Bone Regeneration

Dental treatment may require osseous grafting. Pathologic voids may require grafting to restore osseous anatomy. Various osseous grafting materials have been used and reported. These include autografts, allografts, xenografts, and nonbiological products. Osseous grafts act as a scaffold, maintaining volume while allowing bone formation. Calcium sulfate has been used as an osseous void filler, binder, and grafting material. It possesses many characteristics of an ideal material for bone regeneration. It provides an effective cement for maxillofacial and dental augmentation that is easy to use and cost effective, while not requiring complete soft tissue coverage or a membrane at placement.

Key points

  • Biphasic calcium sulfate has a complete conversion to host bone over a period of 4 to 6 months.

  • The material sets hard, acting like a “bone cement” and has been used for decades in orthopedics.

  • Minimal flap reflection; flap closure is done under tension by stretching without releasing incisions to induce a tension-free flap.

  • No membrane is required, with primary closure not mandatory; when gaps in the soft tissue of 3 mm or less are present, the soft tissue migrates across to close the gap over a short period without inflammation.

  • Various grafting applications are achievable with biphasic calcium sulfate at a more cost-effective material cost and similar clinical results can be achieved as with other grafting products used in dental surgery.


Clinically, there are situations in dental treatment that require osseous grafting. Pathologic voids (defects) or those surgically created during treatment may require grafting to restore the osseous anatomy. Conversely, resorption of the osseous contours may requiring grafting to place implants or augment around those implants to contain the entire implant within bone.

Various osseous grafting materials have been used clinically and reported in dental surgical applications. These include autografts, allografts, xenografts, and nonbiological-derived products (both synthetic and mineral based). Osseous grafts essentially act as a scaffold, maintaining the volume while allowing native bone formation over time. Some materials will resorb fully, whereas others never fully resorb. Autografts and allografts will resorb and, depending on mineralization and compaction if cortical, cancellous or a mixture resorbs quickly (cancellous) or takes longer (cortical). Xenografts, specifically bovine materials do not fully resorb and residual particles remain long term. Synthetic graft materials, depending on their chemistry, may be replaced by conversion to host bone or remain partially or fully. The goal of grafting is conversion to native host bone that has vascularity that will remain in the long term, restoring the area to function; thus, selection of the material to be used is important to achieve that goal.

With those goals in mind, calcium sulfate, a natural mineral and one of the oldest biomaterials, has been used as a bone void filler, binder, grafting material, and as a delivery vehicle for pharmacologic agents and growth factors for more than 120 years, having a longer history of clinical use than most currently available biomaterials. The material has been used in a wide range of clinical applications in orthopedic, plastic surgery, oncologic, and maxillofacial applications in the treatment of osseous voids and traumatic or inflammatory bone deficiencies. Calcium sulfate exists in 3 different forms; calcium sulfate anhydrate, calcium sulfate dehydrate, and calcium sulfate hemihydrate. The difference between these chemical species is represented by the amount of water molecules residing within a single molecule unit. The crystalline structure defines its physical, mechanical, and dissolution properties. The hemihydrate state of hydration exists as either an α or a β form, both of which are found in medical-grade calcium sulfate products. When this hemihydrate is mixed with water, a dehydrate is formed in a mild exothermic reaction with crystallization taking place, and the material sets and hardens. Calcium sulfate as an augmentation material was first reported by Dressman in 1892 to obliterate bone cavities caused by tuberculosis. Later, in the 1920s and 1930s, Nystrom, and Edberg reported results on the use of calcium sulfate plaster of Paris as bone filler without any reported postoperative complications. An extensive review in 1966 regarding the use of calcium sulfate reported the material as a simple, inexpensive substance that offers many advantages as a graft material for bone filling. Studies have demonstrated that calcium sulfate is resorbable and is well tolerated by the tissues, acting primarily as a space filler, restoring morphologic contour, and preventing soft tissue ingrowth into the defects during the healing phase. , Peltier and colleagues confirmed the osteoconductive properties of calcium sulfate allowing ingrowth of blood vessels (angiogensis) and osteogenic cells. When calcium sulfate is implanted in the body, over time (short term) it completely dissolves leaving behind calcium phosphate deposits that stimulate bone growth. , Evidence has been reported that biphasic calcium sulfate not only serves as a 3-dimensional scaffold but also is able to promote osteoinduction. Therefore, it is considered a bioactive material.

A study reported 26 patients who had been treated with calcium sulfate for unicameral bone cysts, with a follow-up of 1 to 20 years. Of the study participants, 24 had successful healing of the defect with bone formation in the cyst, without complications or the need for additional surgery. Another study reporting on 110 patients treated with calcium sulfate, primarily for osseous defects in the skull and facial bones, concluded that calcium sulfate was an outstanding bone graft substitute that ensured bone formation and produced results comparable with, if not better than, autogenous bone graft. Extensive research has accumulated during the past few decades confirming the effective and safe use of calcium sulfate in both orthopedic and dental applications, consistently reporting high biocompatibility. In dental (maxillofacial and periodontal) applications, calcium sulfate has been used in a variety of clinical applications, including periodontal defect repair, the treatment of osteomyelitis, radicular cyst defect repair, sinus augmentation, socket preservation, ridge augmentation, and as an adjunct to dental implant placement. , Following graft placement, it can be monitored radiologically; during its placement, it appears radiopaque, after 2 to 3 weeks it appears radiolucent, and it regains radiopacity after 12 weeks, reflecting the transformation of the material into newly formed uncalcified osteoid turning gradually to calcified young native bone.

Following placement, during the healing phase, calcium sulfate dissolves into its component elements naturally found in the body. When placed in direct contact with viable host bone, new bone growth occurs in apposition to the calcium of the graft material. Calcium sulfate bioresorption studies and clinical experience have shown consistent osteoconduction and complete resorption, replaced by newly formed bone that is ultimately remodeled. Calcium ions activate platelets to release bone morphogenetic proteins and platelet-derived growth factors that stimulate proliferation and osteogenic differentiation of mesenchymal stem cells. , This makes this osseous graft material well tolerated and nonimmunogenic, with no adverse reactions or failure to heal being reported in the literature. ,

Biphasic calcium sulfate acts as a cement, and its hard structure after fast setting prevents infiltration of epithelio-conjunctive cells into the material, acting as a barrier membrane. Yet, connective cells are able to proliferate over the surface of the material, promoting rapid healing of the overlaying soft tissue. Therefore, its related surgical protocols are less invasive compared with other grafting materials in which a tension-free flap and primary closure are mandatory. The opposite is found with biphasic calcium sulfate surgical protocols, indicating minimal flap reflection, and flap closure is done under tension with no releasing incisions to induce a tension-free flap, taking advantage of the flexibility of the mobile mucosa to stretch the flap into place for closure. Thus, the flap and graft are not influenced by muscle movements during the healing phase. In addition, maximal closure with graft exposure of 3 mm is acceptable. The hardness and stability of the biphasic calcium sulfate placed into the defect being grafted means that no membrane or other intermediary barrier is needed. Biphasic calcium sulfate graft material has been shown not to compromise the desired results. Soft tissue cells at the flap margin proliferate over the exposed hardened graft, closing the flap margin fairly quickly over a few days to a week or so.

Calcium sulfate is considered to be one of the bone graft materials of choice in orthopedics due to its excellent osteoconductive bioactivity capacity. , It can be concluded that calcium sulfate is a biocompatible osteoconductive bioactive material that is well tolerated by the tissues when used for the treatment of osseous defects and guided tissue regeneration in animals and humans.

Biphasic calcium sulfate

In maxillofacial applications, however, difficulties with hardening calcium sulfate in the presence of saliva and bleeding have hampered its routine use. This obstacle to its use dentally was overcome in 2010 by Dr Amos Yahav by modifying the material behavior without changing its chemical structure or adding any additives making it biphasic. The biphasic calcium sulfate form allows the calcium sulfate to harden in the presence of saliva and blood, expanding its use in the maxillofacial arena. As calcium sulfate is a completely resorbable synthetic material with short-term space-maintaining abilities, in the case of large osseous defects, the use of biphasic calcium sulfate as a composite graft in a mixture slows the resorption time allowing space maintenance, and the host replaces it with early bone. This is available as an already-made composite graft product called Bond Apatite (Augma Biomaterials), a biphasic calcium sulfate composite bone graft cement containing an average of one-third hydroxyapatite in a controlled particle distribution. The hydroxyapatite particles are of various sizes and shapes of 90 μm to 1 mm ( Fig. 1 ). On setting, the material has a needle-like crystal structure ( Fig. 2 ). This allows maintenance of the material in the defect for a much longer period, as the calcium sulfate component resorbs first, with later (slower) resorption of the hydroxyapatite component. This allows space maintenance of the defect while the host vascularizes the grafted area and develops bone, preventing soft tissue ingrowth. The cement has 2 resorption pattern mechanisms related to its components. The biphasic calcium sulfate portion has a resorption pattern of 4 to 10 weeks, which enables fast bone modeling and angiogenesis formation between the hydroxyapatite (HA) particles that act as a longer space maintainer to slow down the overall resorption of the graft. The small to middle-sized HA particles resorb completely after 3 to 5 months, then the larger particles, which are less than 10% by volume, remain for a longer period until complete resorption takes place. The resorption mechanism of the HA particles within the Bond Apatite cement is unique; the HA particles do not integrate with the newly formed bone. Instead, they become encapsulated by connective tissue where degradation occurs as the connective tissue undergoes ossification into a vital host bone.

Fig. 1
HA consists of particles of different sizes and shapes incorporated within the biphasic calcium sulfate matrix (scanning electron microscopy).

Fig. 2
Postsetting structure of biphasic calcium sulfate at higher magnification, which is composed of needle-like crystals presenting microporosity (1–50 μm) and macroporosity (300–800 μm) promoting growth factor infiltration angiogenesis formation and cell proliferation (scanning electron microscopy).

Histologically, in samples taken at 3 months after graft placement, new bone can be observed in close approximation to remaining residual scaffold particles of Bond Apatite ( Fig. 3 ). Analysis at this stage of healing demonstrates ∼10% of residual graft particles surrounded by connective tissue. At 8 months after graft placement, histologically, little remains of the Bond Apatite and bone marrow is noted in the organizing new bone ( Fig. 4 ). Some areas of connective tissue are also noted, indicating that the graft is maturing and the host is converting the graft material into native bone without any observed inflammatory process. Analysis at 8 months demonstrates the components of the sample to be 79% bone, 11% bone marrow, 7% connective tissue, and only 3% residual graft particles.

Fig. 3
Histology of Bond Apatite graft specimen at 3 months after graft placement showing residual graft scaffold (RS) and new bone (NB) within the sample studied.

Fig. 4
Histology of Bond Apatite graft specimen at 8 months after graft placement showing ( right ) bone ( purple ), bone marrow ( blue ), connective tissue ( green ), and residual graft particles ( yellow ).

Bond Apatite is provided in a double-compartment syringe with one side containing the composite mixture of biphasic calcium sulfate powder with hydroxyapatite and the other compartment containing sterile saline solution. Advancing the syringe shaft until the first plunger on the syringe reaches the blue line marked on the syringe activates the material. The syringe cap is then removed, and the graft is ready for placement directly into the osseous defect. After placement into the defect, sterile gauze is pressed firmly over the graft for 3 seconds to remove residual moisture and harden the material, while compressing it to the osseous bed. Soft tissue is then reapproximated by stretching, and sutures are placed to fixate the flap margins. The flap should be positioned in direct contact with the graft with tension and secured with sutures. A membrane is not required between the graft material and soft tissue. Exposure of the graft material of up to 3 mm does not require membrane coverage or mobilization of the soft tissue to achieve primary closure. Because of the biocompatible nature of the biphasic calcium sulfate and its set hardness, any minimal exposure will result in peripheral soft tissue migration to cover the material without loss of graft material in the interim period.

As a salt, the graft material has bacteriostatic qualities, which are induced by the presence of sodium chloride in the physiologic saline used to mix the powder with the liquid. The cement obtained after mixing the biphasic calcium sulfate powder with the physiologic saline has bonding qualities. After mixing, it is deposited into the osseous defect in a dehydrated (wet) form. The material is then compressed with sterile gauze for 3 seconds to remove any residual liquid, resulting in a dehydrated crystallized form, which hardens and sticks to the osseous defect walls, thus forming a stable block unlike graft materials in granule or paste form. Bond Apatite may be used in small and large defects, such as socket grafting, periodontal defects, lateral ridge widening, and horizontal sinus augmentation (crestal and lateral approaches).

Clinical applications

Extraction Socket Preservation (Grafting)

Extraction socket grafting is often indicated to preserve the osseous crestal margins and prevent resorption during healing ( Fig. 5 ). This may also be performed in anticipation of implant placement at a later date or simultaneous with the extraction. After extraction, the sockets are thoroughly curetted to remove any residual tissue or pathologic matter. Bond Apatite is mixed and placed into the extraction socket by injection from the syringe. It is not necessary to place a membrane over the graft material. However, exposure of several millimeters (>3 mm) of set material at the superior aspect of the crest requires a simple collagen sponge with average resorption of 7 to 10 days, which should be secured in place to cover and protect the exposed material during the first healing stage until soft tissue proliferation takes place above its surface; this does not affect the clinical results. Sutures are placed to help maintain the soft tissue margins with the collagen sponge in contact with the graft material during initial healing ( Fig. 6 ). After 4 months of site healing, the previously exposed areas at the superior aspect of the crest are covered with keratinized gingiva ( Fig. 7 ). A radiograph confirms osseous fill of the extraction sockets ( Fig. 8 ). The area is flapped for implant placement, demonstrating osseous fill of the sockets ( Fig. 9 ), and a core sample is removed by trephine ( Fig. 10 ). Implants are placed as planned and a radiograph is taken ( Fig. 11 ). Histologic evaluation of the core specimen demonstrates residual particles of Bond Apatite with young bone in proximity with the few remaining particles ( Figs. 12 and 13 ). The remaining graft particles will convert while the implants are integrating.

Mar 3, 2020 | Posted by in General Dentistry | Comments Off on Bone Regeneration
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