GÖSTA GRANSTRÖM 813cancer patients have survived their disease and are have found that advanced age is not a contraindica-alive and successfully rehabilitated with the OI con- tion. In our active patient ﬁles we have 2 irradiatedcept.10 Mean survival time for those cancer patients patients who are both 100 years old and are stillstill alive today is 16 years, compared with 10 years satisﬁed implant wearers after more than 20 years.mean survival time for those who have died. Becauseof the long expected survival of cancer patients, we SMOKING, ALCOHOLare therefore committed to rehabilitating them ac- Several studies have shown that implant failures arecording to the OI concept. On the other hand, we higher among smokers.11 Because a high percentagemust plan for a rehabilitation that will last for at least10 to 20 years. Therefore, implant survival is of great of patients with cancers of the head and neck regionimportance in this respect. are heavy smokers and alcohol abusers, restriction of these drugs in the planning procedure is recom- TUMOR TYPE AND TUMOR SURGERY mended. Whether this statement is also valid for irra- A vast variety of cancers can occur in the head and diated patients is unclear at present.10neck region. The size and location of tumor mightdiffer, so each patient would need quite differentrehabilitation procedures including bone grafts, bone What Factors From Radiotherapy Mightcontaining ﬂaps and soft tissue ﬂaps in conjunction Affect OI?with OI surgery. The rehabilitation must therefore be RADIOTHERAPY BEFORE/AFTER TUMOR SURGERYindividualized for the speciﬁc patient. The manage-ment of these patients is complex and should occur There are different cancer therapy approacheswithin a team setting. In our implant unit at the throughout the world. In Sweden there is a longDepartment of Otolaryngology, Head and Neck Sur- tradition of irradiating most cancer patients beforegery (Göteborg University, Gothenburg, Sweden), we tumor surgery. However, from the surgical point ofhave been working very closely in a team consisting view, it is advantageous to perform tumor surgeryof an oral radiologist, oral surgeon, prosthodontist, before irradiation. Healing of the surgical wound thenmaxillofacial surgeon, ear nose and throat surgeon, proceeds more rapidly with fewer complications suchplastic surgeon, and anaplastologist to plan and per- as reduced soft tissue healing time, denuded bone,form the variety of required procedures. When ﬁstula formation, and infections.12 If osseointegrationneeded, other specialists such as speech therapists, is taking place at the same time as tumor surgery, thedieticians, and physiotherapists have been consulted beneﬁt of installing OI implants in nonirradiated bonebefore treatment. is then achieved. In our ﬁles of patients treated during the last 25years, we have found no factor related to speciﬁc RADIOTHERAPY BEFORE/AFTER OI SURGERYdrawbacks for the OI-concept regarding tumor type, As a consequence of the practice standards in Swe-size, stage, local nodes, or metastasis. Likewise, no den, the majority of our cancer patients have beenspeciﬁc tumor surgery factor, such as local resections irradiated before osseointegration surgery. Most ofor neck dissection, was related to speciﬁc problemsencountered with the OI concept.10 When the im- the discussion in this article is therefore related to ourplant team and cancer team work closely together, experience in the irradiated patient. The reverse sit-optimal planning for the rehabilitation is achieved. uation (irradiation with implants already placed in theFor example, questions such as: can bone necessary radiation ﬁeld), however, may be encountered clini-for OI implants in the tumor cavity be saved, and can cally. There are relatively few studies addressing out-implants be installed at the time of tumor surgery, can comes of irradiating already-placed implants, but frombe answered before surgery. One must also be aware our previous studies it appears that implant failuresthat there are speciﬁc cancer patients with such com- during a short-term follow-up were not particularlyplicated defects, with such poor tissue quality and high.13 However, according to newer data, implantother negative contributing factors, that using os- failures have increased during a longer follow-up.10seointegration might be impossible. Other solutions This phenomenon, that implant failures in irradiatedmust be sought for those patients. bone increase with longer follow-up time, makes it important to deﬁne the follow-up time of each study GENDER, AGE when discussing beneﬁts and drawbacks from OI in We have found no evidence in our ﬁles that implant irradiated bone. Reporting success with only 2 to 3survival or complications differ between female and years follow-up may give a false impression that OImale cancer patients. This holds true even in those surgery in irradiated bone is simple and straightfor-cases where osteoporosis may exist.10 Likewise, we ward.
814 PLACEMENT OF DENTAL IMPLANTS IN IRRADIATED BONE IRRADIATION DOSE TYPE OF IRRADIATION SOURCE: FRACTIONATION From the available literature, it seems some authors Most studies published on osseointegration in irra-have recommended that OI surgery is safe in patients diated tissues have used 60Co as the source for radio-who have been irradiated at doses below 50 to 55 therapy since it is still the most commonly used typeGy.14-16 By deﬁning this selection criterium, no pro- of radiation. Thus, the data discussed in this sectiontective measures were found necessary. On the other are mainly related to the effects from 60Co therapy.hand, patients irradiated above 55 Gy would not be Other radiation sources are available, and have beenrehabilitated with OI implants. That would exclude used, the effects of which remain uncertain atthe majority of cancer patients at our institution from present. Other fractionation schemes, such as twicerehabilitation. From an ethical standpoint, it is ques- per day treatment, have been used and calculated astionable to leave such a large portion of cancer pa- cumulative radiation effect.10 With the developmenttients without rehabilitation. We have therefore set of higher energy radiotherapy protocols and super- fractionation, it is likely that in time other effects onout to rehabilitate all patients despite the dose of osseointegration will be identiﬁed. Brachytherapy isradiotherapy. Consequently, some patients have been also a part of modern oncologic treatment, and itsrehabilitated at extremely high doses (Ͼ120 Gy). Im- effect on bone tissues is different than external beamplant survival at this high dosage has been very low, radiotherapy. Again, too little is known about theand the risk for osteoradionecrosis (ORN) is high. effect on osseointegration today. Further studies willNevertheless, it is important to deﬁne the limitations have to be performed addressing these questions.for the OI concept. The dose Gy (previously termed rad) is furthermore TIME FROM RADIOTHERAPY TO OI SURGERYmisleading because this denomination does not ac-count for the number of fractions given. If the term This factor has been shown to affect osseointegra-“cumulative radiation effect” is applied and calculated tion.3,12,18 Contrary to what one would believe, irra-as (Total time of treatment/Number of treat- diation from decades ago seems to have a more neg- ative effect on implant survival than recentlyments)Ϫ0.11 ϫ Dose per treatment ϫ Number of treat- administered radiotherapy. This may be attributed toments0.65 17, a more reliable estimation of irradiation earlier forms of radiation therapy being of lower en-dose can be obtained. Data then show that below a ergy; whereas today, higher energy forms of radiationcumulative radiation effect of 18 to 20, relatively few are typically delivered. A further explanation could beimplants will fail (corresponding to 48 to 65 Gy given the progressive endarteritis taking place in the irradi-as standard fractionation radiotherapy), whereas im- ated bone, which is known to increase with time.20plant failures increase at higher doses. In our experi- Patients and their dentists seem to forget aboutence, at doses above cumulative radiation effect 40 irradiation a long time ago. Sometimes it is argued that(120 Gy, standard fractionation), all implants have no speciﬁc precautions need to be undertaken justfailed.3,10,18,19 because radiotherapy took place such a long time ago. Implants in the same jaw might have been ex- Contrary to this, these patients need to be handledposed to different irradiation doses. For example, a with the utmost care. In relation to the discussion inpatient treated for a tonsillar carcinoma will have a this article, these patients should be handled at insti-higher irradiation dose in the posterior mandible tutions/clinics in the practice of treating cancer pa-than in the anterior portion. It is therefore neces- tients. Thorough planning, careful surgery, and HBOsary to calculate irradiation dose at each implant are required.site before surgery to determine the optimum in-stallation site for implants. Newer forms of focused ADJUVANT CHEMOTHERAPYradiation (such as intensity modulated radiation Many oncologic treatments use chemotherapy astherapy) produce reverse planned non-homoge- part of cancer treatment, which is most commonly anous 3-dimensional treatment volumes that deliv- combination of radiation therapy and chemotherapy.ered increased dose. The consequence is that im- Whether chemotherapy (in most cases a combinationplants installed in the same region might fall into of 5-ﬂuorouracil/cisplatin/methotrexate/bleomycine/highly differing radiation dose gradients. Patients vincristine) affects osseointegration is less well docu-that have received irradiation to other parts of the mented. In a retrospective investigation, it was shownbody, not including the craniofacial region, would that chemotherapy given near the time of OI surgeryhave an expected implant survival in the craniofa- had a negative effect on implant survival.21 Implantcial region comparable to nonirradiated patients. survival was affected less when chemotherapy wasNo speciﬁc precautions would be needed in these administered some time before or within 1 monthpatients. after OI surgery. In later studies that included a higher
GÖSTA GRANSTRÖM 815number of implants, and followed patients for a plastic material. In these situations, defects of the lips,longer period of time, it seemed as if chemotherapy in cheeks, or maxilla are replaced as part of the treat-longer-term perspective has a negative effect on os- ment. Such combined intraoral and extraoral cases areseointegration, comparable to irradiation.10 not common at our institution. BONE BED, GRAFTED BONE RETENTION The quality of the bone bed appears to be of utmost Implant survival in irradiated bone has been shownimportance for a successful result of OI surgery. If the to depend on retention of the prosthesis to a highbone has a reduced capacity for healing after irradia- degree.10,12,18 The highest implant survival was notedtion it is expected that it will integrate the implants for ﬁxed-retention prostheses. The lowest implantless effectively. Grafted bone that will replace bone in survival was seen for facial prostheses anchored onan irradiation ﬁeld will act more like the nonirradiated the combination of clips and magnets on cantileverbone.16,22-24 Therefore, the discussion in this article is extensions.18 In the oral cavity, overdentures haverestricted to bone that has been irradiated and not been shown to be associated with higher implantreplaced by grafts. failures.26,27 SOFT TISSUEImplant Factors Eckert et al28 noted that signiﬁcant problems in LENGTH patients with irradiated implants were related to the soft tissues. Gingivitis was more common in these Several reports have shown a higher incidence of patients than normally observed. Cover-screw muco-implant failures when using short implants.25 Failure sal perforations were observed over the areas of 17%rates for short implants are increased when they are of implants during the healing period between stage-1placed into irradiated bone.10,18,26 Very short (3 to 7 and stage-2 surgery.29 August et al,30 using the ﬁxedmm) implants were particularly prone to failure.10 mandibular implant system in 18 patients irradiatedOne would thus recommend using the longest possi- before or after implant installation, reported in-ble implants to optimize bicortical anchorage. creased problems with the soft tissues. Early soft tissue complications included soft tissue overgrowth, IMPLANT DESIGN AND SURFACE tongue ulceration, and intraoral wound dehiscence. The author’s experience is limited to screw-shaped Late complications included ﬁstula formation. Watz-implants with machined surfaces that have been used inger et al31 reported an increased degree of theconsecutively and consequently where chosen for gingivitis in irradiated patients. This was mainly re-our studies. It is difﬁcult to judge from the literature if lated to poor oral hygiene. Necrosis of soft tissues inother implant designs would perform better in the the ﬂoor of the mouth was observed in 5.2% of pa-irradiated tissue. There is recent data showing that a tients.2relatively rougher surface might improve osseointe-gration.25 Whether this is also a beneﬁt for the irradi- RISK FOR ORN IN RELATION TO IMPLANT SURGERYated patient is not known. It appears that the risk of ORN is the primary reason that implant therapy is not commonly pursued ABUTMENTS in previously irradiated patients. The incidence of this Loading in the long axis of implants has been severe complication may be underreported in theshown to distribute forces optimally. In tumor cavi- international literature. Some authors refuse to useties, however, this has not always been possible to implant placement, considering the risk for ORN asobtain. So-called console abutments are used in areas overshadowing the possible beneﬁt of providing pros-of limited space for facial prosthetics. Their distribu- thetic restoration.32 Several groups report incidentaltion of load often leads to cantilever effects that might cases developing ORN.2,3,31,33 In their report frombe negative for long-term survival of the implants (see 1998, Wagner et al33 described 1 (1.6%) case of ORNbelow). with related failure of 5 implants. The authors were of the opinion that this rate of incidence is below an PROSTHESIS estimated risk of 5% reported in other studies. Esser Cancer patients may have defects from tumor sur- and Wagner2 reported 2 cases (3.4%) of ORN devel-gery that extend well beyond loss of teeth. The im- opment related to implant surgery. In our material,plant-supported prosthesis must therefore be ORN has appeared in those patients irradiated withplanned, designed, and constructed for each patient. extremely high doses after combined pre- and post-At our institution, in several cases, parts of the jaw- operative radiotherapy.10 Minimum surgical trauma tobone and soft tissues needed to be replaced by allo- the mandible is known to cause ORN in the time
816 PLACEMENT OF DENTAL IMPLANTS IN IRRADIATED BONEperiod close to radiotherapy.20 Such trauma may typ- the irradiated bone. Further, the force necessary toically be associated with extraction or surgery for an unscrew the implants (removal torque) has beenOI. shown to be reduced by irradiation, but increased with HBO.43 Interestingly, the recorded effects are measurable not only in experimental animals but alsoSo, Why Use HBO? clinically in patients.42 Thus, there is comprehensive Based on the discussion above, in 1988, we made experimental evidence that supports the use of HBOthe choice to use HBO as part of the treatment pro- to reduce irradiation-induced effects and to increasetocol for irradiated implant patients. The reason for osseointegration.choosing this modality was that it was at that time theonly known treatment available that could be used CLINICAL STUDIESclinically and that was known to counteract the neg- Today, there are more than 100 scientiﬁc publica-ative effects of irradiation. As we were beginning to tions dealing with OIs in irradiated tissues. In antreat patients at higher risk, such as those who had attempt to summarize the results on implant survival,been exposed to high-dose radiation therapy, our an analysis of the data available in 2001 was per-main goal was to reduce implant failure rates that formed.42 The material comprised reports from 4,392were considered by our group to be unacceptably OIs. Implant survival was calculated from the differ-high. Our choice was based on the scientiﬁc knowl- ent studies and plotted as a Kaplan-Meier function.edge of HBO’s effects on irradiated tissues. The exact Different regions of insertion were separated frommechanism that oxygen exerts at the subcellular level each other, as was material from irradiated, nonirra-remains to be explored. Recent data shows that oxy- diated, and HBO-treated patients.42 With increasinggen under hyperbaric conditions acts synergistically follow-up time, all regions showed an increasing im-with several growth factors, which stimulate bone plant failure after irradiation that was higher whengrowth and turnover, and other studies show that compared with nonirradiated patients. HBO im-oxygen can act as a growth factor by itself.34 proved implant survival in all regions that were sub- For a detailed description of the mechanisms and jected to radiation therapy. It should also be appreci-performance of HBO, the reader is referred to a re- ated that because of its compact structure, theview article by Kindwall et al.35 A detailed discussion mandible is a relatively radioresistant bone. In theof HBO effects in relation to osseointegration has also irradiated mandible, implant survival will remain highbeen published.36,37 Principally, HBO has been for many years, but with longer follow-up times, im-shown to improve angiogenesis,38,39 and bone metab- plant failures appear and after 10 years, failures areolism and bone turnover.40,41 In relation to radiother- high (more than 50%). Compared to the mandible, theapy, HBO can thus counteract some of the negative maxilla is less radioresistant and failures appear after 5effects from irradiation and actually act as a stimulator years. By 10 years, as in the mandible, implant failuresof osseointegration.40 are high.42 A multivariate analysis was performed on 107 irra- EXPERIMENTAL STUDIES diated patients who altogether had 631 OI implants Several studies have been performed to analyze the installed in different regions. Irradiation increased theeffects from radiotherapy in the bone surrounding OI failure of implants in all regions compared with non-implants, and the effects from HBO. For a detailed irradiated controls. HBO improved implant survival indescription of the experimental data and discussion, all regions (except temporal-parietal) with signiﬁ-the reader is referred to references 34, 40, and 42. cance at the P Ͻ .001 level, using the Wilcoxon-RankPrincipally, irradiation will have an effect on the bone- test.10 Implants in the oral maxilla performed betterforming cells (osteoblasts and osteocytes) that will than the average implant site. The implant sites thatreduce their capacity for new bone synthesis. The performed poorest were the frontal bone, zygoma,principal resorptive cells in bone, the osteoclasts, can mandible, and nasal maxilla.10migrate into the bone after radiotherapy and continue Advocates against the use of adjunctive HBO forbone resorption. With time, there might be an imbal- irradiated implant patients usually argue that there areance where resorption exceeds formation. Radiother- no double-blind, controlled clinical studies proving itsapy will also reduce the number of capillaries in the efﬁcacy.44 If one considers such a study to be level 1Bbone because of a progressive endarteritis. With in- evidence according to the American Heart Associa-creasing time, a hypovascular bone bed might occur tion (AHA), similar to the National Cancer Institute’sthat is less well adapted to host OI implants. (NCI) level 1ii,45 as the ideal study, then that is true. In the above-cited studies, HBO has been shown to However, today there is 1 AHA level 1C study dis-increase formation of new formed bone, increase the cussed above.42 Furthermore, there are 4 AHA level 3bone turnover, and increase the vascular supply to NCI 2 studies conducted on the topic.3,18,29,46 Addi-
GÖSTA GRANSTRÖM 817tionally, there are 38 clinical studies published at cases, patients pay most of the OI procedure (no HBOlevels AHA 5 and NCI 3ii that show an increased risk necessary).for implant failure in irradiated patients compared The cost for HBO must also be placed in relation towith nonirradiated controls. There are also 9 clinical avoidance of complications. For example, the cost forstudies evaluating the possibility that HBO prevents 30 HBO treatments (implant protocol) is equivalent toimplant failure at AHA levels 3 to 5 and NCI levels 2 to just 1 day at an intensive care unit at the Sahlgrenska3ii. These show a lower risk for implant failure after University Hospital (Gothenberg, Sweden). The costadjuvant HBO, equal to nonirradiated tissues. If one for the treatment of just 1 patient with ORN is equiv-correlates these studies to each other, the risk for alent to the treatment of the HBO protocol for 40implant failure without HBO prevention would be implant patients at the same hospital.734 implants out of 3,431 (21.4%; variance 0 to100%); and with HBO prevention 147 out of 1,085 SAFETY AND SIDE EFFECTSimplants (13.5%; variance 0 to 16.8%). However, en- HBO is regulated by strict standards in each coun-couraging results are already reported in the scientiﬁc try. Side effects from HBO are mostly related to difﬁ-literature; the present author strongly supports ran- culties in equalizing the pressure in the middle ears.domized, controlled studies. Currently, there is a sin- This can be overcome by transmyringeal grommets.gle-blinded, controlled multicenter study being con- Transitional myopia is described by 30% of patientsducted and the goal of the study is to evaluate OI on long-term treatment. Vision invariably returns toimplant failures in irradiated bone. The study further normal within weeks after completion of therapy. Inaims to evaluate the effects of HBO on implant sur- centers where HBO is practiced, long-term evalua-vival. Colleagues with an interest in the study are tions show the procedure to be safe and comfortablehereby invited to participate. Information and enroll- for the patients with very few side effects. There arement can be obtained at http://www.oxynet.org/ hyperbaric chambers available in all countries whereProtocolsIndex.htm. OI surgery is performed. A list of chamber availability In 2 articles published in 1997 by Larsen47 (as can be obtained from http://uhms.org (in the US) andprotagonist) and Keller48 (as antagonist) in the Jour- http://www.oxynet.org (Europe).nal of Oral and Maxillofacial Surgery, these authors In conclusion, there is sufﬁcient scientiﬁc evidencedebated the use of HBO for OI implants in irradiated to show a higher failure rate of OI implants in irradi-mandibles. At that time, there were only 19 publica- ated patients. This high failure rate can be reduced bytions available addressing this question. Despite the adjunctive HBO. Important aspects to consider whenauthors referring to essentially the same publications, comparing outcomes with or without HBO are: re-they came to different conclusions regarding the ac- gion of installation, irradiation dose and timing, adju-tual failure rate in irradiated mandibles. The same vant chemotherapy, quality of the bone bed, implantproblem can also be revealed in the above-cited stud- surgery, implant length and design, prosthetic reten-ies that report failures of implants from 0% to 100%. tion, soft tissue, and risk for ORN. It is important thatThese differences in reported treatment outcomes irradiated cancer patients who require OI implants bemay be attributed mainly to the difference in the treated at institutions/clinics that have experience innumber of implants installed and length of time the the treatment of such patients.7implants had been followed. The higher the numberof implants included in a study and the longer time Referencesthey are followed, the more valid the statistics will be. 1. NIH Consensus Development Program: Dental Implants. Na- tional Institutes of Health Consensus Development Conference Statement, 1988. Available at: http://consensus.nih.gov/1988/ COST FOR PROCEDURE - WHO PAYS? 1988DentalImplants069html.htm. Accessed February 9, 2006 Another argument for not using HBO is the high 2. Esser E, Wagner W: Dental implants following radical oral cancer surgery and adjuvant radiotherapy. Int J Oral Maxillofaccost of the procedure. If the patient has to pay for the Implants 12:552, 1997whole procedure without support from the health 3. Granström G, Tjellström A, Brånemark P-I, et al: Bone-anchoredcare system, this will of course be of substantial im- reconstruction of the irradiated head and neck cancer patient. Otolaryngol Head Neck Surg 108:334, 1993portance in the decision. The cost for HBO in relation 4. Marker P, Siemssen SJ, Bastholt L: Osseointegrated implants forto the OI procedure varies greatly in different coun- prosthetic rehabilitation after treatment of cancer of the oraltries. In Sweden, the cost for HBO would be approx- cavity. Acta Oncol 36:37, 1997 5. Marx RE, Morales MJ: The use of implants in the reconstructionimately 10% of a complete ﬁxed implant-supported of oral cancer patients. Dent Clin North Am 42:177, 1998prosthesis in the upper and lower jaw. The cost for 6. McGhee MA, Stern SJ, Callan D, et al: Osseointegrated implantsHBO and for the OI procedure is fully covered by the in the head and neck cancer patient. Head Neck 19:659, 1997 7. Parel SM, Tjellström A: The United States and Swedish experi-Swedish health care system when rehabilitation in- ence with osseointegration and facial prostheses. Int J Oralvolves cancer patients. In nonirradiated non-cancer Maxillofac Implants 6:75, 1991
818 PLACEMENT OF DENTAL IMPLANTS IN IRRADIATED BONE 8. Tolman DE, Taylor PF: Bone-anchored craniofacial prosthesis 29. Jisander S, Grenthe B, Alberius P: Dental implant survival in the study: Irradiated patients. Int J Oral Maxillofac Implants 11:612, irradiated jaw: A preliminary report. Int J Oral Maxillofac Im- 1996 plants 12:643, 1997 9. Wolfaardt JF, Wilkes GH, Parel SM, et al: Craniofacial osseointe- 30. August M, Bast B, Jackson M, et al: Use of the ﬁxed mandibular gration: The Canadian experience. Int J Oral Maxillofac Im- implant in oral cancer patients. A retrospective study. J Oral plants 8:197, 1993 Maxillofac Surg 56:297, 199810. Granström G: Osseointegration in irradiated tissues. Experi- 31. Watzinger F, Ewers R, Henninger A, et al: Endosteal implants in ence from our ﬁrst 100 treated patients. J Oral Maxillofac Surg the irradiated lower jaw. J Craniomaxillofac Surg 24:237, 1996 2006 (in press) 32. Fischer-Brandies E: Das Risiko enossaler Implantationen nach11. Quirynen M, De Soete M, van Steenberghe D: Infectious risks Radiatio. Quintessence 5:873, 1990 for oral implants: A review of the literature. Clin Oral Implant 33. Wagner W, Esser E, Ostkamp K: Osseointegration of dental Res 13:1, 2002 implants in patients with and without radiotherapy. Acta Oncol12. Granström G: Osseointegration in the irradiated patient, in 37:693, 1998 Tolman D, Brånemark P-I (eds): Osseointegration in Craniofa- 34. Granström G: Pathophysiological basis for HBO in the treat- cial Reconstruction. Chicago, Quintessence, 1998, pp 95-108 ment of healing disorders in radio-injured normal tissues, in13. Granström G, Tjellström A, Albrektsson T: Postimplantation Proceedings of the 5th ECHM Consensus Conference, Lisbon, irradiation for head and neck cancer treatment. Int J Oral 2001, pp 85-93 Maxillofac Implants 8:495, 1993 35. Kindwall E, Gottlieb L, Larsson D: Hyperbaric oxygen therapy14. Esposito M, Hirsch J-M, Lekholm U, et al: Biological factors in plastic surgery. A review article. Plast Reconstr Surg 88:898, contributing to failures of osseointegrated oral implants. II: 1991 Etiopathogenesis. Eur J Oral Sci 106:721, 1998 36. Granström G: The use of hyperbaric oxygen to prevent implant15. Keller EE: Placement of dental implants in the irradiated man- ﬁxture loss in the irradiated patient, in Worthington P, Bråne- dible: A protocol without adjunctive hyperbaric oxygen. J Oral mark P-I (eds): Advanced Osseointegration Surgery. Chicago, Maxillofac Surg 55:972, 1997 Quintessence, 1992, pp 336-34516. Keller EE, Tolman DE, Zuck SL, et al: Mandibular endosseous 37. Johnsson ÅA. On implant integration in irradiated bone. An implants and autogenous bone grafting in irradiated tissue: A experimental study of the effects of hyperbaric oxygenation 10-year retrospective study. Int J Oral Maxillofac Implants 12: and delayed implant placement. Thesis, University of Gothen- 800, 1997 burg, Sweden, 199917. Kirk I, Gray WH, Watson ER: Cumulative radiation effect. Clin 38. Marx R, Ehler W, Tayapongsak P, et al: Relationship of oxygen Radiol 22:145, 1971 dose to angiogenesis induction in irradiated tissue. Am J Surg18. Granström G, Bergström K, Tjellström A, et al: A detailed 160:519, 1994 analysis of titanium implants lost in irradiated tissues. Int J Oral 39. Støore G, Granström G: Osteoradionecrosis of the mandible. A Maxillofac Implants 9:653, 1994 microradiographic study of cortical bone. Scand J Plast Recon-19. Granström G, Tjellström A: Effects of irradiation on osseointe- str Hand Surg 33:307, 1999 gration before and after implant placement. A report of three cases. Int J Oral Maxillofac Implants 12:547, 1997 40. Granström G: Hyperbaric oxygen as a stimulator of osseointe-20. Marx R, Johnson RP: Studies on the radiobiology of osteoradio- gration. Adv Otorhinolaryngol 54:33, 1998 necrosis and their clinical signiﬁcance. Oral Surg Oral Med Oral 41. Johnsson Å A, Sawaii T, Jacobsson M, et al: A histomorphomet- Pathol 64:379, 1987 ric study of bone reactions to titanium implants in irradiated21. Wolfaardt J, Granström G, Friberg B, et al: A retrospective study bone and the effect of hyperbaric oxygen treatment. Int J Oral of the effects of chemotherapy on osseointegration. J Fac Maxillofac Implants 14:699, 1999 Somat Prosth 2:99, 1996 42. Granström G: Radiotherapy, osseointegration and hyperbaric22. Barber HD, Seckinger RJ, Hayden RE, et al: Evaluation of os- oxygen therapy. Periodontology 2000 33:145, 2003 seointegration of endosseous implants in radiated vascularised 43. Johnsson K, Hansson Å, Granström G, et al: The effects of ﬁbula ﬂaps to the mandible. J Oral Maxillofac Surg 53:640, hyperbaric oxygenation on bone to titanium implant interface 1995 strength with or without prior irradiation. Int J Oral Maxillofac23. 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Granström G, Tjellström A, Brånemark P-I: Osseointegrated Prosthodont 11:408, 1998 implants in irradiated bone: A case-controlled study using ad-26. Niimi A, Fujimoto T, Nosaka Y, et al: A Japanese multicenter junctive hyperbaric oxygen therapy. J Oral Maxillofac Surg study of osseointegrated implants placed in irradiated tissues: A 57:493, 1999 preliminary report. Int J Oral Maxillofac Implants 12:259, 1997 47. Larsen PE: Placement of dental implants in the irradiated man-27. Weischer T, Schettler D, Mohe C: Concept of surgical and dible: A protocol involving adjunctive hyperbaric oxygen. implant supported prostheses in rehabilitation of patients with J Oral Maxillofac Surg 55:967, 1997 oral cancer. Int J Oral Maxillofac Implants 11:775, 1996 48. Keller EE: Placement of dental implants in the irradiated man-28. Eckert SE, Desjardins RP, Keller EE, et al: Endosseous implants dible: A protocol without adjunctive hyperbaric oxygen. J Oral in an irradiated tissue bed. J Prosthet Dent 76:45, 1996 Maxillofac Surg 55:972, 1997