. Ann Maxillofac Surg. 2013;3:114–
25. [PMC free article] [PubMed]

6. Sándor GK, Numminen J, Wolff J, Thesleff T, Miettinen A, Tuovinen VJ, et al. Adipose stem cells
used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. Stem Cells Transl
Med. 2014;3:530–40.[PMC free article] [PubMed]

7. Ito K, Yamada Y, Nakamura S, Ueda M. Osteogenic potential of effective bone engineering using
dental pulp stem cells, bone marrow stem cells, and periosteal cells for osseointegration of dental
implants. Int J Oral Maxillofac Implants. 2011;26:947–54. [PubMed]
8. Mendonça JJ, Juiz-Lopez P. Regenerative facial reconstruction of terminal stage
osteoradionecrosis and other advanced craniofacial diseases with adult cultured stem and
progenitor cells. Plast Reconstr Surg.2010;126:1699–709. [PubMed]

9. Smiler D, Soltan M, Albitar M. Toward the identification of mesenchymal stem cells in bone
marrow and peripheral blood for bone regeneration. Implant Dent. 2008;17:236–47. [PubMed]

10. Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D, et al. Autologous bone marrow
stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the
jaw. Head Face Med.2011;7:16. [PMC free article] [PubMed]

11. Sauerbier S, Stricker A, Kuschnierz J, Bühler F, Oshima T, Xavier SP, et al. In vivo comparison of
hard tissue regeneration with human mesenchymal stem cells processed with either the FICOLL
method or the BMAC method. Tissue Eng Part C Methods. 2010;16:215–23. [PubMed]

12. Kasten P, Beyen I, Egermann M, Suda AJ, Moghaddam AA, Zimmermann G, et al. Instant stem
cell therapy: Characterization and concentration of human mesenchymal stem cells in vitro. Eur
Cell Mater.2008;16:47–55. [PubMed]
 Regeneration of mandibular osteoradionecrosis defect
with platelet rich plasma gel.
1. M. SCALA1,
2. M. GIPPONI2,
3. P. MEREU1,
4. P. STRADA3,
5. R. CORVÒ4,
6. A. MURAGLIA5,
7. M. MASSA6,
8. S. BERTOGLIO1,5,
9. P. SANTI7 and
10. F. CAFIERO1
+ Author Affiliations
1. 1Department of Surgical Oncology, National Institute for Cancer Research IST, Genoa, Italy
2. 2General Surgery, Colo-Rectal Unit, St. Martino Hospital, Genoa, Italy
3. 3Blood Transfusion Centre, St. Martino Hospital, Genoa, Italy
4. 4Therapeutic Oncology Centre, Genoa, Italy
5. 5Biorigen SRL., Genoa, Italy
6. 6Plastic Surgery Unit, National Institute for Cancer Research IST, Genoa, Italy
7. 7Plastic Surgery Unit, University of Genoa, School of Medicine, Genoa, Italy
1. Correspondence to: Marco Gipponi, MD, A.O.U. “San Martino” Genova, L.go Rossana Benzi 10, Genova 16132,
Italy. e-mail: marco.gipponi@unige.it

Next Section

Abstract

Osteoradionecrosis (ORN) of the mandible is a major complication of radiation therapy of head and neck cancer
with a potential of occurrence ranging from 5 to 15% of the irradiated patients. Due to the gradual necrotic
process, the mandibular bone becomes necrotic and looses its spontaneous regeneration ability. Containing an
elevated content of mitogenic and osteogenic growth factors, the use of platelet rich plasma (PRP) from autologous
source has been suggested to re-activate the healing process of osteogenesis. Autologous PRP gel was introduced
into the ORN necrotic defect of a 44-year old patient previously treated for squamous cell carcinoma of the tongue,
subsequent to proper surgical debridement. We report post-operative two-year follow-up demonstrated by
panoramic X-ray which showed regain of the mandibular bone continuity with a complete repair of the necrotic
defects. We conclude that this case illustrates an incident of successful regeneration of ORN critical-sized defect of
the mandible by autologous PRP gel.

 Osteoradionecrosis

 mandible

 critical size defect

  platelet rich plasma

 regeneration

Radiation therapy is a treatment modality used in a wide variety of maxillofacial cancer, either
as a primary approach or in conjunction with chemotherapy and surgery. Despite this modality
of cancer treatment, it causes changes in the skeletal system by decreased bone vascularity
and repair capacity, nonetheless it is still preferred as the treatment of choice for the sake of
eliminating the malignant neoplasm.

Mandibular osteoradionecrosis (ORN) is a potentially devastating complication of radiation

therapy of head and neck cancer. Radiation has been proven to impair the function of
osteoblasts, thus decreasing bone matrix production. Due to its superficial location and poor
vascularization the mandible is particularly prone to this undue complication. Osteopenia is the
peculiar x-ray finding of ORN and is typically seen one year after irradiation (1). ORN has been
reported in many studies to occur with an incidence following radiation therapy ranging from 5
to 15% (2). Patients suffering from poor dental health show a higher risk for this side effect.
Systemic promoting factors may also include tobacco or alcohol consumption, malnutrition and
a poor general condition. Recently, treatment schedules with bisphosphonates therapy have
been included among risk factors as they may inhibit angiogenesis and induce apoptosis apart
from their virtuous role in inhibiting of osteoclasts and treating bone resorptive disease (3, 4).
Being affected by the necrotic progressive process, the mandibular bone undergoes
degradation of the roots leading to teeth exfoliation, rendering a suitable environment for
possible infections leading to a source of severe pain.
Proper vascularisation is well known to be a primary requirement for bone regeneration and
repair (5-8). In 1983, Marx proposed a protocol for management of ORN of the mandible based
on a vascularization improvement strategy (9). This protocol consisted of a treatment modality
starting from a conservative approach with the aim to eventually reduce the need of radical
resection and reconstruction of the mandible. In fact the non conservative treatment has an
elevated potential for adverse side effects and functional sequalea. The suggested conservative
approach was based on the use of selective antibiotic therapy associated with hyperbaric
oxygen (HBO) therapy enhancing wound healing through an increase in tissue oxygen tension,
resulting in vascular proliferation and healthy bone regeneration. Patients with extensive ORN
or in whom non-invasive therapy was ineffective often require aggressive resection and
reconstruction associated with a microvascular composite flap. The procedure was based on
the introduction a non-irradiated blood supply into the region, thus improving the chance for
wound healing and bone viability (10-13). Both conservative approaches include the regime of a
long term antiseptic/antibiotic treatment scheduled for at least 10 weeks after ORN resolution.
Considerable time and resources are required afterward to manage ORN by these approaches,
especially in patients who had been free of cancer for many years (3, 14).
Recent studies, report the possibility of bone regeneration by using platelets rich plasma (PRP)
with promising results (15-20). PRP is the portion of blood containing the concentrate of
platelets which are rich in mitogenic growth factors (GF) such as platelet derived growth factors
(PDGFs), transforming growth factor beta TGF-β, epidermal growth factor EGF, insulin like
growth factor IGF and vascular endothelial growth factor VEGF. Growth factors entrapped
within the alpha granules in the platelets corpuscles are released upon a process called
‘platelets activation’ that consists of bursting the granules to release their GF content. This
occurs primarily by thrombin. Within their environment of release, such GF play a crucial role in
orchestrating the molecular cascade of healing. The benefit of the introduction of such GF into
a healing lesion might be emphasized especially in critical-size defects. These defects, by
definition, bypassed a certain size beyond which the natural healing process becomes
compromised where the tissue destruction cannot be reversed into regeneration. The
therapeutic advantage of PRP in this type of defect is the introduction of the ‘right’
concentrated GF that are missing for the healing process and their introduction in natural
proportions necessary for a proper interaction to stimulate the different pathways that
ultimately lead to the activation of gene expression and production of the necessary proteins
for healing (21, 22).

In this case report, we investigated the effect of autologous PRP for regeneration of the
mandibular necrotic defects in a cancer patients who previously underwent radiation therapy.
We speculated that the concentrated mitogenic and vascular enhancing GF within the PRP
would improve bone regeneration in the necrotic defects by recruiting vessels and enhancing
cell migration from the healthy surrounding bone tissue.

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Case Report

A white Caucasian male age of 44 was diagnosed for oral squamous cell carcinoma (SCC) of the left half of the
tongue. The procedures of diagnosis, surgical intervention and follow up were carried out in the Institute of Cancer
Research IST-Genova and were approved by the Institutional Ethics Committee.

A partial left glossectomy was performed with conservative neck dissection (CND) and bilateral suprahyoid lymph
node dissection. Pathological staging of the tumor was PT1pN0. Following surgery, the patient received adjuvant
radiotherapy (RT). The schedule consisted of 33 visits, 5 visits per week; each consisted of a dose of 200 cGy with
a total dose of 6600 cGy. Lonidamine - an indazole carboxylic acid that has been shown to be synergistic with
radiotherapy- was added to the radiotherapeutic protocol (23). After four years, the patient showed up edentulous,
with stomatitis, purulent abscesses and exposed alveolar processes of the right mandible. He reported xerostomia
and teeth exfoliation during the previous years. The panoramic X-ray showed diffuse alveolar resorption together
with mandibular radiolusencies thus a diagnosis for ORN was subsequently made (Figure 1A). Pus bacterial culture
evidenced the presence of Prevotella melaninogenica and Prevotella buccae (isolated from anaerobic culture)
andStreptococcus anginosus. The patient was treated with Moxifloxacin Hydrochloride 600 mg daily dose for 20
days, subjected to regular oral antisepsis and eventually scheduled for regenerative surgery with autologous PRP.
During surgery, the necrotic bone was removed and the PRP gel was introduced into the defect area. A panoramic
X-ray was performed two years later (Figure 1B).
Platelets rich plasma gel preparation. Patients were hosted at the Immunohematology Centre – St. Martino
Hospital, Genoa, Italy two days before surgery. A quantity of 450 ml of whole blood was collected and
immediately centrifuged at 200g for 30 minutes to separate packed red blood cells and PRP. The red blood cells
were reinfused to the patient while the PRP was re-centrifuged at 2000g for 5 minutes to precipitate the platelets
and separate the platelets poor plasma (PPP) from the platelets concentrate (PC). PPP was immediately frozen at
−80°C in a mechanical refrigerator then at 4°C for 18 hours for spontaneous thawing while the PC was preserved at
22°C in continuous agitation.
With regards to the quality control of the product, PC had a platelet count equal to 60×10 9, residual leucocytes equal
to 0.2×109, and maximum volume of 30 ml. The cryoprecipitate had factor VIII equal to 70 μl/100 ml, fibrinogen
equal to 140 mg/unit and maximum volume of 30 ml. Autologous thrombin was prepared from 27 ml of blood
collected into three sterile tubes containing 1ml of acid-citrate-dextrose (ACD) anticoagulant solution. Tubes were
centrifuged at 900g for 10 minutes and then plasma was transferred into a second sterile tube. One ml of sterile
calcium chloride was added to each 5ml of plasma. The tubes were incubated for 30 minutes at 37°C. The plasma
clot was then re-centrifuged for 10 minutes at 900g. The supernatant thrombin was stored at −30°C until the time of
use.

At the time of surgery, equal volumes of PC and cryoprecipitate were mixed in a sterile Petri's dish and 1ml of
thrombin and 1 ml of calcium gluconate were added to each 10 ml of the PC-cryoprecipitate mixture. The gel
resulted ready for application after 10-15 minutes of adding thrombin and calcium ions.

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Figure 1.

Panoramic X-ray films. A. Pre-operative panoramic radiograph shows multiple radiolucent and sclerotic areas
with poorly defined borders in the right mandible extended to the left mandible as well as recent extraction sockets.
B. Post-operative panoramic radiograph shows regeneration of the bone and regain of the alveolar bone mass after
reconstructive surgery.

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Results

The regenerative treatment with PRP did not show any complications; the patient was discharged the day after the
surgical procedure. There was no evidence of postoperative infection or any oro-mandibular fistulae. The
mandibular bone repaired completely after being covered by mucosa with evidence of surgical wound healing
within 8 postoperative days.

After the reconstructive surgery, the 2-year follow up panoramic radiograph showed complete regain of the alveolar
bone mass and mandibular bone regeneration in the place of the large irregular radiolucency (Figure 1 A and B).
Previous SectionNext Section
Discussion

Mandibular osteoradionecrosis is an aggressive complication of head and neck radiotherapy. Its management
requires thorough surgical debridement together with HBO application, microvascular reconstruction or a
combination of both (13). These integrated treatment modalities require considerable time and expenses. Some
studies reported HBO to be of doubtful benefit while a second reconstructive procedure could be needed as a result
of flap failure (13, 24-26).
Recently, relevance has been given to the use of platelet-rich plasma (PRP) alone or in combination with bone graft
materials by obtaining bone regeneration through bioengineering (22, 27-31). In this study, we report successful
restoration of mandibular integrity and continuity of an advanced ORN defect based solely on the debridement of
the lesion and the regenerative potential of the PRP without concomitant HBO therapy. The reported case involved
an advanced deterioration of the necrotic process with bone sequestration which then lead to the exposure of the
alveolar process with associated superimposed infection (32).
Based on the poor vascularisation of the mandibular bone, the destructive effect of the radiation on the bone
forming cells cannot be simply faced by bone deposition through new osteogenic cells recruitment that would
otherwise occur in highly vascularized tissues. Progressively, the necrotic process compromises the integrity of the
mandibular trabecular structure leading to bone sequestration and teeth exfoliation thus favouring an environment
for infection. Introducing the PRP rich in mitogenic and chemotactic factors into such a necrotic defect was
expected to be the best simulation to a natural healing process that might occur on the basis of an adequate
vascularization. During tissue healing process, blood platelets are the main source to release necessary GFs for this
process. Upon vessel injury, the platelets stick to the subendothelial tissue collagen proteins and form the platelets
plug that stabilizes the clot within the fibrin meshwork. Platelets are activated by the thrombin involved in the
cascade of healing by releasing their polypeptides content crucial for signalling the local mesenchymal and
epidermal cells migration, division and consequently collagen and glycosaminoglycans synthesis. PDGF is a potent
mitogen and chemotactic factor for osteogenic cells. It stimulates bone collagen synthesis in addition to its
angiogenic properties. It is chemotactic to polymorphonucleocytes, macrophages, fibroblasts, stimulates the
production of fibronectin molecules necessary for cellular adhesion, migration and hyaluronic acid that helps
wound contraction with remodeling. TGF-beta stimulates the proliferation of osteoblasts precursors together with
stimulating bone collagen synthesis and it has a direct action on the differentiation function of the osteoblasts. It
was found to favor bone formation by inhibiting the formation of osteoclasts in addition to its angiogenic,
chemotactic and anabolic functions. Insulin-like GF enhances new bone formation by increasing the expression of
type I collagen and increasing the rate of matrix deposition. In combination with PDGF it enhances the rate and
quality of wound healing. VEGF is involved in the process in which new blood vessels invade devascularized tissue
and is mitogenic to endothelial cells (33-38). Understanding the interaction between such factors and their
environment allows the opportunity to understand the molecular cascade of events that would help us to recapitulate
the natural healing process if it had been compromised. Furthermore, it should be emphasised the role of adequate
debridement to eliminate necrotic bone and to allow the introduced GF to recruit osteogenic cells and vessels from
the healthy exposed bone. The complex issue of the role of such factors in orchestrating the healing process is
encountered as each GF may be involved in different regeneration pathways and a single pathway may involve
several GF (22, 39).

In this case report, a successful regeneration of the mandibular integrity was obtained by introducing the platelets
GF into the necrotic defect mimicking the natural healing process otherwise compromised by inadequate
vascularization. To our knowledge, this is the first study that reports beneficial effects of PRP on ORN defect
healing with a two-year follow up period. In this case, we did not test if the ORN was resistant to HBO (Marx stage
III disease) thus we cannot assume that PRP is effective in such case. We should eventually remark that the patient
had edentulous mandible after the regenerative procedure, which might have also reduced complications that
usually occur in the presence of periodontal pathologies or septic foci.

In conclusion, we believe that the use of PRP associated to conservative strategies for ORN treatment may reduce
or eliminate the need for invasive procedures such as the resection and reconstruction of the mandible with vascular
flaps.

 Received March 11, 2010.

 Revision received April 26, 2010.
 Accepted May 3, 2010.
 Copyright © 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights
reserved
Previous Section

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