An estimated 47 million

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1 RESEARCH Melvin H. Amler, DDS, MS KEY WORDS Dry socket Osteitis Fibrous healing Healing stages Extraction wounds Disturbed healing of a dental extraction wound can cause severe pain and can jeopardize attempts at dental implants or other treatments. The pathogenesis of disturbed healing was studied by histological examination of 221 postoperative biopsies taken for diagnostic purposes from human extraction wounds at different stages of healing. A relationship was observed between the healing stages and different disturbances such as dry socket, suppurative osteitis, necrotizing osteitis, and fibrous healing. Melvin H. Amler is an adjunt professor in the Department of Oral Medicine and Pathology, New York University, College of Dentistry, New York, NY INTRODUCTION An estimated 47 million teeth are extracted annually in the United States for a wide range of clinical indications. 1 The vast majority of the resulting extraction wounds heal normally without adverse incident over approximately 6 weeks. A minority of extraction wounds, estimated at 1.0 to 3.0%, 2 heal improperly or incompletely. Because wound healing is a complex process that can be influenced positively and negatively by many factors, 3 5 the problem posed by disturbed healing is not limited to the localized symptoms, as disturbed healing can also complicate or even jeopardize dental implant and other procedures. The most common healing disturbance, known as dry socket, is characterized by detritus, grayish slough, severe pain, and foul odor. Other healing disturbances are suppurative osteitis, necrotizing osteitis, and fibrous healing. Extraction wounds heal normally in five overlapping stages, which have been described previously by this laboratory on the basis of screened subjects. 6 8 In the first stage, an initial clot forms as a coagulum of red blood cells and white blood cells in the same ratio as is found in the circulating blood; the clotting is accompanied by the precipitation of fibrin in situ. In the second stage, healthy granulation tissue replaces the clot over a 4- to 5-day period. This tissue is characterized by residual red blood cells, heightened influx of white blood cells, reticuloendothelial cells, and cords of endothelial cells associated with the elaboration of capillaries. In the third stage, connective tissue gradually replaces granulation tissue over approximately days. The young preosseous tissue is characterized by the appearance of young spindle-shaped fibroblasts, collagen fibers, metachromatic ground substances, and the presence of alkaline phosphatase. In the fourth stage, bone formation begins on the seventh day with the formation of a fibrillar, poorly calcified osteoid at the base and periphery of the socket. Bone trabeculae fill at least two thirds of the socket fundus by the 38th day. In the fifth stage, closure of epithelium begins as regeneration on the fourth day, with complete fusion in clo- Journal of Oral Implantology 179

2 FIGURES 1 4. FIGURE 1. Normal healing of a postextraction alveolar socket at 2 days. Fibrin, stained by the Papanicolau method, is arranged in an orderly progression of concentric whorls (magnification l00). FIGURE 2. Dry socket 2 days postextraction stained with HE. Fibrin strands have lost symmetry, and the vacuolization of clot is apparent (magnification l00). FIGURE 3. Normal healing at 4 days postextraction, stained with HE. Remnant of original clot is in center, and granulation tissue is in process of replacing the clot. Beginning of connective tissue is forming on peripheral areas (magnification l00). FIGURE 4. Dry socket at 4 days postextraction, stained with HE. Detritus, fibrinolysis, and brown-staining hemosiderin deposits can be observed (magnification l00). 180 Vol. XXV/ No. Three/ 1999

3 Melvin H. Amler sure of the socket after days. Mast cell migration into the epithelium from the underlying connective tissue begins during the first week and is essentially completed by the seventh week. Knowledge of these stages helps explain the pathogenesis of healing disturbances. This paper describes a relationship, observed by this laboratory and others, 9,10 between different healing disturbances and the stages of normal healing. MATERIALS AND METHODS Postoperative biopsy specimens were taken for diagnostic purposes from human extraction wounds at postoperative times ranging from 2 days to 2 months. As a criterion for inclusion in this observational study, patients medical histories and available records were screened for current or previous systemic problems to avoid variables (such as severe nutritional deficiencies, endocrine problems, or cardiovascular disturbance) that might cause particular problems in wound healing. The same biopsy technique was used as in previous studies, 6 8 with only local anesthesia. Specific anesthetic solutions could not be standardized because biopsy specimens were obtained intermittently over an extended time period from various exodontia clinics. Removal of mature alveolar bone was avoided in this biopsy technique in order to obviate the need for decalcification. Avoiding the need for decalcification and the subsequent fixation of all biopsy tissues in Helly s solution (Zenker 5% formalin) facilitated the application of histochemical tests. Tissues were paraffin blocked, cut to 5 m, and then stained. For routine histological examination, tissues were stained with hematoxylin and eosin (HE). Additionally, for determining acid polysaccharide ground substance, tissues were stained with 0.05% toluidine blue; for alkaline phosphatase, with Gomori s stain 11 ; for connective tissue, with Mallory s stain 12 ; for calcium, with von Kossa s stain 13 ; for fibrin, with Papanicolaou stain adapted for tissue sections 14 ; and for mast cells and basophilia, with the Giemsa method. 15 RESULTS A total of 221 diagnostic biopsy specimens met inclusion criteria, of which 185 were diagnosed as normally healing wounds and 36 as disturbed healing. The following figures illustrate the morphologic characteristics typically found in the normal and disturbed biopsy specimens. Normal healing at 2 days is shown in Fig 1. Organization of the clot is apparent by the fibrin strands presenting in a typical whorl formation. Dry socket at 2 days is shown in Fig 2. Fibrin strands have lost their symmetry and manifest a complete breakdown of clot organization, with vacuolization apparent throughout the section. Figure 3 shows normal healing at 4 days. Remainder of the original blood clot can be observed in the center of the section; granulation tissue surrounds and reduces the clot by orderly resorption. At the peripheral portion of the section is the beginning of an infiltrate of connective tissue that is in turn eroding the granulation tissue. In Fig 4, we see dry socket at 4 days. There is a complete breakdown of the healing process, with detritus, fibrinolysis, and brown staining hemosiderin deposits resulting from the disintegration of the blood clot by putrefaction rather than orderly resorption, as occurs in normal healing (observed in Fig 3, where the granulation tissue replaces the clot). Normal healing at 10 days is shown in Fig 5. The lavender stain indicates acid polysaccharide ground substance of connective tissue. The remainder of the granulation tissue (light stained tissue) can be observed in the center of section. The intensity of lavender stain is proportional to the maturity of connective tissue development and can be observed in upper and lower areas of the section. By this evaluation, the lower area is further in development than the upper area. The development of alkaline phosphatase is an integral element of the ground substance. In this section, the connective tissue can be observed to be infiltrating and replacing the granulation tissue by orderly progression similar to the process by which granulation tissue previously replaced the original blood clot, as in Fig 3. In Fig 6, we see suppurative osteitis at 20 days. There is no significant organization of healing. The granulation tissue, which in normal healing replaces the blood clot, has disintegrated with an influx of pyogenic cells, primarily neutrophils, and a scattering of lymphocytes, plasma cells, and monocytes. This disorganization contrasts with the normal overlapping progression of connective tissue seen in Fig 5. Figure 7 also shows suppurative osteitis at 20 days. In an occasional case of suppurative osteitis, there appears to be a hyperplasia of plasma cells. In another case, a hyperplasia of monocytes was noted. There is no apparent rationale for the presence of these specific cell types. Necrotizing osteitis at 30 days is shown in Fig 8. There has been interference in the development of connective tissue to replace the granulation tissue, which has degenerated into a pyogenic infiltrate. A spicule of a bone sequestrum can be observed among the inflammatory cells. In Fig 9, we see fibrous healing at 60 days. This was an asymptomatic postoperative case with no evidence of ossification. The section shows bundles of collagen fibers creating a dense, relatively avascular connective tissue with a mild scattering of inflammatory cells. Finally, Fig 10 shows normal healing at 20 days. Mast cell migration from the underlying connective tissue into the basal cell layer of the epithelium is seen in this figure. DISCUSSION Healing of extraction wounds is not a major clinical concern because most ex- Journal of Oral Implantology 181

4 FIGURES 5 8. FIGURE 5. Normal socket healing at 10 days postextraction, stained with toluidine blue for metachromasia. Degree of lavender color is proportional to degree of ground substance formation, indicating maturity of connective tissue formation. Central light staining area is remainder of granulation tissue (magnification 250). FIGURE 6. Suppurative osteitis section at 20 days postextraction, stained with HE. There is an influx of pyogenic cells, primarily neutrophils, with a scattering of lymphocytes, plasma cells, and monocytes (magnification l00). FIGURE 7. Suppurative osteitis section at 20 days postextraction, stained with HE. There is hyperplasia of plasma cells throughout (magnification 250). FIGURE 8. Necrotizing osteitis section at 30 days, stained with HE. A spicule of bone sequestrum is present among inflammatory cells (magnification l00). 182 Vol. XXV/ No. Three/ 1999

5 Melvin H. Amler FIGURES FIGURE 9. Fibrous healing biopsy at 60 days postextraction, stained with HE. Bundles of collagen fibers create a dense connective tissue with a scattering of inflammatory cells (magnification l00). FIGURE 10. Biopsy of a normally healing wound at 20 days postextraction, stained by the Giemsa method. There is the usual progression of mast cell migration into the basal cell layer of the epithelium (magnification 250. traction wounds, like most mouth wounds, heal rapidly under normal conditions. The occasional exception, however, can cause great discomfort and delayed healing, thereby interfering with subsequent dental treatments. Histologic examination of normally healing extraction wounds at different postextraction intervals demonstrates migration of progressively more highly developed tissues into the wound until the entire alveolar socket is at least two thirds filled with cancellous bone and covered over with epithelium. Disturbances can occur at any stage of the healing process and can intercept the normal migration of replacement tissues (Table 1). Disruption at any stage could be significant. Dry socket results from disturbances in the healing progression from blood clot to granulation tissue. Failure or interference in the mechanism of the granulation tissue development to replace the clot results in disintegration of the blood clot by putrefaction rather than by orderly resorption, giving rise to the well-known symptoms of dry socket. Suppurative osteitis is the result of failure or interference in the mechanism of connective tissue development. It is usually the result of infection and is manifested clinically as a pyogenic discharge from the postextraction socket. Histologic examination of these cases (Figs 6, 7) reveals a breakdown of the granulation tissue with an influx of pyogenic cells, usually with a preponderance of neutrophils and a scattering of plasma cells and monocytes. On occasion, a hyperplasia, primarily of plasma cells (Fig 7) or monocytes, has been observed. In necrotizing osteitis, bone sequestrae will be noted among the inflammatory cells (Fig 8). Fibrous healing occurs when young connective tissue replaces granulation tissue without the normal sequence of bone formation (Fig 9). Implants may not be appropriate in sites where fibrous healing has occurred. The disorder is usually asymptomatic but can be detected radiographically as a circumscribed radiolucence in the area of the socket fundus that is occasionally mistaken for a granuloma or cyst. Fibrous healing occasionally follows a difficult surgical extraction 2 or the resolution of suppurative or necrotizing osteitis. The epithelial fusion schedule of extraction wounds, noted at days when healing was uneventful, is now dependent on the pathological processes that have taken place in the healing disorders, and the time schedule is indeterminate. No mast cell migration was noted in any of the subject biopsies of extraction wound disturbances in this study. On the other hand, in normal extraction wound healing, 16,17 the migration of mast cells into the epithelium was found to be rapid until Journal of Oral Implantology 183

6 TABLE 1 Correspondence of stages of healing to healing disturbances First Appearance Postoperatively Stage of Normal Healing Healing Disturbance Same day 2 3 d 4d 7d 20 d Blood clot Healthy granulation tissue Connective tissue Bone formation Epithelial closure approximately 2 weeks; migration then peaked by the seventh week, whereupon exfoliation took place with the sloughing epithelium (Fig 10). SUMMARY The problems created by disturbances in normal extraction wound healing are not limited to localized symptoms but can also complicate proposed implant and other dental procedures. Each disturbance of extraction wound healing derives its well-known feature from the particular stage of normal healing that is disarranged. Dry socket results from disturbances in the healing progression from blood clot to granulation tissue. Failure or interference in the mechanism of the granulation tissue development results in the disintegration of the blood clot by putrefaction rather than by orderly resorption. Suppurative or necrotizing osteitis results from disarrangement of the healing progession of granulation tissue through connective tissue. Fibrous healing occurs as the result of disarrangement in healing from connective tissue to bone development. Hemorrhage Dry socket Suppurative osteitis or necrotizing osteitis Fibrous healing None known ACKNOWLEDGMENTS The author gratefully acknowledges the assistance of Dr. Steven Salman in the procurement of diagnostic biopsies. This study was supported, in part, from NIDCR/NIH Research Grant P20 DE and from L. Linkow Professorship Grant in Implant Dentistry. REFERENCES 1. American Dental Association Survey. Chicago: American Dental Association; 1994: Shafer WG, Hine MK, Levy BM. A Textbook of Oral Pathology, 3rd ed. Philadelphia: WB Saunders; 1984: Robson MC, Mustoe TA, Hunt TK. The future of recombinant growth factors in wound healing. Am J Surg. 1998;176: Burk N. Dry socket. Mo Dent Assoc J. 1975;55: Colby RC. The general practitioner s perspective of the etiology, prevention and treatment of dry socket. Gen Dent. 1997;454: Amler MH, Johnson PL, Salman I. Histological and histochemical investigations of human alveolar socket healing in undisturbed extraction wounds. J Am Dent Assoc. 1960;61: Amler MH. Lag phase factor in bone healing and suggested application to marrow grafting. J Periodontal Res. 1981;16: Amler MH. The age factor in human alveolar bone repair. J Oral Implant. 1993;19: Turcotte JY. Alveolitis current opinion. Can Dent Assoc. 1997;63: Roche Y, Gogly B. Etiopathology of dry socket. Acualities Odonto-Stomat. 1990;44: Gomori G. Microscopic Histochemistry Principles and Practice. Chicago: University of Chicago Press; 1952: Mallory FB. Pathological Technique. Philadelphia: WB Saunders Co; 1938: Lillie RD. Histopathologic Technique and Practical Histochemistry, 3rd ed. New York: McGraw Hill Book Co; 1976: Johnson PL, Klein M. Application of the Papanicolaou stain to paraffin sections. Stain Technol. 1956;31: McClung R, ed. Handbook of Microscopic Technique for Workers in Both Animal and Plant Tissues. New York: Hafner; 1961: Sryjanen SM, Syrjanen KJ. Mast cells in healing process of the extraction wound in man. Proc Finn Dent Soc. 1977;73: Amler MH, Jacobs MS, Amler RW. Mast cell migration during the epithelization of extraction wounds. Ann Dent. 1987;46: Vol. XXV/ No. Three/ 1999