RESEARCH AND EDUCATION SECTION EDITOR LOUIS J. BOUC:HER Osseointegration and its experimental background Per-Ingvar University Brinemark, M.D., Ph.D.* of G6teborg and Institute for Applied Biotechnology, Gateborg, Sweden 0 sseointegration in clinical dentistry depends on an understanding o:f the healing and reparative capacities of hard and soft tissues. Its objective is a predictable tissue response to the placement of tooth root analogues. Such a response must be a highly differentiated one, and one that becomes organized according to functional dema:nds. Since 1952, we have studied the concept of tissue4ntegrated prostheses at the Laboratory of Vital Microscopy at the University of Lund, and subsequently at the Laboratory for Experimental Biology at the University of GGteborg. Our collaborators in this research have included representatives from medical and dental faculties, various research institutes, and departments of technology. The basic aim has been to define limits for clinical implantation procedures that will allow bone and marrow tissues to heal fully and remain as such, rather than heal as a low differentiated scar tissue with unpredictable sequelae. The studies involved analyses of tissue injury and repair in diverse sites in different animals, with particular reference to microvascular structure and function. Special emphasis was placed on analyzing the disturbances caused in the intravascular rhelology of blood by means of a series of different methodological approaches. The objective of this article is a brief review of the various investigations that have led to the clinical application of osseointegration. CONCEPT DEVELOPMENT The initial concept of osseointegration stemmed from vital microscopic studies of the bone marrow of the rabbit fibula., which was uncovered for visual inspection in a modified intravital microscope at high resolution in accordance with a very gentle surgical preparation technique. With special instrumentation, the marrow could be studied in transillumination in vivo, and in situ, after the covering bone was ground Presented at the Toronto Conference on Osseointegration in Clinical Dentistry, Toronto, Ont., Canada, and the Academy of Denture Prosthetics, San Diego, Calif. *Professor and Head, Laboratory of Experimental Biology, Department of Anatomy. THE JOURNAL OF PROSTHETIC DENTISTRY down to a thickness of only 10 to 20 pm. Circulation was maintained in this thin layer of bone and with very few signs of microvascular damage, which is the earliest and most sensitive indication of tissue injury. These intravascular studies of bone marrow circulation also revealed the intimate circulatory connection among marrow, bone, and joint tissue compartments. Subsequent studies of the regeneration of bone and marrow emphasized the close functional connection between marrow and bone in the repair of bone defects. We, therefore, performed a series of in vivo studies on bone, marrow, and joint tissue with particular emphasis on tissue reaction to various kinds of injury: mechanical, thermal, chemical, and rheologic. We were also concerned with the various therapeutic possibilities to minimize the effect of such trauma. Aiming at a restitution ad integrum, we further sought to identify additional traumatic factors such as wound disinfectants and to explore the development of procedures that promote predictable healing of differentiated tissues. We also performed long-term in vivo microscopic studies of bone and marrow response to implanted titanium chambers of a screw-shaped design. These studies in the early 1960s strongly suggested the possibility of osseointegration since the optical chambers could not be removed from the adjacent bone once they had healed in. We observed that the titanium chambers were inseparably incorporated within the bone tissue, which actually grew into very thin spaces in the titanium. Interdisciplinary clinical cooperation with plastic surgeons and otolaryngologists enabled us to study the repair of mandibular defects and replacement of ossicles by means of autologous bone grafts. Desired anatomic shapes of bone grafts were preformed in rabbits and dogs and subsequently applied clinically with long-term follow-up. In an extensive series, the repair of major mandibular and tibia1 defects in dogs was studied. Various procedures were used, with the most successful being the one based on the prior integration of titanium fixtures on both sides of the defect to be created later. When the fixtures had become safely incorporated within the bone, a defect 399 BRlhNEMARK Fig. 1. A, Schematic representation of experimental defects in mandible and tibia in dog that were reconstructed by means of autologous marrow and spongious bone grafts stabilized by titanium splints secured to osseointegrated fixtures in both sides of defect. B, Topography of lower leg in dog at time of resection of tibia. Two lateral tibia1 stabilizers were used. Periosteum was completely removed in area of defect. C, Reconstructed tibia 3 years later with stabilizers removed. D, Radiograph illustrates anatomy of stabilizing-fixtures and splints. was created, the topographical relation between the cut edges was maintained by titanium splints, and the tissue defect was compensated for by an autologous graft of trabecular bone and marrow (Figs. 1 and 2). Separate studies were performed on the healing and anchorage stability of titanium tooth root implants or fixtures of various sizes and designs. We found that when such an implant was introduced into the marrow cavity, and following an adequate immobilized healing period, a shell of compact cortical bone was formed around the implant without any apparent soft tissue intervention between normal bone and the surface of the implant (Fig. 3). We observed a direct correlation among microtopography of the titanium surface, the absence of contamination, the preparatory handling of the bone site, and the histologic pattern elicited in the adjacent bone. In a separate study, fixtures were installed in the tail vertebrae of dogs with successful integration even when abutments were allowed to pierce through the skin. On the basis of the findings in these experimental studies, we decided to perform a series of experiments that would enable us to develop clinical reconstructive procedures for the treatment of major mandibular defects, including advanced edentulous states. It was 400 felt that both osseointegration and autologous bone grafts would be useful in these clinical defect situations. Teeth were extracted in dogs and replaced by osseointegrated screw-shaped titanium implants (Fig. 4). Fixed prostheses were connected after an initial healing time of 3 to 4 months without loading (Fig. 5). In this manner, the fixtures were allowed to heal under a mucoperiosteal flap, which was then pierced for abutment connection and subsequent prosthetic treatment. The anterior teeth, including the canines, were usually retained and the premolars and first molars removed. Different types of prosthetic designs were used; we started with a design similar to the one used for complete dentures and ended up with a gold porcelain fixed prosthesis (Fig. 6). Radiologic and histologic analyses of the anchoring tissues showed that integration could be maintained for 10 years in dogs with maintained healthy bone tissue and without progressive inflammatory reactions. At the time the animals were killed, the titanium fixtures could not be removed from the host bone unless cut away. The anchorage capacity of the separate implants was determined as 100 kg in the lower jaw SEPTEMBER 1983 VOLUME 50 NUMBER 3 Fig. 2. A, Experimental defect in dog’s mandible reconstructed with stabilizing buccal antcllingual titanium splints and autologous marrow and spongious bone graft anchored to integrated fixtures. B, Reconstructed area 6 months later. Fig. 3. A to C, Experimental titanium fixture incorporated in dog’s tibia illustrating new bone formation around fixture in medullary cavity. and 30 to 50 kg in the upper jaw. Efforts to extract the implants led to fractures in the jaw bone per se, not at the actual interface. Microradiographic analyses revealed load-related remodeling of the jaw bone around the implant, even in those cases where the implants were in very close proximity to the nasal and sinus mucoperiosteum at installation. In order to reconstruct severely resorbed edentulous jaws, we developed a special grafting procedure. It was THE JOURNAL OF PROSTHETIC DENTISTRY based on preformation of the graft at the donor site to the desired anatomy. At the same time, we integrated fixtures in the graft-to-be. The bone graft was made to adapt to the required anatomy within a titanium mold. Donor sites were tibiae and ribs of rabbits and dogs. These long-term experimental studies suggested the possibility of achieving and maintaining bone anchorage under unlimited loading of dental prostheses in the 401 BRANEMARK Fig. 4. A, In first experimental studies, a combination of subperiosteal and transosseous titanium implants was used. This was found to provide anchorage but also uncontrolled soft tissue reactions. Therefore, separate screw-shaped titanium fixtures were developed, B, which were finally designed after experimental evaluation of about 50 different types of implants. Fig. 5. Diagrammatic representation of main steps and procedures for anchorage of a prosthesis to osseointegrated jaw bone fixtures. A, Preoperative situation. B, Fixture installed and covered by mucoperiosteal tissues. C, Abutment connected to fixture after a healing period. D and E, Prosthesis attached to abutment. dog attached to osseointegrated fixtures. Soft tissue penetration of titanium abutments could be used without untoward reactions in edentulous jaws, and also for the attachment of‘titanium chambers for vital microscopy in rabbit and dog tibiae. We carried out vital microscopic studies on human microcirculation and intravascular behavior of blood cells at high resolution by means of an implanted optical titanium chamber in a twin-pedicled skin tube on the inside of the left upper arm of healthy volunteers. The tissue reaction as revealed by intravascular rheologic phenomena was studied in long-term experiments in these chambers without indications of inflammatory processes. It, therefore, seemed reasonable to assume that bone anchorage according to the principle of osseointegration might also work in humans, and we treated our first edentulous patients in 1965. In those edentulous jaws where the remaining bone was inadequate for fixture anchorage, a composite reconstruction procedure was developed. 402 A procedure of preformation was applied with the proximal metaphysis of the tibia used as the donor site. The combination of preformed grafts with integrated fixtures provided good long-term clinical results. Immediate autologous bone and marrow grafts are now being tried; and our longitudinal experiences indicate that with an extremely careful prosthodontic procedure, immediate bone grafts can also provide good long-term results. They have the advantage of requiring only one major surgical procedure as compared to two for the preformed graft, but the disadvantage of less predictable survival of the grafted bone. In those patients in whom the loss of jaw bone is not limited to the alveolus but also includes a discontinuity of the jaw bone, a preformed autologous bone graft from the iliac bone has been used and has provided good, predictable, long-term results. In accordance with the same basic principle as for preformed alveolar bone grafts, the desired graft is prepared in the iliac bone with a few connections left to the compact bone SEPTEMBER 1983 VOLUME 50 NUMBER 3 OSSEOINTEGRATION Fig. 6. A, Edentulous upper and lower jaw in a dog with three fixtures integrated in each jaw. B, An acrylic resin prosthesis. C, A chrome-cobalt superstructure. D, Two fix,tures support a prosthesis made of porcelain baked to metal with molar tooth as a cantilevered abutment. and the marrow tissue. The graft-to-be is partly surrounded by a. titanium mold and a titanium foil. Fixtures are installed in two directions to produce anchorage for a splint connecting the graft to the remaining part of the mandible and to provide anchorage for a fixed partial denture. Clinical long-term follow-up has shown that the grafted bone remains in its prepared shape even in the articular region. OSSEOINTEGRATION IN CLINICAL DENTISTRY The edentulous jaw is a typical example of a tissue defect that causes different degrees of functional disturbances. A well-fitting denture appears to be an acceptable alternative to natural teeth as long as the anatomy of the residual hard and soft tissues provides good retention for the prosthesis. Progressive loss of alveolar bone tends to undermine the relative stability of the denture and can create severe problems of both a functional and psychosocial nature (Fig. 7). Different procedures have been advocated to anchor dental prostheses in the soft or hard tissues of the edentulous mouth. However, long-term clinical follow- THE JOURNAL OF PROSTHETIC DENTISTRY ups indicate that such procedures do not provide predictable and good long-term function. Attempts at anchoring an implant by means of a regenerated fibrous tissue layer forming a simulated periodontal ligament have also been unsuccessful. It has been stated in bone reconstruction literature that direct anchorage to living bone of load-bearing implants does not work in the long run. Contrary to this concept, we now suggest that the edentulous jaw can be provided with jaw bone-anchored prostheses according to the principle of osseointegration with good and predictable long-term prognosis. Orthopedic reconstructions that use nonbiologic prosthetic materials frequently rely on implant anchorage by a space filler of so-called bone cement: methyl methacrylate. The induced surgical and chemical trauma results in death of osteocytes at the anchorage interface. After an initial period of adequate implant retention, the damaged bone becomes resorbed and the implant is subsequently kept in place only by low differentiated soft tissue, a kind of scar tissue. The implant is then separated from healthy bone by a soft tissue layer, which provides inadequate reten- 403 BRANEMARK Fig. 7. Radiographs of main types of resorption anatomy in patients comprising our clinical material. A, Orthopantomogram showing advanced resorption. B, Profile radiogram showing extreme resorption. C, D, and E, Typical progressive bone loss in edentulous jaw at 5-year interval. F, Diagrammatic representation of lower jaw morphology corresponding to jaw bone topography represented in C and E, respectively. Fig. 8. Schematic representation of anchorage unit based on principle of screw-connected components: fixture, abutment, and center screw for prosthesis attachment. Apical part of titanium fixture is designed to cut and thread bottom of fixture site. tion as well as shielding of the surrounding bone from the load stimulus required for adequate bony remodeling and maintenance. This will also occur even if the preparation of the implant site provides adequate anatomic congruence between the geometry of the implant and the bone site since both surgical and immediate loading trauma will lead to the formation of a thin layer of connective tissue at the bone-implant interface. In a long-term context, such an interface constitutes a locus minoris resistentiae that allows small relative movements between implant and bone. This suggests a risk of inflammatory reactions and a propagation of bacteria and their products from the oral cavity to the anchorage region if the implant is connected to an abutment that pierces skin or mucous membrane. On the other hand, the osseointegrated implant is directly connected to living remodeling bone without any intermediate soft tissue component; therefore, it provides directly transferred loads to the anchoring bone. The decisive problem is to allow bone SEPTEMBER 1983 VOLUME 50 NUMBER 3 OSSEOINTEGRATION Fig. 9. A, Radiograph of a lower jaw fixture that, together with three other fixtures, has supported a full arch prosthesis for 17 years. B, Densitometric profile measured along dashed line (Kontron IBAS image analysis system, Munich, West Germany). An important feature is “condensation” of bone toward interface zone. C 2 6 1 7 a Fig. 10. Diagrammatic representation of biology of osseointegration. A, Threaded bone site cannot be made perfectly congruent to implant. Object of making threaded socket in bo’ne is to provide immobilization immediately after installation and during initial healing period. Diagram is based on relative dimensions of fixture and fixture site. 2 = hematoma in closed cavity, 2 = Contact between fixture and bone (immobilization); bordered by fixture and bone; 3 = bone that was damaged by unavoidable thermal and mechanical trauma; 4 = original undamaged bone; and 5 = fixture. B, During unloaded healing period, hematoma becomes transformed into new bone through callus formation (6). 7 = Damaged bone, which also heals, undergoes revascularization, and de- and remineralization. C, After healing period, vital bone tissue is in close contact with fixture surface, without any other intermediate tissue. Border zone bone (8) remodels in response to masticatory load applied. D, In unsuccessful implants, nonmineralized connective tissue (9), constituting a kind of pseudoarthrosis, forms in border zone at implant. This development can be initiated by excessive preparation trauma, infection, loa.ding too early in the healing period before adequate mineralization and organization of .hard tissue has taken place, or supraliminal loading at any time, even many years after integration has been established. Osseointegration cannot be reconstituted. Connective tissue can become organized to a certain degree, but in our opinion it is not a proper anchoring tissue because of its inadequate mechanical and biologic capacities, which result in creation of a locus minoris resistentiae. q THE JOURNAL OF PROSTHETIC DENTISTRY 405 BRANEMARK Fig. 11. A, Successfully integrated lower jaw fixtures after 6 years of function. B, Fixture on left is not osseointegrated, although it is indirectly immobilized by prosthesis that is stabilized by remaining integrated fixtures. and marrow tissues to heal as such and not as low differentiated scar tissue. In order to create osseointegration, the preparation of the bone must be done so that minimal tissue injury is produced. In the handling of the edentulous jaw, it is important to recognize a few principles that are valid for all implant procedures. A minimal amount of remaining bone should be removed, and the basic topography of the region should not be changed. The retention of the original or transitional denture should be maintained during the healing period. If osseointegration is not obtained and the implant is removed or if for some other reason the patient wants to return to conventional denture wear, this should then function in the same way as before installation of the implants. Only one shape and dimension of implant should be required, and after 20 years of experimental and clinical development we have selected a screw-shaped implant made of pure titanium. Its dimensions of an outer diameter of 3.7 mm and a length of 10 mm allow its use in almost every edentulous jaw, regardless of the volume and topography of the remaining bone tissue (Fig. 8). Both prostheses and abutments are connected to the fixtures by screws so that the prostheses can be removed from the abutments and the abutment from the fixture for technical adjustments. The abutment can also be removed and the mucoperiosteum closed over the fixture for shorter periods of time or permanently. The existence of a titanium fixture in the jaw bone does not seem to cause adverse effects, and bone resorption arising from disuse atrophy appears to be reduced. If osseointegration is lost, the fixtures can be 406 removed, with new bone formation observed in the implant site and preservation of the original jaw bone anatomy. In this way even if osseointegration is not achieved or maintained, the jaw bone is not destroyed or left with major defects. Healing time for bone tissue requires that fixtures implanted in carefully prepared sites in the jaw bone be left in situ without load bearing for a period of 3 to 6 months. This period depends on the varying repair potential of the edentulous jaw bone. When abutments have been connected by the prosthesis, the jaw bone around the implant remodels over a period of 1 or more years until a “steady state” is reached. This state is characterized by negligible’ bone resorption and appears to be maintained. During the remodeling phase, some marginal bone is lost as a consequence of the installation surgical trauma and adaptation to the masticatory load (Fig. 9). Even with extreme care at the surgical preparation stage of the fixture site (Fig. lo), the bone at the interface is injured (A) and the required alignment at the 400 A level cannot be produced mechanically. It is provided by newly formed bone tissue (B), a biologic process that requires approximately 3 to 6 months. When a controlled load is applied to the bone through the implant, the bone remodels to an architecture related to the direction and magnitude of the load (C) . If the surgical trauma is too intense or if the load is applied too early or without proper control, osseointegration is not achieved (D), with a connective tissue anchorage resulting. Sometimes such a soft tissue layer is extremely thin: only a few microns wide. It may then provide a variable short-term anchorage, but in the long run the attachment’s prognosis becomes dubious. The soft tissue layer tends to increase in width; therefore, such a fixture should be removed and eventually replaced (Fig. 11). When osseointegration has been obtained and the fixtures are subjected to load-bearing under controlled conditions, the placement of the fixtures can be limited to the area between the mental foramina in the lower jaw and between the anterior sinus recesses in the upper jaw. Cantilevered extensions can be used so that an adequate replacement dentition can be provided. Fixtures can be positioned even distal to the sinus and mental foramen; but, because this is not required for the edentulous reconstruction per se and can actually cause clinical problems, it seems rational to restrict anchorage to these sites. A minimum of four fixtures appears to be adequate for support of a full arch prosthesis in the edentulous jaw (Fig. 12, A and B). However, if morphologically feasible, six fixtures are installed to provide a certain SEPTEMBER 1983 VOLUME 50 NUMBER 3 OSSEOINTEGRATION Fig. 12. A and B, Diagrammatic and orthopantomographic representation of four osseointegrated fixtures supporting upper and lower full arch prostheses. Orthopantomogram shows topography of reconstruction after 6 years. C and D, If adequate space is available between maxillary sinuses or mandibular foramina, six fixtures are installed as support. E, This profile radiogram illustrates how prosthesis can be extended to provide an. adequate dentition even in molar region. THE JOURNAL OF PROSTHETIC DENTISTRY 407 BRANEMARK Biopsies from the mucoperiosteum around the transepithelial abutment show a similar appearance of the soft tissue cells providing a seal toward the oral cavity. Biophysical and biochemical analyses of long-term experimental and clinical material indicate that there is in fact an active interchange between the implanted titanium fixture and the soft and hard tissues, which eventually results in improved anchorage over the years. OTHER B .O Fig. 13. Diagrammatic representation of jaw bone anatomy in a frontal sagittal section illustrates biomechanical situation for implants in relation to various degrees of resorption of alveolar process. A, Normal anatomy as compared with extreme bone resorption prevailing in most of treated patients. B, In extreme resorption a very unfavorable leverage situation develops. This is due to distance between jaw bone and occlusal plane and to direction of implants that support prosthesis (see Fig. 12, E). reserve should a fixture not become integrated or lose its integration over the years (Fig. 12, C and D). While extremely careful surgical handling of the hard and soft tissues is required to achieve osseointegration of the implants, the maintenance of the osseointegration relies on equally careful prosthodontic therapy. Careful and frequent control and adjustment of occlusion are essential. The artificial teeth are made of acrylic resin, which tends to compensate for the resilience of the periodontium. Most of the edentulous patients treated by osseointegration present an extreme degree of alveolar bone resorption. The vertical dimensions of the tissue defect to be covered by the prosthesis demand particular skill and consideration in its design to ensure load bearing without mechanical failures and at the same time to make sure that phonetic and cosmetic requirements are met (Fig. 13). Clinical evidence for the lasting integration of prosthesis-loaded fixtures has been obtained from osseointegrated fixtures that were removed along with surrounding bone because of mechanical rather than biologic failures. Fig. 14 shows a typical example of a well-functioning integrated upper jaw fixture removed by trephine with surrounding bone after 6 years of clinical function. The bone could not be removed from the (integrated) fixtures without destroying the interface. Under the light microscope, the anatomic congruence of the anchoring bone to the geometry of the (scrutinized) fixture is illustrated; and, in scanning electron microscopy, processes of osteoblasts seem to grow on the titanium surface. 408 APPLICATIONS Extraoral application of titanium fixtures has been used since 1976. A specially designed fixture has been used to anchor hearing aids for bone-conducting devices. It is placed behind the ear in patients with certain audiologic impairments. Similar fixtures have also been used as anchorage for auricular epitheses (maxillofacial prostheses). A special procedure for handling the skin and subcutaneous tissue relationship to the abutment enabled us to handle soft tissue problems, and all installed fixtures became and have remained integrated. Fifteen patients were supplied with this kind of bone-conducting hearing aid between 1977 and 1982. Eighteen patients were provided with 20 auricular epitheses attached to 78 fixtures between 1979 and 1982. Using the same basic anchorage principle, we are now developing methods, for example, for tissue integration of epitheses that replace the orbital sections of the maxilla. Osseointegration has also been applied to long bones in the reconstruction of damaged or diseased joints. So far, osseointegrated fixtures have been used as anchorage for joint prostheses in the metacarpophalangeal joints. There seems to be two advantages with the osseointegrated joint prosthesis: (1) direct anchorage to living remodeling bone provides important mechanical stability for the function of the joint and the hand and (2) the mechanical components constituting the joint itself are facultatively removable from the fixtures. Therefore, a replacement joint mechanism can easily be installed in the future as a result of wear of components, or if a better design or material becomes available. Work is now in progress to explore the possible value of osseointegrated joint prostheses in the distal radioulnar joint and in the elbow joint as well as in joint replacement in the lower extremity, particularly the knee and the hip joints. Finally, preliminary studies have been performed on the attachment of prosthetic substitutes for lost fingers, hands, and arms and lower legs to osseointegrated fixtures by means of skin-penetrating abutments as the method of connection. SEPTEMBER 1983 VOLUME 50 NUMBER 3 OSSEOINTEGRATION Fig. 14. A, Upper jaw fixtures with surrounding bone removed because of failure of mechanical components after 6 years of function with persisting integration. Specimen was removed by a trephine and cut longitudinally into two halves with a diamond disk. B, In light microscopy, bone threads of fixture site are clearly defined. C, Highresolution scanning electron micrograph of an osteoblast with its cellular processes adapted to surface of fixture shown in A. In conclusion!, I have attempted to present an overview of the conceptual development and the experimental and clinical application of osseointegration. Its long-term clinical dental application has already been demonstrated and documented in Sweden. I hope that my material will provoke and catalyze similar experimental work and clinical application elsewhere. THE JOURNAL OF PROSTHETIC DENTISTRY REFERENCES A reference list enumerating the relevant research referred to in this overview is available from the author under the following headings: 1. Blood as a mobile tissue and studies on intravascular rheology of blood 2. Vital microscopy techniques 409 BRANEMARK 3. Microvascular structure and function in normal and diseased conditions 4. Tissue injury and repair 5. Tissue-integrated prostheses in oral and craniofacial reconstruction 6. Immediate and preformed autologous grafts 7. Bone, marrow, joint, and tendon anatomy, physiology, and pathophysiology For the list of references, write: Prof. P-I. Brinemark Institute for Applied Biotechnology Box 33053 S-400 33 Gijteborg Sweden 410 The invaluable assistance of the late Viktor Kuikka is acknowledged. He helped design and develop the mechanical components used for anchorage as well as the surgical instruments. Reprint requests to: DR. GEORGEA. ZARB UNIVERXR OF TORONTO FACULTYOF DENTISTRY 124 EDWARDST. TORONTO, ONT. M5G lG6 CANADA SEPTEMBER 1983 VOLUME 50 NUMBER 3
